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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Pyridylalkylamidiner, fremgangsmåte til
deres fremstilling samt deres anvendelse
som legemiddel.
Oppfinnelsen vedrører nye pyridylalkylamidiner, flere fremgangsmåter til deres fremstilling samt deres anvendelse som legemiddel, spesielt som antidiabetika.
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);
Journal of Medicinal Chemistry 16, 885-893 (197327. Slike amidiner har imidlertid den ulempe at virkningsinntreden foregår relativt sent.
Det er blitt funnet at de nye pyridylalkylamidiner med
hvori
R^betyr H, alkyl, alkoksy, eventuelt substituert fenyl,
benzyl,
2 betyr H eller alkyl,
R^betyr H, alkyl, eventuelt substituert fenyl, benzyl,
fenetyl,
R^ betyr alkyl, eventuelt substituert fenyl, cykloalkyl
eller heteroaryl, benzyl,
Rrbetyr H, alkyl, eventuelt substituert fenyl, benzyl, Rg betyr alkyl,
Rj betyr H eller alkyl,
X, Y, Z betyr en enkeltbinding eller en metylengruppe og hvori
R^ og Rg også kan være forbundet med en enkeltbinding, samt deres syreaddisjonssalter med fysiologisk tålbare syrer har sterkt antihyperglykemiske egenskaper.
Videre ble det funnet at man får pyridylalkylamidiner med formel I, når enten
a) reaksjonsdyktige amidderivater med formel II
hvori
R^ og Rg har overnevnte betydning og
Rg betyr alkoksy, alkyltio, halogen, acyloksy, acyltio,
oksyfosforylhalogenider, halogentionyloksy, alkylsulfonyloksy, eventuelt substituert arylsulfonyloksy, tiofosforylhalogenider, omsettes med aminer med formel III
hvori
R^, R2, R^, R^, X, Y og Z har overnevnte betydning, eventuelt i nærvær av syrebindende midler eller i nærvær av syrer, eller
b) reaksjonsdyktige amidderivater med formel IV
hvori
R^, Rg, R^og Rg har overnevnte betydning og Rg betyr halogen, alkoksy, alkyltio, O-SC^-OCH^, BP^,
POCl^, AlCl^,
og hvori de ved Rg og R^angitte alkoksy- og alkyltio-grupper også
kan være sluttet til en ring, omsettes med aminer med formel III, eventuelt i nærvær av syrebindere.
Noen av amidderivatene med formel IV foreligger uteluk-kende i form B (f.eks. 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).
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.
Overfor de allerede kjente difenylmetylamidiner [_~ J. Med. CHem. _l6, 885-892 (19732/ har ^e fordelen med en sterkere virkning
og en hurtigere virkningsinntreden. Stoffene ifølge oppfinnelsen er således en berikelse av farmasien.
Anvender man 2-(a-aminobenzyl)-pyridin og 2-metoksy-l-pyrrolin som utgangsstoffer, så kan reaksjonsforløpet gjengis ved følgende formelskjema:
F remgangsmåte a).
Anvender man 2-(ct-aminobenzyl)-pyridin og l-metyl-2,2-dietoksypyrrolidin som utgangsstoffer, så kan reaksjonsforløpet gjengis med følgende formelskjema:
F remgangsmåte 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;
R^betyr fortrinnsvis H og alkyl med 1 til 4 karbonatomer,
R^betyr fortrinnsvis H, rettlinjet eller forgrenet alkyl med 1 til 4 karbonatomer, benzyl, fenetyl,og eventuelt med halogen substituert fenyl;
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.
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).
