SK285909B6 - Deriváty a analógy galantamínu, spôsob ich výroby, ich použitie na výrobu liečiva, spôsob výroby tohto liečiva a spôsob separácie (+) a (-) izomérov racemických derivátov a analógov galantamínu - Google Patents

Info

Publication number

SK285909B6

SK285909B6 SK1702-2001A SK17022001A SK285909B6 SK 285909 B6 SK285909 B6 SK 285909B6 SK 17022001 A SK17022001 A SK 17022001A SK 285909 B6 SK285909 B6 SK 285909B6

Authority

SK

Slovakia

Prior art keywords

group

ring

nmr

mmol

alkyl

Prior art date

2000-03-31

Links

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• 238000000034 method Methods 0.000 title claims abstract description 95
• ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 title claims abstract description 31
• 239000003814 drug Substances 0.000 title claims description 18
• 238000002360 preparation method Methods 0.000 title abstract description 29
• 238000011282 treatment Methods 0.000 claims abstract description 41
• 230000002490 cerebral effect Effects 0.000 claims abstract description 4
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 579
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 294
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 267
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 229
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 174
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 160
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 122
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 117
• ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical class O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 claims description 115
• 239000002904 solvent Substances 0.000 claims description 114
• -1 triethylsilyl Chemical group 0.000 claims description 94
• 239000000203 mixture Substances 0.000 claims description 88
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 80
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 78
• 239000000460 chlorine Chemical group 0.000 claims description 72
• 239000013078 crystal Substances 0.000 claims description 72
• AIXQQSTVOSFSMO-RBOXIYTFSA-N Norgalanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CNCC[C@]23[C@@H]1C[C@@H](O)C=C2 AIXQQSTVOSFSMO-RBOXIYTFSA-N 0.000 claims description 71
• YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 60
• 150000001875 compounds Chemical class 0.000 claims description 58
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 53
• 229910052739 hydrogen Inorganic materials 0.000 claims description 49
• 239000000725 suspension Substances 0.000 claims description 45
• 229910052757 nitrogen Inorganic materials 0.000 claims description 43
• 235000013350 formula milk Nutrition 0.000 claims description 40
• JPVBTFOTYRZBLR-UHFFFAOYSA-N 2h-2-benzazepin-6-ol Chemical compound N1C=CC=C2C(O)=CC=CC2=C1 JPVBTFOTYRZBLR-UHFFFAOYSA-N 0.000 claims description 37
• 229910052799 carbon Inorganic materials 0.000 claims description 37
• 125000001424 substituent group Chemical group 0.000 claims description 37
• 229910052760 oxygen Inorganic materials 0.000 claims description 33
• 239000003208 petroleum Substances 0.000 claims description 32
• 239000002253 acid Substances 0.000 claims description 31
• 125000000217 alkyl group Chemical group 0.000 claims description 30
• 229910052717 sulfur Inorganic materials 0.000 claims description 29
• 229960003980 galantamine Drugs 0.000 claims description 27
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
• 239000001301 oxygen Substances 0.000 claims description 21
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 19
• 230000007850 degeneration Effects 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
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 18
• 229910052801 chlorine Inorganic materials 0.000 claims description 18
• 239000001257 hydrogen Substances 0.000 claims description 17
• 150000003839 salts Chemical class 0.000 claims description 17
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 15
• 201000010099 disease Diseases 0.000 claims description 15
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
• 125000005647 linker group Chemical group 0.000 claims description 15
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 15
• 125000004434 sulfur atom Chemical group 0.000 claims description 15
• 229910052731 fluorine Inorganic materials 0.000 claims description 14
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 14
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 14
• 230000008569 process Effects 0.000 claims description 14
• 125000000623 heterocyclic group Chemical group 0.000 claims description 13
• 125000001841 imino group Chemical group [H]N=* 0.000 claims description 13
• 239000007790 solid phase Substances 0.000 claims description 13
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• 210000004027 cell Anatomy 0.000 claims description 12
• 125000004122 cyclic group Chemical group 0.000 claims description 12
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
• SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical class [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 12
• 230000001640 apoptogenic effect Effects 0.000 claims description 11
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 10
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 10
• 230000015572 biosynthetic process Effects 0.000 claims description 10
• 239000011737 fluorine Chemical group 0.000 claims description 10
• 229910052740 iodine Inorganic materials 0.000 claims description 10
• 238000011321 prophylaxis Methods 0.000 claims description 10
• 238000003786 synthesis reaction Methods 0.000 claims description 10
• FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 9
• 125000003118 aryl group Chemical group 0.000 claims description 9
• 229910052794 bromium Inorganic materials 0.000 claims description 9
• 125000004432 carbon atom Chemical group C* 0.000 claims description 9
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
• FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 8
• 125000003545 alkoxy group Chemical group 0.000 claims description 8
• 238000002425 crystallisation Methods 0.000 claims description 8
• 230000008025 crystallization Effects 0.000 claims description 8
• 125000005842 heteroatom Chemical group 0.000 claims description 8
• SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 8
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
• 239000003960 organic solvent Substances 0.000 claims description 8
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
• 208000018737 Parkinson disease Diseases 0.000 claims description 7
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
• 238000000605 extraction Methods 0.000 claims description 7
