NO750876L - - Google Patents
Info
- Publication number
- NO750876L NO750876L NO750876A NO750876A NO750876L NO 750876 L NO750876 L NO 750876L NO 750876 A NO750876 A NO 750876A NO 750876 A NO750876 A NO 750876A NO 750876 L NO750876 L NO 750876L
- Authority
- NO
- Norway
- Prior art keywords
- alkyl
- benzyl
- optionally substituted
- methyl
- pyridyl
- Prior art date
Links
- -1 Rj means H Chemical group 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 30
- 239000002253 acid Substances 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 150000001408 amides Chemical class 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 9
- 150000007513 acids Chemical class 0.000 claims description 6
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- 239000011230 binding agent Substances 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 3
- 201000005577 familial hyperlipidemia Diseases 0.000 claims description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000005035 acylthio group Chemical group 0.000 claims description 2
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 2
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 2
- 239000003472 antidiabetic agent Substances 0.000 claims 1
- 229940125708 antidiabetic agent Drugs 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 231100000252 nontoxic Toxicity 0.000 claims 1
- 230000003000 nontoxic effect Effects 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000000203 mixture Substances 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- 150000001409 amidines Chemical class 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000013543 active substance Substances 0.000 description 6
- 235000011121 sodium hydroxide Nutrition 0.000 description 6
- 238000009835 boiling Methods 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- UEWDJCZJEIBPKX-UHFFFAOYSA-N 2,2-diethoxy-1-methylpyrrolidine Chemical compound CCOC1(OCC)CCCN1C UEWDJCZJEIBPKX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 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 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- FUYNPLQVSXOYDD-UHFFFAOYSA-N (3-methylpyridin-2-yl)-phenylmethanamine Chemical compound CC1=CC=CN=C1C(N)C1=CC=CC=C1 FUYNPLQVSXOYDD-UHFFFAOYSA-N 0.000 description 2
- PNFHBTVWEDYLGB-UHFFFAOYSA-N (3-methylpyridin-2-yl)-phenylmethanone Chemical compound CC1=CC=CN=C1C(=O)C1=CC=CC=C1 PNFHBTVWEDYLGB-UHFFFAOYSA-N 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- QYGNDKJRRNVSEC-UHFFFAOYSA-N 5-methoxy-3,4-dihydro-2h-pyrrole Chemical compound COC1=NCCC1 QYGNDKJRRNVSEC-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000002058 anti-hyperglycaemic effect Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- JBKVHLHDHHXQEQ-UHFFFAOYSA-N epsilon-caprolactam Chemical compound O=C1CCCCCN1 JBKVHLHDHHXQEQ-UHFFFAOYSA-N 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- XTEGVFVZDVNBPF-UHFFFAOYSA-L naphthalene-1,5-disulfonate(2-) Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1S([O-])(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-L 0.000 description 2
- XTEGVFVZDVNBPF-UHFFFAOYSA-N naphthalene-1,5-disulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- BAEZXIOBOOEPOS-UHFFFAOYSA-N phenyl(pyridin-2-yl)methanamine Chemical compound C=1C=CC=NC=1C(N)C1=CC=CC=C1 BAEZXIOBOOEPOS-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- YASIJBZPJZUSNT-UHFFFAOYSA-N (2-methylphenyl)-pyridin-2-ylmethanamine Chemical compound CC1=CC=CC=C1C(N)C1=CC=CC=N1 YASIJBZPJZUSNT-UHFFFAOYSA-N 0.000 description 1
- QMZJADVJDRSQAP-UHFFFAOYSA-N (4-methylphenyl)-pyridin-2-ylmethanamine Chemical compound C1=CC(C)=CC=C1C(N)C1=CC=CC=N1 QMZJADVJDRSQAP-UHFFFAOYSA-N 0.000 description 1
- XUFDMPZZAIRCGV-UHFFFAOYSA-N 1,1-diethoxy-n,n-dimethylethanamine Chemical compound CCOC(C)(N(C)C)OCC XUFDMPZZAIRCGV-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- GGYVTHJIUNGKFZ-UHFFFAOYSA-N 1-methylpiperidin-2-one Chemical compound CN1CCCCC1=O GGYVTHJIUNGKFZ-UHFFFAOYSA-N 0.000 description 1
- LTHFMKSCCBAWAT-UHFFFAOYSA-N 2,2-dimethyl-1-pyridin-2-ylpropan-1-one Chemical compound CC(C)(C)C(=O)C1=CC=CC=N1 LTHFMKSCCBAWAT-UHFFFAOYSA-N 0.000 description 1
- DHGUMNJVFYRSIG-UHFFFAOYSA-N 2,3,4,5-tetrahydropyridin-6-amine Chemical compound NC1=NCCCC1 DHGUMNJVFYRSIG-UHFFFAOYSA-N 0.000 description 1
- BWSLINKKCILOEB-UHFFFAOYSA-N 2-(pyridin-2-ylmethyl)aniline Chemical compound NC1=CC=CC=C1CC1=CC=CC=N1 BWSLINKKCILOEB-UHFFFAOYSA-N 0.000 description 1
- IMRWILPUOVGIMU-UHFFFAOYSA-N 2-bromopyridine Chemical compound BrC1=CC=CC=N1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 description 1
- ITXNDDPDABTCBO-UHFFFAOYSA-N 2-chloro-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1Cl ITXNDDPDABTCBO-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- XZAJERQRTFFKNB-UHFFFAOYSA-N 2-phenyl-1-pyridin-3-ylethanamine Chemical compound C=1C=CN=CC=1C(N)CC1=CC=CC=C1 XZAJERQRTFFKNB-UHFFFAOYSA-N 0.000 description 1
- NJLNPSNPLSKMMA-UHFFFAOYSA-N 2-phenyl-1-pyridin-4-ylethanamine Chemical compound C=1C=NC=CC=1C(N)CC1=CC=CC=C1 NJLNPSNPLSKMMA-UHFFFAOYSA-N 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- UJFFAAQNLMNRIM-UHFFFAOYSA-N 3-(2-pyridin-2-ylethyl)aniline Chemical compound NC1=CC=CC(CCC=2N=CC=CC=2)=C1 UJFFAAQNLMNRIM-UHFFFAOYSA-N 0.000 description 1
- KFJRPNNTWKWJHB-UHFFFAOYSA-N 3-(2-pyridin-4-ylethyl)aniline Chemical compound NC1=CC=CC(CCC=2C=CN=CC=2)=C1 KFJRPNNTWKWJHB-UHFFFAOYSA-N 0.000 description 1
- JSXDHOISXRKLGG-UHFFFAOYSA-N 3-chloro-n,n-dimethylbenzamide Chemical compound CN(C)C(=O)C1=CC=CC(Cl)=C1 JSXDHOISXRKLGG-UHFFFAOYSA-N 0.000 description 1
- WBXZCDIZXWDPBL-UHFFFAOYSA-N 3-methylpyridine-2-carbonitrile Chemical compound CC1=CC=CN=C1C#N WBXZCDIZXWDPBL-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- FARSXMMESQDZMY-UHFFFAOYSA-N 4-chloro-n,n-dimethylbenzamide Chemical compound CN(C)C(=O)C1=CC=C(Cl)C=C1 FARSXMMESQDZMY-UHFFFAOYSA-N 0.000 description 1
- DYDRCANRNSAYJA-UHFFFAOYSA-N 4-chloro-n-methylbenzamide Chemical compound CNC(=O)C1=CC=C(Cl)C=C1 DYDRCANRNSAYJA-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- BXYQVGFHMYTNBX-UHFFFAOYSA-N 5-methylazepan-2-one Chemical compound CC1CCNC(=O)CC1 BXYQVGFHMYTNBX-UHFFFAOYSA-N 0.000 description 1
- YNTUHDRALXNDEQ-UHFFFAOYSA-N 6-methoxy-2,3,4,5-tetrahydropyridine Chemical compound COC1=NCCCC1 YNTUHDRALXNDEQ-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 1
- QDHFDXDMKYJPSC-UHFFFAOYSA-N N-ethylphenylacetamide Chemical compound CCNC(=O)CC1=CC=CC=C1 QDHFDXDMKYJPSC-UHFFFAOYSA-N 0.000 description 1
