PL210019B1 - Związki pirydynoilopiperydyny, sposób ich wytwarzania i zastosowanie oraz sposób wytwarzania związków pośrednich do ich syntezy - Google Patents

Info

Publication number

PL210019B1

PL210019B1 PL372845A PL37284503A PL210019B1 PL 210019 B1 PL210019 B1 PL 210019B1 PL 372845 A PL372845 A PL 372845A PL 37284503 A PL37284503 A PL 37284503A PL 210019 B1 PL210019 B1 PL 210019B1

Authority

PL

Poland

Prior art keywords

methyl

compound

ylcarbonyl

pyridin

alkyl

Prior art date

2002-03-29

Links

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• 239000000556 agonist Substances 0.000 title description 10
• YSWVIKAWHDUJFE-UHFFFAOYSA-N piperidin-1-yl(pyridin-2-yl)methanone Chemical class C=1C=CC=NC=1C(=O)N1CCCCC1 YSWVIKAWHDUJFE-UHFFFAOYSA-N 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 149
• 238000000034 method Methods 0.000 claims abstract description 46
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 27
• 239000001257 hydrogen Substances 0.000 claims abstract description 25
• 208000019695 Migraine disease Diseases 0.000 claims abstract description 20
• 150000003839 salts Chemical class 0.000 claims abstract description 20
• 239000002253 acid Substances 0.000 claims abstract description 17
• 206010027599 migraine Diseases 0.000 claims abstract description 17
• 230000008569 process Effects 0.000 claims abstract description 12
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 11
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 11
• 241000124008 Mammalia Species 0.000 claims abstract description 7
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 45
• 239000002904 solvent Substances 0.000 claims description 45
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
• 238000006243 chemical reaction Methods 0.000 claims description 32
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 24
• 229910052757 nitrogen Inorganic materials 0.000 claims description 21
• JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 19
• 238000002360 preparation method Methods 0.000 claims description 18
• 239000000460 chlorine Chemical group 0.000 claims description 16
• XEDHVZKDSYZQBF-UHFFFAOYSA-N lasmiditan Chemical compound C1CN(C)CCC1C(=O)C1=CC=CC(NC(=O)C=2C(=CC(F)=CC=2F)F)=N1 XEDHVZKDSYZQBF-UHFFFAOYSA-N 0.000 claims description 15
• FEYDZHNIIMENOB-UHFFFAOYSA-N 2,6-dibromopyridine Chemical compound BrC1=CC=CC(Br)=N1 FEYDZHNIIMENOB-UHFFFAOYSA-N 0.000 claims description 14
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
• 239000003814 drug Substances 0.000 claims description 12
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
• 125000006239 protecting group Chemical group 0.000 claims description 10
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
• 229910052744 lithium Inorganic materials 0.000 claims description 8
• 239000012299 nitrogen atmosphere Substances 0.000 claims description 8
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 7
• WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 7
• 125000003386 piperidinyl group Chemical group 0.000 claims description 7
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 7
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
• 229910052794 bromium Inorganic materials 0.000 claims description 6
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
• 125000002393 azetidinyl group Chemical group 0.000 claims description 5
• 125000001246 bromo group Chemical group Br* 0.000 claims description 5
• 229910052801 chlorine Chemical group 0.000 claims description 5
• 238000004519 manufacturing process Methods 0.000 claims description 4
• XGABIOSYJHFORX-UHFFFAOYSA-N n,n-dimethylpiperidine-4-carboxamide Chemical compound CN(C)C(=O)C1CCNCC1 XGABIOSYJHFORX-UHFFFAOYSA-N 0.000 claims description 4
• FILKGCRCWDMBKA-UHFFFAOYSA-N 2,6-dichloropyridine Chemical compound ClC1=CC=CC(Cl)=N1 FILKGCRCWDMBKA-UHFFFAOYSA-N 0.000 claims description 3
• QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 3
• 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
• 229910052799 carbon Inorganic materials 0.000 claims description 2
• 239000003937 drug carrier Substances 0.000 claims description 2
• 239000008024 pharmaceutical diluent Substances 0.000 claims description 2
• FHOGFJWVHBGYIU-UHFFFAOYSA-N (6-bromopyridin-2-yl)-piperidin-4-ylmethanone Chemical compound BrC1=CC=CC(C(=O)C2CCNCC2)=N1 FHOGFJWVHBGYIU-UHFFFAOYSA-N 0.000 claims 1
• 150000002431 hydrogen Chemical class 0.000 claims 1
• 239000000543 intermediate Substances 0.000 abstract description 30
• 206010015866 Extravasation Diseases 0.000 abstract description 19
• 230000036251 extravasation Effects 0.000 abstract description 19
• 230000015572 biosynthetic process Effects 0.000 abstract description 8
• 238000003786 synthesis reaction Methods 0.000 abstract description 7
• 125000000753 cycloalkyl group Chemical group 0.000 abstract description 6
• 230000002401 inhibitory effect Effects 0.000 abstract description 6
• 101000941893 Felis catus Leucine-rich repeat and calponin homology domain-containing protein 1 Proteins 0.000 abstract description 4
