DK170670B1 - Kondenserede diazepinoner, fremgangsmåde til deresfremstilling, lægemidler indeholdende en sådan diazepinon, samt anvendelse af sådanne diazepinoner til fremstilling af lægemidler - Google Patents

Info

Publication number

DK170670B1

DK170670B1 DK669187A DK669187A DK170670B1 DK 170670 B1 DK170670 B1 DK 170670B1 DK 669187 A DK669187 A DK 669187A DK 669187 A DK669187 A DK 669187A DK 170670 B1 DK170670 B1 DK 170670B1

Authority

DK

Denmark

Prior art keywords

piperidinyl

methyl

dihydro

ethyl

pyrido

Prior art date

1986-12-20

Links

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• DHZYXWMZLAKTQV-UHFFFAOYSA-N diazepin-3-one Chemical class O=C1C=CC=CN=N1 DHZYXWMZLAKTQV-UHFFFAOYSA-N 0.000 title claims abstract description 21
• 238000000034 method Methods 0.000 title claims description 24
• 239000003814 drug Substances 0.000 title claims description 9
• 230000008569 process Effects 0.000 title claims description 8
• 238000004519 manufacturing process Methods 0.000 title claims description 4
• 238000002360 preparation method Methods 0.000 title description 11
• 229940079593 drug Drugs 0.000 title description 3
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 157
• 150000001875 compounds Chemical class 0.000 claims abstract description 101
• 150000003839 salts Chemical class 0.000 claims abstract description 24
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 21
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 18
• 239000001257 hydrogen Substances 0.000 claims abstract description 17
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 14
• 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 14
• 239000000460 chlorine Chemical group 0.000 claims abstract description 13
• 229910052801 chlorine Inorganic materials 0.000 claims abstract description 12
• 208000006218 bradycardia Diseases 0.000 claims abstract description 9
• 125000002947 alkylene group Chemical group 0.000 claims abstract description 8
• 230000036471 bradycardia Effects 0.000 claims abstract description 7
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 6
• 229920006395 saturated elastomer Polymers 0.000 claims abstract description 4
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 153
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 144
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 143
• -1 5, 10-Dihydro-5 - [[[2- [2 - [(dimethylamino) methyl] -1-piperidinyl] ethyl] amino] carbonyl] -1H-dibenzo [b, e ] [1,4] diazepin-11-one Chemical compound 0.000 claims description 107
• 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 99
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 36
• 238000006243 chemical reaction Methods 0.000 claims description 30
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
• 125000004914 dipropylamino group Chemical group C(CC)N(CCC)* 0.000 claims description 27
• 239000002904 solvent Substances 0.000 claims description 27
• 125000004432 carbon atom Chemical group C* 0.000 claims description 20
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
• 238000009835 boiling Methods 0.000 claims description 11
• 125000003386 piperidinyl group Chemical group 0.000 claims description 10
• 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 9
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 9
• 239000011541 reaction mixture Substances 0.000 claims description 9
• 150000007522 mineralic acids Chemical class 0.000 claims description 8
• 150000007524 organic acids Chemical class 0.000 claims description 8
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 7
• 235000005985 organic acids Nutrition 0.000 claims description 7
• 150000007530 organic bases Chemical class 0.000 claims description 7
• 239000007858 starting material Substances 0.000 claims description 7
• 239000002585 base Substances 0.000 claims description 6
• 125000005843 halogen group Chemical group 0.000 claims description 6
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• 239000003054 catalyst Substances 0.000 claims description 5
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
• 150000004985 diamines Chemical class 0.000 claims description 5
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
• 150000001340 alkali metals Chemical group 0.000 claims description 4
• 150000001342 alkaline earth metals Chemical group 0.000 claims description 4
• 239000012442 inert solvent Substances 0.000 claims description 4
• 150000007529 inorganic bases Chemical class 0.000 claims description 4
• PJUPMXXMRDMORI-UHFFFAOYSA-N 9-chloro-n-[2-[2-(diethylaminomethyl)piperidin-1-yl]ethyl]-6-oxo-5h-pyrido[2,3-b][1,4]benzodiazepine-11-carboxamide Chemical compound CCN(CC)CC1CCCCN1CCNC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=C(Cl)C=C21 PJUPMXXMRDMORI-UHFFFAOYSA-N 0.000 claims description 3
• KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical group ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 3
• 229910052783 alkali metal Inorganic materials 0.000 claims description 3
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
• 239000012948 isocyanate Substances 0.000 claims description 3
• 150000002513 isocyanates Chemical class 0.000 claims description 3
