JP2002515503A - オピオイド受容体のサブタイプへの高い親和性を有する新規１，３，８−トリアザスピロ〔４，５〕デカノン - Google Patents
オピオイド受容体のサブタイプへの高い親和性を有する新規１，３，８−トリアザスピロ〔４，５〕デカノンInfo
- Publication number
- JP2002515503A JP2002515503A JP2000549615A JP2000549615A JP2002515503A JP 2002515503 A JP2002515503 A JP 2002515503A JP 2000549615 A JP2000549615 A JP 2000549615A JP 2000549615 A JP2000549615 A JP 2000549615A JP 2002515503 A JP2002515503 A JP 2002515503A
- Authority
- JP
- Japan
- Prior art keywords
- phenyl
- spiro
- triaza
- alkyl
- oxo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 102000003840 Opioid Receptors Human genes 0.000 title claims abstract description 5
- 108090000137 Opioid Receptors Proteins 0.000 title claims abstract description 5
- JDPQWHLMBJZURR-UHFFFAOYSA-N decan-5-one Chemical compound CCCCCC(=O)CCCC JDPQWHLMBJZURR-UHFFFAOYSA-N 0.000 title 1
- ZAJNGDIORYACQU-UHFFFAOYSA-N methyl n-octyl ketone Natural products CCCCCCCCC(C)=O ZAJNGDIORYACQU-UHFFFAOYSA-N 0.000 title 1
- -1 aminophenyl Chemical group 0.000 claims abstract description 120
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 102
- 239000001257 hydrogen Substances 0.000 claims abstract description 101
- 150000001875 compounds Chemical class 0.000 claims abstract description 95
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 74
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 68
- 150000003839 salts Chemical class 0.000 claims abstract description 51
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 50
- 230000001457 vasomotor Effects 0.000 claims abstract description 36
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 32
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 27
- 238000011282 treatment Methods 0.000 claims abstract description 27
- 208000035475 disorder Diseases 0.000 claims abstract description 25
- 206010060800 Hot flush Diseases 0.000 claims abstract description 24
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 18
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract description 17
- 239000003446 ligand Substances 0.000 claims abstract description 17
- 208000033830 Hot Flashes Diseases 0.000 claims abstract description 16
- 150000002894 organic compounds Chemical class 0.000 claims abstract description 15
- 206010061218 Inflammation Diseases 0.000 claims abstract description 13
- 230000004054 inflammatory process Effects 0.000 claims abstract description 13
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 13
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 12
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims abstract description 12
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims abstract description 12
- 125000002541 furyl group Chemical group 0.000 claims abstract description 12
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims abstract description 12
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 12
- 206010021639 Incontinence Diseases 0.000 claims abstract description 11
- 125000004450 alkenylene group Chemical group 0.000 claims abstract description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 11
- 208000019695 Migraine disease Diseases 0.000 claims abstract description 10
- 206010040047 Sepsis Diseases 0.000 claims abstract description 10
