EA007966B1 - Пиридиноилпиперидины как агонисты 5-ht - Google Patents
Пиридиноилпиперидины как агонисты 5-ht Download PDFInfo
- Publication number
- EA007966B1 EA007966B1 EA200401282A EA200401282A EA007966B1 EA 007966 B1 EA007966 B1 EA 007966B1 EA 200401282 A EA200401282 A EA 200401282A EA 200401282 A EA200401282 A EA 200401282A EA 007966 B1 EA007966 B1 EA 007966B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- substituted
- alkyl
- pyridin
- group
- methylpiperidin
- Prior art date
Links
- 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 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 169
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 52
- 239000001257 hydrogen Substances 0.000 claims abstract description 52
- 238000000034 method Methods 0.000 claims abstract description 51
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 44
- 150000003839 salts Chemical class 0.000 claims abstract description 41
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 31
- 238000011282 treatment Methods 0.000 claims abstract description 28
- 208000019695 Migraine disease Diseases 0.000 claims abstract description 24
- 206010015866 Extravasation Diseases 0.000 claims abstract description 23
- 239000002253 acid Substances 0.000 claims abstract description 23
- 230000036251 extravasation Effects 0.000 claims abstract description 23
- 206010027599 migraine Diseases 0.000 claims abstract description 23
- 241000124008 Mammalia Species 0.000 claims abstract description 22
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 14
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 8
- 230000002265 prevention Effects 0.000 claims abstract description 7
- -1 methyl pyrrolyl Chemical group 0.000 claims description 115
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 88
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 46
- 239000002904 solvent Substances 0.000 claims description 44
- 238000006243 chemical reaction Methods 0.000 claims description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 28
- 125000001424 substituent group Chemical group 0.000 claims description 25
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- 125000005843 halogen group Chemical group 0.000 claims description 21
- 108090000623 proteins and genes Proteins 0.000 claims description 20
- 102000004169 proteins and genes Human genes 0.000 claims description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 13
- 230000001537 neural effect Effects 0.000 claims description 13
- FEYDZHNIIMENOB-UHFFFAOYSA-N 2,6-dibromopyridine Chemical compound BrC1=CC=CC(Br)=N1 FEYDZHNIIMENOB-UHFFFAOYSA-N 0.000 claims description 12
- 125000003277 amino group Chemical group 0.000 claims description 12
- 208000035475 disorder Diseases 0.000 claims description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 12
- 230000003993 interaction Effects 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 125000006239 protecting group Chemical group 0.000 claims description 10
- 125000001544 thienyl group Chemical group 0.000 claims description 10
- 125000002541 furyl group Chemical group 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 125000004076 pyridyl group Chemical group 0.000 claims description 9
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 9
- 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 8
- 125000001041 indolyl group Chemical group 0.000 claims description 8
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims description 7
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 7
- 229910052744 lithium Inorganic materials 0.000 claims description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 125000003386 piperidinyl group Chemical group 0.000 claims description 6
- 125000001984 thiazolidinyl group Chemical group 0.000 claims description 6
- 125000001246 bromo group Chemical group Br* 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 239000012634 fragment Substances 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 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
- 125000002393 azetidinyl group Chemical group 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims description 3
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 3
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
- 125000001425 triazolyl group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 239000008024 pharmaceutical diluent Substances 0.000 claims description 2
- BWBONKHPVHMQHE-UHFFFAOYSA-N tiocarlide Chemical group C1=CC(OCCC(C)C)=CC=C1NC(=S)NC1=CC=C(OCCC(C)C)C=C1 BWBONKHPVHMQHE-UHFFFAOYSA-N 0.000 claims description 2
- 229960002171 tiocarlide Drugs 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 1
- 230000004064 dysfunction Effects 0.000 claims 1
- 125000000335 thiazolyl group Chemical group 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 32
- 230000003213 activating effect Effects 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 230000002401 inhibitory effect Effects 0.000 abstract description 7
- 230000008569 process Effects 0.000 abstract description 4
- 101000941893 Felis catus Leucine-rich repeat and calponin homology domain-containing protein 1 Proteins 0.000 abstract 1
- 125000001475 halogen functional group Chemical group 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 210
- 239000000203 mixture Substances 0.000 description 102
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 87
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 56
- 239000011541 reaction mixture Substances 0.000 description 56
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- 102000005962 receptors Human genes 0.000 description 42
- 108020003175 receptors Proteins 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 38
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 35
- 239000012458 free base Substances 0.000 description 31
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 29
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
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- 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 17
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 16
- 238000001819 mass spectrum Methods 0.000 description 16
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- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 16
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- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 15
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
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Landscapes
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- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
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| US36908802P | 2002-03-29 | 2002-03-29 | |
| PCT/US2003/008455 WO2003084949A1 (en) | 2002-03-29 | 2003-03-27 | Pyridinoylpiperidines as 5-ht1f agonists |
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| EA200401282A1 EA200401282A1 (ru) | 2005-02-24 |
| EA007966B1 true EA007966B1 (ru) | 2007-02-27 |
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| EA200401282A EA007966B1 (ru) | 2002-03-29 | 2003-03-27 | Пиридиноилпиперидины как агонисты 5-ht |
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| AU2004232799A1 (en) | 2003-04-18 | 2004-11-04 | Eli Lilly And Company | (Piperidinyloxy)phenyl, (piperidinyloxy)pyridinyl, (piperidinylsulfanyl)phenyl and (piperidinylsulfanyl)pyridinyl compounds as 5-HT1F agonists |
| AU2003903597A0 (en) * | 2003-07-11 | 2003-07-24 | Jakov Vaisman | Treatment of premature ejaculation |
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