• 101150039275 Htr1f gene Proteins 0.000 abstract description 2
• 230000003213 activating effect Effects 0.000 abstract description 2
• 230000002265 prevention Effects 0.000 abstract description 2
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 3
• 125000000623 heterocyclic group Chemical group 0.000 abstract 2
• 125000001475 halogen functional group Chemical group 0.000 abstract 1
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 189
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 109
• 239000000203 mixture Substances 0.000 description 83
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 69
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 59
• -1 5-substituted piperidin-3-yl-indoles Chemical class 0.000 description 57
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 54
• 239000000243 solution Substances 0.000 description 54
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 47
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 46
• 239000012141 concentrate Substances 0.000 description 44
• 235000008504 concentrate Nutrition 0.000 description 43
• 239000011541 reaction mixture Substances 0.000 description 43
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 38
• 239000012458 free base Substances 0.000 description 32
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 31
• 238000003756 stirring Methods 0.000 description 31
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
• QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 24
• 239000000284 extract Substances 0.000 description 23
• 108010053303 serotonin 1F receptor Proteins 0.000 description 22
• 239000007787 solid Substances 0.000 description 22
• 239000000047 product Substances 0.000 description 21
• 235000019439 ethyl acetate Nutrition 0.000 description 20
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 19
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 19
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
• 238000005481 NMR spectroscopy Methods 0.000 description 17
• 239000004480 active ingredient Substances 0.000 description 17
• 238000009472 formulation Methods 0.000 description 17
• 239000012044 organic layer Substances 0.000 description 17
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 16
• 206010047139 Vasoconstriction Diseases 0.000 description 16
• 230000000694 effects Effects 0.000 description 16
• VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 16
• 239000003921 oil Substances 0.000 description 16
• 238000010992 reflux Methods 0.000 description 16
• MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 16
• 239000000725 suspension Substances 0.000 description 16
• 230000025033 vasoconstriction Effects 0.000 description 16
• KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 15
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 15
• 238000001819 mass spectrum Methods 0.000 description 15
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
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• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
• 229910021529 ammonia Inorganic materials 0.000 description 13
• 208000035475 disorder Diseases 0.000 description 13
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• 229910002027 silica gel Inorganic materials 0.000 description 13
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
• 238000004587 chromatography analysis Methods 0.000 description 12
• 239000004615 ingredient Substances 0.000 description 12
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 11
• MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 11
• 239000003153 chemical reaction reagent Substances 0.000 description 11
• 125000001424 substituent group Chemical group 0.000 description 11
• 210000001519 tissue Anatomy 0.000 description 11
• YLTJVIIEHKBRPA-UHFFFAOYSA-N (6-aminopyridin-2-yl)-(1-methylpiperidin-4-yl)methanone Chemical compound C1CN(C)CCC1C(=O)C1=CC=CC(N)=N1 YLTJVIIEHKBRPA-UHFFFAOYSA-N 0.000 description 10
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
• 229960000583 acetic acid Drugs 0.000 description 10
• 239000010410 layer Substances 0.000 description 10
• 229910000069 nitrogen hydride Inorganic materials 0.000 description 10
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 10
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• 239000003826 tablet Substances 0.000 description 10
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• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
• 230000027455 binding Effects 0.000 description 9
• 210000004027 cell Anatomy 0.000 description 9
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• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
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• CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 7
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
• 235000019270 ammonium chloride Nutrition 0.000 description 7
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• KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 7
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