- 125000004802 cyanophenyl group Chemical group 0.000 claims abstract description 10
- 206010027599 migraine Diseases 0.000 claims abstract description 10
- 125000005037 alkyl phenyl group Chemical group 0.000 claims abstract description 9
- 230000002093 peripheral effect Effects 0.000 claims abstract description 9
- 230000009471 action Effects 0.000 claims abstract description 6
- 125000004419 alkynylene group Chemical group 0.000 claims abstract description 6
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims abstract description 6
- RGICCULPCWNRAB-UHFFFAOYSA-N 2-[2-(2-hexoxyethoxy)ethoxy]ethanol Chemical compound CCCCCCOCCOCCOCCO RGICCULPCWNRAB-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 55
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 45
- 239000000203 mixture Substances 0.000 claims description 36
- 125000003545 alkoxy group Chemical group 0.000 claims description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 29
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 27
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 27
- 229910052736 halogen Inorganic materials 0.000 claims description 26
- 150000002367 halogens Chemical class 0.000 claims description 26
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 25
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims description 25
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 19
- 238000004519 manufacturing process Methods 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 125000001151 peptidyl group Chemical group 0.000 claims description 15
- 102100028646 Nociceptin receptor Human genes 0.000 claims description 14
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 14
- 108010020615 nociceptin receptor Proteins 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 claims description 12
- 125000000539 amino acid group Chemical group 0.000 claims description 12
- 150000001413 amino acids Chemical group 0.000 claims description 10
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 claims description 9
- 125000000332 coumarinyl group Chemical group O1C(=O)C(=CC2=CC=CC=C12)* 0.000 claims description 9
- 125000001041 indolyl group Chemical group 0.000 claims description 9
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000001931 aliphatic group Chemical group 0.000 claims description 7
- 125000004104 aryloxy group Chemical group 0.000 claims description 7
- 210000004899 c-terminal region Anatomy 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 7
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 7
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 6
- 208000011117 substance-related disease Diseases 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 5
- SGDZJZUYXLTSIQ-UHFFFAOYSA-N 3-(5-aminopentyl)-8-(naphthalen-1-ylmethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one Chemical compound C1CN(CC=2C3=CC=CC=C3C=CC=2)CCC21C(=O)N(CCCCCN)CN2C1=CC=CC=C1 SGDZJZUYXLTSIQ-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 206010013654 Drug abuse Diseases 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 4
