WO2004089922A2 - Inhibiteurs des canaux calciques comprenant du benzhydryle espace de la piperazine - Google Patents
Inhibiteurs des canaux calciques comprenant du benzhydryle espace de la piperazine Download PDFInfo
- Publication number
- WO2004089922A2 WO2004089922A2 PCT/CA2004/000539 CA2004000539W WO2004089922A2 WO 2004089922 A2 WO2004089922 A2 WO 2004089922A2 CA 2004000539 W CA2004000539 W CA 2004000539W WO 2004089922 A2 WO2004089922 A2 WO 2004089922A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- phenyl
- fluoro
- bis
- piperazin
- hexyl
- Prior art date
Links
- 102000003922 Calcium Channels Human genes 0.000 title claims abstract description 35
- 108090000312 Calcium Channels Proteins 0.000 title claims abstract description 35
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 title claims abstract description 19
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 title description 12
- 239000003112 inhibitor Substances 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 121
- 230000000694 effects Effects 0.000 claims abstract description 27
- 125000004193 piperazinyl group Chemical group 0.000 claims abstract description 9
- 108091006146 Channels Proteins 0.000 claims description 42
- 239000000203 mixture Substances 0.000 claims description 37
- 125000001424 substituent group Chemical group 0.000 claims description 32
- 229910052757 nitrogen Inorganic materials 0.000 claims description 28
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 21
- 125000005842 heteroatom Chemical group 0.000 claims description 17
- 125000003342 alkenyl group Chemical group 0.000 claims description 15
- 125000005843 halogen group Chemical group 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 229910052717 sulfur Inorganic materials 0.000 claims description 14
- 125000000304 alkynyl group Chemical group 0.000 claims description 12
- 125000005647 linker group Chemical group 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 7
- 125000002947 alkylene group Chemical group 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 230000002452 interceptive effect Effects 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000005018 aryl alkenyl group Chemical group 0.000 claims description 3
- 229910001424 calcium ion Inorganic materials 0.000 claims description 3
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims 2
- KWVFXCVHYOLFNX-UHFFFAOYSA-N 1-(1,3-benzodioxol-5-ylmethyl)-4-[6,6-bis(4-fluorophenyl)hexyl]piperazine Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCCCN1CCN(CC=2C=C3OCOC3=CC=2)CC1 KWVFXCVHYOLFNX-UHFFFAOYSA-N 0.000 claims 1
- LIYFZWGHCBXXMR-UHFFFAOYSA-N 1-[4-(1,3-benzothiazol-2-yl)piperazin-1-yl]-6,6-bis(4-fluorophenyl)hexan-1-one Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCCC(=O)N1CCN(C=2SC3=CC=CC=C3N=2)CC1 LIYFZWGHCBXXMR-UHFFFAOYSA-N 0.000 claims 1
- BXQXDBCUCOHWAV-UHFFFAOYSA-N 1-[4-(2-anilinoethyl)piperazin-1-yl]-6,6-bis(4-fluorophenyl)hexan-1-one Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCCC(=O)N1CCN(CCNC=2C=CC=CC=2)CC1 BXQXDBCUCOHWAV-UHFFFAOYSA-N 0.000 claims 1
- DRBJWKBCCWABCG-UHFFFAOYSA-N 1-[4-(3,4-dimethoxybenzoyl)piperazin-1-yl]-6,6-bis(4-fluorophenyl)hexan-1-one Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)N1CCN(C(=O)CCCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 DRBJWKBCCWABCG-UHFFFAOYSA-N 0.000 claims 1
- PJBAXJSEDXDPOU-UHFFFAOYSA-N 1-[4-(3,5-ditert-butylbenzoyl)piperazin-1-yl]-6,6-bis(4-fluorophenyl)hexan-1-one Chemical compound CC(C)(C)C1=CC(C(C)(C)C)=CC(C(=O)N2CCN(CC2)C(=O)CCCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)=C1 PJBAXJSEDXDPOU-UHFFFAOYSA-N 0.000 claims 1
- HCCUPFWMVFHHQT-UHFFFAOYSA-N 1-[4-(4-bromobenzoyl)piperazin-1-yl]-6,6-bis(4-fluorophenyl)hexan-1-one Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCCC(=O)N1CCN(C(=O)C=2C=CC(Br)=CC=2)CC1 HCCUPFWMVFHHQT-UHFFFAOYSA-N 0.000 claims 1
- WHRDRCYBGWDOEN-UHFFFAOYSA-N 1-[4-(4-tert-butylbenzoyl)piperazin-1-yl]-6,6-bis(4-fluorophenyl)hexan-1-one Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)N1CCN(C(=O)CCCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 WHRDRCYBGWDOEN-UHFFFAOYSA-N 0.000 claims 1
- SNXMRAJPZLZZFT-UHFFFAOYSA-N 1-[4-[2-(2,4-dichlorophenoxy)ethyl]piperazin-1-yl]-6,6-bis(4-fluorophenyl)hexan-1-one Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCCC(=O)N1CCN(CCOC=2C(=CC(Cl)=CC=2)Cl)CC1 SNXMRAJPZLZZFT-UHFFFAOYSA-N 0.000 claims 1
- PSRGIXGZLGGOSO-UHFFFAOYSA-N 1-[4-[2-(2,4-difluorophenoxy)ethyl]piperazin-1-yl]-6,6-bis(4-fluorophenyl)hexan-1-one Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCCC(=O)N1CCN(CCOC=2C(=CC(F)=CC=2)F)CC1 PSRGIXGZLGGOSO-UHFFFAOYSA-N 0.000 claims 1
- VIAUSJSHIODTCE-UHFFFAOYSA-N 1-[4-[2-(3,4-dimethoxyphenoxy)ethyl]piperazin-1-yl]-6,6-bis(4-fluorophenyl)hexan-1-one Chemical compound C1=C(OC)C(OC)=CC=C1OCCN1CCN(C(=O)CCCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 VIAUSJSHIODTCE-UHFFFAOYSA-N 0.000 claims 1
- CPTKYPFGVHVBBO-UHFFFAOYSA-N 1-[4-[2-(benzylamino)ethyl]piperazin-1-yl]-6,6-bis(4-fluorophenyl)hexan-1-one Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCCC(=O)N1CCN(CCNCC=2C=CC=CC=2)CC1 CPTKYPFGVHVBBO-UHFFFAOYSA-N 0.000 claims 1
