ES2371230T3 - Derivados de ciclohexano espirocíclicos sustituidos. - Google Patents
Derivados de ciclohexano espirocíclicos sustituidos. Download PDFInfo
- Publication number
- ES2371230T3 ES2371230T3 ES09724314T ES09724314T ES2371230T3 ES 2371230 T3 ES2371230 T3 ES 2371230T3 ES 09724314 T ES09724314 T ES 09724314T ES 09724314 T ES09724314 T ES 09724314T ES 2371230 T3 ES2371230 T3 ES 2371230T3
- Authority
- ES
- Spain
- Prior art keywords
- cyclohexane
- indole
- amine
- phenyl
- dimethyl
- 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.)
- Active
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 149
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 102
- 239000000203 mixture Substances 0.000 claims abstract description 101
- -1 -30 OR13 Chemical group 0.000 claims abstract description 66
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 61
- 125000003118 aryl group Chemical group 0.000 claims abstract description 57
- 125000001424 substituent group Chemical group 0.000 claims abstract description 46
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 34
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 23
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 21
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 15
- 238000006467 substitution reaction Methods 0.000 claims abstract description 15
- 229910006069 SO3H Inorganic materials 0.000 claims abstract description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 14
- 125000003367 polycyclic group Polymers 0.000 claims abstract description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 8
- 125000002723 alicyclic group Chemical group 0.000 claims abstract description 6
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 6
- 125000004429 atom Chemical group 0.000 claims abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000002950 monocyclic group Chemical group 0.000 claims abstract description 4
- 239000001301 oxygen Substances 0.000 claims abstract description 4
- 239000011593 sulfur Substances 0.000 claims abstract description 4
- 125000001183 hydrocarbyl group Chemical group 0.000 claims abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 127
- RERZNCLIYCABFS-UHFFFAOYSA-N harmaline Chemical compound C1CN=C(C)C2=C1C1=CC=C(OC)C=C1N2 RERZNCLIYCABFS-UHFFFAOYSA-N 0.000 claims description 112
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 89
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 58
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 31
- 239000003814 drug Substances 0.000 claims description 23
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 16
- 208000002193 Pain Diseases 0.000 claims description 15
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 14
- CGLYBEYFUQIRIS-UHFFFAOYSA-N 3'-benzyl-n,n-dimethyl-1'-phenylspiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1C(N(C)C)(C=2C=CC=CC=2)CCC2(C3=C(C4=CC=CC=C4N3)CCN2)C1CC1=CC=CC=C1 CGLYBEYFUQIRIS-UHFFFAOYSA-N 0.000 claims description 11
- 229940079593 drug Drugs 0.000 claims description 8
- ZRVFZCWVNBOHAP-UHFFFAOYSA-N 3'-[(3-fluorophenyl)methyl]-n,n-dimethyl-1'-phenylspiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1C(N(C)C)(C=2C=CC=CC=2)CCC2(C3=C(C4=CC=CC=C4N3)CCN2)C1CC1=CC=CC(F)=C1 ZRVFZCWVNBOHAP-UHFFFAOYSA-N 0.000 claims description 7
- XLEGHKKTFZALDA-UHFFFAOYSA-N 3'-fluoro-n,n-dimethyl-1'-phenylspiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1CC2(C3=C(C4=CC=CC=C4N3)CCN2)C(F)CC1(N(C)C)C1=CC=CC=C1 XLEGHKKTFZALDA-UHFFFAOYSA-N 0.000 claims description 7
- 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 claims description 7
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 7
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 7
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 5
- 230000003444 anaesthetic effect Effects 0.000 claims description 5
- NNHQQQAFJCVHTJ-UHFFFAOYSA-N n,n-dimethyl-1'-phenyl-3'-phenylsulfanylspiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1C(N(C)C)(C=2C=CC=CC=2)CCC2(C3=C(C4=CC=CC=C4N3)CCN2)C1SC1=CC=CC=C1 NNHQQQAFJCVHTJ-UHFFFAOYSA-N 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
- WYEZTUIJZFLRTP-UHFFFAOYSA-N 2',2'-difluoro-n,n-dimethyl-1'-phenylspiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1CC2(C3=C(C4=CC=CC=C4N3)CCN2)CC(F)(F)C1(N(C)C)C1=CC=CC=C1 WYEZTUIJZFLRTP-UHFFFAOYSA-N 0.000 claims description 4
- ILNCEOIGYRKHIT-UHFFFAOYSA-N 3'-fluoro-n,n-dimethyl-1'-phenylspiro[4,9-dihydro-3h-pyrano[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1CC2(C3=C(C4=CC=CC=C4N3)CCO2)C(F)CC1(N(C)C)C1=CC=CC=C1 ILNCEOIGYRKHIT-UHFFFAOYSA-N 0.000 claims description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 4
- DBWJRYDBOSDJPY-UHFFFAOYSA-N 3',3',6-trifluoro-1'-(3-fluorophenyl)-n,n-dimethylspiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1CC2(C3=C(C4=CC(F)=CC=C4N3)CCN2)C(F)(F)CC1(N(C)C)C1=CC=CC(F)=C1 DBWJRYDBOSDJPY-UHFFFAOYSA-N 0.000 claims description 3
- KJRIQDNHVYBMSO-UHFFFAOYSA-N 3',5',6-trifluoro-1'-(3-fluorophenyl)-n,n-dimethylspiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1C(F)C2(C3=C(C4=CC(F)=CC=C4N3)CCN2)C(F)CC1(N(C)C)C1=CC=CC(F)=C1 KJRIQDNHVYBMSO-UHFFFAOYSA-N 0.000 claims description 3
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 3
- 238000002483 medication Methods 0.000 claims description 3
- 208000011580 syndromic disease Diseases 0.000 claims description 3
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 claims description 3
- XDUIXKLBEZFBMU-FOCLMDBBSA-N (e)-1-[1'-(dimethylamino)-2',2'-difluoro-1'-(3-fluorophenyl)spiro[4,9-dihydro-3h-pyrido[3,4-b]indole-1,4'-cyclohexane]-2-yl]-3-phenylprop-2-en-1-one Chemical compound C1C(F)(F)C(N(C)C)(C=2C=C(F)C=CC=2)CCC1(C1=C(C2=CC=CC=C2N1)CC1)N1C(=O)\C=C\C1=CC=CC=C1 XDUIXKLBEZFBMU-FOCLMDBBSA-N 0.000 claims description 2
- NWNVIDLCAYEQJL-FOCLMDBBSA-N (e)-1-[1'-(dimethylamino)-2'-fluoro-1'-(3-fluorophenyl)spiro[4,9-dihydro-3h-pyrido[3,4-b]indole-1,4'-cyclohexane]-2-yl]-3-phenylprop-2-en-1-one Chemical compound C1C(F)C(N(C)C)(C=2C=C(F)C=CC=2)CCC1(C1=C(C2=CC=CC=C2N1)CC1)N1C(=O)\C=C\C1=CC=CC=C1 NWNVIDLCAYEQJL-FOCLMDBBSA-N 0.000 claims description 2
- WKWVMYRSWNLYBP-FOCLMDBBSA-N (e)-1-[4'-(dimethylamino)-2',2'-difluoro-4'-(3-fluorophenyl)spiro[4,9-dihydro-3h-pyrido[3,4-b]indole-1,1'-cyclohexane]-2-yl]-3-phenylprop-2-en-1-one Chemical compound FC1(F)CC(N(C)C)(C=2C=C(F)C=CC=2)CCC1(C1=C(C2=CC=CC=C2N1)CC1)N1C(=O)\C=C\C1=CC=CC=C1 WKWVMYRSWNLYBP-FOCLMDBBSA-N 0.000 claims description 2