Som eksempler skal nevnes (sammenlign også tabell 4):
2- (a:;aminobenzyl)-pyridin,
3- (a-aminobenzy1)-pyridin,
4- (a-aminobenzyl)-pyridin,
2- /_—a-(aminometyl)-benzyl7-pyridin3
3- £~ a-(aminometyl)-benzyl7-pyridin,
4- /_-a-(aminometyl)-benzyl/-pyridin,
2-(a-aminofenetyl)-pyridin,
2- (3-aminofenetyl)-pyridin,
3- (a-aminofenety1)-pyridin,
3- (fl-aminofenetyl)-pyridin,
4- (a-aminofenetyl)-pyridin,
4-(3-aminofenetyl)-pyridin,
2-(a-aminobenzyl)-3-metylpyridin,
2-(a-aminobenzyl)-4-metylpyridin,
2- (artammnobenzyl)-6-metylpyridin,
4-(a-aminobenzyl)-2-metylpyridin,
2-(a-amino-2-metylbenzyl)-pyridin,
2-(a-amino-3-metylbenzyl)-pyridin,
2- (a-amino-4-metylbenzyl)-pyridin,
3- /~3-(aminometyl)-fenyletyl7-pyridin,
4- /_""3- (aminomety 1) - f ene ty l/-pyr idin,
2-_/<->l-amino-2-(2-pyridyl)-etyl7-pyridin,
2-/_~2-amino-2- (3-pyridyl) -etyl7-pyridin,
2-/_-2-amino-2-( 4-pyridyl)-etyl7-pyridin,
2- _/-l-amino-2-( 4-pyridyl)-etyl7-pyridin,
3- /_~"l-amino-2- (4-pyridyl) -etyl7-pyridin,
4- /"~l-amino-2- (4-pyridyl) -etyl7-pyridin.
De ifølge oppfinnelsen anvendbare amidderivater er generelt definert med formlene II og IV. Her betyr
R,- fortrinnsvis H, rettlinjet eller forgrenet alkyl med 1 til 4 karbonatomer, eventuelt med klor eller metyl substituert fenyl, benzyl,
Rg betyr fortrinnsvis rettlinjet eller forgrenet alkyl med 1 til 4 karbonatomer,
R^ betyr fortrinnsvis H, rettlinjet eller forgrenet alkyl med 1 til 4 karbonatomer,
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.
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.
Som eksempler for disse amider skal nevnes: N-metylformamid,
N-t-butylformamid,
N-metylacetamid,
N-i-propylacetamid,
N-metylpropionsyreamid,
N-metylisosmørsyreamid,
N-metylvaleriansyreamid,
4,4-dimetyl-acetidinon-(2), pyrrolidon-(2),
3-metylpyrrolidon-(2),
N,N-dimetylformamid,
N,N-dimetylacetamid,
N,N-dimetylpropionsyreamid, N,N-dimetylsmørsyreamid,
NjN-dimetylisosmørsyreamid, N,N-dimetylvaleriansyreamid, N,N-dietylformamid,
3- metylpyrrolidon-(5),
2-metylpyrrolidon-(5) »
valerolaktam,
kaprolaktam,
y-metylkaprolaktam,
N-metylbenzamid,
N-tert.-butylbenzamid,
2-klor-N-metylbenzamid,
4- klor-N-metylbenzamid,
4-N-dimetylbenzamid,
N-mety1-fenyleddiksyreamid, N-etyl-fenyleddiksyreamid, N,N-dietylacetamid,
N,N-dietylpropionsyreamid, N,N-dietylisosmørsyreamid,
l,4,4-trimetyl-acetidinon-(2),
1-metylpyrrolidon-(2),
1.2- dimetylpyrrolidon-(5),
1.3- dimetylpyrrolidon-(5),
1,3-dimetylpyrrolidon-(2),
l-etylpyrrolidon-(2),
1-n-butylpyrrolidon-(2),
N-metylvalerolaktam,
N-metylkaprolaktam,
N,y-dimetylkaprolaktam,
N,N-dimetylbenzamid,
3- klor-N,N-dimetylbenzamid,
4- klor-N,N-dimetylbenzamid,
4,N,N-trimetylbenzamid,
N,N-dimetylfenyleddiksyreamid,
N,N-dietylfenyleddiksyreamid.
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.
Reaksjonstemperaturen kan varieres innen et stort om-råde. Vanligvis arbeider man mellom -70°C og +200°C, fortrinnsvis mellom -30°C og +150°C.
Som syrebindere kan dét anvendes alle vanlige syrebind-ingsmidler. Hertil hører fortrinnsvis trietylamin, N,N-dimetylani-lin, pyridin.
Som syretilsetning kan det anvendes alle vanlige syrer. Hertil hører fortrinnsvis klorhydrogen, benzensulfonsyre, toluen-
sulfonsyre.
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.