- MSRLBTSINZJZCF-UHFFFAOYSA-N methyl 2-[8-[(4-bromophenyl)methyl]-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetate Chemical compound C1CN(CC=2C=CC(Br)=CC=2)CCC21C(=O)N(CC(=O)OC)CN2C1=CC=CC=C1 MSRLBTSINZJZCF-UHFFFAOYSA-N 0.000 claims description 4
- HNBDRPTVWVGKBR-UHFFFAOYSA-N methyl pentanoate Chemical compound CCCCC(=O)OC HNBDRPTVWVGKBR-UHFFFAOYSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000002685 pulmonary effect Effects 0.000 claims description 3
- CLFKIGWGBCIRBX-NDEPHWFRSA-N (2s)-5-(diaminomethylideneamino)-2-[[2-[[2-[8-(naphthalen-1-ylmethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetyl]amino]acetyl]amino]pentanamide Chemical compound C1CN(CC=2C3=CC=CC=C3C=CC=2)CCC21C(=O)N(CC(=O)NCC(=O)N[C@@H](CCCN=C(N)N)C(N)=O)CN2C1=CC=CC=C1 CLFKIGWGBCIRBX-NDEPHWFRSA-N 0.000 claims description 2
- CFGDBBHLAYTFAV-NDEPHWFRSA-N (2s)-6-amino-2-[[2-[8-(naphthalen-1-ylmethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetyl]amino]hexanamide Chemical compound C1CN(CC=2C3=CC=CC=C3C=CC=2)CCC21C(=O)N(CC(=O)N[C@@H](CCCCN)C(N)=O)CN2C1=CC=CC=C1 CFGDBBHLAYTFAV-NDEPHWFRSA-N 0.000 claims description 2
- LHFNWZUAQBBRPN-UHFFFAOYSA-N 2-[7-[8-(naphthalen-1-ylmethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]heptyl]guanidine Chemical compound C1CN(CC=2C3=CC=CC=C3C=CC=2)CCC21C(=O)N(CCCCCCCN=C(N)N)CN2C1=CC=CC=C1 LHFNWZUAQBBRPN-UHFFFAOYSA-N 0.000 claims description 2
- CYMSVIZVTSWNFI-UHFFFAOYSA-N 2-[8-(naphthalen-1-ylmethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]-n-[3-(2-oxopyrrolidin-1-yl)propyl]acetamide Chemical compound C1CCC(=O)N1CCCNC(=O)CN(C(C12CCN(CC=3C4=CC=CC=C4C=CC=3)CC2)=O)CN1C1=CC=CC=C1 CYMSVIZVTSWNFI-UHFFFAOYSA-N 0.000 claims description 2
- RULBIQSXEOCZPD-UHFFFAOYSA-N 2-[[2-[8-(naphthalen-1-ylmethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetyl]amino]acetamide Chemical compound C1CN(CC=2C3=CC=CC=C3C=CC=2)CCC21C(=O)N(CC(=O)NCC(=O)N)CN2C1=CC=CC=C1 RULBIQSXEOCZPD-UHFFFAOYSA-N 0.000 claims description 2
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 claims description 2
- 125000006512 3,4-dichlorobenzyl group Chemical group [H]C1=C(Cl)C(Cl)=C([H])C(=C1[H])C([H])([H])* 0.000 claims description 2
- 125000003974 3-carbamimidamidopropyl group Chemical group C(N)(=N)NCCC* 0.000 claims description 2
- MWMMMRSHWNKLBY-UHFFFAOYSA-N 3-ethyl-8-(naphthalen-1-ylmethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one Chemical compound C1CN(CC=2C3=CC=CC=C3C=CC=2)CCC21C(=O)N(CC)CN2C1=CC=CC=C1 MWMMMRSHWNKLBY-UHFFFAOYSA-N 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 claims description 2
- XOORPMTVJNDQIW-UHFFFAOYSA-N methyl 2-[4-oxo-1-phenyl-8-(3-phenylpropyl)-1,3,8-triazaspiro[4.5]decan-3-yl]acetate Chemical compound C1CN(CCCC=2C=CC=CC=2)CCC21C(=O)N(CC(=O)OC)CN2C1=CC=CC=C1 XOORPMTVJNDQIW-UHFFFAOYSA-N 0.000 claims description 2
- AXFOGZBOOCGBDV-UHFFFAOYSA-N methyl 2-[4-oxo-8-(3-phenoxypropyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetate Chemical compound C1CN(CCCOC=2C=CC=CC=2)CCC21C(=O)N(CC(=O)OC)CN2C1=CC=CC=C1 AXFOGZBOOCGBDV-UHFFFAOYSA-N 0.000 claims description 2
- NPLSSFAZPJPKQE-UHFFFAOYSA-N methyl 2-[4-oxo-8-(4-phenoxybutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetate Chemical compound C1CN(CCCCOC=2C=CC=CC=2)CCC21C(=O)N(CC(=O)OC)CN2C1=CC=CC=C1 NPLSSFAZPJPKQE-UHFFFAOYSA-N 0.000 claims description 2