- VIASYJOUNFCJCN-UHFFFAOYSA-N 1-[4-[2-[(4-chlorophenyl)methylamino]ethyl]piperazin-1-yl]-6,6-bis(4-fluorophenyl)hexan-1-one Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCCC(=O)N1CCN(CCNCC=2C=CC(Cl)=CC=2)CC1 VIASYJOUNFCJCN-UHFFFAOYSA-N 0.000 claims 1
- CDYDWCPPDZIFJI-UHFFFAOYSA-N 1-[4-[2-[(4-tert-butylphenyl)methylamino]ethyl]piperazin-1-yl]-6,6-bis(4-fluorophenyl)hexan-1-one Chemical compound C1=CC(C(C)(C)C)=CC=C1CNCCN1CCN(C(=O)CCCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 CDYDWCPPDZIFJI-UHFFFAOYSA-N 0.000 claims 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims 1
- LSMCZRHVZVUYQM-UHFFFAOYSA-N 2-[2-[4-[6,6-bis(4-fluorophenyl)hexyl]piperazin-1-yl]ethylsulfanyl]-1,3-benzothiazole Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCCCN1CCN(CCSC=2SC3=CC=CC=C3N=2)CC1 LSMCZRHVZVUYQM-UHFFFAOYSA-N 0.000 claims 1
- MBLRTKXFRMCWNN-UHFFFAOYSA-N 2-[4-[6,6-bis(4-fluorophenyl)hexyl]piperazin-1-yl]-1,3-benzothiazole Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCCCN1CCN(C=2SC3=CC=CC=C3N=2)CC1 MBLRTKXFRMCWNN-UHFFFAOYSA-N 0.000 claims 1
- NAYFHNYQVWMGPO-UHFFFAOYSA-N 2-[4-[6,6-bis(4-fluorophenyl)hexyl]piperazin-1-yl]-n-[(3,4,5-trimethoxyphenyl)methyl]ethanamine Chemical compound COC1=C(OC)C(OC)=CC(CNCCN2CCN(CCCCCC(C=3C=CC(F)=CC=3)C=3C=CC(F)=CC=3)CC2)=C1 NAYFHNYQVWMGPO-UHFFFAOYSA-N 0.000 claims 1
- ILKLNJALSWEXDH-UHFFFAOYSA-N 2-[4-[6,6-bis(4-fluorophenyl)hexyl]piperazin-1-yl]pyrimidine Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCCCN1CCN(C=2N=CC=CN=2)CC1 ILKLNJALSWEXDH-UHFFFAOYSA-N 0.000 claims 1
- PRFCNFBEYSWBGY-UHFFFAOYSA-N 2-[4-[[4-[6,6-bis(4-fluorophenyl)hexyl]piperazin-1-yl]methyl]-2,6-ditert-butylphenoxy]-n,n-dimethylethanamine Chemical compound C1=C(C(C)(C)C)C(OCCN(C)C)=C(C(C)(C)C)C=C1CN1CCN(CCCCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 PRFCNFBEYSWBGY-UHFFFAOYSA-N 0.000 claims 1
- ITSLOYOUMFJGNK-UHFFFAOYSA-N 4-[6,6-bis(4-fluorophenyl)hexanoyl]-1-(3,5-ditert-butyl-4-methoxybenzoyl)piperazin-2-one Chemical compound C1=C(C(C)(C)C)C(OC)=C(C(C)(C)C)C=C1C(=O)N1C(=O)CN(C(=O)CCCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 ITSLOYOUMFJGNK-UHFFFAOYSA-N 0.000 claims 1
- COKCFPZZAWMJSF-UHFFFAOYSA-N 4-[6,6-bis(4-fluorophenyl)hexanoyl]-1-[(3,4,5-trimethoxyphenyl)methyl]piperazin-2-one Chemical compound COC1=C(OC)C(OC)=CC(CN2C(CN(CC2)C(=O)CCCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)=O)=C1 COKCFPZZAWMJSF-UHFFFAOYSA-N 0.000 claims 1
- KHACYUFNZGHCOQ-UHFFFAOYSA-N 4-[6,6-bis(4-fluorophenyl)hexanoyl]-1-[(3,5-ditert-butyl-4-methoxyphenyl)methyl]piperazin-2-one Chemical compound C1=C(C(C)(C)C)C(OC)=C(C(C)(C)C)C=C1CN1C(=O)CN(C(=O)CCCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 KHACYUFNZGHCOQ-UHFFFAOYSA-N 0.000 claims 1
- VHUOZRBECXGDFH-UHFFFAOYSA-N 4-[6,6-bis(4-fluorophenyl)hexanoyl]-1-[2-(4-fluorophenoxy)ethyl]piperazin-2-one Chemical compound C1=CC(F)=CC=C1OCCN1C(=O)CN(C(=O)CCCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 VHUOZRBECXGDFH-UHFFFAOYSA-N 0.000 claims 1
- PHYMYYKBDVGTRI-UHFFFAOYSA-N 4-[6,6-bis(4-fluorophenyl)hexyl]-1-[(3,4,5-trimethoxyphenyl)methyl]piperazin-2-one Chemical compound COC1=C(OC)C(OC)=CC(CN2C(CN(CCCCCC(C=3C=CC(F)=CC=3)C=3C=CC(F)=CC=3)CC2)=O)=C1 PHYMYYKBDVGTRI-UHFFFAOYSA-N 0.000 claims 1
- MYIQYYKACSYYJO-UHFFFAOYSA-N 4-[6,6-bis(4-fluorophenyl)hexyl]-1-[(3,4,5-trimethoxyphenyl)methyl]piperazine-2-carboxylic acid Chemical compound COC1=C(OC)C(OC)=CC(CN2C(CN(CCCCCC(C=3C=CC(F)=CC=3)C=3C=CC(F)=CC=3)CC2)C(O)=O)=C1 MYIQYYKACSYYJO-UHFFFAOYSA-N 0.000 claims 1
- HBQGTGNLAHZYCY-UHFFFAOYSA-N 4-[[4-[6,6-bis(4-fluorophenyl)hexyl]piperazin-1-yl]methyl]-2,6-dibromophenol Chemical compound C1=C(Br)C(O)=C(Br)C=C1CN1CCN(CCCCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 HBQGTGNLAHZYCY-UHFFFAOYSA-N 0.000 claims 1
- LGWUJYVVGNWGQS-UHFFFAOYSA-N 4-[[4-[6,6-bis(4-fluorophenyl)hexyl]piperazin-1-yl]methyl]-2,6-dimethoxyphenol Chemical compound COC1=C(O)C(OC)=CC(CN2CCN(CCCCCC(C=3C=CC(F)=CC=3)C=3C=CC(F)=CC=3)CC2)=C1 LGWUJYVVGNWGQS-UHFFFAOYSA-N 0.000 claims 1
- AMMLIKZUXHUTJS-UHFFFAOYSA-N 4-[[4-[6,6-bis(4-fluorophenyl)hexyl]piperazin-1-yl]methyl]-2,6-ditert-butylphenol Chemical compound CC(C)(C)C1=C(O)C(C(C)(C)C)=CC(CN2CCN(CCCCCC(C=3C=CC(F)=CC=3)C=3C=CC(F)=CC=3)CC2)=C1 AMMLIKZUXHUTJS-UHFFFAOYSA-N 0.000 claims 1
- QGSGSHFXGZXJFU-UHFFFAOYSA-N 6,6-bis(4-fluorophenyl)-1-[4-(1-hydroxy-2h-pyridine-4-carbonyl)piperazin-1-yl]hexan-1-one Chemical compound C1=CN(O)CC=C1C(=O)N1CCN(C(=O)CCCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 QGSGSHFXGZXJFU-UHFFFAOYSA-N 0.000 claims 1
- FZJIZFZMYRGIEH-UHFFFAOYSA-N 6,6-bis(4-fluorophenyl)-1-[4-(2-phenoxyethyl)piperazin-1-yl]hexan-1-one Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCCC(=O)N1CCN(CCOC=2C=CC=CC=2)CC1 FZJIZFZMYRGIEH-UHFFFAOYSA-N 0.000 claims 1
- CDIUZULUXKSCMT-UHFFFAOYSA-N 6,6-bis(4-fluorophenyl)-1-[4-(3,4,5-trimethoxybenzoyl)piperazin-1-yl]hex-5-en-1-one Chemical compound COC1=C(OC)C(OC)=CC(C(=O)N2CCN(CC2)C(=O)CCCC=C(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)=C1 CDIUZULUXKSCMT-UHFFFAOYSA-N 0.000 claims 1