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
• 238000004519 manufacturing process Methods 0.000 claims description 7
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
• 201000006417 multiple sclerosis Diseases 0.000 claims description 7
• 229920006395 saturated elastomer Polymers 0.000 claims description 7
• 239000011593 sulfur Substances 0.000 claims description 7
• 206010002660 Anoxia Diseases 0.000 claims description 6
• 241000976983 Anoxia Species 0.000 claims description 6
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 6
• 150000001408 amides Chemical class 0.000 claims description 6
• 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 6
• 230000007953 anoxia Effects 0.000 claims description 6
• 125000005099 aryl alkyl carbonyl group Chemical group 0.000 claims description 6
• 210000004556 brain Anatomy 0.000 claims description 6
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
• 206010012601 diabetes mellitus Diseases 0.000 claims description 6
• 206010015037 epilepsy Diseases 0.000 claims description 6
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
• 230000007954 hypoxia Effects 0.000 claims description 6
• 239000011630 iodine Chemical group 0.000 claims description 6
• 125000003003 spiro group Chemical group 0.000 claims description 6
• 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 6
• 206010002091 Anaesthesia Diseases 0.000 claims description 5
• 206010003497 Asphyxia Diseases 0.000 claims description 5
• 208000003174 Brain Neoplasms Diseases 0.000 claims description 5
• 208000010496 Heart Arrest Diseases 0.000 claims description 5
• 208000023105 Huntington disease Diseases 0.000 claims description 5
• 206010027202 Meningitis bacterial Diseases 0.000 claims description 5
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 5
• 150000001413 amino acids Chemical class 0.000 claims description 5
• 230000037005 anaesthesia Effects 0.000 claims description 5
• 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 5
• 201000009904 bacterial meningitis Diseases 0.000 claims description 5
• 238000002512 chemotherapy Methods 0.000 claims description 5
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
• 238000009792 diffusion process Methods 0.000 claims description 5
• 125000000524 functional group Chemical group 0.000 claims description 5
• 210000002569 neuron Anatomy 0.000 claims description 5
• 231100000572 poisoning Toxicity 0.000 claims description 5
• 230000000607 poisoning effect Effects 0.000 claims description 5
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 5
• 238000001959 radiotherapy Methods 0.000 claims description 5
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
• 150000008575 L-amino acids Chemical class 0.000 claims description 4
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
• 208000030886 Traumatic Brain injury Diseases 0.000 claims description 4
• 125000003342 alkenyl group Chemical group 0.000 claims description 4
• 125000000304 alkynyl group Chemical group 0.000 claims description 4
• 125000003277 amino group Chemical group 0.000 claims description 4
• 125000004104 aryloxy group Chemical group 0.000 claims description 4
• 230000000694 effects Effects 0.000 claims description 4
• 238000005516 engineering process Methods 0.000 claims description 4
• 238000001640 fractional crystallisation Methods 0.000 claims description 4
• 125000002883 imidazolyl group Chemical group 0.000 claims description 4
• 210000003205 muscle Anatomy 0.000 claims description 4
• 125000004193 piperazinyl group Chemical group 0.000 claims description 4
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
• 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims description 4
• BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical group C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 4
• 229920002554 vinyl polymer Polymers 0.000 claims description 4
• DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 3
• DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 3
• CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
• 208000005374 Poisoning Diseases 0.000 claims description 3
• YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 3
• 125000001931 aliphatic group Chemical group 0.000 claims description 3
• FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 3
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 3
• 235000015097 nutrients Nutrition 0.000 claims description 3
• BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
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• GWYPDXLJACEENP-UHFFFAOYSA-N 1,3-cycloheptadiene Chemical group C1CC=CC=CC1 GWYPDXLJACEENP-UHFFFAOYSA-N 0.000 claims description 2
• FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical group C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 claims description 2
• HPOIPOPJGBKXIR-UHFFFAOYSA-N 3,6-dimethoxy-10-methyl-galantham-1-ene Natural products O1C(C(=CC=2)OC)=C3C=2CN(C)CCC23C1CC(OC)C=C2 HPOIPOPJGBKXIR-UHFFFAOYSA-N 0.000 claims description 2
• 125000005330 8 membered heterocyclic group Chemical group 0.000 claims description 2
• 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 2
• LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
• LPCKPBWOSNVCEL-UHFFFAOYSA-N Chlidanthine Natural products O1C(C(=CC=2)O)=C3C=2CN(C)CCC23C1CC(OC)C=C2 LPCKPBWOSNVCEL-UHFFFAOYSA-N 0.000 claims description 2
• MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
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• FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 claims description 2
• 125000002723 alicyclic group Chemical group 0.000 claims description 2
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• 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 2
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 2
• 125000005018 aryl alkenyl group Chemical group 0.000 claims description 2
• 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 2
• 125000005015 aryl alkynyl group Chemical group 0.000 claims description 2
• ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical group C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 2
• 125000001246 bromo group Chemical group Br* 0.000 claims description 2
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 2
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• 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
• MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical group C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 claims description 2
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• BGLNUNCBNALFOZ-WMLDXEAASA-N galanthamine Natural products COc1ccc2CCCC[C@@]34C=CCC[C@@H]3Oc1c24 BGLNUNCBNALFOZ-WMLDXEAASA-N 0.000 claims description 2
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