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 description 1
- ZWXPDGCFMMFNRW-UHFFFAOYSA-N N-methylcaprolactam Chemical compound CN1CCCCCC1=O ZWXPDGCFMMFNRW-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- CYTYCFOTNPOANT-UHFFFAOYSA-N Perchloroethylene Chemical group ClC(Cl)=C(Cl)Cl CYTYCFOTNPOANT-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 238000005266 casting Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 150000004658 ketimines Chemical class 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- IXHFNEAFAWRVCF-UHFFFAOYSA-N n,2-dimethylpropanamide Chemical compound CNC(=O)C(C)C IXHFNEAFAWRVCF-UHFFFAOYSA-N 0.000 description 1
- ULKWBVNMJZUEBD-UHFFFAOYSA-N n,n,4-trimethylbenzamide Chemical compound CN(C)C(=O)C1=CC=C(C)C=C1 ULKWBVNMJZUEBD-UHFFFAOYSA-N 0.000 description 1
- CLJWSVLSCYWCMP-UHFFFAOYSA-N n,n-diethyl-2-methylpropanamide Chemical compound CCN(CC)C(=O)C(C)C CLJWSVLSCYWCMP-UHFFFAOYSA-N 0.000 description 1
- AJFDBNQQDYLMJN-UHFFFAOYSA-N n,n-diethylacetamide Chemical compound CCN(CC)C(C)=O AJFDBNQQDYLMJN-UHFFFAOYSA-N 0.000 description 1
- UXDAWVUDZLBBAM-UHFFFAOYSA-N n,n-diethylbenzeneacetamide Chemical compound CCN(CC)C(=O)CC1=CC=CC=C1 UXDAWVUDZLBBAM-UHFFFAOYSA-N 0.000 description 1
- YKOQQFDCCBKROY-UHFFFAOYSA-N n,n-diethylpropanamide Chemical compound CCN(CC)C(=O)CC YKOQQFDCCBKROY-UHFFFAOYSA-N 0.000 description 1
- FHVMATOIMUHQRC-UHFFFAOYSA-N n,n-dimethyl-2-phenylacetamide Chemical compound CN(C)C(=O)CC1=CC=CC=C1 FHVMATOIMUHQRC-UHFFFAOYSA-N 0.000 description 1
- IMNDHOCGZLYMRO-UHFFFAOYSA-N n,n-dimethylbenzamide Chemical compound CN(C)C(=O)C1=CC=CC=C1 IMNDHOCGZLYMRO-UHFFFAOYSA-N 0.000 description 1
- VIJUZNJJLALGNJ-UHFFFAOYSA-N n,n-dimethylbutanamide Chemical compound CCCC(=O)N(C)C VIJUZNJJLALGNJ-UHFFFAOYSA-N 0.000 description 1
- BNODIVYXTGTUPS-UHFFFAOYSA-N n,n-dimethylpentanamide Chemical compound CCCCC(=O)N(C)C BNODIVYXTGTUPS-UHFFFAOYSA-N 0.000 description 1
- MBHINSULENHCMF-UHFFFAOYSA-N n,n-dimethylpropanamide Chemical compound CCC(=O)N(C)C MBHINSULENHCMF-UHFFFAOYSA-N 0.000 description 1
- NDUJCZFHWKDEAP-UHFFFAOYSA-N n-benzhydryl-2,3,4,5-tetrahydropyridin-6-amine Chemical compound N1CCCC\C1=N/C(C=1C=CC=CC=1)C1=CC=CC=C1 NDUJCZFHWKDEAP-UHFFFAOYSA-N 0.000 description 1
- KYPSUESMQNATHW-UHFFFAOYSA-N n-benzhydrylpyridin-2-amine Chemical compound C=1C=CC=NC=1NC(C=1C=CC=CC=1)C1=CC=CC=C1 KYPSUESMQNATHW-UHFFFAOYSA-N 0.000 description 1
- RKEXPBCMGJAOLM-UHFFFAOYSA-N n-methyl-2-phenylacetamide Chemical compound CNC(=O)CC1=CC=CC=C1 RKEXPBCMGJAOLM-UHFFFAOYSA-N 0.000 description 1
- NCCHARWOCKOHIH-UHFFFAOYSA-N n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1 NCCHARWOCKOHIH-UHFFFAOYSA-N 0.000 description 1
- XKEKKGKDCHCOSA-UHFFFAOYSA-N n-methylpentanamide Chemical compound CCCCC(=O)NC XKEKKGKDCHCOSA-UHFFFAOYSA-N 0.000 description 1
- QJQAMHYHNCADNR-UHFFFAOYSA-N n-methylpropanamide Chemical compound CCC(=O)NC QJQAMHYHNCADNR-UHFFFAOYSA-N 0.000 description 1
- IHPHPGLJYCDONF-UHFFFAOYSA-N n-propylacetamide Chemical compound CCCNC(C)=O IHPHPGLJYCDONF-UHFFFAOYSA-N 0.000 description 1
- HYWWTHOGCJXTRI-UHFFFAOYSA-N n-tert-butylbenzamide Chemical compound CC(C)(C)NC(=O)C1=CC=CC=C1 HYWWTHOGCJXTRI-UHFFFAOYSA-N 0.000 description 1
- SDLAKRCBYGZJRW-UHFFFAOYSA-N n-tert-butylformamide Chemical compound CC(C)(C)NC=O SDLAKRCBYGZJRW-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- XDYKWHGBZMOSDC-UHFFFAOYSA-N phenyl(pyridin-3-yl)methanamine Chemical compound C=1C=CN=CC=1C(N)C1=CC=CC=C1 XDYKWHGBZMOSDC-UHFFFAOYSA-N 0.000 description 1
- DNIOUOCUBMTIDC-UHFFFAOYSA-N phenyl(pyridin-4-yl)methanamine Chemical compound C=1C=NC=CC=1C(N)C1=CC=CC=C1 DNIOUOCUBMTIDC-UHFFFAOYSA-N 0.000 description 1
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridine hydrochloride Substances [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229950011008 tetrachloroethylene Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/53—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen atoms
- C07D213/50—Ketonic radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
Description
Pyridylalkylamidiner, fremgangsmåte tilPyridylalkylamidines, process for
deres fremstilling samt deres anvendelsetheir manufacture as well as their use
som legemiddel.as medicine.
Oppfinnelsen vedrører nye pyridylalkylamidiner, flere fremgangsmåter til deres fremstilling samt deres anvendelse som legemiddel, spesielt som antidiabetika. The invention relates to new pyridylalkylamidines, several methods for their preparation and their use as medicine, especially as antidiabetics.
Det er allerede kjent at amidiner, som eksempelvis N-(difenylmetyl)-piperidin-2-imin har en blodsukkersenkende virkning l_ sammenlign Journal of Medicinal Chemistry 16, 679-683 (1973); It is already known that amidines, such as N-(diphenylmethyl)-piperidin-2-imine have a blood sugar-lowering effect, compare Journal of Medicinal Chemistry 16, 679-683 (1973);
Journal of Medicinal Chemistry 16, 885-893 (197327. Slike amidiner har imidlertid den ulempe at virkningsinntreden foregår relativt sent. Journal of Medicinal Chemistry 16, 885-893 (197327. However, such amidines have the disadvantage that the onset of action takes place relatively late.
Det er blitt funnet at de nye pyridylalkylamidiner med It has been found that the new pyridylalkylamidines with
hvori in which
R^betyr H, alkyl, alkoksy, eventuelt substituert fenyl, R^means H, alkyl, alkoxy, optionally substituted phenyl,
benzyl,benzyl,
2 betyr H eller alkyl,2 means H or alkyl,
R^betyr H, alkyl, eventuelt substituert fenyl, benzyl, R^means H, alkyl, optionally substituted phenyl, benzyl,
fenetyl,phenethyl,
R^ betyr alkyl, eventuelt substituert fenyl, cykloalkyl R 1 means alkyl, optionally substituted phenyl, cycloalkyl
eller heteroaryl, benzyl,or heteroaryl, benzyl,
Rrbetyr H, alkyl, eventuelt substituert fenyl, benzyl, Rg betyr alkyl, R means H, alkyl, optionally substituted phenyl, benzyl, Rg means alkyl,
Rj betyr H eller alkyl,Rj means H or alkyl,
X, Y, Z betyr en enkeltbinding eller en metylengruppe og hvori X, Y, Z means a single bond or a methylene group and wherein
R^ og Rg også kan være forbundet med en enkeltbinding, samt deres syreaddisjonssalter med fysiologisk tålbare syrer har sterkt antihyperglykemiske egenskaper. R^ and Rg can also be connected by a single bond, and their acid addition salts with physiologically tolerable acids have strong antihyperglycemic properties.