- RFTGSCXHGGPDDA-FOCLMDBBSA-N (e)-1-[4'-(dimethylamino)-2',6'-difluoro-4'-(3-fluorophenyl)spiro[4,9-dihydro-3h-pyrido[3,4-b]indole-1,1'-cyclohexane]-2-yl]-3-phenylprop-2-en-1-one Chemical compound FC1CC(N(C)C)(C=2C=C(F)C=CC=2)CC(F)C1(C1=C(C2=CC=CC=C2N1)CC1)N1C(=O)\C=C\C1=CC=CC=C1 RFTGSCXHGGPDDA-FOCLMDBBSA-N 0.000 claims description 2
- COWSYUCZXXZURJ-SDNWHVSQSA-N (e)-1-[4'-(dimethylamino)-2',6-difluoro-4'-(3-fluorophenyl)spiro[4,9-dihydro-3h-pyrido[3,4-b]indole-1,1'-cyclohexane]-2-yl]-3-phenylprop-2-en-1-one Chemical compound FC1CC(N(C)C)(C=2C=C(F)C=CC=2)CCC1(C1=C(C2=CC(F)=CC=C2N1)CC1)N1C(=O)\C=C\C1=CC=CC=C1 COWSYUCZXXZURJ-SDNWHVSQSA-N 0.000 claims description 2
- QSIWIUOGISVJRD-FOCLMDBBSA-N (e)-1-[4'-(dimethylamino)-2'-fluoro-4'-(3-fluorophenyl)spiro[4,9-dihydro-3h-pyrido[3,4-b]indole-1,1'-cyclohexane]-2-yl]-3-phenylprop-2-en-1-one Chemical compound FC1CC(N(C)C)(C=2C=C(F)C=CC=2)CCC1(C1=C(C2=CC=CC=C2N1)CC1)N1C(=O)\C=C\C1=CC=CC=C1 QSIWIUOGISVJRD-FOCLMDBBSA-N 0.000 claims description 2
- QERFEDFJCNNUNU-UHFFFAOYSA-N 2',2',6-trifluoro-1'-(3-fluorophenyl)-n,n-dimethylspiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1CC2(C3=C(C4=CC(F)=CC=C4N3)CCN2)CC(F)(F)C1(N(C)C)C1=CC=CC(F)=C1 QERFEDFJCNNUNU-UHFFFAOYSA-N 0.000 claims description 2
- PRYJGPVLQGEIHP-UHFFFAOYSA-N 2',6-difluoro-1'-(3-fluorophenyl)-n,n-dimethylspiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1CC2(C3=C(C4=CC(F)=CC=C4N3)CCN2)CC(F)C1(N(C)C)C1=CC=CC(F)=C1 PRYJGPVLQGEIHP-UHFFFAOYSA-N 0.000 claims description 2
- KRSPNUVHHWJPBX-UHFFFAOYSA-N 2'-[(dimethylamino)methyl]-n,n-dimethyl-1'-phenylspiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound CN(C)CC1CC2(C3=C(C4=CC=CC=C4N3)CCN2)CCC1(N(C)C)C1=CC=CC=C1 KRSPNUVHHWJPBX-UHFFFAOYSA-N 0.000 claims description 2
- VMWCVNRWKYXQMS-UHFFFAOYSA-N 2'-fluoro-1'-(3-fluorophenyl)-n,n-dimethylspiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1CC2(C3=C(C4=CC=CC=C4N3)CCN2)CC(F)C1(N(C)C)C1=CC=CC(F)=C1 VMWCVNRWKYXQMS-UHFFFAOYSA-N 0.000 claims description 2
- JBGGXKNSLOKVFU-UHFFFAOYSA-N 2'-fluoro-n,n-dimethyl-1'-phenylspiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1CC2(C3=C(C4=CC=CC=C4N3)CCN2)CC(F)C1(N(C)C)C1=CC=CC=C1 JBGGXKNSLOKVFU-UHFFFAOYSA-N 0.000 claims description 2
- GCNWPMUGPBWWBO-UHFFFAOYSA-N 2'-fluoro-n,n-dimethyl-1'-phenylspiro[4,9-dihydro-3h-pyrano[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1CC2(C3=C(C4=CC=CC=C4N3)CCO2)CC(F)C1(N(C)C)C1=CC=CC=C1 GCNWPMUGPBWWBO-UHFFFAOYSA-N 0.000 claims description 2
- RJLKEYGXHXIEMB-UHFFFAOYSA-N 2-[5'-(dimethylamino)-5'-phenylspiro[4,9-dihydro-3h-pyrano[3,4-b]indole-1,2'-cyclohexane]-1'-yl]acetonitrile Chemical compound C1CC2(C3=C(C4=CC=CC=C4N3)CCO2)C(CC#N)CC1(N(C)C)C1=CC=CC=C1 RJLKEYGXHXIEMB-UHFFFAOYSA-N 0.000 claims description 2
- MHEHAGBCOANASI-UHFFFAOYSA-N 2-[5'-(dimethylamino)-5'-phenylspiro[4,9-dihydro-3h-pyrano[3,4-b]indole-1,2'-cyclohexane]-1'-yl]ethanol Chemical compound C1CC2(C3=C(C4=CC=CC=C4N3)CCO2)C(CCO)CC1(N(C)C)C1=CC=CC=C1 MHEHAGBCOANASI-UHFFFAOYSA-N 0.000 claims description 2
- YZTKCOYZTZVEIJ-UHFFFAOYSA-N 3',3'-difluoro-1'-(3-fluorophenyl)-n,n-dimethylspiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1CC2(C3=C(C4=CC=CC=C4N3)CCN2)C(F)(F)CC1(N(C)C)C1=CC=CC(F)=C1 YZTKCOYZTZVEIJ-UHFFFAOYSA-N 0.000 claims description 2
- GLVOEKNNFRACJC-UHFFFAOYSA-N 3',3'-difluoro-n,n-dimethyl-1'-phenylspiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1CC2(C3=C(C4=CC=CC=C4N3)CCN2)C(F)(F)CC1(N(C)C)C1=CC=CC=C1 GLVOEKNNFRACJC-UHFFFAOYSA-N 0.000 claims description 2
- KRZPNWSAXBSKRL-UHFFFAOYSA-N 3',5'-difluoro-1'-(3-fluorophenyl)-n,n-dimethylspiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1C(F)C2(C3=C(C4=CC=CC=C4N3)CCN2)C(F)CC1(N(C)C)C1=CC=CC(F)=C1 KRZPNWSAXBSKRL-UHFFFAOYSA-N 0.000 claims description 2
- MPELBLISKJKROZ-UHFFFAOYSA-N 3',6-difluoro-1'-(3-fluorophenyl)-n,n-dimethylspiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1CC2(C3=C(C4=CC(F)=CC=C4N3)CCN2)C(F)CC1(N(C)C)C1=CC=CC(F)=C1 MPELBLISKJKROZ-UHFFFAOYSA-N 0.000 claims description 2
- PFTQUJMDHFHCOT-UHFFFAOYSA-N 3'-(4-fluorophenyl)-n,n-dimethyl-1'-phenylspiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1C(N(C)C)(C=2C=CC=CC=2)CCC2(C3=C(C4=CC=CC=C4N3)CCN2)C1C1=CC=C(F)C=C1 PFTQUJMDHFHCOT-UHFFFAOYSA-N 0.000 claims description 2
- KKCUMJYKWDYCQU-UHFFFAOYSA-N 3'-[(4-fluorophenyl)methyl]-n,n-dimethyl-1'-phenylspiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1C(N(C)C)(C=2C=CC=CC=2)CCC2(C3=C(C4=CC=CC=C4N3)CCN2)C1CC1=CC=C(F)C=C1 KKCUMJYKWDYCQU-UHFFFAOYSA-N 0.000 claims description 2
- YJTZWNKGTJGABL-UHFFFAOYSA-N 3'-benzyl-n,n-dimethyl-1'-phenylspiro[4,9-dihydro-3h-pyrano[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1C(N(C)C)(C=2C=CC=CC=2)CCC2(C3=C(C4=CC=CC=C4N3)CCO2)C1CC1=CC=CC=C1 YJTZWNKGTJGABL-UHFFFAOYSA-N 0.000 claims description 2
- HNRGFZLGEXVUCB-UHFFFAOYSA-N 3'-fluoro-1'-(3-fluorophenyl)-n,n-dimethylspiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1CC2(C3=C(C4=CC=CC=C4N3)CCN2)C(F)CC1(N(C)C)C1=CC=CC(F)=C1 HNRGFZLGEXVUCB-UHFFFAOYSA-N 0.000 claims description 2
- 208000019901 Anxiety disease Diseases 0.000 claims description 2
- 206010006895 Cachexia Diseases 0.000 claims description 2
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 2
- 208000020401 Depressive disease Diseases 0.000 claims description 2
- 206010012735 Diarrhoea Diseases 0.000 claims description 2
- 208000030814 Eating disease Diseases 0.000 claims description 2
- 208000019454 Feeding and Eating disease Diseases 0.000 claims description 2
- 206010020772 Hypertension Diseases 0.000 claims description 2
- 208000001953 Hypotension Diseases 0.000 claims description 2
- 208000020358 Learning disease Diseases 0.000 claims description 2
- 208000026139 Memory disease Diseases 0.000 claims description 2
- 208000019695 Migraine disease Diseases 0.000 claims description 2
- 208000008589 Obesity Diseases 0.000 claims description 2
- 208000026251 Opioid-Related disease Diseases 0.000 claims description 2
- 208000004880 Polyuria Diseases 0.000 claims description 2
- 208000003251 Pruritus Diseases 0.000 claims description 2
- 206010039966 Senile dementia Diseases 0.000 claims description 2
- 201000001880 Sexual dysfunction Diseases 0.000 claims description 2
- 208000009205 Tinnitus Diseases 0.000 claims description 2
- 206010046543 Urinary incontinence Diseases 0.000 claims description 2
- 208000022531 anorexia Diseases 0.000 claims description 2
- 230000001773 anti-convulsant effect Effects 0.000 claims description 2
- 239000001961 anticonvulsive agent Substances 0.000 claims description 2
- 229960003965 antiepileptics Drugs 0.000 claims description 2
- 239000002249 anxiolytic agent Substances 0.000 claims description 2
- 230000000949 anxiolytic effect Effects 0.000 claims description 2