- VYIOQABFDCPSOF-UHFFFAOYSA-N methyl 2-[8-(2-naphthalen-1-ylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetate Chemical compound C1CN(CCC=2C3=CC=CC=C3C=CC=2)CCC21C(=O)N(CC(=O)OC)CN2C1=CC=CC=C1 VYIOQABFDCPSOF-UHFFFAOYSA-N 0.000 claims description 2
- WCQKBEVLPQRDKU-UHFFFAOYSA-N methyl 2-[8-(3-cyano-3,3-diphenylpropyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetate Chemical compound C1CN(CCC(C#N)(C=2C=CC=CC=2)C=2C=CC=CC=2)CCC21C(=O)N(CC(=O)OC)CN2C1=CC=CC=C1 WCQKBEVLPQRDKU-UHFFFAOYSA-N 0.000 claims description 2
- HVCVBUXEGVWNKM-UHFFFAOYSA-N methyl 2-[8-[(3,4-dichlorophenyl)methyl]-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetate Chemical compound C1CN(CC=2C=C(Cl)C(Cl)=CC=2)CCC21C(=O)N(CC(=O)OC)CN2C1=CC=CC=C1 HVCVBUXEGVWNKM-UHFFFAOYSA-N 0.000 claims description 2
- XFZSGOVQPRDFLO-UHFFFAOYSA-N methyl 2-[8-[(3-cyanophenyl)methyl]-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetate Chemical compound C1CN(CC=2C=C(C=CC=2)C#N)CCC21C(=O)N(CC(=O)OC)CN2C1=CC=CC=C1 XFZSGOVQPRDFLO-UHFFFAOYSA-N 0.000 claims description 2
- PFVLHTORQLGLQD-UHFFFAOYSA-N methyl 2-[8-[(4-nitrophenyl)methyl]-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetate Chemical compound C1CN(CC=2C=CC(=CC=2)[N+]([O-])=O)CCC21C(=O)N(CC(=O)OC)CN2C1=CC=CC=C1 PFVLHTORQLGLQD-UHFFFAOYSA-N 0.000 claims description 2
- WJRYQSOYLZBRQM-UHFFFAOYSA-N methyl 2-[8-[2-(4-fluorophenoxy)ethyl]-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetate Chemical compound C1CN(CCOC=2C=CC(F)=CC=2)CCC21C(=O)N(CC(=O)OC)CN2C1=CC=CC=C1 WJRYQSOYLZBRQM-UHFFFAOYSA-N 0.000 claims description 2
- NXWPCBWSNUFZHT-UHFFFAOYSA-N methyl 2-[8-[5-(1,3-dioxoisoindol-2-yl)pentyl]-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetate Chemical compound C1CN(CCCCCN2C(C3=CC=CC=C3C2=O)=O)CCC21C(=O)N(CC(=O)OC)CN2C1=CC=CC=C1 NXWPCBWSNUFZHT-UHFFFAOYSA-N 0.000 claims description 2
- DCONGZODFMASFS-UHFFFAOYSA-N n-(3-aminopropyl)-2-[8-(naphthalen-1-ylmethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetamide Chemical compound C1CN(CC=2C3=CC=CC=C3C=CC=2)CCC21C(=O)N(CC(=O)NCCCN)CN2C1=CC=CC=C1 DCONGZODFMASFS-UHFFFAOYSA-N 0.000 claims description 2
- 229940080818 propionamide Drugs 0.000 claims description 2
- 201000009032 substance abuse Diseases 0.000 claims description 2
- 231100000736 substance abuse Toxicity 0.000 claims description 2
- 201000001119 neuropathy Diseases 0.000 claims 2
- 230000007823 neuropathy Effects 0.000 claims 2
- 208000033808 peripheral neuropathy Diseases 0.000 claims 2
- MGULTWWXMQOMPK-UHFFFAOYSA-N methyl 2-[4-oxo-1-phenyl-8-(2-phenylethyl)-1,3,8-triazaspiro[4.5]decan-3-yl]acetate Chemical compound C1CN(CCC=2C=CC=CC=2)CCC21C(=O)N(CC(=O)OC)CN2C1=CC=CC=C1 MGULTWWXMQOMPK-UHFFFAOYSA-N 0.000 claims 1
- RDNGLQKLSYVRNI-UHFFFAOYSA-N methyl 2-[8-[(6,7-dimethoxy-2-oxochromen-4-yl)methyl]-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetate Chemical compound C1CN(CC=2C=3C=C(OC)C(OC)=CC=3OC(=O)C=2)CCC21C(=O)N(CC(=O)OC)CN2C1=CC=CC=C1 RDNGLQKLSYVRNI-UHFFFAOYSA-N 0.000 claims 1
- GOAWKPMSVDFYDE-UHFFFAOYSA-N methyl 2-[8-[2-(1,3-dioxoisoindol-2-yl)ethyl]-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetate Chemical compound C1CN(CCN2C(C3=CC=CC=C3C2=O)=O)CCC21C(=O)N(CC(=O)OC)CN2C1=CC=CC=C1 GOAWKPMSVDFYDE-UHFFFAOYSA-N 0.000 claims 1