Videre ble det funnet at man får pyridylalkylamidiner med formel I, når enten Furthermore, it was found that pyridylalkylamidines of formula I are obtained when either
a) reaksjonsdyktige amidderivater med formel IIa) reactive amide derivatives of formula II
hvori in which
R^ og Rg har overnevnte betydning og R^ and Rg have the above meaning and
Rg betyr alkoksy, alkyltio, halogen, acyloksy, acyltio, Rg means alkoxy, alkylthio, halogen, acyloxy, acylthio,
oksyfosforylhalogenider, halogentionyloksy, alkylsulfonyloksy, eventuelt substituert arylsulfonyloksy, tiofosforylhalogenider, omsettes med aminer med formel III oxyphosphoryl halides, halothionyloxy, alkylsulfonyloxy, optionally substituted arylsulfonyloxy, thiophosphoryl halides, are reacted with amines of formula III
hvori in which
R^, R2, R^, R^, X, Y og Z har overnevnte betydning, eventuelt i nærvær av syrebindende midler eller i nærvær av syrer, eller R^, R2, R^, R^, X, Y and Z have the above meaning, possibly in the presence of acid-binding agents or in the presence of acids, or
b) reaksjonsdyktige amidderivater med formel IVb) reactive amide derivatives of formula IV
hvori in which
R^, Rg, R^og Rg har overnevnte betydning og Rg betyr halogen, alkoksy, alkyltio, O-SC^-OCH^, BP^, R^, Rg, R^ and Rg have the above meaning and Rg means halogen, alkoxy, alkylthio, O-SC^-OCH^, BP^,
POCl^, AlCl^,POCl^, AlCl^,
og hvori de ved Rg og R^angitte alkoksy- og alkyltio-grupper ogsåand in which those at Rg and R^ indicate alkoxy and alkylthio groups as well
kan være sluttet til en ring, omsettes med aminer med formel III, eventuelt i nærvær av syrebindere. may be joined to a ring, reacted with amines of formula III, possibly in the presence of acid binders.
Noen av amidderivatene med formel IV foreligger uteluk-kende i form B (f.eks. R^= BF^). Some of the amide derivatives with formula IV exist exclusively in form B (e.g. R^=BF^).
Amidiner med formel I kan også fåes, idet det tilsvarende substituerte keten-ON-acetal, som kan fremstilles etter vanlige metoder l_ sammenlign blant annet Zeitschrift fur Chemie 9., 213 ( 1969 W, omsettes med aminer med formel III ifølge fremgangsmåte b). Amidines of formula I can also be obtained, as the corresponding substituted ketene-ON-acetal, which can be prepared according to usual methods 1_ compare, among others, Zeitschrift fur Chemie 9., 213 (1969 W, is reacted with amines of formula III according to method b).
Overraskende viser pyridylalkylamidinene ifølge oppfinnelsen en sterk antihyperglykemisk virkning i orale kullhydratbelast-ningsforsøk. I forhold til de hittil oppnåelige sulfonylurinstoff-forbindelser og biguanidforbindelser har de den fordel at de også virker i fravær av insulin på alloksandiabetiske dyr. Surprisingly, the pyridylalkylamidines according to the invention show a strong antihyperglycaemic effect in oral carbohydrate loading tests. In relation to the hitherto obtainable sulfonylurea compounds and biguanide compounds, they have the advantage that they also work in the absence of insulin on alloxan-diabetic animals.
Overfor de allerede kjente difenylmetylamidiner [_~ J. Med. CHem. _l6, 885-892 (19732/ har ^e fordelen med en sterkere virkning Compared to the already known diphenylmethylamidines [_~ J. Med. CHem. _l6, 885-892 (19732/ has the advantage of a stronger effect
og en hurtigere virkningsinntreden. Stoffene ifølge oppfinnelsen er således en berikelse av farmasien. and a faster onset of action. The substances according to the invention are thus an enrichment of the pharmacy.
Anvender man 2-(a-aminobenzyl)-pyridin og 2-metoksy-l-pyrrolin som utgangsstoffer, så kan reaksjonsforløpet gjengis ved følgende formelskjema: If 2-(a-aminobenzyl)-pyridine and 2-methoxy-l-pyrroline are used as starting materials, the course of the reaction can be reproduced by the following formula:
F remgangsmåte a). Procedure a).
Anvender man 2-(ct-aminobenzyl)-pyridin og l-metyl-2,2-dietoksypyrrolidin som utgangsstoffer, så kan reaksjonsforløpet gjengis med følgende formelskjema: If 2-(ct-aminobenzyl)-pyridine and 1-methyl-2,2-diethoxypyrrolidine are used as starting materials, the course of the reaction can be reproduced with the following formula:
F remgangsmåte b). Procedure b).
De ifølge oppfinnelsen anvendbare aminer er generelt definert med formel III. Her betyr R, fortrinnsvis H, alkyl med 1 til 4 karbonatomer, alkoksy med 1 til 4 karbonatomer, benzyl og eventuelt med halogen substituert fenyl; The amines which can be used according to the invention are generally defined by formula III. Here, R, preferably H, means alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, benzyl and optionally halogen-substituted phenyl;
R^betyr fortrinnsvis H og alkyl med 1 til 4 karbonatomer, R^ preferably means H and alkyl with 1 to 4 carbon atoms,
R^betyr fortrinnsvis H, rettlinjet eller forgrenet alkyl med 1 til 4 karbonatomer, benzyl, fenetyl,og eventuelt med halogen substituert fenyl; R2 preferably means H, straight or branched alkyl with 1 to 4 carbon atoms, benzyl, phenethyl, and optionally halogen-substituted phenyl;
R^betyr fortrinnsvis rettlinjet eller forgrenet alkyl med 1 til 4 karbonatomer, cykloalkyl, fenyl, som eventuelt kan være substituert med halogen, alkyl, alkoksy, nitro eller karbetoksy en- eller flere ganger, benzyl, fenetyl og eventuelt substituert heteroaryl, spesielt 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-tienyl, 3-tienyl, 2-furyl. R^means preferably straight or branched alkyl with 1 to 4 carbon atoms, cycloalkyl, phenyl, which may optionally be substituted with halogen, alkyl, alkoxy, nitro or carbethoxy one or more times, benzyl, phenethyl and optionally substituted heteroaryl, especially 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 2-furyl.
De ifølge oppfinnelsen anvendbare aminer med formel III er allerede kjent eller lar seg fremstille etter kjente fremgangsmåter, f.eks. av de tilsvarende ketoner over oksimene eller ved re-duksjon av de tilsvarende iminer med NaBH^ (sammenlign fremstillings-eksempler). The amines of formula III which can be used according to the invention are already known or can be prepared according to known methods, e.g. of the corresponding ketones over the oximes or by reduction of the corresponding imines with NaBH^ (compare production examples).
Som eksempler skal nevnes (sammenlign også tabell 4): Examples should be mentioned (compare also table 4):
2- (a:;aminobenzyl)-pyridin,2-(α:;aminobenzyl)-pyridine,
3- (a-aminobenzy1)-pyridin,3-(α-aminobenzyl)-pyridine,
4- (a-aminobenzyl)-pyridin, 4-(α-aminobenzyl)-pyridine,
2- /_—a-(aminometyl)-benzyl7-pyridin3 2- /_-α-(aminomethyl)-benzyl7-pyridine3
3- £~ a-(aminometyl)-benzyl7-pyridin, 3- £~ a-(aminomethyl)-benzyl7-pyridine,
4- /_-a-(aminometyl)-benzyl/-pyridin, 4- /_-α-(aminomethyl)-benzyl/-pyridine,
2-(a-aminofenetyl)-pyridin,2-(a-aminophenethyl)-pyridine,
2- (3-aminofenetyl)-pyridin,2-(3-aminophenethyl)-pyridine,
3- (a-aminofenety1)-pyridin,3-(α-aminophenethyl)-pyridine,
3- (fl-aminofenetyl)-pyridin,3-(fl-aminophenethyl)-pyridine,
4- (a-aminofenetyl)-pyridin,4-(α-aminophenethyl)-pyridine,
4-(3-aminofenetyl)-pyridin, 4-(3-aminophenethyl)-pyridine,
2-(a-aminobenzyl)-3-metylpyridin, 2-(α-aminobenzyl)-3-methylpyridine,
2-(a-aminobenzyl)-4-metylpyridin, 2-(α-aminobenzyl)-4-methylpyridine,
2- (artammnobenzyl)-6-metylpyridin, 2-(artammnobenzyl)-6-methylpyridine,
4-(a-aminobenzyl)-2-metylpyridin, 4-(a-aminobenzyl)-2-methylpyridine,
2-(a-amino-2-metylbenzyl)-pyridin, 2-(α-amino-2-methylbenzyl)-pyridine,
2-(a-amino-3-metylbenzyl)-pyridin, 2-(a-amino-3-methylbenzyl)-pyridine,
2- (a-amino-4-metylbenzyl)-pyridin, 2-(α-amino-4-methylbenzyl)-pyridine,
3- /~3-(aminometyl)-fenyletyl7-pyridin, 3- /~3-(aminomethyl)-phenylethyl7-pyridine,
4- /_""3- (aminomety 1) - f ene ty l/-pyr idin, 4- /_""3-(Aminomethyl 1)-phenethyl/-pyridine,
2-_/<->l-amino-2-(2-pyridyl)-etyl7-pyridin, 2-_/<->1-amino-2-(2-pyridyl)-ethyl7-pyridine,
2-/_~2-amino-2- (3-pyridyl) -etyl7-pyridin, 2-(2-amino-2-(3-pyridyl)-ethyl-7-pyridine,
2-/_-2-amino-2-( 4-pyridyl)-etyl7-pyridin, 2-(_-2-amino-2-(4-pyridyl)-ethyl7-pyridine,
2- _/-l-amino-2-( 4-pyridyl)-etyl7-pyridin, 2-_/-1-amino-2-(4-pyridyl)-ethyl-7-pyridine,
3- /_~"l-amino-2- (4-pyridyl) -etyl7-pyridin, 3- /_~"1-amino-2-(4-pyridyl)-ethyl 7-pyridine,
4- /"~l-amino-2- (4-pyridyl) -etyl7-pyridin.4- /"~1-Amino-2-(4-pyridyl)-ethyl 7-pyridine.