- 238000011260 co-administration Methods 0.000 claims description 2
- 208000010877 cognitive disease Diseases 0.000 claims description 2
- 206010061428 decreased appetite Diseases 0.000 claims description 2
- 208000035475 disorder Diseases 0.000 claims description 2
- 235000014632 disordered eating Nutrition 0.000 claims description 2
- 239000006185 dispersion Substances 0.000 claims description 2
- 230000035619 diuresis Effects 0.000 claims description 2
- 206010015037 epilepsy Diseases 0.000 claims description 2
- 230000036543 hypotension Effects 0.000 claims description 2
- 230000008991 intestinal motility Effects 0.000 claims description 2
- 201000003723 learning disability Diseases 0.000 claims description 2
- 230000003137 locomotive effect Effects 0.000 claims description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 2
- 206010027599 migraine Diseases 0.000 claims description 2
- 230000037023 motor activity Effects 0.000 claims description 2
- 239000003158 myorelaxant agent Substances 0.000 claims description 2
- UCXKCVSRPRXNKY-UHFFFAOYSA-N n,n,2',3'-tetramethyl-1'-phenylspiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1CC2(C3=C(C4=CC=CC=C4N3)CCN2)C(C)C(C)C1(N(C)C)C1=CC=CC=C1 UCXKCVSRPRXNKY-UHFFFAOYSA-N 0.000 claims description 2
- RYODGLNJVMNULD-UHFFFAOYSA-N n,n,2',3'-tetramethyl-1'-phenylspiro[4,9-dihydro-3h-pyrano[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1CC2(C3=C(C4=CC=CC=C4N3)CCO2)C(C)C(C)C1(N(C)C)C1=CC=CC=C1 RYODGLNJVMNULD-UHFFFAOYSA-N 0.000 claims description 2
- UCTFYYFNWCAFMK-UHFFFAOYSA-N n,n,2',5'-tetramethyl-1'-phenylspiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound CC1CC2(C3=C(C4=CC=CC=C4N3)CCN2)C(C)CC1(N(C)C)C1=CC=CC=C1 UCTFYYFNWCAFMK-UHFFFAOYSA-N 0.000 claims description 2
- SKJFHHTYCHHBBE-UHFFFAOYSA-N n,n,2',5'-tetramethyl-1'-phenylspiro[4,9-dihydro-3h-pyrano[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound CC1CC2(C3=C(C4=CC=CC=C4N3)CCO2)C(C)CC1(N(C)C)C1=CC=CC=C1 SKJFHHTYCHHBBE-UHFFFAOYSA-N 0.000 claims description 2
- RUFLMMQNVCNTJQ-UHFFFAOYSA-N n,n,2',6'-tetramethyl-1'-phenylspiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound CC1CC2(C3=C(C4=CC=CC=C4N3)CCN2)CC(C)C1(N(C)C)C1=CC=CC=C1 RUFLMMQNVCNTJQ-UHFFFAOYSA-N 0.000 claims description 2
- PSRDSDYIWKJTIE-UHFFFAOYSA-N n,n,2',6'-tetramethyl-1'-phenylspiro[4,9-dihydro-3h-pyrano[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound CC1CC2(C3=C(C4=CC=CC=C4N3)CCO2)CC(C)C1(N(C)C)C1=CC=CC=C1 PSRDSDYIWKJTIE-UHFFFAOYSA-N 0.000 claims description 2
- QGZWBJTYAKMGRJ-UHFFFAOYSA-N n,n,2'-trimethyl-1'-phenylspiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound CC1CC2(C3=C(C4=CC=CC=C4N3)CCN2)CCC1(N(C)C)C1=CC=CC=C1 QGZWBJTYAKMGRJ-UHFFFAOYSA-N 0.000 claims description 2
- KRRZOKBQPUYLES-UHFFFAOYSA-N n,n,2'-trimethyl-1'-phenylspiro[4,9-dihydro-3h-pyrano[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound CC1CC2(C3=C(C4=CC=CC=C4N3)CCO2)CCC1(N(C)C)C1=CC=CC=C1 KRRZOKBQPUYLES-UHFFFAOYSA-N 0.000 claims description 2
- YMGSLIMVZOTETA-UHFFFAOYSA-N n,n,3',5'-tetramethyl-1'-phenylspiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1C(C)C2(C3=C(C4=CC=CC=C4N3)CCN2)C(C)CC1(N(C)C)C1=CC=CC=C1 YMGSLIMVZOTETA-UHFFFAOYSA-N 0.000 claims description 2
- SBJZSFPMOHWNID-UHFFFAOYSA-N n,n,3',5'-tetramethyl-1'-phenylspiro[4,9-dihydro-3h-pyrano[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1C(C)C2(C3=C(C4=CC=CC=C4N3)CCO2)C(C)CC1(N(C)C)C1=CC=CC=C1 SBJZSFPMOHWNID-UHFFFAOYSA-N 0.000 claims description 2
- SLURKLDOWUTATD-UHFFFAOYSA-N n,n,3'-trimethyl-1'-phenylspiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1CC2(C3=C(C4=CC=CC=C4N3)CCN2)C(C)CC1(N(C)C)C1=CC=CC=C1 SLURKLDOWUTATD-UHFFFAOYSA-N 0.000 claims description 2
- MYQFKYSMZXDVBP-UHFFFAOYSA-N n,n-dimethyl-1',2'-diphenylspiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C=1C=CC=CC=1C1(N(C)C)CCC2(C3=C(C4=CC=CC=C4N3)CCN2)CC1C1=CC=CC=C1 MYQFKYSMZXDVBP-UHFFFAOYSA-N 0.000 claims description 2
- ZAOBJDLDTDGRGP-UHFFFAOYSA-N n,n-dimethyl-1',2'-diphenylspiro[4,9-dihydro-3h-pyrano[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C=1C=CC=CC=1C1(N(C)C)CCC2(C3=C(C4=CC=CC=C4N3)CCO2)CC1C1=CC=CC=C1 ZAOBJDLDTDGRGP-UHFFFAOYSA-N 0.000 claims description 2
- ACWMLPFQBDSQPW-UHFFFAOYSA-N n,n-dimethyl-3'-methylsulfanyl-1'-phenylspiro[2,3,4,9-tetrahydropyrido[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1CC2(C3=C(C4=CC=CC=C4N3)CCN2)C(SC)CC1(N(C)C)C1=CC=CC=C1 ACWMLPFQBDSQPW-UHFFFAOYSA-N 0.000 claims description 2
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims description 2
- 230000004770 neurodegeneration Effects 0.000 claims description 2
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 2
- 239000002858 neurotransmitter agent Substances 0.000 claims description 2
- 230000001777 nootropic effect Effects 0.000 claims description 2
- 235000020824 obesity Nutrition 0.000 claims description 2
- 239000000014 opioid analgesic Substances 0.000 claims description 2
- 231100000872 sexual dysfunction Toxicity 0.000 claims description 2
- 231100000886 tinnitus Toxicity 0.000 claims description 2
- QYAKJKQHHRPYMN-SDNWHVSQSA-N (e)-1-[4'-(dimethylamino)-2',2',6-trifluoro-4'-(3-fluorophenyl)spiro[4,9-dihydro-3h-pyrido[3,4-b]indole-1,1'-cyclohexane]-2-yl]-3-phenylprop-2-en-1-one Chemical compound FC1(F)CC(N(C)C)(C=2C=C(F)C=CC=2)CCC1(C1=C(C2=CC(F)=CC=C2N1)CC1)N1C(=O)\C=C\C1=CC=CC=C1 QYAKJKQHHRPYMN-SDNWHVSQSA-N 0.000 claims 1
- BSVSFYLZURLGTN-SDNWHVSQSA-N (e)-1-[4'-(dimethylamino)-2',6,6'-trifluoro-4'-(3-fluorophenyl)spiro[4,9-dihydro-3h-pyrido[3,4-b]indole-1,1'-cyclohexane]-2-yl]-3-phenylprop-2-en-1-one Chemical compound FC1CC(N(C)C)(C=2C=C(F)C=CC=2)CC(F)C1(C1=C(C2=CC(F)=CC=C2N1)CC1)N1C(=O)\C=C\C1=CC=CC=C1 BSVSFYLZURLGTN-SDNWHVSQSA-N 0.000 claims 1
- 208000024891 symptom Diseases 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 162
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 147
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 102
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 88
- 239000012074 organic phase Substances 0.000 description 71
- 239000000243 solution Substances 0.000 description 47
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 44
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 44
- 125000001309 chloro group Chemical group Cl* 0.000 description 42
- 239000007787 solid Substances 0.000 description 39
- 239000008346 aqueous phase Substances 0.000 description 38
- 239000011541 reaction mixture Substances 0.000 description 38
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 36
- 125000004093 cyano group Chemical group *C#N 0.000 description 31