- KHMFXQKJRQEUNH-UHFFFAOYSA-N n-(2-aminoethyl)-2-[8-(naphthalen-1-ylmethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetamide Chemical compound C1CN(CC=2C3=CC=CC=C3C=CC=2)CCC21C(=O)N(CC(=O)NCCN)CN2C1=CC=CC=C1 KHMFXQKJRQEUNH-UHFFFAOYSA-N 0.000 claims 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 427
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 153
- 239000011347 resin Substances 0.000 description 115
- 229920005989 resin Polymers 0.000 description 115
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 63
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 58
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 52
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 48
- 239000000243 solution Substances 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 26
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 25
- 239000002904 solvent Substances 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 17
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 15
- 150000001408 amides Chemical group 0.000 description 15
- 239000000843 powder Substances 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
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- 230000001052 transient effect Effects 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (11)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK0681/98 | 1998-05-18 | ||
| DK68198 | 1998-05-18 | ||
| DK71198 | 1998-05-20 | ||
| DK0711/98 | 1998-05-20 | ||
| DK72998 | 1998-05-26 | ||
| DKPA199800927 | 1998-07-10 | ||
| DK199900111 | 1999-01-29 | ||
| DKPA199900111 | 1999-01-29 | ||
| DK199800729 | 1999-01-29 | ||
| DK199800927 | 1999-01-29 | ||
| PCT/DK1999/000266 WO1999059997A1 (fr) | 1998-05-18 | 1999-05-14 | Nouvelles 1,3,8-triazaspiro[4.5]decanones possedant une affinite elevee pour les sous-types du recepteur opioide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2002515503A true JP2002515503A (ja) | 2002-05-28 |
Family
ID=27512746
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2000549615A Pending JP2002515503A (ja) | 1998-05-18 | 1999-05-14 | オピオイド受容体のサブタイプへの高い親和性を有する新規１，３，８−トリアザスピロ〔４，５〕デカノン |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1080091A1 (fr) |
| JP (1) | JP2002515503A (fr) |
| AU (1) | AU3809999A (fr) |
| WO (1) | WO1999059997A1 (fr) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006514934A (ja) * | 2002-11-26 | 2006-05-18 | アレックザ ファーマシューティカルズ， インコーポレイテッド | 疼痛治療用薬剤製造のためのロキサピンまたはアモキサピンの使用 |
| JP2006516239A (ja) * | 2002-05-31 | 2006-06-29 | ユーロ−セルティーク エス．エイ． | 疼痛を処置または防止するために有用なトリアザスピロ化合物 |
| JP2013528660A (ja) * | 2010-06-18 | 2013-07-11 | アルトス・セラピューティクス・リミテッド・ライアビリティ・カンパニー | Ｄ２アンタゴニスト、その合成方法および使用方法 |
Families Citing this family (30)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2237047T3 (es) * | 1998-10-23 | 2005-07-16 | Pfizer Inc. | Compuestos de 1,3,8-triazaespiro(4,5)decanona como agonistas del receptor orl1. |
| AU1382901A (en) * | 1999-11-17 | 2001-05-30 | Novo Nordisk A/S | Novel triazaspirodecanones with high affinity for opioid receptor subtypes |
| AU1623801A (en) | 1999-11-19 | 2001-05-30 | Palatin Technologies, Inc. | Opioid metallopeptide compositions and methods |