- YYKXKCPJBKZHFW-UHFFFAOYSA-N 6,6-bis(4-fluorophenyl)-1-[4-(4-hydroxy-3,5-dimethoxybenzoyl)piperazin-1-yl]hexan-1-one Chemical compound COC1=C(O)C(OC)=CC(C(=O)N2CCN(CC2)C(=O)CCCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)=C1 YYKXKCPJBKZHFW-UHFFFAOYSA-N 0.000 claims 1
- NLTXYPKISRMGHT-UHFFFAOYSA-N 6,6-bis(4-fluorophenyl)-1-[4-(9h-thioxanthen-9-yl)piperazin-1-yl]hexan-1-one Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCCC(=O)N1CCN(C2C3=CC=CC=C3SC3=CC=CC=C32)CC1 NLTXYPKISRMGHT-UHFFFAOYSA-N 0.000 claims 1
- JMYWPLIZPDJINL-UHFFFAOYSA-N 6,6-bis(4-fluorophenyl)-1-[4-[2-(3,4,5-trimethoxyphenoxy)ethyl]piperazin-1-yl]hexan-1-one Chemical compound COC1=C(OC)C(OC)=CC(OCCN2CCN(CC2)C(=O)CCCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)=C1 JMYWPLIZPDJINL-UHFFFAOYSA-N 0.000 claims 1
- ZNBKTONPFWDASM-UHFFFAOYSA-N 6,6-bis(4-fluorophenyl)-1-[4-[2-(4-methoxyphenoxy)ethyl]piperazin-1-yl]hexan-1-one Chemical compound C1=CC(OC)=CC=C1OCCN1CCN(C(=O)CCCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 ZNBKTONPFWDASM-UHFFFAOYSA-N 0.000 claims 1
- UFPIIRIZGUYSCA-UHFFFAOYSA-N 6,6-bis(4-fluorophenyl)-1-[4-[2-[(4-methylphenyl)methylamino]ethyl]piperazin-1-yl]hexan-1-one Chemical compound C1=CC(C)=CC=C1CNCCN1CCN(C(=O)CCCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 UFPIIRIZGUYSCA-UHFFFAOYSA-N 0.000 claims 1
- AEQLFICAFUJLAB-UHFFFAOYSA-N 6,6-bis(4-fluorophenyl)-1-[4-[2-[(4-propan-2-ylphenyl)methylamino]ethyl]piperazin-1-yl]hexan-1-one Chemical compound C1=CC(C(C)C)=CC=C1CNCCN1CCN(C(=O)CCCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 AEQLFICAFUJLAB-UHFFFAOYSA-N 0.000 claims 1
- NCALEGZCXVEGNC-UHFFFAOYSA-N 6,6-bis(4-fluorophenyl)-1-[4-[4-(trifluoromethoxy)benzoyl]piperazin-1-yl]hexan-2-one Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCC(=O)CN1CCN(C(=O)C=2C=CC(OC(F)(F)F)=CC=2)CC1 NCALEGZCXVEGNC-UHFFFAOYSA-N 0.000 claims 1
- SJQWGRRXLOQUBP-UHFFFAOYSA-N 6,6-bis(4-fluorophenyl)-5-hydroxy-1-[4-(3,4,5-trimethoxybenzoyl)piperazin-1-yl]hexan-1-one Chemical compound COC1=C(OC)C(OC)=CC(C(=O)N2CCN(CC2)C(=O)CCCC(O)C(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)=C1 SJQWGRRXLOQUBP-UHFFFAOYSA-N 0.000 claims 1
- JYODDRMVGKQHFY-UHFFFAOYSA-N 6,6-bis(4-fluorophenyl)-6-hydroxy-1-[4-(3,4,5-trimethoxybenzoyl)piperazin-1-yl]hexan-1-one Chemical compound COC1=C(OC)C(OC)=CC(C(=O)N2CCN(CC2)C(=O)CCCCC(O)(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)=C1 JYODDRMVGKQHFY-UHFFFAOYSA-N 0.000 claims 1
- SCHFZKZGOXKHME-UHFFFAOYSA-N 9,9-bis(4-fluorophenyl)-1-[4-[(3,4,5-trimethoxyphenyl)methyl]piperazin-1-yl]nonan-1-one Chemical compound COC1=C(OC)C(OC)=CC(CN2CCN(CC2)C(=O)CCCCCCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)=C1 SCHFZKZGOXKHME-UHFFFAOYSA-N 0.000 claims 1
- HJUAMXQYAKKEQL-UHFFFAOYSA-N 9,9-diphenyl-1-[4-[(3,4,5-trimethoxyphenyl)methyl]piperazin-1-yl]nonan-1-one Chemical compound COC1=C(OC)C(OC)=CC(CN2CCN(CC2)C(=O)CCCCCCCC(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 HJUAMXQYAKKEQL-UHFFFAOYSA-N 0.000 claims 1
- DNDSVBYIWSIFKN-UHFFFAOYSA-N [4-[4-[bis(4-fluorophenyl)methoxy]butyl]piperazin-1-yl]-(3,4,5-trimethoxyphenyl)methanone Chemical compound COC1=C(OC)C(OC)=CC(C(=O)N2CCN(CCCCOC(C=3C=CC(F)=CC=3)C=3C=CC(F)=CC=3)CC2)=C1 DNDSVBYIWSIFKN-UHFFFAOYSA-N 0.000 claims 1
- DQYMRJZVWUVEHQ-UHFFFAOYSA-N [4-[6,6-bis(4-fluorophenyl)hexyl]piperazin-1-yl]-(3,5-ditert-butyl-4-methoxyphenyl)methanone Chemical compound C1=C(C(C)(C)C)C(OC)=C(C(C)(C)C)C=C1C(=O)N1CCN(CCCCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 DQYMRJZVWUVEHQ-UHFFFAOYSA-N 0.000 claims 1
- 125000003277 amino group Chemical group 0.000 claims 1
- LDPMLQFNGFUQGN-UHFFFAOYSA-N ethyl 4-[6,6-bis(4-fluorophenyl)hexyl]-1-[(3,4,5-trimethoxyphenyl)methyl]piperazine-2-carboxylate Chemical compound C1CN(CC=2C=C(OC)C(OC)=C(OC)C=2)C(C(=O)OCC)CN1CCCCCC(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 LDPMLQFNGFUQGN-UHFFFAOYSA-N 0.000 claims 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims 1
- IEZUPBJDCXBYMI-UHFFFAOYSA-N n-[2-[4-[6,6-bis(4-fluorophenyl)hexanoyl]piperazin-1-yl]-2-oxoethyl]-4-chlorobenzamide Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCCC(=O)N1CCN(C(=O)CNC(=O)C=2C=CC(Cl)=CC=2)CC1 IEZUPBJDCXBYMI-UHFFFAOYSA-N 0.000 claims 1
- LHLNEAHNUCOGMT-UHFFFAOYSA-N n-[2-[4-[6,6-bis(4-fluorophenyl)hexanoyl]piperazin-1-yl]-2-oxoethyl]-4-fluorobenzamide Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCCC(=O)N1CCN(C(=O)CNC(=O)C=2C=CC(F)=CC=2)CC1 LHLNEAHNUCOGMT-UHFFFAOYSA-N 0.000 claims 1
- QIZTUXBMCKTHOD-UHFFFAOYSA-N n-[2-[4-[6,6-bis(4-fluorophenyl)hexanoyl]piperazin-1-yl]-2-oxoethyl]-4-methylbenzamide Chemical compound C1=CC(C)=CC=C1C(=O)NCC(=O)N1CCN(C(=O)CCCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 QIZTUXBMCKTHOD-UHFFFAOYSA-N 0.000 claims 1
- KALIUZCWZNSFOJ-UHFFFAOYSA-N n-[2-[4-[6,6-bis(4-fluorophenyl)hexanoyl]piperazin-1-yl]-2-oxoethyl]-4-tert-butylbenzamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)NCC(=O)N1CCN(C(=O)CCCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 KALIUZCWZNSFOJ-UHFFFAOYSA-N 0.000 claims 1