- 238000000034 method Methods 0.000 description 31
- 125000001246 bromo group Chemical group Br* 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 27
- 238000002844 melting Methods 0.000 description 27
- 230000008018 melting Effects 0.000 description 27
- 239000002904 solvent Substances 0.000 description 27
- 238000004587 chromatography analysis Methods 0.000 description 26
- 150000002576 ketones Chemical class 0.000 description 26
- 239000002244 precipitate Substances 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 25
- 238000000746 purification Methods 0.000 description 24
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 23
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 18
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 18
- 235000019341 magnesium sulphate Nutrition 0.000 description 18
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 17
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- 229910052938 sodium sulfate Inorganic materials 0.000 description 17
- 235000011152 sodium sulphate Nutrition 0.000 description 17
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 14
- 239000003153 chemical reaction reagent Substances 0.000 description 13
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical class C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- 125000000217 alkyl group Chemical group 0.000 description 12
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 11
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 239000007832 Na2SO4 Substances 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- 230000005764 inhibitory process Effects 0.000 description 10
- APJYDQYYACXCRM-UHFFFAOYSA-N tryptamine Chemical compound C1=CC=C2C(CCN)=CNC2=C1 APJYDQYYACXCRM-UHFFFAOYSA-N 0.000 description 10
- DEOPEYZZVGZQFC-UHFFFAOYSA-N 4-(dimethylamino)-4-phenylcyclohexan-1-one Chemical compound C=1C=CC=CC=1C1(N(C)C)CCC(=O)CC1 DEOPEYZZVGZQFC-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 9
- 230000002378 acidificating effect Effects 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 9
- 108020001612 μ-opioid receptors Proteins 0.000 description 9
- KDWHIPFNEMGVPW-UHFFFAOYSA-N 4-(dimethylamino)-2-fluoro-4-phenylcyclohexan-1-one Chemical compound C=1C=CC=CC=1C1(N(C)C)CCC(=O)C(F)C1 KDWHIPFNEMGVPW-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 108010020615 nociceptin receptor Proteins 0.000 description 8
- 229940005483 opioid analgesics Drugs 0.000 description 8
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 7
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 229960001701 chloroform Drugs 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 6
- 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 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 150000001934 cyclohexanes Chemical class 0.000 description 6
- 229940043279 diisopropylamine Drugs 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 239000012047 saturated solution Substances 0.000 description 6
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 208000000094 Chronic Pain Diseases 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 239000012670 alkaline solution Substances 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 235000019270 ammonium chloride Nutrition 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 5
- 150000002902 organometallic compounds Chemical class 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 229910052723 transition metal Inorganic materials 0.000 description 5
- 150000003624 transition metals Chemical class 0.000 description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 4
- KMLPEYHLAKSCGX-UHFFFAOYSA-N 2-aminocyclohexan-1-one Chemical class NC1CCCCC1=O KMLPEYHLAKSCGX-UHFFFAOYSA-N 0.000 description 4
- UVCJYZLJGYDDNQ-UHFFFAOYSA-N 4-(dimethylamino)-2-[(3-fluorophenyl)methyl]-4-phenylcyclohexan-1-one Chemical compound C1C(N(C)C)(C=2C=CC=CC=2)CCC(=O)C1CC1=CC=CC(F)=C1 UVCJYZLJGYDDNQ-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- 229910010084 LiAlH4 Inorganic materials 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 208000005298 acute pain Diseases 0.000 description 4
- 150000001450 anions Chemical class 0.000 description 4
- 239000012300 argon atmosphere Substances 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 230000027455 binding Effects 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- OILAIQUEIWYQPH-UHFFFAOYSA-N cyclohexane-1,2-dione Chemical compound O=C1CCCCC1=O OILAIQUEIWYQPH-UHFFFAOYSA-N 0.000 description 4
- 238000001212 derivatisation Methods 0.000 description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 150000002466 imines Chemical class 0.000 description 4
- 239000012280 lithium aluminium hydride Substances 0.000 description 4
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- 208000004296 neuralgia Diseases 0.000 description 4
- 230000002981 neuropathic effect Effects 0.000 description 4
- 208000021722 neuropathic pain Diseases 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- TUYRDYNJCNPKJB-UHFFFAOYSA-N 2-benzyl-4-(dimethylamino)-4-phenylcyclohexan-1-one Chemical compound C1C(N(C)C)(C=2C=CC=CC=2)CCC(=O)C1CC1=CC=CC=C1 TUYRDYNJCNPKJB-UHFFFAOYSA-N 0.000 description 3
- BATOFUOTFXUVEN-UHFFFAOYSA-N 4-(dimethylamino)-2-methyl-4-phenylcyclohexan-1-one Chemical compound C1CC(=O)C(C)CC1(N(C)C)C1=CC=CC=C1 BATOFUOTFXUVEN-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 150000001345 alkine derivatives Chemical class 0.000 description 3
- 230000004075 alteration Effects 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 125000002757 morpholinyl group Chemical group 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000011049 pearl Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 239000011877 solvent mixture Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 125000001544 thienyl group Chemical group 0.000 description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical class OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 3
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 2
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 2
- QLUYYYSFMIWXRZ-UHFFFAOYSA-N 2-[[5-(dimethylamino)-2-oxo-5-phenylcyclohexyl]methyl]isoindole-1,3-dione Chemical compound C1CC(=O)C(CN2C(C3=CC=CC=C3C2=O)=O)CC1(N(C)C)C1=CC=CC=C1 QLUYYYSFMIWXRZ-UHFFFAOYSA-N 0.000 description 2
- NJLYCNZOTQCQMC-UHFFFAOYSA-N 2-hexa-2,4-diynyl-1,6-dioxaspiro[4.4]non-3-ene Chemical compound C1=CC(CC#CC#CC)OC11OCCC1 NJLYCNZOTQCQMC-UHFFFAOYSA-N 0.000 description 2