De ifølge oppfinnelsen anvendbare amidderivater er generelt definert med formlene II og IV. Her betyr The amide derivatives which can be used according to the invention are generally defined by the formulas II and IV. Here means
R,- fortrinnsvis H, rettlinjet eller forgrenet alkyl med 1 til 4 karbonatomer, eventuelt med klor eller metyl substituert fenyl, benzyl, R, - preferably H, straight or branched alkyl with 1 to 4 carbon atoms, optionally with chlorine or methyl substituted phenyl, benzyl,
Rg betyr fortrinnsvis rettlinjet eller forgrenet alkyl med 1 til 4 karbonatomer, Rg means preferably straight or branched alkyl with 1 to 4 carbon atoms,
R^ betyr fortrinnsvis H, rettlinjet eller forgrenet alkyl med 1 til 4 karbonatomer, R^ preferably means H, straight or branched alkyl with 1 to 4 carbon atoms,
Rg og R q betyr fortrinnsvis alkoksy med 1 til 4 karbonatomer i alkyldelen eller R^ og Rg kan også være sammenknyttet med hverandre ved hjelp av en enkeltbinding, således at det oppstår en fire- til syvleddet ring. Rg and Rq preferably mean alkoxy with 1 to 4 carbon atoms in the alkyl part or R^ and Rg can also be connected to each other by means of a single bond, so that a four- to seven-membered ring is formed.
De reaksjonsdyktige amidderivater II og IV fremstilles etter de vanlige fremgangsmåter fra litteraturkjente amider [_ sammenlign blant annet Chimia 27, 65-68 (1973) og Zeitschrift fur Chemie 9, 201-213 (196927. The reactive amide derivatives II and IV are prepared according to the usual methods from amides known in the literature [_ compare, among others, Chimia 27, 65-68 (1973) and Zeitschrift fur Chemie 9, 201-213 (196927.
Som eksempler for disse amider skal nevnes: N-metylformamid, Examples of these amides include: N-methylformamide,
N-t-butylformamid,N-t-butylformamide,
N-metylacetamid,N-methylacetamide,
N-i-propylacetamid, N-i-propylacetamide,
N-metylpropionsyreamid, N-methylpropionic acid amide,
N-metylisosmørsyreamid, N-methylisobutyric acid amide,
N-metylvaleriansyreamid, N-methylvaleric acid amide,
4,4-dimetyl-acetidinon-(2), pyrrolidon-(2), 4,4-Dimethyl-acetidinone-(2), pyrrolidone-(2),
3-metylpyrrolidon-(2), 3-methylpyrrolidone-(2),
N,N-dimetylformamid,N,N-Dimethylformamide,
N,N-dimetylacetamid, N,N-dimethylacetamide,
N,N-dimetylpropionsyreamid, N,N-dimetylsmørsyreamid, N,N-dimethylpropionic acid amide, N,N-dimethylbutyric acid amide,
NjN-dimetylisosmørsyreamid, N,N-dimetylvaleriansyreamid, N,N-dietylformamid, NjN-dimethylisobutyric acid amide, N,N-dimethylvaleric acid amide, N,N-diethylformamide,
3- metylpyrrolidon-(5), 3- methylpyrrolidone-(5),
2-metylpyrrolidon-(5) »2-methylpyrrolidone-(5) »
valerolaktam,valerolactam,
kaprolaktam,caprolactam,
y-metylkaprolaktam,γ-methylcaprolactam,
N-metylbenzamid,N-methylbenzamide,
N-tert.-butylbenzamid, N-tert-butylbenzamide,
2-klor-N-metylbenzamid, 2-chloro-N-methylbenzamide,
4- klor-N-metylbenzamid, 4-chloro-N-methylbenzamide,
4-N-dimetylbenzamid, 4-N-dimethylbenzamide,
N-mety1-fenyleddiksyreamid, N-etyl-fenyleddiksyreamid, N,N-dietylacetamid, N-methyl-phenylacetic acid amide, N-ethyl-phenylacetic acid amide, N,N-diethylacetamide,
N,N-dietylpropionsyreamid, N,N-dietylisosmørsyreamid, N,N-diethylpropionic acid amide, N,N-diethylisobutyric acid amide,
l,4,4-trimetyl-acetidinon-(2),1,4,4-trimethyl-acetidinone-(2),
1-metylpyrrolidon-(2),1-methylpyrrolidone-(2),
1.2- dimetylpyrrolidon-(5),1.2-Dimethylpyrrolidone-(5),
1.3- dimetylpyrrolidon-(5),1.3-Dimethylpyrrolidone-(5),
1,3-dimetylpyrrolidon-(2),1,3-dimethylpyrrolidone-(2),
l-etylpyrrolidon-(2),l-ethylpyrrolidone-(2),
1-n-butylpyrrolidon-(2),1-n-butylpyrrolidone-(2),
N-metylvalerolaktam,N-methylvalerolactam,
N-metylkaprolaktam,N-methylcaprolactam,
N,y-dimetylkaprolaktam,N,y-dimethylcaprolactam,
N,N-dimetylbenzamid,N,N-Dimethylbenzamide,
3- klor-N,N-dimetylbenzamid,3-chloro-N,N-dimethylbenzamide,
4- klor-N,N-dimetylbenzamid,4-chloro-N,N-dimethylbenzamide,
4,N,N-trimetylbenzamid,4,N,N-trimethylbenzamide,
N,N-dimetylfenyleddiksyreamid,N,N-dimethylphenylacetic acid amide,
N,N-dietylfenyleddiksyreamid.N,N-diethylphenylacetic acid amide.
Som fortynningsmiddel for reaksjonene a) og b) ifølge oppfinnelsen kommer det på tale alle oppløsningsmidler. Hertil hører fortrinnsvis hydrokarboner" som ligroin, benzen, toluen, etere som dietyleter, tetrahydrofuran, dioksan, halogenerte hydrokarboner som metylenklorid, kloroform, karbontetraklorid, tetrakloretylen, klorbenzen, sulfoksyder som dimetylsulfoksyd, sulfoner som tetra-metylensulfon, alkoholer som metanol, etanol, propanol, butanol, basiske forbindelser som pyridin, N,N-dimetylanilin og vann. Disse fortynningsmidler kan anvendes alene eller i blanding. Derved bestemmes på i og for seg kjent måte valg av egnet oppløsnings- eller fortynningsmiddel ved stabilitet og reaksjonsevne av de eventuelle reaksjonskomponenter. Anvendelse av oppløsnings- og fortynningsmidler er hensiktsmessige i de fleste tilfeller, men ikke ubetinget nødvendig. Diluents for reactions a) and b) according to the invention include all solvents. These preferably include hydrocarbons such as ligroin, benzene, toluene, ethers such as diethyl ether, tetrahydrofuran, dioxane, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, tetrachloroethylene, chlorobenzene, sulfoxides such as dimethyl sulfoxide, sulfones such as tetramethylene sulfone, alcohols such as methanol, ethanol, propanol , butanol, basic compounds such as pyridine, N,N-dimethylaniline and water. These diluents can be used alone or in a mixture. Thereby, the choice of a suitable solvent or diluent is determined in a known manner by the stability and reactivity of the possible reaction components. The use of solvents and diluents is appropriate in most cases, but not absolutely necessary.
Reaksjonstemperaturen kan varieres innen et stort om-råde. Vanligvis arbeider man mellom -70°C og +200°C, fortrinnsvis mellom -30°C og +150°C. The reaction temperature can be varied within a large range. Generally, one works between -70°C and +200°C, preferably between -30°C and +150°C.
Som syrebindere kan dét anvendes alle vanlige syrebind-ingsmidler. Hertil hører fortrinnsvis trietylamin, N,N-dimetylani-lin, pyridin. As acid binders, all common acid binders can be used. These preferably include triethylamine, N,N-dimethylaniline, pyridine.
Som syretilsetning kan det anvendes alle vanlige syrer. Hertil hører fortrinnsvis klorhydrogen, benzensulfonsyre, toluen- All common acids can be used as acid additives. These preferably include hydrogen chloride, benzenesulfonic acid, toluene
sulfonsyre.sulfonic acid.