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
• 239000003960 organic solvent Substances 0.000 claims description 3
• 230000000737 periodic effect Effects 0.000 claims description 3
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
• 239000002798 polar solvent Substances 0.000 claims description 3
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
• HCDXLUKTYFLIEM-UHFFFAOYSA-N 1,2-benzodiazepin-5-one Chemical compound O=C1C=CN=NC2=CC=CC=C12 HCDXLUKTYFLIEM-UHFFFAOYSA-N 0.000 claims description 2
• 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
• 125000004634 hexahydroazepinyl group Chemical group N1(CCCCCC1)* 0.000 claims description 2
• 238000011065 in-situ storage Methods 0.000 claims description 2
• 150000002736 metal compounds Chemical class 0.000 claims description 2
• 125000002757 morpholinyl group Chemical group 0.000 claims description 2
• 239000012458 free base Substances 0.000 claims 2
• GILSTWNXNNVASG-UHFFFAOYSA-N 4-[[[2-[2-[(diethylamino)methyl]-piperidin-1-yl]ethyl]amino]carbonyl]-1,3-dimethyl-1,4,9,10-tetrahydropyrazolo[4,3-e]pyrido[2,3-b][1,4]diazepin-10-one Chemical compound CCN(CC)CC1CCCCN1CCNC(=O)N1C2=CC=CN=C2NC(=O)C2=C1C(C)=NN2C GILSTWNXNNVASG-UHFFFAOYSA-N 0.000 claims 1
• 206010003119 arrhythmia Diseases 0.000 claims 1
• 230000006793 arrhythmia Effects 0.000 claims 1
• 239000000969 carrier Substances 0.000 claims 1
• 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims 1
• 239000012038 nucleophile Substances 0.000 claims 1
• 239000000546 pharmaceutical excipient Substances 0.000 claims 1
• 239000002253 acid Substances 0.000 abstract description 8
• 230000001515 vagal effect Effects 0.000 abstract description 5
• 229910052736 halogen Inorganic materials 0.000 abstract description 4
• 150000002367 halogens Chemical class 0.000 abstract description 4
• 229910052717 sulfur Inorganic materials 0.000 abstract description 2
• 150000002431 hydrogen Chemical group 0.000 abstract 4
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract 2
• 206010049765 Bradyarrhythmia Diseases 0.000 abstract 1
• PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical group FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 abstract 1
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 271
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 168
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 141
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 132
• 239000013078 crystal Substances 0.000 description 109
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 75
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 67
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
• KSSXNHGPIDAUAS-UHFFFAOYSA-N 1,4-benzodiazepin-6-one Chemical compound N1=CC=NC=C2C(=O)C=CC=C21 KSSXNHGPIDAUAS-UHFFFAOYSA-N 0.000 description 44
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
• 239000003480 eluent Substances 0.000 description 40
• 239000002985 plastic film Substances 0.000 description 36
• 229910021529 ammonia Inorganic materials 0.000 description 35
• 239000000203 mixture Substances 0.000 description 35
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 34
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 33
• QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 33
• 239000000243 solution Substances 0.000 description 32
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
• 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 29
• ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Natural products CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 29
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
• WTQIDDAZNKRWMF-UHFFFAOYSA-N 6-oxo-5h-pyrido[2,3-b][1,4]benzodiazepine-11-carbonyl chloride Chemical compound O=C1NC2=CC=CN=C2N(C(=O)Cl)C2=CC=CC=C21 WTQIDDAZNKRWMF-UHFFFAOYSA-N 0.000 description 25
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 25
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 23
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 20
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 20
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 20
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 19
• DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 18
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 17
• 230000000694 effects Effects 0.000 description 17
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 15
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• YZPAKBGVJIVPEU-UHFFFAOYSA-N 1,2-benzodiazepin-6-one Chemical compound N1=NC=CC=C2C(=O)C=CC=C21 YZPAKBGVJIVPEU-UHFFFAOYSA-N 0.000 description 14
• UJWQYKYQDVBFTA-UHFFFAOYSA-N 2-[2-(diethylaminomethyl)piperidin-1-yl]ethanamine Chemical compound CCN(CC)CC1CCCCN1CCN UJWQYKYQDVBFTA-UHFFFAOYSA-N 0.000 description 14
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 14
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• 235000011152 sodium sulphate Nutrition 0.000 description 6
• 239000008096 xylene Substances 0.000 description 6
• PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 5
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 5
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