- OWUSZQBIDNFEGY-UHFFFAOYSA-N 3-[5-(dimethylamino)-2-oxo-5-phenylcyclohexyl]propanenitrile Chemical compound C=1C=CC=CC=1C1(N(C)C)CCC(=O)C(CCC#N)C1 OWUSZQBIDNFEGY-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- GUUVPOWQJOLRAS-UHFFFAOYSA-N Diphenyl disulfide Chemical compound C=1C=CC=CC=1SSC1=CC=CC=C1 GUUVPOWQJOLRAS-UHFFFAOYSA-N 0.000 description 2
- 206010013710 Drug interaction Diseases 0.000 description 2
- 102100021469 Equilibrative nucleoside transporter 1 Human genes 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- 230000005526 G1 to G0 transition Effects 0.000 description 2
- 101000822020 Homo sapiens Equilibrative nucleoside transporter 1 Proteins 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 208000004454 Hyperalgesia Diseases 0.000 description 2
- 208000035154 Hyperesthesia Diseases 0.000 description 2
- 206010065390 Inflammatory pain Diseases 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 108090000137 Opioid Receptors Proteins 0.000 description 2
- 102000003840 Opioid Receptors Human genes 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000006929 Pictet-Spengler synthesis reaction Methods 0.000 description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 238000005575 aldol reaction Methods 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000001118 alkylidene group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 238000005576 amination reaction Methods 0.000 description 2
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 2
- 125000005219 aminonitrile group Chemical group 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 239000012964 benzotriazole Substances 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 150000005690 diesters Chemical class 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000012039 electrophile Substances 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000003682 fluorination reaction Methods 0.000 description 2
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 2
- 230000033444 hydroxylation Effects 0.000 description 2
- 238000005805 hydroxylation reaction Methods 0.000 description 2
- PSCMQHVBLHHWTO-UHFFFAOYSA-K indium(iii) chloride Chemical compound Cl[In](Cl)Cl PSCMQHVBLHHWTO-UHFFFAOYSA-K 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 102000051367 mu Opioid Receptors Human genes 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000003791 organic solvent mixture Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- NWVVVBRKAWDGAB-UHFFFAOYSA-N p-methoxyphenol Chemical compound COC1=CC=C(O)C=C1 NWVVVBRKAWDGAB-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 2
- 229910000105 potassium hydride Inorganic materials 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 238000006268 reductive amination reaction Methods 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 239000012363 selectfluor Substances 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 150000003852 triazoles Chemical class 0.000 description 2
- 238000001665 trituration Methods 0.000 description 2
- 230000009278 visceral effect Effects 0.000 description 2
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 2
- AUEWUQZCOOYAKM-SDNWHVSQSA-N (e)-1-[1'-(dimethylamino)-2',6-difluoro-1'-(3-fluorophenyl)spiro[4,9-dihydro-3h-pyrido[3,4-b]indole-1,4'-cyclohexane]-2-yl]-3-phenylprop-2-en-1-one Chemical compound C1C(F)C(N(C)C)(C=2C=C(F)C=CC=2)CCC1(C1=C(C2=CC(F)=CC=C2N1)CC1)N1C(=O)\C=C\C1=CC=CC=C1 AUEWUQZCOOYAKM-SDNWHVSQSA-N 0.000 description 1
- WOGITNXCNOTRLK-VOTSOKGWSA-N (e)-3-phenylprop-2-enoyl chloride Chemical compound ClC(=O)\C=C\C1=CC=CC=C1 WOGITNXCNOTRLK-VOTSOKGWSA-N 0.000 description 1
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- FHGWEHGZBUBQKL-UHFFFAOYSA-N 1,2-benzothiazepine Chemical compound S1N=CC=CC2=CC=CC=C12 FHGWEHGZBUBQKL-UHFFFAOYSA-N 0.000 description 1
- KPZGRMZPZLOPBS-UHFFFAOYSA-N 1,3-dichloro-2,2-bis(chloromethyl)propane Chemical compound ClCC(CCl)(CCl)CCl KPZGRMZPZLOPBS-UHFFFAOYSA-N 0.000 description 1
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- SCBZBMXPJYMXRC-UHFFFAOYSA-N 1-(bromomethyl)-3-fluorobenzene Chemical compound FC1=CC=CC(CBr)=C1 SCBZBMXPJYMXRC-UHFFFAOYSA-N 0.000 description 1
- UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical compound C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000001617 2,3-dimethoxy phenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- FFFIRKXTFQCCKJ-UHFFFAOYSA-N 2,4,6-trimethylbenzoic acid Chemical compound CC1=CC(C)=C(C(O)=O)C(C)=C1 FFFIRKXTFQCCKJ-UHFFFAOYSA-N 0.000 description 1
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 1
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 1
- MNELAFNGGZMCMI-UHFFFAOYSA-N 2-(1h-pyrrolo[2,3-b]pyridin-3-yl)ethanol Chemical compound C1=CC=C2C(CCO)=CNC2=N1 MNELAFNGGZMCMI-UHFFFAOYSA-N 0.000 description 1
- UUSLLECLCKTJQF-UHFFFAOYSA-N 2-(bromomethyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CBr)C(=O)C2=C1 UUSLLECLCKTJQF-UHFFFAOYSA-N 0.000 description 1
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 1
- ZUYKJZQOPXDNOK-UHFFFAOYSA-N 2-(ethylamino)-2-thiophen-2-ylcyclohexan-1-one;hydrochloride Chemical class Cl.C=1C=CSC=1C1(NCC)CCCCC1=O ZUYKJZQOPXDNOK-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- FZZMTSNZRBFGGU-UHFFFAOYSA-N 2-chloro-7-fluoroquinazolin-4-amine Chemical compound FC1=CC=C2C(N)=NC(Cl)=NC2=C1 FZZMTSNZRBFGGU-UHFFFAOYSA-N 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- RCIGPOBMYPKFBY-UHFFFAOYSA-N 2-methoxynaphthalene-1-carboximidamide Chemical compound C1=CC=CC2=C(C(N)=N)C(OC)=CC=C21 RCIGPOBMYPKFBY-UHFFFAOYSA-N 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- VIKBNMWOLLIQPG-UHFFFAOYSA-N 2-methyldecanedioic acid Chemical class OC(=O)C(C)CCCCCCCC(O)=O VIKBNMWOLLIQPG-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- JSIAIROWMJGMQZ-UHFFFAOYSA-N 2h-triazol-4-amine Chemical class NC1=CNN=N1 JSIAIROWMJGMQZ-UHFFFAOYSA-N 0.000 description 1
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 description 1
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- AJHPGXZOIAYYDW-UHFFFAOYSA-N 3-(2-cyanophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)NC(C(O)=O)CC1=CC=CC=C1C#N AJHPGXZOIAYYDW-UHFFFAOYSA-N 0.000 description 1
- UBLAMKHIFZBBSS-UHFFFAOYSA-N 3-Methylbutyl pentanoate Chemical compound CCCCC(=O)OCCC(C)C UBLAMKHIFZBBSS-UHFFFAOYSA-N 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- AJSWOFGOXSEBNS-UHFFFAOYSA-N 3-phenylprop-2-en-1-one Chemical compound O=[C]C=CC1=CC=CC=C1 AJSWOFGOXSEBNS-UHFFFAOYSA-N 0.000 description 1
- BIEUCOBQTXIMBK-UHFFFAOYSA-N 4-(dimethylamino)-4-phenyl-2-thiophen-2-ylcyclohexan-1-one Chemical compound C1C(N(C)C)(C=2C=CC=CC=2)CCC(=O)C1C1=CC=CS1 BIEUCOBQTXIMBK-UHFFFAOYSA-N 0.000 description 1