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,
1-mety1-N-/<->fenyl-(4-pyridyl)-metyl/-pyrrolidin-2-imin, N-/_~~fenyl- ( 4-pyridyl)-me ty_l7-pyrr olidin-2-imin,
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-_/~benzyl- ( 3-pyridyl)-mety l7-pyrr ol idin-2-imin,
N-_/—benzyl- ( 4-pyridyl) -metyl7-pyrrolidin-2-imin.
Anvendelse_ ayde virksomme stoffer ifølge oppfinnelsen.
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.
De virksomme stoffer ifølge oppfinnelsen kan overføres på kjent måte i de vanlige formuleringer som tabletter osv. Anvendelsesmetoder.
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.
Virkningen av de virksomme stoffer ifølge oppfinnelsen skal forklares nærmere ved hjelp av følgende anvendelseseksempel A (sammenlign tabell 1).
Eksempel 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.
Frems t i llingseksemp ler if ølge fremgangs måtevariant __ a) . Eksempel 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.
Eksempel 2.
22,1 g (0,1 mol) 2-(ct-aminobenzyl)-pyridin-hydroklorid,
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
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.
På samme måte ble det fremstillet de i tabell 2 oppførte amidiner.
Frem s ti. 11 i n g s e k sempler ifølge fremgangsmåtev a r i ant b ) .
Eksempel 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.
Eksem pel 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.
På samme måte ble det fremstilt de i tabell 3 oppførte amidiner.
Forklaring til tabell 3:
Forkortelser: A = etanol, Ac = aceton, Ae = eter, E = eddikester,
H = n-heksan, I = isopropanol, L = ligroin, M = metanol,
NDS = 1,5-naftalindisulfonat, P = petroleter.
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).
Fremsti lling av utgang sstoffene:
Eksempel 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.
Fremstilling av ketonoksim.
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)
(3-metyl-2-pyridyl)-fenylketonoksim med smeltepunkt l63_171°C (blanding av syn- og anti-form).
Fremsti lling av ketonet.
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.
Eksempel 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.
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.
På samme måte som i eksempel I ble de i tabell 4 opp-førte aminer fremstilt.
Ketonet for eksempel XXXIII er nytt og kan fremstilles som følger:
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.
Forklaring til tabell 4:
a) Oppløsningsmiddel: A = etanol, E = eddikester, I = isopropanol, P = petroleter, W = vann,
b) syn- og anti-form,
c) syn- og anti-form ga identiske produkter,
d) det tilsvarende ketimin (J. Heterocyclic Chem. 5, l6l-164) ble redusert med NaBH^i metanolisk oppløsning,
e) J. Heterocyclic Chem. 5, l6l-l64 (1968),
f) utgangsketonet (smeltepunkt 82-84°C (I)) ble dannet etter den for 4-pyridylmety1-4-pyridy1-keton omtalte;
fremgangsmåte (J. Org. Chem. 22, 939 (1957)).
Claims (5)
1. Pyridylalkylamidiner med formel I
hvori
R-^ betyr H, alkyl, alkoksy, eventuelt substituert fenyl,
benzyl,
R2 betyr H eller alkyl,
Rj betyr H, alkyl, eventuelt substituert fenyl, benzyl,
fenetyl,
R^ betyr alkyl, eventuelt substituert fenyl, cykloalkyl
eller heteroaryl, benzyl,
Rj_ betyr H, alkyl, eventuelt substituert fenyl, benzyl, Rg betyr alkyl,
Rrj betyr H eller alkyl,
X, Y, Z betyr en enkeltbinding eller en metylengruppe, og hvori
R^ og Rg også kan være forbundet ved en enkeltbinding, samt deres syreaddisjonssalter med fysiologisk tålbare syrer.