Ved gjennomføring av fremgangsmåten ifølge oppfinnelsen anvender man vanligvis på 1 mol amin også 1 mol reaksjonsdyktig amidderivat. Undertiden er det himidlertid hensiktsmessig å anvende inntil 100$ overskudd av reaksjonsdyktig amidderivat. When carrying out the method according to the invention, 1 mol of amine is usually also used with 1 mol of a reactive amide derivative. Sometimes, however, it is appropriate to use up to 100% excess of reactive amide derivative.
Som nye virksomme stoffer skal det i detalj eksempelvis nevnes (sammenlign også tabell 2 og 3): l-metyl-N-/_ fenyl- (2-pyridyl)-metyl/-pyrrolidin-2-imin, N-/~(fenyl-(2-pyridyl)-metyl7-pyrrolidin-2-imin, l-metyl-N-/_ fenyl- (3-pyridyl) -metyl/-pyrr olidin-2-imin, N-/_ fenyl- (3-pyr idyl)-me ty_l/-pyrr olidin-2-imin, As new active substances the following should be mentioned in detail (compare also tables 2 and 3): l-methyl-N-/_ phenyl-(2-pyridyl)-methyl/-pyrrolidin-2-imine, N-/~(phenyl -(2-pyridyl)-methyl7-pyrrolidin-2-imine, l-methyl-N-(3-pyridyl)-methyl-pyrrolidin-2-imine, N-/_phenyl-(3- pyr idyl)-methy_l/-pyrr olidin-2-imine,
1-mety1-N-/<->fenyl-(4-pyridyl)-metyl/-pyrrolidin-2-imin, N-/_~~fenyl- ( 4-pyridyl)-me ty_l7-pyrr olidin-2-imin, 1-methyl-N-/<->phenyl-(4-pyridyl)-methyl/-pyrrolidine-2-imine, N-/_~~phenyl-( 4-pyridyl)-methyl_l7-pyrrolidine-2-imine ,
N, N-dime ty 1-N' -/_ fenyl- (2-pyridyl)-metyl7-formamidin, N, N-dime t y 1-N' -/"fenyl- (3-pyridyl) -metyl/-f or mamidin, N,N-dimety1-N'- £~ fenyl-(4-pyridyl)-metyl7-formamidin, N, N-dimety 1-N' - l_ fenyl- ( 2-pyridyl)-metyl7-acetamidin, N,N-dimetyl-N' - 1_ fenyl- (2-pyridyl)-mety_l/-propionsyreamidin, N, N-dime ty 1-N1 -_/"" fenyl- (2-pyridy1)-metyl7-valeriansyreamidin, N,N-dimety 1-N * -[_ fenyl-(2-pyridyl)-metyl7-åsosmørsyreamidin, N, N-dime ty 1-N' - 1_ fenyl- ( 3-pyridyl) -metyl/-is osmørsyreamidin , N,N-dimety 1-N' -/_ fenyl- (4-pyridyl) -mety 1/-isosmørsyreamidin, N, N-dime ty 1-N ' - 1_ benzyl- (2-pyridyl)-met y_l/- is osmørsyreamidin, N, N-dime ty 1-N' -[_ benzyl- (3-pyridyl) -met yl7-is osmørsyreamidin, N,N-dimety1-N'- jT~benzyl-(4-pyridyl)-metyl7-is osmørsyreamidin, l-metyl-N-_/—cykloheksyl- (2-pyridyl)-metyl7-pyrrolidin-2-imin, 1-mety l-N-/_~cykloheksyl- ( 3-pyridyl) -mety l7-pyr r olidin-2-imin, l-metyl-N-/_ cykloheksyl- ( 4-pyridyl) -metyl7-pyrrolidin-2-imin, N,NMdimety1-N'- f~ (2-pyridyl)-(2-tienyl)-metyl/-isosmørsyreamidin, N,N-dimety1-N'- £~(3-pyridyl)-(2-tienyl)-metyl7-isosmørsyreamidin, N, N-dime ty 1-N' -_/"( 4-pyridyl)- (2-tienyl )-metyl7-is osmørsyreamidin, 1-mety 1-N- 1_ fenyl- (2-pyridyl)pmetyl/-piperidin-2-imin, l-metyl-N-/_ fenyl- ( 3-pyridyl) -mety_l/-piperidin-2-imin, l-metyl-N-_/ fenyl- (4-pyridyl)-metyl/-piperidin-2-imin, 1-mety 1-N-/_ benzyl- ( 2-pyridyl)-metyl/-piperidin-2-imin, l-metyl-N-/_ benzyl- (4-pyridyl)-metyl/-piperidin-2-imin, l-metyl-N-/_—(2-pyridyl) - (2-tienyl)-metyl7-piperidin-2-imin, _ l-metyl-N-/_—(3-pyridyl) -(2-tienyl)-metyl7-piperidin-2-imin, l-metyl-N-/_~(4-pyridyl) - (2-tienyl) -metyl7-piperidin-2-imin, 1-mety 1-N- 1_ (2-pyridyl) - (3-tienyl) -mety3.7-piperidin-2-imin, l-metyl-N-_/ (2-furyl) - (2-pyridyl) -mety 3_7-piperidin-2-imin, 1, 3-dimetyl-N-/_ fenyl- (2-pyridyl) -me ty_l7-pyrr olidin-2 -imin, 1, 3-dimety l-N-_/ fenyl- (3-pyridyl)-mety3.7-pyrrolidin-2-imin, 1, 3-dimetyl-N-/_ fenyl - ( 4-pyridyl) -mety3.7-pyrrolidin-2-imin, 1, 4-dimetyl-N-_/ fenyl - (2-pyr idyl)-me tyl./-pyrr ol idin-2-imin, 1, 4-dimetyl-N-/-f enyl- (3-pyridyl) -mety_l7-pyrrolidin-2-imin, 1, 4-dimetyl-N-/_ fenyl- (4-pyridyl) -me tyl7-pyrr olidin-2 -imin, 1, 5-dimetyl-N-/_ fenyl- (2-pyridyl) -mety_l7-pyrrolidin-2-imin, 1,5-dimetyl-N-/<->fenyl-(3-pyridyl)-metyl7-pyrrolidin-2-imin, 1,5-dimetyl-N-/-fenyl- ( 4-pyridyl) -metyl7-pyrrolidin-2-imin, 1,4,4-trimety1-N-/~fenyl-(2-pyridyl)-metyl7-acetidin-2-imin, 1, 4, 4-trimetyl-N-/-f enyl- (4-pyridyl) -mety_l7-azetidin-2-imin, 4 ,4-dimetyl-N-/_ fenyl- (2-pyridyl)-metyl7-azetidin-2-imin, 4 , 4-dimetyl-N-/ fenyl- (3-pyridyl) -met y 3.7-az et idin-2 -imin. l-metyl-N-/_ benzyl- (2-pyridyl)-metyl7-pyrrolidin-2-imin} l-metyl-N-/_ benzyl- ( 3-pyridyl) -me tyl7-pyrr oli din-2 -imin, 1-metyl-N-/~ benzyl- ( 4-pyridyl)-mety 3.7-py r ro li din-2-imin, 1-metyl-N-_/~fenyl- (2-pikolyl) -metyl7-pyrrolidin-2-imin, l-metyl-N-_/—f enyl- (3-pikolyl )-metyl7-pyrrolidin-2-imin, 1-mety1-N-/"fenyl-(4-pikoly1)-metyl7-pyrrolidin-2-imin, N-/_ benzyl- (2-pyridy 1)-metyl7-pyrrolidin-2-imin, N, N-dime ty 1-N' -/_ phenyl-(2-pyridyl)-methyl7-formamidine, N, N-dime ty 1-N' -/"phenyl-(3-pyridyl)-methyl/-f or mamide, N,N-dimethyl-N'- £~ phenyl-(4-pyridyl)-methyl7-formamidine, N,N-dimethyl 1-N' - l_ phenyl-( 2-pyridyl)-methyl7-acetamidine, N ,N-dimethyl-N' - 1_ phenyl-(2-pyridyl)-methyl-1/-propionic acid amidine, N, N-dimethyl 1-N1 -_/"" phenyl-(2-pyridyl)-methyl7-valeric acid amidine, N, N-dimethyl 1-N * -[_ phenyl-(2-pyridyl)-methyl7-isobutyric acid amidine, N, N-dimethy 1-N' - 1_ phenyl-( 3-pyridyl)-methyl/-is osbutyric acid amidine , N, N-dimethyl 1-N' -/_ phenyl-(4-pyridyl)-methyl 1/-isobutyric acid amidine, N, N-dimethyl 1-N' - 1_ benzyl-(2-pyridyl)-methyl_1/- isosbutyric acid amidine . osbutyric acid amidine, 1-methyl-N-_/—cyclohexyl-(2-pyridyl)-methyl7-pyrrolidin-2-imine, 1-methyl-N-/_~cyclohexyl-( 3-pyridyl)-methyl 7-pyr r olidin- 2-imine, 1-methyl-N-(/_ cyclohexyl-(4-pyridyl)-methyl7-pyrrolidin-2-imine, N,NMdimethyl 1-N'- f~ (2-pyridyl)-(2-thienyl)-methyl/-isobutyric amidine, N,N-dimethyl-N'- £~(3-pyridyl)-(2-thienyl)-methyl7-isobutyric amidine . Piperidin-2-imine, l-methyl-N-/_ phenyl-( 3-pyridyl)-methyl/- piperidin-2-imine, l-methyl-N-_/ phenyl-(4-pyridyl)-methyl/- Piperidin-2-imine, 1-methyl 1-N-/_ benzyl-( 2-pyridyl)-methyl/-piperidin-2-imine, 1-methyl-N-/_ benzyl-(4-pyridyl)-methyl/ -piperidin-2-imine, 1-methyl-N-(2-pyridyl)-(2-thienyl)-methyl7-piperidin-2-imine, 1-methyl-N-(2-pyridyl ) -(2-thienyl)-methyl7-piperidin-2-imine, 1-methyl-N-(4-pyridyl)-(2-thienyl)-methyl7-piperidin-2-imine, 1-methyl 1- N- 1_ (2-pyridyl)-(3-thienyl)-methyl 3,7-piperidin-2-imine, 1-methyl-N-_/ (2-furyl)-(2-pyridyl)-methyl 3_7-piperidin- 2-imine, 1, 3-dimethyl-N-/_ phenyl-(2-pyridyl)-methyl_17-pyrrolidine-2-imine, 1, 3-dimethyl-N-_/ phenyl-(3-pyridyl)-methyl .7-pyrrolidin-2-imine, 1,3-dimethyl-N-/_ phenyl-(4-pyridyl)-methyl3,7-py rrolidin-2-imine, 1, 4-dimethyl-N-_/ phenyl - (2-pyr idyl)-methyl./-pyrr ol idin-2-imine, 1, 4-dimethyl-N-/-phenyl -(3-pyridyl)-methyl-17-pyrrolidine-2-imine, 1,4-dimethyl-N-(4-pyridyl)-methyl-7-pyrrolidine-2-imine, 1,5-dimethyl-N -/_ phenyl-(2-pyridyl)-methyl_17-pyrrolidin-2-imine, 1,5-dimethyl-N-/<->phenyl-(3-pyridyl)-methyl7-pyrrolidin-2-imine, 1,5 -dimethyl-N-/-phenyl-(4-pyridyl)-methyl7-pyrrolidin-2-imine, 1,4,4-trimethyl-N-/~phenyl-(2-pyridyl)-methyl7-acetidin-2-imine , 1, 4, 4-trimethyl-N-(4-pyridyl)-methyl-17-azetidin-2-imine, 4,4-dimethyl-N-(2-pyridyl)-methyl-7- azetidine-2-imine, 4,4-dimethyl-N-/phenyl-(3-pyridyl)-meth y 3,7-az etidin-2-imine. 