- ALYNCZNDIQEVRV-PZFLKRBQSA-N 4-amino-3,5-ditritiobenzoic acid Chemical compound [3H]c1cc(cc([3H])c1N)C(O)=O ALYNCZNDIQEVRV-PZFLKRBQSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 125000006519 CCH3 Chemical group 0.000 description 1
- 101100167062 Caenorhabditis elegans chch-3 gene Proteins 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 241000206575 Chondrus crispus Species 0.000 description 1
- 101150065749 Churc1 gene Proteins 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 238000005751 Larock synthesis reaction Methods 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- OKJIRPAQVSHGFK-UHFFFAOYSA-N N-acetylglycine Chemical compound CC(=O)NCC(O)=O OKJIRPAQVSHGFK-UHFFFAOYSA-N 0.000 description 1
- 229920000388 Polyphosphate Chemical class 0.000 description 1
- 102100038239 Protein Churchill Human genes 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 206010038678 Respiratory depression Diseases 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- 108010046516 Wheat Germ Agglutinins Proteins 0.000 description 1
- RSWGJHLUYNHPMX-ONCXSQPRSA-N abietic acid Chemical compound C([C@@H]12)CC(C(C)C)=CC1=CC[C@@H]1[C@]2(C)CCC[C@@]1(C)C(O)=O RSWGJHLUYNHPMX-ONCXSQPRSA-N 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 description 1
- 150000008043 acidic salts Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 1
- 230000003070 anti-hyperalgesia Effects 0.000 description 1
- 230000003502 anti-nociceptive effect Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000005418 aryl aryl group Chemical group 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 238000006254 arylation reaction Methods 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical group N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000005872 benzooxazolyl group Chemical group 0.000 description 1
- 125000005874 benzothiadiazolyl group Chemical group 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- BJFLSHMHTPAZHO-UHFFFAOYSA-N benzotriazole Chemical compound [CH]1C=CC=C2N=NN=C21 BJFLSHMHTPAZHO-UHFFFAOYSA-N 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 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 description 1
- WQPDQJCBHQPNCZ-UHFFFAOYSA-N cyclohexa-2,4-dien-1-one Chemical compound O=C1CC=CC=C1 WQPDQJCBHQPNCZ-UHFFFAOYSA-N 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004856 decahydroquinolinyl group Chemical group N1(CCCC2CCCCC12)* 0.000 description 1
- 125000004855 decalinyl group Chemical group C1(CCCC2CCCCC12)* 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- BCQZXOMGPXTTIC-UHFFFAOYSA-N halothane Chemical compound FC(F)(F)C(Cl)Br BCQZXOMGPXTTIC-UHFFFAOYSA-N 0.000 description 1
- 229960003132 halothane Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- FYAQQULBLMNGAH-UHFFFAOYSA-N hexane-1-sulfonic acid Chemical compound CCCCCCS(O)(=O)=O FYAQQULBLMNGAH-UHFFFAOYSA-N 0.000 description 1
- UYXAWHWODHRRMR-UHFFFAOYSA-N hexobarbital Chemical compound O=C1N(C)C(=O)NC(=O)C1(C)C1=CCCCC1 UYXAWHWODHRRMR-UHFFFAOYSA-N 0.000 description 1
- 229960002456 hexobarbital Drugs 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- ODBLHEXUDAPZAU-UHFFFAOYSA-N isocitric acid Chemical compound OC(=O)C(O)C(C(O)=O)CC(O)=O ODBLHEXUDAPZAU-UHFFFAOYSA-N 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical class [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000002032 methanolic fraction Substances 0.000 description 1
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- XXYDNDDLCYHHNL-UHFFFAOYSA-N n,n,3'-trimethyl-1'-phenylspiro[4,9-dihydro-3h-pyrano[3,4-b]indole-1,4'-cyclohexane]-1'-amine Chemical compound C1CC2(C3=C(C4=CC=CC=C4N3)CCO2)C(C)CC1(N(C)C)C1=CC=CC=C1 XXYDNDDLCYHHNL-UHFFFAOYSA-N 0.000 description 1
- RLKHFSNWQCZBDC-UHFFFAOYSA-N n-(benzenesulfonyl)-n-fluorobenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(F)S(=O)(=O)C1=CC=CC=C1 RLKHFSNWQCZBDC-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 1
- 229960004127 naloxone Drugs 0.000 description 1
- 238000004848 nephelometry Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000001190 organyl group Chemical group 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 239000001205 polyphosphate Chemical class 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- 229920000137 polyphosphoric acid Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000003236 psychic effect Effects 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000004353 pyrazol-1-yl group Chemical group [H]C1=NN(*)C([H])=C1[H] 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- HZXJVDYQRYYYOR-UHFFFAOYSA-K scandium(iii) trifluoromethanesulfonate Chemical compound [Sc+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F HZXJVDYQRYYYOR-UHFFFAOYSA-K 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- JPJIEXKLJOWQQK-UHFFFAOYSA-K trifluoromethanesulfonate;yttrium(3+) Chemical compound [Y+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F JPJIEXKLJOWQQK-UHFFFAOYSA-K 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 208000009935 visceral pain Diseases 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
-
- 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
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- 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
- C07D471/12—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 three hetero rings
- C07D471/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
- C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Psychiatry (AREA)
- Addiction (AREA)
- Pain & Pain Management (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Nutrition Science (AREA)
- Anesthesiology (AREA)
- Hospice & Palliative Care (AREA)
- Child & Adolescent Psychology (AREA)
- Dermatology (AREA)
- Gynecology & Obstetrics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Urology & Nephrology (AREA)
- Obesity (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP08005808 | 2008-03-27 | ||
| EP08005808 | 2008-03-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2371230T3 true ES2371230T3 (es) | 2011-12-28 |
Family
ID=39506563
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES09724314T Active ES2371230T3 (es) | 2008-03-27 | 2009-03-25 | Derivados de ciclohexano espirocíclicos sustituidos. |
Country Status (28)
| Country | Link |
|---|---|
| US (1) | US8293758B2 (enExample) |
| EP (1) | EP2260042B1 (enExample) |
| JP (1) | JP5597188B2 (enExample) |
| KR (1) | KR101615505B1 (enExample) |
| CN (1) | CN102046633B (enExample) |
| AR (1) | AR071068A1 (enExample) |
| AT (1) | ATE525379T1 (enExample) |