- FWQMYVBRNFZZSJ-UHFFFAOYSA-N n-[2-[4-[6,6-bis(4-fluorophenyl)hexanoyl]piperazin-1-yl]-2-oxoethyl]benzamide Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCCC(=O)N1CCN(C(=O)CNC(=O)C=2C=CC=CC=2)CC1 FWQMYVBRNFZZSJ-UHFFFAOYSA-N 0.000 claims 1
- QARZAPLUFNCNOL-UHFFFAOYSA-N n-[2-[4-[6,6-bis(4-fluorophenyl)hexyl]piperazin-1-yl]-2-oxoethyl]-4-chlorobenzamide Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCCCN1CCN(C(=O)CNC(=O)C=2C=CC(Cl)=CC=2)CC1 QARZAPLUFNCNOL-UHFFFAOYSA-N 0.000 claims 1
- LRIXGBSUPQSJQG-UHFFFAOYSA-N n-[2-[4-[6,6-bis(4-fluorophenyl)hexyl]piperazin-1-yl]-2-oxoethyl]-4-fluorobenzamide Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCCCN1CCN(C(=O)CNC(=O)C=2C=CC(F)=CC=2)CC1 LRIXGBSUPQSJQG-UHFFFAOYSA-N 0.000 claims 1
- ZYBSCUTTXWUZQV-UHFFFAOYSA-N n-[2-[4-[6,6-bis(4-fluorophenyl)hexyl]piperazin-1-yl]-2-oxoethyl]-4-methylbenzamide Chemical compound C1=CC(C)=CC=C1C(=O)NCC(=O)N1CCN(CCCCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 ZYBSCUTTXWUZQV-UHFFFAOYSA-N 0.000 claims 1
- ZCVSFUHOLIUBBT-UHFFFAOYSA-N n-[2-[4-[6,6-bis(4-fluorophenyl)hexyl]piperazin-1-yl]-2-oxoethyl]-4-propan-2-ylbenzamide Chemical compound C1=CC(C(C)C)=CC=C1C(=O)NCC(=O)N1CCN(CCCCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 ZCVSFUHOLIUBBT-UHFFFAOYSA-N 0.000 claims 1
- JYRQTNDCLYJCAF-UHFFFAOYSA-N n-[2-[4-[6,6-bis(4-fluorophenyl)hexyl]piperazin-1-yl]-2-oxoethyl]benzamide Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCCCN1CCN(C(=O)CNC(=O)C=2C=CC=CC=2)CC1 JYRQTNDCLYJCAF-UHFFFAOYSA-N 0.000 claims 1
- WLBFVQZVEJNLKW-UHFFFAOYSA-N n-[2-[4-[6,6-bis(4-fluorophenyl)hexyl]piperazin-1-yl]ethyl]aniline Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCCCN1CCN(CCNC=2C=CC=CC=2)CC1 WLBFVQZVEJNLKW-UHFFFAOYSA-N 0.000 claims 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims 1
- DEOPQFVATDITAI-UHFFFAOYSA-N tert-butyl n-[4-[2-[4-[6,6-bis(4-fluorophenyl)hexanoyl]piperazin-1-yl]ethoxy]-2,3,6-trimethylphenyl]carbamate Chemical compound CC1=C(NC(=O)OC(C)(C)C)C(C)=CC(OCCN2CCN(CC2)C(=O)CCCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)=C1C DEOPQFVATDITAI-UHFFFAOYSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 47
- 239000000243 solution Substances 0.000 description 32
- 238000003786 synthesis reaction Methods 0.000 description 30
- 230000015572 biosynthetic process Effects 0.000 description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 229910001868 water Inorganic materials 0.000 description 21
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- 235000019439 ethyl acetate Nutrition 0.000 description 20
- 239000000047 product Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- 108090000699 N-Type Calcium Channels Proteins 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 17
- 102000004129 N-Type Calcium Channels Human genes 0.000 description 16
- 208000002193 Pain Diseases 0.000 description 16
- 238000004440 column chromatography Methods 0.000 description 15
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 14
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 11
- 102000003691 T-Type Calcium Channels Human genes 0.000 description 11
- 108090000030 T-Type Calcium Channels Proteins 0.000 description 11
- 230000000284 resting effect Effects 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 229910052791 calcium Inorganic materials 0.000 description 10
- 239000011575 calcium Substances 0.000 description 10
- 230000000415 inactivating effect Effects 0.000 description 10
- 230000005764 inhibitory process Effects 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- 230000002779 inactivation Effects 0.000 description 8
- 230000028161 membrane depolarization Effects 0.000 description 8
- 230000036407 pain Effects 0.000 description 8
- 229940127291 Calcium channel antagonist Drugs 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 230000027455 binding Effects 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 125000000623 heterocyclic group Chemical group 0.000 description 6
- 230000036278 prepulse Effects 0.000 description 6
- 206010010904 Convulsion Diseases 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 125000002252 acyl group Chemical group 0.000 description 5
- 239000003963 antioxidant agent Substances 0.000 description 5
- 230000003078 antioxidant effect Effects 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 230000008061 calcium-channel-blocking effect Effects 0.000 description 5
- -1 diphenylhydroxymethyl Chemical group 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 230000001537 neural effect Effects 0.000 description 5
- 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 4
- 208000019901 Anxiety disease Diseases 0.000 description 4
- 0 BC1(*C)C=CC(C(*)(*N2CCN(C)CC2)c2ccccc2)=CC=C1 Chemical compound BC1(*C)C=CC(C(*)(*N2CCN(C)CC2)c2ccccc2)=CC=C1 0.000 description 4
- 208000000094 Chronic Pain Diseases 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000007995 HEPES buffer Substances 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- 208000005298 acute pain Diseases 0.000 description 4
- 210000003050 axon Anatomy 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 4
- AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 description 4
- 239000000480 calcium channel blocker Substances 0.000 description 4
- 230000001419 dependent effect Effects 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 210000003292 kidney cell Anatomy 0.000 description 4
- 229910001629 magnesium chloride Inorganic materials 0.000 description 4
- 208000004296 neuralgia Diseases 0.000 description 4
- 210000002569 neuron Anatomy 0.000 description 4
- 208000021722 neuropathic pain Diseases 0.000 description 4
- 150000004885 piperazines Chemical class 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 238000012216 screening Methods 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- JQSAYKKFZOSZGJ-UHFFFAOYSA-N 1-[bis(4-fluorophenyl)methyl]-4-[(2,3,4-trimethoxyphenyl)methyl]piperazine Chemical compound COC1=C(OC)C(OC)=CC=C1CN1CCN(C(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 JQSAYKKFZOSZGJ-UHFFFAOYSA-N 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 241000282326 Felis catus Species 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000036506 anxiety Effects 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 206010003119 arrhythmia Diseases 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 229910052788 barium Inorganic materials 0.000 description 3
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 206010015037 epilepsy Diseases 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 229950007692 lomerizine Drugs 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- CQHWTFRZWJFWEH-UHFFFAOYSA-N methyl 3,5-ditert-butyl-4-methoxybenzoate Chemical compound COC(=O)C1=CC(C(C)(C)C)=C(OC)C(C(C)(C)C)=C1 CQHWTFRZWJFWEH-UHFFFAOYSA-N 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000003518 presynaptic effect Effects 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- OPRMQYRVKPBTOH-UHFFFAOYSA-N 1-[bromo(dimethoxy)methyl]-2-methoxybenzene Chemical compound COC1=CC=CC=C1C(Br)(OC)OC OPRMQYRVKPBTOH-UHFFFAOYSA-N 0.000 description 2
- JFRGBSJZRDLEDI-UHFFFAOYSA-N 2-(3,4-dimethoxyphenoxy)ethanol Chemical compound COC1=CC=C(OCCO)C=C1OC JFRGBSJZRDLEDI-UHFFFAOYSA-N 0.000 description 2
- XLICOLVSHXFUJG-UHFFFAOYSA-N 3,5-ditert-butyl-4-methoxybenzoic acid Chemical compound COC1=C(C(C)(C)C)C=C(C(O)=O)C=C1C(C)(C)C XLICOLVSHXFUJG-UHFFFAOYSA-N 0.000 description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 2
- SXHGFKOVRIYWNF-UHFFFAOYSA-N 6,6-bis(4-fluorophenyl)-1-piperazin-1-ylhexan-1-one Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCCC(=O)N1CCNCC1 SXHGFKOVRIYWNF-UHFFFAOYSA-N 0.000 description 2
- QOYHHIBFXOOADH-UHFFFAOYSA-N 8-[4,4-bis(4-fluorophenyl)butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCN1CCC2(C(NCN2C=2C=CC=CC=2)=O)CC1 QOYHHIBFXOOADH-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- 208000007848 Alcoholism Diseases 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 206010058019 Cancer Pain Diseases 0.000 description 2
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 2
- 208000001640 Fibromyalgia Diseases 0.000 description 2
- 206010019196 Head injury Diseases 0.000 description 2
- 101001047090 Homo sapiens Potassium voltage-gated channel subfamily H member 2 Proteins 0.000 description 2
- 206010020853 Hypertonic bladder Diseases 0.000 description 2
- 206010065390 Inflammatory pain Diseases 0.000 description 2
- 229930194542 Keto Natural products 0.000 description 2
- 102000004016 L-Type Calcium Channels Human genes 0.000 description 2
- 108090000420 L-Type Calcium Channels Proteins 0.000 description 2
- 208000019695 Migraine disease Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 208000001294 Nociceptive Pain Diseases 0.000 description 2
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 2
- 108010075750 P-Type Calcium Channels Proteins 0.000 description 2
- 108700012358 P/Q-type calcium channel Proteins 0.000 description 2
- 102000050761 P/Q-type calcium channel Human genes 0.000 description 2
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 2
- 208000004550 Postoperative Pain Diseases 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 102100022807 Potassium voltage-gated channel subfamily H member 2 Human genes 0.000 description 2
- 108010010469 Qa-SNARE Proteins Proteins 0.000 description 2
- 201000001880 Sexual dysfunction Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- 102000050389 Syntaxin Human genes 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 229910001626 barium chloride Inorganic materials 0.000 description 2
- WDIHJSXYQDMJHN-UHFFFAOYSA-L barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 2
- 239000005388 borosilicate glass Substances 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 206010013663 drug dependence Diseases 0.000 description 2
- XWZHSYWFWDKJHI-UHFFFAOYSA-N ethyl piperazine-2-carboxylate Chemical compound CCOC(=O)C1CNCCN1 XWZHSYWFWDKJHI-UHFFFAOYSA-N 0.000 description 2
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229960003532 fluspirilene Drugs 0.000 description 2