1-methyl-N-(2-pyridyl)-methyl-7-pyrrolidin-2-imine} 1-methyl-N-(3-pyridyl)-methyl-7-pyrrolidine-2-imine , 1-methyl-N-/~benzyl-(4-pyridyl)-methyl 3,7-pyrrolidin-2-imine, 1-methyl-N-_/~phenyl-(2-picolyl)-methyl7-pyrrolidine -2-imine, 1-methyl-N-_/-phenyl-(3-picolyl)-methyl-7-pyrrolidine-2-imine, 1-methyl-N-/"phenyl-(4-picolyl)-methyl-7-pyrrolidine -2-imine, N-(2-pyridyl)-methyl-7-pyrrolidin-2-imine,
N-_/~benzyl- ( 3-pyridyl)-mety l7-pyrr ol idin-2-imin, N-_/~benzyl-(3-pyridyl)-methyl 7-pyrrolidine-2-imine,
N-_/—benzyl- ( 4-pyridyl) -metyl7-pyrrolidin-2-imin.N-_/-benzyl-(4-pyridyl)-methyl-7-pyrrolidin-2-imine.
Anvendelse_ ayde virksomme stoffer ifølge oppfinnelsen.Application_ ayde active substances according to the invention.
De virksomme stoffer ifølge oppfinnelsen senker blod-sukkeret av dyr og mennesker og påvirker fettstoffskiftet gunstig, således at de kan anvendes til behandling av Diabetes mellitus og fettstoffskifteforstyrrelser (f.eks. Hyperlipemier, Adipositas). Formuleringer. The active substances according to the invention lower the blood sugar of animals and humans and have a beneficial effect on fat metabolism, so that they can be used for the treatment of diabetes mellitus and fat metabolism disorders (e.g. Hyperlipemia, Adiposity). Formulations.
De virksomme stoffer ifølge oppfinnelsen kan overføres på kjent måte i de vanlige formuleringer som tabletter osv. Anvendelsesmetoder. The active substances according to the invention can be transferred in a known manner in the usual formulations such as tablets etc. Application methods.
De virksomme stoffer ifølge oppfinnelsen kan anvendes på vanlig måte, spesielt oralt, rektalt og parenteralt i dosisområde på 1 - 100 mg/kg/dag, fordelt på 1 - 6 administreringer, nemlig før eller/og under eller/og etter måltidet. The active substances according to the invention can be used in the usual way, especially orally, rectally and parenterally in a dose range of 1 - 100 mg/kg/day, divided into 1 - 6 administrations, namely before or/and during or/and after the meal.
Virkningen av de virksomme stoffer ifølge oppfinnelsen skal forklares nærmere ved hjelp av følgende anvendelseseksempel A (sammenlign tabell 1). The effect of the active substances according to the invention shall be explained in more detail with the help of the following application example A (compare table 1).
Eksempel A.Example A.
Porsøksanordning til virkningspåvisning av stoffene ifølge oppfinnelsen på rotter: Por frembringelse av en elementær hyperglykemi etter applikasjon av kullhydrater for rotter (n = 6) 2,5 g/kg glukose pr. os. Hver gang seks andre rotter får i tillegg, og nemlig enten sam-tidig eller 15 eller 30 minutter på forhånd, de i eksemplene angitte stoffer i en i tabellen oppførte dosering som suspensjon i tragant-slim administrert gjennom en sluksonde. Blodglykosen bestemmes i de angitte tidsintervaller etter glukoseapplikasjonen i blodet fra den retroorbitale venepleksus med en autoanalysør /~"Technicon", ifølge Hoffmann: J. biol. Chem. 120, 51 (193727. Por search device for detecting the effect of the substances according to the invention on rats: Por production of an elementary hyperglycaemia after application of carbohydrates to rats (n = 6) 2.5 g/kg glucose per us. Each time six other rats receive in addition, and namely either simultaneously or 15 or 30 minutes beforehand, the substances indicated in the examples in a dosage listed in the table as a suspension in tragacanth mucus administered through a gavage tube. The blood glucose is determined at the indicated time intervals after the glucose application in the blood from the retroorbital venous plexus with an autoanalyzer /~"Technicon", according to Hoffmann: J. biol. Chem. 120, 51 (193727.
Frems t i llingseksemp ler if ølge fremgangs måtevariant __ a) . Eksempel 1. Provide examples of how to proceed __ a) . Example 1.
18,4 g (0,1 mol) 2-(a-aminobenzyl)-pyridin, 13,8 g (0,14 mol) 2-metoksy-l-pyrrolin ble oppvarmet sammen med 1 g p-toluensulfon-syre i en destillasjonsapparatur 1 time ved l60°C (badtemperatur). Derved destillerte det over langsomt metanol. Deretter ble reaksjonsblandingen oppløst i fortynnet saltsyre og ekstrahert med kloroform. Den vandige fase ble adskilt ved tilsetning av natronlut, gjort alkalisk og ekstrahert flere ganger med kloroform. Kloroformfasen ble tørket over NagSOjjog deretter inndampet i vakuum. Residuet ble omkrystallisert fra litt aceton. Det ble dannet 15 g ( 60% av det teoretiske) N-_/~fenyl-(2-pyridyl)-mety l7-pyrrolidin-2-imin med smeltepunkt 110°C. 18.4 g (0.1 mol) of 2-(α-aminobenzyl)-pyridine, 13.8 g (0.14 mol) of 2-methoxy-l-pyrroline were heated together with 1 g of p-toluenesulfonic acid in a distillation apparatus for 1 hour at 160°C (bath temperature). Thereby, methanol was distilled over slowly. The reaction mixture was then dissolved in dilute hydrochloric acid and extracted with chloroform. The aqueous phase was separated by the addition of caustic soda, made alkaline and extracted several times with chloroform. The chloroform phase was dried over Na2SO4 and then evaporated in vacuo. The residue was recrystallized from a little acetone. 15 g (60% of the theoretical) N-_/~phenyl-(2-pyridyl)-methyl 7-pyrrolidin-2-imine with a melting point of 110°C were formed.