| AU (1) | AU2009228647B2 (enExample) |
| BR (1) | BRPI0910607A2 (enExample) |
| CA (1) | CA2719742C (enExample) |
| CL (1) | CL2009000731A1 (enExample) |
| CO (1) | CO6251244A2 (enExample) |
| CY (1) | CY1112095T1 (enExample) |
| DK (1) | DK2260042T3 (enExample) |
| EC (1) | ECSP11010529A (enExample) |
| ES (1) | ES2371230T3 (enExample) |
| HR (1) | HRP20110721T1 (enExample) |
| IL (1) | IL208278A (enExample) |
| MX (1) | MX2010009955A (enExample) |
| NZ (1) | NZ587831A (enExample) |
| PE (1) | PE20091650A1 (enExample) |
| PL (1) | PL2260042T3 (enExample) |
| PT (1) | PT2260042E (enExample) |
| RU (1) | RU2497824C2 (enExample) |
| SI (1) | SI2260042T1 (enExample) |
| TW (1) | TWI450899B (enExample) |
| WO (1) | WO2009118173A1 (enExample) |
| ZA (1) | ZA201007645B (enExample) |
Families Citing this family (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102006033114A1 (de) * | 2006-07-18 | 2008-01-24 | Grünenthal GmbH | Spirocyclische Azaindol-Derivate |
| BRPI0906245A2 (pt) | 2008-03-24 | 2015-06-30 | Medivation Technologies Inc | Composto, método para tratar um distúrbio cognitivo, psicótico, mediado por neurotransmissor ou um distúrbio neuronal em indivíduo, uso de um composto, composição farmacêutica e kit |
| WO2009120717A2 (en) | 2008-03-24 | 2009-10-01 | Medivation Technologies, Inc. | Pyrido [3, 4-b] indoles and methods of use |
| SI2271613T1 (sl) | 2008-03-27 | 2014-08-29 | Grunenthal Gmbh | Hidroksimetilcikloheksilamini |
| US8288430B2 (en) | 2008-03-27 | 2012-10-16 | Grunenthal Gmbh | Spiro(5.5)undecane derivatives |
| AR071066A1 (es) | 2008-03-27 | 2010-05-26 | Gruenenthal Chemie | Derivados de (hetero) aril-ciclohexano |
| RU2532545C2 (ru) | 2008-03-27 | 2014-11-10 | Грюненталь Гмбх | Замещенные производные 4-аминоциклогексана |
| CA2719743A1 (en) | 2008-03-27 | 2009-10-01 | Gruenenthal Gmbh | Substituted cyclohexyldiamines |
| TWI450899B (zh) | 2008-03-27 | 2014-09-01 | 被取代之螺環環已烷衍生物 | |
| CN102711466A (zh) | 2009-09-23 | 2012-10-03 | 梅迪维新技术公司 | 桥连杂环化合物及其使用方法 |
| CA2775328A1 (en) | 2009-09-23 | 2011-03-31 | Medivation Technologies, Inc. | Pyrido[4,3-b]indoles and methods of use |
| UA107943C2 (xx) * | 2009-11-16 | 2015-03-10 | Lilly Co Eli | Сполуки спіропіперидину як антагоністи рецептора orl-1 |
| TWI582092B (zh) * | 2010-07-28 | 2017-05-11 | 歌林達股份有限公司 | 順式－四氫－螺旋（環己烷－１,１’－吡啶［３,４－b］吲哚）－４－胺－衍生物 |
| AU2011287955B2 (en) | 2010-08-04 | 2015-07-09 | Grünenthal GmbH | Pharmaceutical dosage form comprising 6'-fluoro-(N-methyl- or N,N-dimethyl-)-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indol]-4-amine for the treatment of neuropathic pain |
| AR084209A1 (es) * | 2010-12-08 | 2013-05-02 | Gruenenthal Gmbh | Metodo para la sintesis de derivados de aminociclohexanona sustituidos |
| CN103476416B (zh) | 2011-02-18 | 2016-09-21 | 梅迪维新技术公司 | 治疗高血压的化合物和方法 |
| US8835488B2 (en) * | 2011-03-23 | 2014-09-16 | Trevena, Inc. | Opioid receptor ligands and methods of using and making same |
| HRP20161283T1 (hr) * | 2011-12-12 | 2016-11-18 | Grünenthal GmbH | KRUTI OBLICI (1R,4R)-6'-FLUORO-N,N-DIMETIL-4-FENIL-4',9'-DIHIDRO-3'H-SPIRO[CIKLOHEKSAN-1,1'-PIRANO[3,4,b]INDOL]-4-AMIN HIDROKLORIDA |
| TW201607923A (zh) | 2014-07-15 | 2016-03-01 | 歌林達有限公司 | 被取代之氮螺環（４．５）癸烷衍生物 |
| PL3169666T3 (pl) | 2014-07-15 | 2019-03-29 | Grünenthal GmbH | Podstawione pochodne azaspiro(4,5)dekanu |
| US10588889B2 (en) | 2015-12-14 | 2020-03-17 | Trevena, Inc. | Methods of treating hyperalgesia |
| CN116284027B (zh) * | 2023-01-10 | 2025-07-11 | 云南大学 | 一种多取代五环螺吲哚啉衍生物及其制备方法 |
Family Cites Families (56)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1055203A (en) | 1964-09-16 | 1967-01-18 | Ici Ltd | -ß-carboline derivatives, a process for their manufacture, and compositions containing them |
| US4065573A (en) * | 1976-06-03 | 1977-12-27 | The Upjohn Company | 4-Amino-4-phenylcyclohexanone ketal compositions and process of use |
| US4115589A (en) * | 1977-05-17 | 1978-09-19 | The Upjohn Company | Compounds, compositions and method of use |
| US4366172A (en) | 1977-09-29 | 1982-12-28 | The Upjohn Company | 4-Amino-cyclohexanols, their pharmaceutical compositions and methods of use |
| CH643502A5 (de) * | 1980-03-25 | 1984-06-15 | Alusuisse | Metalldose mit membranverschluss. |
| US4291039A (en) * | 1980-08-08 | 1981-09-22 | Miles Laboratories, Inc. | Tetrahydro β-carbolines having anti-hypertensive activity |
| DE3309596A1 (de) * | 1982-08-05 | 1984-04-05 | Basf Ag, 6700 Ludwigshafen | 2-substituierte 1-(3'-aminoalkyl)-1,2,3,4-tetrahydro-ss-carboline, ihre herstellung und verwendung als arzneimittel |
| US5328905A (en) | 1987-07-20 | 1994-07-12 | Duphar International Research B.V. | 8,9-anellated-1,2,3,4-tetrahydro-β-carboline derivatives |
| EP0620222A3 (en) * | 1993-04-14 | 1995-04-12 | Lilly Co Eli | Tetrahydro-beta-carbolines. |
| US5631265A (en) * | 1994-03-11 | 1997-05-20 | Eli Lilly And Company | 8-substituted tetrahydro-beta-carbolines |
| US5861408A (en) * | 1995-05-19 | 1999-01-19 | Eli Lilly And Company | Tetrahydro-Beta-Carbolines |
| GB0012240D0 (en) * | 2000-05-19 | 2000-07-12 | Merck Sharp & Dohme | Therapeutic agents |
| DE10123163A1 (de) | 2001-05-09 | 2003-01-16 | Gruenenthal Gmbh | Substituierte Cyclohexan-1,4-diaminderivate |
| DE10135636A1 (de) | 2001-07-17 | 2003-02-06 | Gruenenthal Gmbh | Substituierte 4-Aminocyclohexanole |
| WO2003008731A1 (en) | 2001-07-18 | 2003-01-30 | Dipiemme Dies And Plastic Machinery S.R.L. | A corrugated/undulated sheet having protuberances in the grooves defined by the corrugations; process and apparatus |
| DE10213051B4 (de) | 2002-03-23 | 2013-03-07 | Grünenthal GmbH | Substituierte 4-Aminocyclohexanole |
| TWI329111B (en) * | 2002-05-24 | 2010-08-21 | X Ceptor Therapeutics Inc | Azepinoindole and pyridoindole derivatives as pharmaceutical agents |
| US7595311B2 (en) * | 2002-05-24 | 2009-09-29 | Exelixis, Inc. | Azepinoindole derivatives as pharmaceutical agents |
| DE10252665A1 (de) | 2002-11-11 | 2004-06-03 | Grünenthal GmbH | 4-Aminomethyl-1-aryl-cyclohexylamin-Derivate |
| DE10252666A1 (de) | 2002-11-11 | 2004-08-05 | Grünenthal GmbH | N-Piperidyl-cyclohexan-Derivate |
| DE10252667A1 (de) * | 2002-11-11 | 2004-05-27 | Grünenthal GmbH | Spirocyclische Cyclohexan-Derivate |
| DE10252650A1 (de) | 2002-11-11 | 2004-05-27 | Grünenthal GmbH | Cyclohexyl-Harnstoff-Derivate |
| AU2003287995A1 (en) * | 2002-11-12 | 2004-06-03 | Grunenthal Gmbh | 4-alkyl/4-alkenyl/4-alkynyl methyl/-1-arylcyclohexylamine derivatives |
| AU2003296564A1 (en) | 2002-11-12 | 2004-06-03 | Grunenthal Gmbh | 4-hydroxymethyl-1-aryl-cyclohexylamine derivatives |