- 210000002683 foot Anatomy 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 102000040854 high voltage-gated calcium channel activity Human genes 0.000 description 2
- 108091092197 high voltage-gated calcium channel activity Proteins 0.000 description 2
- 210000000548 hind-foot Anatomy 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 206010027599 migraine Diseases 0.000 description 2
- 239000003176 neuroleptic agent Substances 0.000 description 2
- 230000002981 neuropathic effect Effects 0.000 description 2
- 201000001119 neuropathy Diseases 0.000 description 2
- 230000007823 neuropathy Effects 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- 208000020629 overactive bladder Diseases 0.000 description 2
- 208000033808 peripheral neuropathy Diseases 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 231100000872 sexual dysfunction Toxicity 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- 230000001256 tonic effect Effects 0.000 description 2
- 206010044652 trigeminal neuralgia Diseases 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- OLVHMSHRQVRWGR-UHFFFAOYSA-N 1-(4-fluorophenyl)hexan-1-one Chemical compound CCCCCC(=O)C1=CC=C(F)C=C1 OLVHMSHRQVRWGR-UHFFFAOYSA-N 0.000 description 1
- MDLAAYDRRZXJIF-UHFFFAOYSA-N 1-[4,4-bis(4-fluorophenyl)butyl]-4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol Chemical compound C1CC(O)(C=2C=C(C(Cl)=CC=2)C(F)(F)F)CCN1CCCC(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 MDLAAYDRRZXJIF-UHFFFAOYSA-N 0.000 description 1
- SABBVHAYMQDMEA-UHFFFAOYSA-N 1-[6-bromo-1-(4-fluorophenyl)hexyl]-4-fluorobenzene Chemical compound C1=CC(F)=CC=C1C(CCCCCBr)C1=CC=C(F)C=C1 SABBVHAYMQDMEA-UHFFFAOYSA-N 0.000 description 1
- ZBIAKUMOEKILTF-UHFFFAOYSA-N 2-[4-[4,4-bis(4-fluorophenyl)butyl]-1-piperazinyl]-N-(2,6-dimethylphenyl)acetamide Chemical compound CC1=CC=CC(C)=C1NC(=O)CN1CCN(CCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 ZBIAKUMOEKILTF-UHFFFAOYSA-N 0.000 description 1
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 1
- RGHQKFQZGLKBCF-UHFFFAOYSA-N 2-bromoethyl acetate Chemical compound CC(=O)OCCBr RGHQKFQZGLKBCF-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- SMFFZOQLHYIRDA-UHFFFAOYSA-N 3,4-dimethoxyphenol Chemical compound COC1=CC=C(O)C=C1OC SMFFZOQLHYIRDA-UHFFFAOYSA-N 0.000 description 1
- YEXOWHQZWLCHHD-UHFFFAOYSA-N 3,5-ditert-butyl-4-hydroxybenzoic acid Chemical compound CC(C)(C)C1=CC(C(O)=O)=CC(C(C)(C)C)=C1O YEXOWHQZWLCHHD-UHFFFAOYSA-N 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- CBNCLHBPJYBGGT-UHFFFAOYSA-N 4-[6,6-bis(4-fluorophenyl)hexanoyl]piperazin-2-one Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCCC(=O)N1CC(=O)NCC1 CBNCLHBPJYBGGT-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- XZFKSXGKGIPNRR-UHFFFAOYSA-N 6,6-bis(4-fluorophenyl)hex-5-enoic acid Chemical compound C=1C=C(F)C=CC=1C(=CCCCC(=O)O)C1=CC=C(F)C=C1 XZFKSXGKGIPNRR-UHFFFAOYSA-N 0.000 description 1
- KZVMSFVXRMZDSY-UHFFFAOYSA-N 6,6-bis(4-fluorophenyl)hexanoic acid Chemical compound C=1C=C(F)C=CC=1C(CCCCC(=O)O)C1=CC=C(F)C=C1 KZVMSFVXRMZDSY-UHFFFAOYSA-N 0.000 description 1
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- ABDKAPXRBAPSQN-UHFFFAOYSA-N Brenzkatechindimethylether Natural products COC1=CC=CC=C1OC ABDKAPXRBAPSQN-UHFFFAOYSA-N 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010053398 Clonic convulsion Diseases 0.000 description 1
- 208000022497 Cocaine-Related disease Diseases 0.000 description 1
- 108020004635 Complementary DNA Proteins 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
- 108010052832 Cytochromes 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
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 208000011688 Generalised anxiety disease Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- 125000000520 N-substituted aminocarbonyl group Chemical group [*]NC(=O)* 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 206010057852 Nicotine dependence Diseases 0.000 description 1
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 1
- 208000026251 Opioid-Related disease Diseases 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 206010061334 Partial seizures Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 229920005372 Plexiglas® Polymers 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 108010027023 Q-Type Calcium Channels Proteins 0.000 description 1
- 206010041250 Social phobia Diseases 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical class [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000025569 Tobacco Use disease Diseases 0.000 description 1
- 206010043994 Tonic convulsion Diseases 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 206010046543 Urinary incontinence Diseases 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 208000028311 absence seizure Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 208000029650 alcohol withdrawal Diseases 0.000 description 1
- 125000004419 alkynylene group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000002932 anti-schizophrenic effect Effects 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 150000001669 calcium Chemical class 0.000 description 1