Eksempel 2. Example 2.
22,1 g (0,1 mol) 2-(ct-aminobenzyl)-pyridin-hydroklorid, 22.1 g (0.1 mol) 2-(ct-aminobenzyl)-pyridine hydrochloride,
17 g O-metylvalerolaktim og 40; ml absolutt etanol ble hatt sammen og hensatt 3 dager ved værelsestemperatur. Deretter ble oppløsningsmidlet fjernet i vakuum og residuet gjort alkalisk. Deretter ble det ekstrahert flere ganger med kloroform. Kloroformbasen ble tørket over ,Na2SOij og inndampet. Residuet ble oppløst i etanol og tilsetning 17 g of O-methylvalerolactim and 40; ml of absolute ethanol were mixed and set aside for 3 days at room temperature. The solvent was then removed in vacuo and the residue made alkaline. It was then extracted several times with chloroform. The chloroform base was dried over Na 2 SO 4 and evaporated. The residue was dissolved in ethanol and addition
av etanolisk oppløsning utfelt av naftalin-1,5-disulfonsyre som salt. Det ble dannet 28,5 g (52$ av det teoretiske)(N-/"fenyl-(2-pyridyl)-metyl7-piperidin-2-imin naftalin-1,5-disulfonat av smeltepunkt 275 - 278°C. of ethanolic solution precipitated by naphthalene-1,5-disulfonic acid as a salt. 28.5 g (52% of the theoretical) (N-/"phenyl-(2-pyridyl)-methyl 7-piperidin-2-imine naphthalene-1,5-disulfonate of melting point 275-278°C were formed.
På samme måte ble det fremstillet de i tabell 2 oppførte amidiner. In the same way, the amidines listed in Table 2 were prepared.
Frem s ti. 11 i n g s e k sempler ifølge fremgangsmåtev a r i ant b ) . Forward s ten. 11 in g s e xamples according to procedure v a r i ant b) .
Eksempel 13• Example 13•
I en destillasjonsapparatur ble 26 g (0,14 mol) 2-(ot-aminobenzyl)-pyridin oppvarmet sammen med 40 g 1,1-dietoksy-l-(dimetylamino)-etan ved 130°C (badtemperatur). Det destillerte langsomt etanol over. Etter 30 minutter ble blandingen avkjølet og inndampet i vakuum. Det ble dannet et krystallinsk residu, som ble omkrystallisert fra petroleter. Det fremkom 26,6 g (73$ av det teoretiske ) N, N-dime ty 1-N ' -/~fenyl- (2-pyridyl) -mety 3.7-acetamidin med smeltepunkt 64-66°C. In a distillation apparatus, 26 g (0.14 mol) of 2-(o-aminobenzyl)-pyridine were heated together with 40 g of 1,1-diethoxy-1-(dimethylamino)-ethane at 130° C. (bath temperature). Ethanol slowly distilled over. After 30 minutes, the mixture was cooled and evaporated in vacuo. A crystalline residue was formed, which was recrystallized from petroleum ether. 26.6 g (73% of the theoretical value) of N,N-dimethyl 1-N' -/~phenyl-(2-pyridyl)-methyl 3,7-acetamidine with a melting point of 64-66°C were obtained.
Eksem pel 14. Example number 14.
I en destillasjonsapparatur ble det oppvarmet 31,7 g (0,17 mol) 2-(a-aminobenzyl)-pyridin sammen med 45 g 2,2-dietoksy-1-metylpyrrolidin i 30 minutter ved 130°C (badtemperatur). Deretter ble det inndampet i vakuum og residuet omkrystallisert fra etanol. Det fremkom 29,5 g (65$ av det teoretiske) 1-metyl-N-/~feny1-(2-pyridy1)-metyl7-pyrrolidin-2-imin av smeltepunkt ll4°C. In a distillation apparatus, 31.7 g (0.17 mol) of 2-(α-aminobenzyl)-pyridine were heated together with 45 g of 2,2-diethoxy-1-methylpyrrolidine for 30 minutes at 130° C. (bath temperature). It was then evaporated in vacuo and the residue recrystallized from ethanol. 29.5 g (65% of the theoretical) of 1-methyl-N-[phenyl]-(2-pyridyl)-methyl-7-pyrrolidine-2-imine of melting point 114°C were obtained.
På samme måte ble det fremstilt de i tabell 3 oppførte amidiner. The amidines listed in Table 3 were prepared in the same way.
Forklaring til tabell 3: Explanation to table 3:
Forkortelser: A = etanol, Ac = aceton, Ae = eter, E = eddikester,Abbreviations: A = ethanol, Ac = acetone, Ae = ether, E = acetic acid,
H = n-heksan, I = isopropanol, L = ligroin, M = metanol, H = n-hexane, I = isopropanol, L = naphtha, M = methanol,
NDS = 1,5-naftalindisulfonat, P = petroleter.NDS = 1,5-naphthalene disulfonate, P = petroleum ether.
a) Det som utgangsstoff anvendte 1,5-dimety1-2,2-dietoksy-pyrrolidin (kokepunkt-^ mm ^ 58-63°C) ble dannet etter den for 2,2-dietoksy-l-metylpyrrolidin omtalte fremgangsmåte (Chem. Ber. 97, 3081-3087). a) The 1,5-dimethyl-2,2-diethoxy-pyrrolidine used as starting material (boiling point-^ mm ^ 58-63°C) was formed according to the method described for 2,2-diethoxy-1-methylpyrrolidine (Chem. Ber. 97, 3081-3087).
Fremsti lling av utgang sstoffene:Production of the starting materials:
Eksempel I.Example I.
Til en oppløsning av 26,7 g (0,126 mol) (3-metyl-2-pyridyl)-fenylketonoksim og 10 g ammoniumacetat i en blanding av 375 ml konsentrert.vandig ammoniakkoppløsning, 250 ml vann og 250 ml etanol haes ved værelsestemperatur i løpet av 2 timer 37,5 g sinkstøp. Deretter ble blandingen oppvarmet ytterligere 3 timer under tilbake-løpskokning.'Etter avkjøling ble det filtrert, filtratet inndampet i vakuum, residuet gjort alkalisk ved tilse.tning av natronlut og ekstrahert med eter. Eterfasen ble tørket over Na2S0^og inndampet på rotasjonsfordamper. Residuet ble destillert i vakuum. Det fremkom 21,2 g (85$ av det teoretiske) 2-(a-aminobenzyl)-3-metylpyridin av kokepunkt 0,4 mm Hg, 136-l42°C. To a solution of 26.7 g (0.126 mol) (3-methyl-2-pyridyl)-phenylketonoxime and 10 g of ammonium acetate in a mixture of 375 ml of concentrated aqueous ammonia solution, 250 ml of water and 250 ml of ethanol are added at room temperature during of 2 hours 37.5 g zinc casting. The mixture was then heated for a further 3 hours under reflux. After cooling, it was filtered, the filtrate evaporated in vacuo, the residue made alkaline by the addition of caustic soda and extracted with ether. The ether phase was dried over Na 2 SO 4 and evaporated on a rotary evaporator. The residue was distilled in vacuo. 21.2 g (85% of theory) of 2-(α-aminobenzyl)-3-methylpyridine of boiling point 0.4 mm Hg, 136-142°C were obtained.
Fremstilling av ketonoksim.Preparation of ketone oxime.
19j7g (0,1 mol) 2-benzoyl-3-metylpyridin og 14 g hydrok-sylamin-hydroklorid ble oppløst i 90 ml pyridin. Blandingen ble oppvarmet 4 timer under tilbakeløpskokning og etter avkjøling innrørt i isvann. Det dannet seg en utfelling som ble frasuget, vasket med vann og tørket over ^ 2^^' Det fremkom 19,1 g (90$ av det teoretiske) 19.7 g (0.1 mol) of 2-benzoyl-3-methylpyridine and 14 g of hydroxylamine hydrochloride were dissolved in 90 ml of pyridine. The mixture was heated for 4 hours under reflux and, after cooling, stirred into ice water. A precipitate formed which was filtered off with suction, washed with water and dried over ^ 2^^' 19.1 g (90$ of the theoretical) were obtained.
(3-metyl-2-pyridyl)-fenylketonoksim med smeltepunkt l63_171°C (blanding av syn- og anti-form). (3-methyl-2-pyridyl)-phenylketonoxime with melting point 163-171°C (mixture of syn- and anti-form).
Fremsti lling av ketonet. Production of the ketone.
