TWI263497B - Pyridinoylpiperidines as 5-HT1F agonists - Google Patents

Info

Publication number

TWI263497B

TWI263497B TW092106334A TW92106334A TWI263497B TW I263497 B TWI263497 B TW I263497B TW 092106334 A TW092106334 A TW 092106334A TW 92106334 A TW92106334 A TW 92106334A TW I263497 B TWI263497 B TW I263497B

Authority

TW

Taiwan

Prior art keywords

group

alkyl

substituted

compound

hydrogen

Prior art date

2002-03-29

Links

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• 239000000556 agonist Substances 0.000 title description 10
• 101710138086 5-hydroxytryptamine receptor 1F Proteins 0.000 title description 2
• 102100036311 5-hydroxytryptamine receptor 1F Human genes 0.000 title description 2
• 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 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 156
• 239000001257 hydrogen Substances 0.000 claims abstract description 69
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 69
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 67
• 239000002253 acid Substances 0.000 claims abstract description 45
• 238000000034 method Methods 0.000 claims abstract description 44
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 41
• 150000003839 salts Chemical class 0.000 claims abstract description 39
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 32
• 241000124008 Mammalia Species 0.000 claims abstract description 31
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 29
• 208000019695 Migraine disease Diseases 0.000 claims abstract description 23
• 206010027599 migraine Diseases 0.000 claims abstract description 23
• 206010015866 Extravasation Diseases 0.000 claims abstract description 20
• 230000036251 extravasation Effects 0.000 claims abstract description 20
• 238000011282 treatment Methods 0.000 claims abstract description 19
• 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 17
• 101000941893 Felis catus Leucine-rich repeat and calponin homology domain-containing protein 1 Proteins 0.000 claims abstract description 9
• 230000002401 inhibitory effect Effects 0.000 claims abstract description 9
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 5
• 230000003213 activating effect Effects 0.000 claims abstract description 5
• 230000002265 prevention Effects 0.000 claims abstract description 4
• -1 N-methylpyrrolyl Chemical group 0.000 claims description 103
• 238000006243 chemical reaction Methods 0.000 claims description 47
• 239000002904 solvent Substances 0.000 claims description 36
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 35
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 33
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 32
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 32
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 30
• 229910052757 nitrogen Inorganic materials 0.000 claims description 27
• JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 25
• 125000001424 substituent group Chemical group 0.000 claims description 25
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
• 102000005962 receptors Human genes 0.000 claims description 24
• 108020003175 receptors Proteins 0.000 claims description 24
• 125000003545 alkoxy group Chemical group 0.000 claims description 21
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 20
• 239000000460 chlorine Substances 0.000 claims description 19
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
• 229910052736 halogen Inorganic materials 0.000 claims description 19
• 150000002367 halogens Chemical group 0.000 claims description 19
• 239000003814 drug Substances 0.000 claims description 18
• 208000035475 disorder Diseases 0.000 claims description 17
• 108010053303 serotonin 1F receptor Proteins 0.000 claims description 17
• 150000001412 amines Chemical class 0.000 claims description 15
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 14
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 13
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 12
• 229910052801 chlorine Inorganic materials 0.000 claims description 12
• 229940079593 drug Drugs 0.000 claims description 12
• 150000002431 hydrogen Chemical group 0.000 claims description 12
• 125000003396 thiol group Chemical class [H]S* 0.000 claims description 12
• 238000002360 preparation method Methods 0.000 claims description 11
• 108090000623 proteins and genes Proteins 0.000 claims description 11
• 229910021529 ammonia Inorganic materials 0.000 claims description 10
• 125000002541 furyl group Chemical group 0.000 claims description 10
• 125000005842 heteroatom Chemical group 0.000 claims description 10
• 102000004169 proteins and genes Human genes 0.000 claims description 10
• FEYDZHNIIMENOB-UHFFFAOYSA-N 2,6-dibromopyridine Chemical compound BrC1=CC=CC(Br)=N1 FEYDZHNIIMENOB-UHFFFAOYSA-N 0.000 claims description 9
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 9
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 9
• 125000004076 pyridyl group Chemical group 0.000 claims description 9
• 229910052731 fluorine Inorganic materials 0.000 claims description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims description 8
• 125000001544 thienyl group Chemical group 0.000 claims description 8
• 229910052717 sulfur Inorganic materials 0.000 claims description 7
• IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims description 6
• 125000006242 amine protecting group Chemical group 0.000 claims description 6
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
• 229910052794 bromium Inorganic materials 0.000 claims description 6
• 239000011737 fluorine Substances 0.000 claims description 6
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 6
• 239000002244 precipitate Substances 0.000 claims description 6
• 238000006467 substitution reaction Methods 0.000 claims description 6
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 5
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 5
• 210000002569 neuron Anatomy 0.000 claims description 5
• 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
• 241001465754 Metazoa Species 0.000 claims description 4
• 125000004414 alkyl thio group Chemical group 0.000 claims description 4
• 230000004064 dysfunction Effects 0.000 claims description 4
• NIHNNTQXNPWCJQ-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims description 4
• 125000002971 oxazolyl group Chemical group 0.000 claims description 4
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
• 125000001246 bromo group Chemical group Br* 0.000 claims description 3
• 125000006239 protecting group Chemical group 0.000 claims description 3
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
• 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 2
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
• 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims description 2
• 125000003072 pyrazolidinyl group Chemical group 0.000 claims description 2
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 2
• 125000001425 triazolyl group Chemical group 0.000 claims description 2
• 229910052727 yttrium Inorganic materials 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
• FNRMMDCDHWCQTH-UHFFFAOYSA-N 2-chloropyridine;3-chloropyridine;4-chloropyridine Chemical compound ClC1=CC=NC=C1.ClC1=CC=CN=C1.ClC1=CC=CC=N1 FNRMMDCDHWCQTH-UHFFFAOYSA-N 0.000 claims 1
• 229920002101 Chitin Polymers 0.000 claims 1
• FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims 1
• KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims 1
• 125000002009 alkene group Chemical group 0.000 claims 1
• 150000004703 alkoxides Chemical class 0.000 claims 1
• 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims 1
• NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims 1
• 125000002883 imidazolyl group Chemical group 0.000 claims 1
• RWHJVIIQVLECOW-UHFFFAOYSA-N lithium;pyridine Chemical compound [Li].C1=CC=NC=C1 RWHJVIIQVLECOW-UHFFFAOYSA-N 0.000 claims 1
• 150000002923 oximes Chemical class 0.000 claims 1
• 229910052707 ruthenium Inorganic materials 0.000 claims 1
• RWSOTUBLDIXVET-UHFFFAOYSA-O sulfonium group Chemical group [SH3+] RWSOTUBLDIXVET-UHFFFAOYSA-O 0.000 claims 1
• 125000004354 sulfur functional group Chemical group 0.000 claims 1
• 239000000543 intermediate Substances 0.000 abstract description 26
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• 238000003786 synthesis reaction Methods 0.000 abstract description 10
• 230000008569 process Effects 0.000 abstract description 4
• 101150039275 Htr1f gene Proteins 0.000 abstract description 2
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 3
• 125000001475 halogen functional group Chemical group 0.000 abstract 1
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