- 230000009460 calcium influx Effects 0.000 description 1
- 230000003913 calcium metabolism Effects 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 230000003185 calcium uptake Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- DJKJXRLREATOMF-UHFFFAOYSA-M cesium;methanesulfonate Chemical compound [Cs+].CS([O-])(=O)=O DJKJXRLREATOMF-UHFFFAOYSA-M 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000002800 charge carrier Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- JCZYXTVBWHAWLL-UHFFFAOYSA-N clopimozide Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCN1CCC(N2C(NC3=CC(Cl)=CC=C32)=O)CC1 JCZYXTVBWHAWLL-UHFFFAOYSA-N 0.000 description 1
- 229950007971 clopimozide Drugs 0.000 description 1
- 238000000975 co-precipitation Methods 0.000 description 1
- 201000006145 cocaine dependence Diseases 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 230000009137 competitive binding Effects 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 150000001893 coumarin derivatives Chemical class 0.000 description 1
- 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 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 125000002228 disulfide group Chemical group 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- OENICUBCLXKLJQ-UHFFFAOYSA-N ethyl 2,3-dibromopropanoate Chemical compound CCOC(=O)C(Br)CBr OENICUBCLXKLJQ-UHFFFAOYSA-N 0.000 description 1
- BQBNYVASXCIAOK-UHFFFAOYSA-N ethyl 4-[(3,4,5-trimethoxyphenyl)methyl]piperazine-2-carboxylate Chemical compound C1CNC(C(=O)OCC)CN1CC1=CC(OC)=C(OC)C(OC)=C1 BQBNYVASXCIAOK-UHFFFAOYSA-N 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 208000029364 generalized anxiety disease Diseases 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 125000004404 heteroalkyl group Chemical group 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 208000023589 ischemic disease Diseases 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 229960001941 lidoflazine Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- BRMYZIKAHFEUFJ-UHFFFAOYSA-L mercury diacetate Chemical compound CC(=O)O[Hg]OC(C)=O BRMYZIKAHFEUFJ-UHFFFAOYSA-L 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 201000005040 opiate dependence Diseases 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 238000012402 patch clamp technique Methods 0.000 description 1
- 229960004505 penfluridol Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000005544 phthalimido group Chemical group 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- YVUQSNJEYSNKRX-UHFFFAOYSA-N pimozide Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCN1CCC(N2C(NC3=CC=CC=C32)=O)CC1 YVUQSNJEYSNKRX-UHFFFAOYSA-N 0.000 description 1
- 229960003634 pimozide Drugs 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 201000008914 temporal lobe epilepsy Diseases 0.000 description 1
- JPUIYTJDHCISHS-UHFFFAOYSA-N tert-butyl 4-[6,6-bis(4-fluorophenyl)hexanoyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C(=O)CCCCC(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 JPUIYTJDHCISHS-UHFFFAOYSA-N 0.000 description 1
- YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000010474 transient expression Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- MDYOLVRUBBJPFM-UHFFFAOYSA-N tropolone Chemical group OC1=CC=CC=CC1=O MDYOLVRUBBJPFM-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4515—Non condensed piperidines, e.g. piperocaine having a butyrophenone group in position 1, e.g. haloperidol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D277/70—Sulfur atoms
- C07D277/74—Sulfur atoms substituted by carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D277/82—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Definitions
- the invention relates to compounds useful in treating conditions associated with abnormal calcium channel function. More specifically, the invention concerns compounds containing substituted or unsubstituted derivatives of 6-membered heterocyclic moieties that are useful in treatment of conditions such as stroke and pain.
- the L, N, P and Q-type channels activate at more positive potentials (high voltage activated) and display diverse kinetics and voltage-dependent properties. There is some overlap in biophysical properties ofthe high voltage-activated channels, consequently phannacological profiles are useful to further distinguish them. Whether the Q- and P-type channels are distinct molecular entities is controversial. Several types of calcium conductances do not fall neatly into any ofthe above categories and there is variability of properties even within a category suggesting that additional calcium channels subtypes remain to be classified.
- neuronal high voltage activated calcium channels are heterooligomeric complexes consisting of at least three distinct subunits ( ⁇ i, ⁇ ⁇ and ⁇ ).
- the ⁇ i subunit is the major pore-forming subunit and contains the voltage sensor and binding sites for calcium channel antagonists.
- the mainly extracellular ⁇ x 2 is disulfide-linked to the transmembrane ⁇ subunit and both are derived from the same gene and are proteolytically cleaved in vivo.