2. Fremgangsmåte til fremstilling av pyridylalkylamidiner med formel I
hvori
betyr H, alkyl, alkoksy, eventuelt substituert fenyl,
benzyl,
R2 betyr H eller alkyl,
R^ betyr H, alkyl, eventuelt substituert fenyl, benzyl, fenetyl,
R^ betyr alkyl, eventuelt substituert fenyl, cykloalkyl eller heteroaryl, benzyl,
R^ betyr H, alkyl, eventuelt substituert fenyl, benzyl, <R> g betyr alkyl,
Ry betyr H eller alkyl,
X, Y, Z betyr en enkeltbinding eller en metylengruppe, og hvori
R^ og Rg også kan være forbundet med en-, enkeltbinding, samt deres syreaddisjonssalter med fysiologisk tålbare syrer, karakterisert ved at entena) omsettes reaksjonsdyktige amidderivater med formel II
hvori
R,- og Rg har overnevnte betydning og Rg betyr alkoksy, alkyltio, halogen, acyloksy, acyltio,
oksyfosforylhalogenider, halogentionyloksy, alkylsulfonyloksy, eventuelt substituert arylsulfonyloksy, tiofosforylhalogenider
med aminer meci formel TTT
hvori
R-^ , R2, R-2; j R[j j X, Y og Z har overnevnte betydning, eventuelt i nærvær av syrebindere eller i nærvær av syrer, ellerb) reaksjonsdyktige amidderivater med formel IV
hvori
R,-, Rg, Ry og Rg har overnevnte betydning og Rg betyr halogen, alkoksy, alkyltio, 0-S02 -OCH^ , BF^ , POCl^ , AlCljj og hvori de ved Rg og R^ angitte alkoksy-og alkyltio-grupper også kan være sluttet til en ring, med aminer med formel III, eventuelt i nærvær av syrebindere.
3. Legemiddel, karakterisert ved et inn-hold av minst ett pyridylalkylamidin ifølge krav 1.
4. Fremgangsmåte til fremstilling av antidiabetiske midler, karakterisert ved at pyridylalkylamidiner ifølge krav 1 blandes med inerte, ikke-toksiske, farmasøytiske egnede bærestoffer.
5. Fremgangsmåte til behandling av diabetes og/eller adipositas og/eller hyperlipemi, karakterisert ved at pyridylalkylamidiner ifølge krav 1 appliseres til mennesker, som lider av diabetes og/eller adipositas og/eller hyperlipemi.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE2415063A DE2415063A1 (de) | 1974-03-28 | 1974-03-28 | Pyridylalkylamidine, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel |
DE19742447258 DE2447258A1 (de) | 1974-10-03 | 1974-10-03 | Pyridylalkylamidine, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel |
Publications (1)
Publication Number | Publication Date |
---|---|
NO750876L true NO750876L (no) | 1975-09-30 |
Family
ID=25766897
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NO750876A NO750876L (no) | 1974-03-28 | 1975-03-14 |
Country Status (8)
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JP (1) | JPS50129721A (no) |
DK (1) | DK133775A (no) |
FI (1) | FI750906A (no) |
FR (1) | FR2265373A1 (no) |
IL (1) | IL46914A0 (no) |
NL (1) | NL7503743A (no) |
NO (1) | NO750876L (no) |
SE (1) | SE7503550L (no) |
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TW575562B (en) * | 1998-02-19 | 2004-02-11 | Agrevo Uk Ltd | Fungicides |
US8362022B2 (en) * | 2008-01-18 | 2013-01-29 | Allergan, Inc. | Selective subtype alpha 2 adrenergic agents and methods for use thereof |
ES2495099T3 (es) * | 2008-12-08 | 2014-09-16 | Allergan, Inc. | Compuestos de N-(1-fenil-2-ariletil)-4,5-dihidro-3H-pirrol-2-amina como moduladores selectivos de subtipo de los adrenoceptores alfa2B o alfa2B y alfa2C |
-
1975
- 1975-03-14 NO NO750876A patent/NO750876L/no unknown
- 1975-03-25 IL IL46914A patent/IL46914A0/xx unknown
- 1975-03-26 DK DK133775A patent/DK133775A/da unknown
- 1975-03-26 FI FI750906A patent/FI750906A/fi not_active Application Discontinuation
- 1975-03-26 SE SE7503550A patent/SE7503550L/xx not_active Application Discontinuation
- 1975-03-26 JP JP50035648A patent/JPS50129721A/ja active Pending
- 1975-03-27 NL NL7503743A patent/NL7503743A/xx unknown
- 1975-03-28 FR FR7509945A patent/FR2265373A1/fr not_active Withdrawn
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JPS50129721A (no) | 1975-10-14 |
IL46914A0 (en) | 1975-05-22 |
FR2265373A1 (en) | 1975-10-24 |
DK133775A (no) | 1975-09-29 |
SE7503550L (no) | 1975-09-29 |
NL7503743A (nl) | 1975-09-30 |
FI750906A (no) | 1975-09-29 |
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