| DE60022226D1 (de) | 1999-12-06 | 2005-09-29 | Euro Celtique Sa | Benzimidazolverbindungen die nociceptinrezeptoraffinität haben |
| JP3989247B2 (ja) | 1999-12-06 | 2007-10-10 | ユーロ−セルティーク エス．エイ． | ノシセプチン受容体親和性を有するトリアゾスピロ化合物 |
| EP1244437A4 (fr) | 1999-12-06 | 2005-02-09 | Euro Celtique Sa | Composes amino tertiaires presentant une affinite pour le recepteur opioide |
| JP2005231995A (ja) * | 1999-12-22 | 2005-09-02 | Meiji Seika Kaisha Ltd | オピオイドδ受容体アゴニスト／アンタゴニストとして有用なスピロ化合物 |
| WO2001060796A1 (fr) * | 2000-02-18 | 2001-08-23 | Meiji Seika Kaisha, Ltd. | DERIVES DE PHENOXYALKYLAMINE UTILES EN TANT QU'AGONISTES DU RECEPTEUR OPIOIDE $g(d) |
| US6846831B2 (en) | 2000-08-15 | 2005-01-25 | Cpd, Llc | Method of treating the syndrome of lipodystrophy |
| EP1365756A2 (fr) * | 2000-08-15 | 2003-12-03 | Cpd, Llc | Methode de traitement du syndrome du diabete de type ii humain |
| US6528520B2 (en) | 2000-08-15 | 2003-03-04 | Cpd, Llc | Method of treating the syndrome of coronary heart disease risk factors in humans |
| US6969712B2 (en) | 2000-11-15 | 2005-11-29 | Banyu Pharmaceutical Co., Ltd. | Benzimidazole derivatives |
| EP1392687B1 (fr) | 2001-04-10 | 2017-02-01 | Janssen Pharmaceuticals, Inc. | Derives de 1,3,8-triazaspiro[4.5]decan-4-one utiles dans le traitement de troubles induits par le recepteur orl-1 |
| BR0209128A (pt) | 2001-04-18 | 2005-11-01 | Euro Celtique Sa | Compostos, composições farmacêuticas, métodos para o tratamento de dores, métodos para a modulação de uma resposta farmacológica e usos de compostos |
| RU2299883C2 (ru) * | 2001-04-18 | 2007-05-27 | Эро-Селтик, С.А. | Соединения спиропиразола, содержащая их фармацевтическая композиция, способ модуляции опиоидного рецептора и способ лечения с применением таких соединений |
| CA2443938C (fr) | 2001-04-18 | 2010-06-22 | R. Richard Goehring | Composes de spiroindene et de spiroindane comme ligands opioides utiles pour le traitement de la douleur |
| EP1598339B1 (fr) | 2001-04-18 | 2009-06-24 | Euro-Celtique S.A. | Derivés de la 1-(4-amino-cyclohexyl)-1,3-dihydro-2h-benzimidazole-2-one et composés similaires pour l'utilisation comme analogues du nociceptin et ligandes du orl1 pour le traitement de la douleur |
| SI1385518T1 (sl) | 2001-04-18 | 2009-02-28 | Euro Celtique Sa | Benzimidazolonske spojine |
| EP1402899A4 (fr) * | 2001-05-08 | 2009-03-11 | Toray Industries | Remedes contre la sepsie |
| WO2002100861A1 (fr) * | 2001-06-13 | 2002-12-19 | Akzo Nobel N.V. | Derives de 1-(3-phenyloxypropyl)piperidine |
| DK1491212T3 (da) | 2002-03-29 | 2012-10-29 | Mitsubishi Tanabe Pharma Corp | Middel til behandling af søvnforstyrrelser |
| JP2005289816A (ja) | 2002-05-14 | 2005-10-20 | Banyu Pharmaceut Co Ltd | ベンズイミダゾール誘導体 |
| AU2003268512A1 (en) | 2002-09-09 | 2004-03-29 | Janssen Pharmaceutica N.V. | Hydroxy alkyl substituted 1,3,8-triazaspiro[4.5]decan-4-one derivatives useful for the treatment of ORL-1 receptor mediated disorders |
| NZ544282A (en) * | 2003-05-23 | 2009-07-31 | Zealand Pharma As | Triaza-spiro compounds as nociceptin analogues and uses thereof |
| WO2007085357A1 (fr) | 2006-01-30 | 2007-08-02 | Euro-Celtique S.A. | Composes cyclo-uree utilises en tant que bloqueurs des canaux calciques |