Til en eterisk oppløsning av fenylmagnesiumbromid (fremstillet av 77,3 g (0,49 mol) brombenzen og 10,2 g (0,42 gramatom) magnesiumspon) ble det ved 20 - 30°C dryppet en oppløsning av 38,6 g (0,32 mol) 2-cyano-3-metylpyridin i en blanding av 240 ml eter og 120 ml benzen. Reaksjonsblandingen ble omrørt 3 timer ved værelsestemperatur. Deretter ble det tildryppet 100 ml H20 og deretter 200 ml halvkonsentrert saltsyre. Blandingen ble omrørt 30 minutter, deretter gjort alkalisk ved tilsetning av natronlut og ekstrahert med eter. Eterfasen ble tørket over Na2S0^og inndampet i rotasjonsfordamper. Residuet ble destillert i vakuum. Det fremkom 53 g (82,4$ av det teoretiske) 2-benzoyl-3-metylpyridin av kokepunkt 0,4 mm Hg, 130 - 142°C. To an ethereal solution of phenylmagnesium bromide (prepared from 77.3 g (0.49 mol) bromobenzene and 10.2 g (0.42 gram atom) magnesium shavings) at 20 - 30°C was dropped a solution of 38.6 g ( 0.32 mol) of 2-cyano-3-methylpyridine in a mixture of 240 ml of ether and 120 ml of benzene. The reaction mixture was stirred for 3 hours at room temperature. Then 100 ml of H 2 O and then 200 ml of semi-concentrated hydrochloric acid were added dropwise. The mixture was stirred for 30 minutes, then made alkaline by the addition of caustic soda and extracted with ether. The ether phase was dried over Na 2 SO 4 and evaporated in a rotary evaporator. The residue was distilled in vacuo. 53 g (82.4% of the theoretical) of 2-benzoyl-3-methylpyridine of boiling point 0.4 mm Hg, 130-142°C were obtained.
Eksempel II. Example II.
9 g (0,03 mol) N-/~~difenyl- (2-pyridy 1)-mety l7-acetamid ble oppløst i 100 ml konsentrert saltsyre og kokt 15 timer under til-bakeløp. Etter avkjøling ble reaksjonsblandingen gjort alkalisk ved tilsetning av natronlut og ekstrahert med kloroform. Den organiske fase ble tørket over Na^O^ og inndampet i vakuum til tørrhet. Residuet ble destillert i vakuum (kokepunkt 0,3 mm Hg, l80 - 190°C) og deretter omkrystallisert fra heksan. Det fremkom 7 g (89$ av det teoretiske) difenyl-(2-pyridyl)-metylamin av smeltepunkt 89°C. Acetamidets fremstilling. 9 g (0.03 mol) N-(~~diphenyl-(2-pyridyl 1)-methyl 7-acetamide was dissolved in 100 ml of concentrated hydrochloric acid and refluxed for 15 hours. After cooling, the reaction mixture was made alkaline by the addition of caustic soda and extracted with chloroform. The organic phase was dried over Na 2 O 4 and evaporated in vacuo to dryness. The residue was distilled in vacuo (boiling point 0.3 mm Hg, 180 - 190°C) and then recrystallized from hexane. 7 g (89% of the theoretical) of diphenyl-(2-pyridyl)-methylamine of melting point 89°C were obtained. Acetamide's preparation.
26,1 g (0,1 mol) difenyl-(2-pyridyl)-metylalkohol, 8,2 g (0,2 mol) acetonitril og 20 ml konsentrert svovelsyre ble rørt sammen ved 0°C og deretter omrørt 15 timer ved værelsestemperatur. Deretter ble reaksjonsblandingen innført i isvann, gjort alkalisk ved tilsetning av natronlut og ekstrahert med metylenklorid. Den organiske fase ble tørket over Na2SO^og inndampet i vakuum. Residuet ble omkrystallisert fra eddikester/n-heksan. Det fremkom 24,3 g ( 80% av det teoretiske) N-/_ difenyl-(2-pyridyl)-metyl7-acetamid av smeltepunkt 153 - 154°C. 26.1 g (0.1 mol) diphenyl-(2-pyridyl)-methyl alcohol, 8.2 g (0.2 mol) acetonitrile and 20 ml concentrated sulfuric acid were stirred together at 0°C and then stirred for 15 hours at room temperature . The reaction mixture was then introduced into ice water, made alkaline by the addition of caustic soda and extracted with methylene chloride. The organic phase was dried over Na 2 SO 4 and evaporated in vacuo. The residue was recrystallized from ethyl acetate/n-hexane. 24.3 g (80% of the theoretical) N-(2-pyridyl)-methyl-7-acetamide of melting point 153 - 154°C were obtained.
På samme måte som i eksempel I ble de i tabell 4 opp-førte aminer fremstilt. In the same way as in example I, the amines listed in Table 4 were prepared.
Ketonet for eksempel XXXIII er nytt og kan fremstilles som følger: The ketone, for example XXXIII, is new and can be prepared as follows:
Til en oppløsning av 28 g (0,44 mol) n-butyllitium i 200 ml n-heksan ble det under nitrogen ved -45°C til -35°C tildryppet en oppløsning av 63,2 g (0,4 mol) 2-brompyridin i 100 ml eter. Hertil ble det ved -35°C dryppet en oppløsning av 32,4 g (0,39 mol) pivalinsyrenitril i 400 ml eter. Reaksjonsblandingen ble omrørt 1 time ved -30°C og deretter oppvarmet langsomt ved 0°C. Deretter ble blandingen gjort sur ved tilsetning av saltsyre og omrørt 1 time ved værelsestemperatur. Deretter ble den vandige fase adskilt, gjort alkalisk ved tilsetning av natronlut og ekstrahert med kloroform. Kloroformfasen ble tørket over Na2S0^og inndampet på rotasjonsfordamper. Residuet ble destillert i vakuum. Det fremkom 44,7 g (67$ av det teoretiske) 2-pivaloylpyridin av kokepunkt 0,3 mm Hg, 65°C. To a solution of 28 g (0.44 mol) of n-butyllithium in 200 ml of n-hexane, a solution of 63.2 g (0.4 mol) of 2 -bromopyridine in 100 ml of ether. To this, a solution of 32.4 g (0.39 mol) pivalic acid nitrile in 400 ml of ether was added dropwise at -35°C. The reaction mixture was stirred for 1 hour at -30°C and then slowly warmed at 0°C. The mixture was then made acidic by the addition of hydrochloric acid and stirred for 1 hour at room temperature. The aqueous phase was then separated, made alkaline by the addition of caustic soda and extracted with chloroform. The chloroform phase was dried over Na 2 SO 4 and evaporated on a rotary evaporator. The residue was distilled in vacuo. 44.7 g (67% of the theoretical) of 2-pivaloylpyridine of boiling point 0.3 mm Hg, 65°C were obtained.
Forklaring til tabell 4: Explanation to table 4:
a) Oppløsningsmiddel: A = etanol, E = eddikester, I = isopropanol, P = petroleter, W = vann, a) Solvent: A = ethanol, E = ethyl acetate, I = isopropanol, P = petroleum ether, W = water,
b) syn- og anti-form,b) syn and anti form,
c) syn- og anti-form ga identiske produkter,c) syn and anti form gave identical products,
d) det tilsvarende ketimin (J. Heterocyclic Chem. 5, l6l-164) ble redusert med NaBH^i metanolisk oppløsning, d) the corresponding ketimine (J. Heterocyclic Chem. 5, 161-164) was reduced with NaBH^ in methanolic solution,
e) J. Heterocyclic Chem. 5, l6l-l64 (1968),e) J. Heterocyclic Chem. 5, 161-164 (1968),
f) utgangsketonet (smeltepunkt 82-84°C (I)) ble dannet etter den for 4-pyridylmety1-4-pyridy1-keton omtalte; f) the starting ketone (melting point 82-84°C (I)) was formed according to the one mentioned for 4-pyridylmethyl-4-pyridy1-ketone;
fremgangsmåte (J. Org. Chem. 22, 939 (1957)). method (J. Org. Chem. 22, 939 (1957)).
Claims (5)
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DE2415063A DE2415063A1 (en) | 1974-03-28 | 1974-03-28 | Pyridyl alkyl-amidine derivs - hypoglycemics which influence flat metabolism for use in diabetes, hyperlipemia and adiposis |
DE19742447258 DE2447258A1 (en) | 1974-10-03 | 1974-10-03 | Pyridyl alkyl-amidine derivs - hypoglycemics which influence flat metabolism for use in diabetes, hyperlipemia and adiposis |
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US8362022B2 (en) * | 2008-01-18 | 2013-01-29 | Allergan, Inc. | Selective subtype alpha 2 adrenergic agents and methods for use thereof |
WO2010077586A1 (en) * | 2008-12-08 | 2010-07-08 | Allergan, Inc. | N-(1-phenyl-2-arylethyl)-4,5-dihydro-3h-pyrrol-2-amine compounds as subtype selective modulators of alpha2b or alpha2b and alpha2c adrenoceptors |
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