| US20060235012A1 (en) * | 2003-06-16 | 2006-10-19 | Chroma Therapeutics Limited | Carboline and betacarboline derivatives for use as hdac enzyme inhibitors |
| US20070276030A1 (en) * | 2003-08-14 | 2007-11-29 | Wyeth | Pyranobenzothiophene derivatives to treat infection with hepatitis c virus |
| DE10360792A1 (de) * | 2003-12-23 | 2005-07-28 | Grünenthal GmbH | Spirocyclische Cyclohexan-Derivate |
| DE10360793A1 (de) | 2003-12-23 | 2005-07-28 | Grünenthal GmbH | Spirocyclische Cyclohexan-Derivate |
| DE102004023506A1 (de) | 2004-05-10 | 2005-12-01 | Grünenthal GmbH | Kettenverlängerte substituierte Cyclohexyl-1,4-diamin-Derivate |
| DE102004023508A1 (de) | 2004-05-10 | 2005-12-08 | Grünenthal GmbH | Säurederivate substituierter Cyclohexyl-1,4-diamine |
| DE102004023507A1 (de) | 2004-05-10 | 2005-12-01 | Grünenthal GmbH | Substituierte Cyclohexylessigsäure-Derivate |
| DE102004023501A1 (de) | 2004-05-10 | 2005-12-01 | Grünenthal GmbH | Oxosubstituierte Cyclohexyl-1,4-diamin-Derivate |
| DE102004023522A1 (de) | 2004-05-10 | 2005-12-01 | Grünenthal GmbH | Substituierte Cyclohexyl-1,4-diamin-Derivate |
| DE102004023632A1 (de) | 2004-05-10 | 2005-12-08 | Grünenthal GmbH | Substituierte Cyclohexylcarbonsäure-Derivate |
| DE102004023635A1 (de) | 2004-05-10 | 2006-04-13 | Grünenthal GmbH | Heteroarylsubstituierte Cyclohexyl-1,4-diamin-Derivate |
| DE102004039382A1 (de) * | 2004-08-13 | 2006-02-23 | Grünenthal GmbH | Spirocyclische Cyclohexan-Derivate |
| CA2588607A1 (en) | 2004-11-23 | 2006-06-01 | Ptc Therapeutics, Inc. | Carbazole, carboline and indole derivatives useful in the inhibition of vegf production |
| DE102005016460A1 (de) * | 2005-04-11 | 2006-10-19 | Grünenthal GmbH | Spriocyclische Cyclohexanderivate zur Behandlung von Substanzabhängigkeit |
| EP1747779A1 (en) * | 2005-07-28 | 2007-01-31 | Laboratorios Del Dr. Esteve, S.A. | Tetrahydro-b-carbolin-sulfonamide derivatives as 5-HT6 ligands |
| US20070149557A1 (en) * | 2005-11-21 | 2007-06-28 | Amgen Inc. | CXCR3 antagonists |
| DE102005061427A1 (de) | 2005-12-22 | 2007-06-28 | Grünenthal GmbH | Substituierte Oxadiazol-Derivate |
| DE102005061429A1 (de) | 2005-12-22 | 2007-06-28 | Grünenthal GmbH | Substituierte Oxazol-Derivate |
| DE102005061428A1 (de) | 2005-12-22 | 2007-08-16 | Grünenthal GmbH | Substituierte Cyclohexylmethyl-Derivate |
| DE102005061430A1 (de) | 2005-12-22 | 2007-07-05 | Grünenthal GmbH | Substituierte Imidazolin-Derivate |
| DE102006019597A1 (de) | 2006-04-27 | 2007-10-31 | Grünenthal GmbH | Spirocyclische Cyclohexan-Derivate |
| DE102006033109A1 (de) * | 2006-07-18 | 2008-01-31 | Grünenthal GmbH | Substituierte Heteroaryl-Derivate |
| DE102006033114A1 (de) * | 2006-07-18 | 2008-01-24 | Grünenthal GmbH | Spirocyclische Azaindol-Derivate |
| DE102006046745A1 (de) * | 2006-09-29 | 2008-04-03 | Grünenthal GmbH | Gemischte ORL1/µ-Agonisten zur Behandlung von Schmerz |
| DE102007009235A1 (de) * | 2007-02-22 | 2008-09-18 | Grünenthal GmbH | Spirocyclische Cyclohexan-Derivate |
| DE102007009319A1 (de) | 2007-02-22 | 2008-08-28 | Grünenthal GmbH | Spirocyclische Cyclohexan-Derivate |
| AR071066A1 (es) | 2008-03-27 | 2010-05-26 | Gruenenthal Chemie | Derivados de (hetero) aril-ciclohexano |
| CA2719743A1 (en) | 2008-03-27 | 2009-10-01 | Gruenenthal Gmbh | Substituted cyclohexyldiamines |
| SI2271613T1 (sl) | 2008-03-27 | 2014-08-29 | Grunenthal Gmbh | Hidroksimetilcikloheksilamini |
| US8288430B2 (en) | 2008-03-27 | 2012-10-16 | Grunenthal Gmbh | Spiro(5.5)undecane derivatives |
| TWI450899B (zh) | 2008-03-27 | 2014-09-01 | 被取代之螺環環已烷衍生物 | |
| RU2532545C2 (ru) | 2008-03-27 | 2014-11-10 | Грюненталь Гмбх | Замещенные производные 4-аминоциклогексана |
-
2009
- 2009-03-25 TW TW098109648A patent/TWI450899B/zh not_active IP Right Cessation
- 2009-03-25 PL PL09724314T patent/PL2260042T3/pl unknown
- 2009-03-25 AU AU2009228647A patent/AU2009228647B2/en not_active Ceased
- 2009-03-25 NZ NZ587831A patent/NZ587831A/en not_active IP Right Cessation
- 2009-03-25 PT PT09724314T patent/PT2260042E/pt unknown
- 2009-03-25 PE PE2009000443A patent/PE20091650A1/es not_active Application Discontinuation
- 2009-03-25 BR BRPI0910607A patent/BRPI0910607A2/pt not_active IP Right Cessation
- 2009-03-25 ES ES09724314T patent/ES2371230T3/es active Active
- 2009-03-25 JP JP2011501144A patent/JP5597188B2/ja not_active Expired - Fee Related
- 2009-03-25 US US12/410,544 patent/US8293758B2/en not_active Expired - Fee Related
- 2009-03-25 AT AT09724314T patent/ATE525379T1/de active
- 2009-03-25 KR KR1020107024134A patent/KR101615505B1/ko not_active Expired - Fee Related
- 2009-03-25 HR HR20110721T patent/HRP20110721T1/hr unknown
- 2009-03-25 CA CA2719742A patent/CA2719742C/en not_active Expired - Fee Related
- 2009-03-25 DK DK09724314.1T patent/DK2260042T3/da active
- 2009-03-25 CN CN200980119293.2A patent/CN102046633B/zh not_active Expired - Fee Related
- 2009-03-25 CL CL2009000731A patent/CL2009000731A1/es unknown
- 2009-03-25 WO PCT/EP2009/002186 patent/WO2009118173A1/de not_active Ceased
- 2009-03-25 AR ARP090101058A patent/AR071068A1/es unknown
- 2009-03-25 SI SI200930079T patent/SI2260042T1/sl unknown
- 2009-03-25 RU RU2010143437/04A patent/RU2497824C2/ru not_active IP Right Cessation
- 2009-03-25 EP EP09724314A patent/EP2260042B1/de not_active Not-in-force
- 2009-03-25 MX MX2010009955A patent/MX2010009955A/es active IP Right Grant
-
2010
- 2010-09-09 CO CO10111547A patent/CO6251244A2/es active IP Right Grant
- 2010-09-21 IL IL208278A patent/IL208278A/en not_active IP Right Cessation
- 2010-10-06 EC EC2011010529A patent/ECSP11010529A/es unknown
- 2010-10-26 ZA ZA2010/07645A patent/ZA201007645B/en unknown
-
2011
- 2011-11-28 CY CY20111101169T patent/CY1112095T1/el unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2371230T3 (es) | Derivados de ciclohexano espirocíclicos sustituidos. | |
| AU2004312147B2 (en) | Spirocyclic cyclohexane derivatives with affinity for the ORL1-receptor | |
| ES2482108T3 (es) | Hidroximetilciclohexilaminas | |
| RU2470933C2 (ru) | Спироциклические производные циклогексана | |
| ES2433205T3 (es) | Derivados de ciclohexano espirocíclicos | |
| US20050187281A1 (en) | Spirocyclic cyclohexane derivatives | |
| ES2375543T3 (es) | Derivados de espiro(5.5)undecano. | |
| ES2544488T3 (es) | Derivados de (hetero)aril-ciclohexano | |
| EP3169666B1 (en) | Substituted azaspiro(4.5)decane derivatives | |
| JP6490187B2 (ja) | 置換アザスピロ（４．５）デカン誘導体 | |
| HK1235783B (en) | Substituted azaspiro(4.5)decane derivatives | |
| HK1235783A1 (en) | Substituted azaspiro(4.5)decane derivatives |