| WO2008051902A2 (fr) | 2006-10-20 | 2008-05-02 | Cpd, Llc | Procédé pour rétablir l'effet de l'incrétine |
| CN101622254B (zh) | 2006-11-28 | 2013-05-29 | 詹森药业有限公司 | 3-(3-氨基-2-(r)-羟基-丙基)-1-(4-氟-苯基)-8-(8-甲基-萘-1-基甲基)-1,3,8-三氮杂-螺[4.5]癸烷-4-酮的盐 |
| JP5490677B2 (ja) | 2007-04-09 | 2014-05-14 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | 不安及び鬱病の処置のためのｏｒｌ−１受容体リガンドとしての１，３，８−三置換−１，３，８−トリアザ−スピロ［４．５］デカン−４−オン誘導体 |
| EP3215154B1 (fr) | 2014-11-07 | 2020-01-29 | Regents of the University of Minnesota | Sels et compositions utiles pour le traitement de maladie |
| US10787423B2 (en) * | 2015-09-14 | 2020-09-29 | The National Institute For Biotechnolgy In The Negev Ltd. | Piperazine and piperidine derivatives, their synthesis and use thereof in inhibiting VDAC oligomerization, apoptosis and mitochondria dysfunction |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE633914A (fr) * | 1962-06-22 | |||
| US3238216A (en) * | 1963-06-20 | 1966-03-01 | Res Lab Dr C Janssen N V | Substituted 1, 3, 8-triaza-spiro (4, 5) decanes |
| US3629267A (en) * | 1968-10-28 | 1971-12-21 | Smith Kline French Lab | Benzoheterocyclicalkyl derivatives of 4-(2-keto -1-benzimidazolinyl)-piperidine 4-(2-keto - 1 - benzimidazolinyl) -1 2 3 6 tetrahydropyridine 1 - phenyl - 1 3 8-triazaspiro(4 5)decan - 4 - one and 2 4 9-triazaspiro(5 5)undecan-1 3 5-trione |
| JPS491573A (fr) * | 1972-04-28 | 1974-01-08 | ||
| US3923993A (en) * | 1973-06-28 | 1975-12-02 | American Home Prod | Process for treating neuroendocrinopathic diseases employing fluspirilene |
| US3863011A (en) * | 1973-06-28 | 1975-01-28 | American Home Prod | Process for treating neuroendocrinopathic diseases employing pimozide |
| US4051248A (en) * | 1975-07-14 | 1977-09-27 | E. R. Squibb & Sons, Inc. | 1,3,8-triazaspiro(4.5)decan-4-one derivatives |
| WO1991013622A1 (fr) * | 1990-03-16 | 1991-09-19 | Beth Israel Hospital Association | Utilisation de spiperone comme agent immunosuppresseur et anti-inflammatoire |
| JPH08500326A (ja) * | 1991-12-27 | 1996-01-16 | ベス イスラエル ホスピタル アソシエイション | 免疫抑制剤としてのスピペロンまたはスピペロン誘導体の使用 |
-
1999
- 1999-05-14 WO PCT/DK1999/000266 patent/WO1999059997A1/fr not_active Application Discontinuation
- 1999-05-14 JP JP2000549615A patent/JP2002515503A/ja active Pending
- 1999-05-14 EP EP99920561A patent/EP1080091A1/fr not_active Withdrawn
- 1999-05-14 AU AU38099/99A patent/AU3809999A/en not_active Abandoned
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006516239A (ja) * | 2002-05-31 | 2006-06-29 | ユーロ−セルティーク エス．エイ． | 疼痛を処置または防止するために有用なトリアザスピロ化合物 |
| JP2011021021A (ja) * | 2002-05-31 | 2011-02-03 | Euro-Celtique Sa | 疼痛を処置または防止するために有用なトリアザスピロ化合物 |
| JP4658595B2 (ja) * | 2002-05-31 | 2011-03-23 | ユーロ−セルティーク エス．エイ． | 疼痛を処置または防止するために有用なトリアザスピロ化合物 |
| JP2006514934A (ja) * | 2002-11-26 | 2006-05-18 | アレックザ ファーマシューティカルズ， インコーポレイテッド | 疼痛治療用薬剤製造のためのロキサピンまたはアモキサピンの使用 |
| JP2013528660A (ja) * | 2010-06-18 | 2013-07-11 | アルトス・セラピューティクス・リミテッド・ライアビリティ・カンパニー | Ｄ２アンタゴニスト、その合成方法および使用方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1999059997A1 (fr) | 1999-11-25 |
| AU3809999A (en) | 1999-12-06 |
| EP1080091A1 (fr) | 2001-03-07 |
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