- the ⁇ subunit is a nonglycosylated, hydrophilic protein with a high affinity of binding to a cytoplasmic region ofthe ⁇ i subunit.
- a fourth subunit, ⁇ is unique to L-type calcium channels expressed in skeletal muscle T-rubules.
- XI A channels are ofthe P/Q type; ⁇ iB represents N; ⁇ ic, tx'io, CU IF and ⁇ is represent L; OC IE represents a novel type of calcium conductance, and (Xio- ⁇ n represent members ofthe T-type family.
- N-type channels which are mainly localized to neurons, have been disclosed, for example, in U.S. Patent No. 5,623,051, the disclosure of which is incorporated herein by reference.
- N-type channels possess a site for binding syntaxin, a protein anchored in the presynaptic membrane. Blocking this interaction also blocks the presynaptic response to calcium influx.
- syntaxin a protein anchored in the presynaptic membrane. Blocking this interaction also blocks the presynaptic response to calcium influx.
- compounds that block the interaction between syntaxin and this binding site would be useful in neural protection and analgesia.
- Such compounds have the added advantage of enhanced specificity for presynaptic calcium channel effects.
- U.S. Patent No. 5,646,149 describes calcium channel antagonists ofthe formula A-Y-B wherein B contains a piperazine or piperidine ring directly linked to Y.
- A which must be an antioxidant; the piperazine or piperidine itself is said to be important.
- the exemplified compounds contain a benzhydril substituent, based on known calcium channel blockers (see below).
- the antioxidant can be a phenyl group containing methoxy and/or hydroxyl substituents.
- the antioxidant In the few compounds where there is an alkylene chain between the CH to which the two phenyl groups are bound and the heterocycle, the antioxidant must be coupled to the heterocycle through an unsubstituted alkylene and in most of these cases the antioxidant is a bicyclic system. Where the antioxidant can simply be a phenyl moiety coupled through an alkynylene, the linker from the heterocycle to the phenyl moieties contains no more than six atoms in the chain.
- U.S. Patent No. 5,703,071 discloses compounds said to be useful in treating ischemic diseases. A mandatory portion of the molecule is a tropolone residue; among the substituents permitted are piperazine derivatives, including their benzhydril derivatives.
- 5,428,038 discloses compounds which are said to exert a neural protective and antiallergic effect. These compounds are coumarin derivatives which may include derivatives of piperazine and other six-membered heterocycles. A permitted substituent on the heterocycle is diphenylhydroxymethyl.
- Certain compounds containing both benzhydril moieties and piperidine or piperazine are known to be calcium channel antagonists and neuroleptic drugs.
- Gould, R.J., et al, Proc. Natl Acad. Sci. USA (1983) 80:5122-5125 describes antischizophrenic neuroleptic drugs such as lidoflazine, fluspirilene, pimozide, clopimozide, and penfluridol. It has also been shown that fluspirilene binds to sites on L-type calcium channels (King, V.K., et al, J. Biol. Chem.
- Lomerizine as developed by Kanebo, K.K., is a known calcium channel blocker; Lomerizine is, however, not specific for N-type channels. A review of publications concerning Lomerizine is found in Dooley, D., Current Opinion in CPNS Investigational Drugs (1999) 1:116-125.
- the present invention is based on the recognition that the combination of a six- membered heterocyclic ring containing at least one nitrogen said nitrogen coupled through a linker to a benzhydril moiety results in effective calcium channel blocking activity. In some cases enhanced specificity for N-type channels and/or T-type channels, or decreased specificity for L-type channels is shown.
- the compounds are useful for treating stroke and pain and other calcium channel-associated disorders, as further described below. By focusing on these moieties, compounds useful in treating indications associated with calcium channel activity are prepared.
- the invention relates to compounds useful in treating conditions such as stroke, anxiety, overactive bladder, inflammatory bowel disease, head trauma, migraine, chronic, neuropathic and acute pain, epilepsy, hypertension, cardiac arrhythmias, and other indications associated with calcium metabolism, including synaptic calcium channel- mediated functions.
- the compounds ofthe invention are benzhydril derivatives of piperazine with substituents that enhance the calcium channel blocking activity ofthe compounds.
- the invention is directed to compounds ofthe formula
- Ar is phenyl, a six-membered or five-membered ring which is heteroaromatic or a fused aromatic or heteroaromatic system, each of which may optionally be substituted with one or more non-interfering substituents;
- X 1 is a linker containing 1-5 members; n is 0 or 1 ; each R ⁇ R 3 is independently a non-interfering non-hydrogen substituent; each 1 is independently 0-5 ; m is 0-4;
- X 2 is a linker comprising a chain of at least 5 members
- A is H, OR, SR, NR 2 , or halo wherein R is H or lower alkyl (1-6C); with the proviso that
- Ar is an optionally substituted five- or six-membered heteroaryl substituent or an optionally substituted fused aromatic or heteroaromatic substituent;
- n 0;
- X 2 is a chain of at least 6 members
- X contains at least one heteroatom selected from N, S and O;
- A is OR, SR, NR 2 or halo, wherein R is H or lower alkyl (1 -6C) and/or (h) Ar is substituted with at least one t-butyl moiety or at least one substituted alkoxy; and/or
- X 1 includes at least one heteroatom selected from O, N and S.
- the compounds are ofthe formula:
- the invention is directed to the compounds of formula
- R is a carboxylic acid group or ester or amide thereof and Ar, R 2 -R 3 , X 1 , 1, n, X 2 and A are defined as above.
- the substituents R -R , on Ar or on substituted alkoxy independently include, as well, one or more halo, CF 3 , CN, OCF, N0 2 , NR 2 , OR, SR, COOR, and/or CONR 2 , wherein R is H or optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, or arylalkenyl, as described above, and wherein S may be oxidized, and wherein two substituents at adjacent positions on the same ring may form a 3-7 membered saturated or unsaturated ring fused to said substituted ring, said fused ring optionally itself substituted and optionally containing one or more heteroatoms (N, S, O) and wherein said fused ring may further be fused to an additional aromatic moiety, as shown, for instance, in compound P35.
- R 2 and R 3 may form a bond or a bridge between the phenyl groups on which they reside -e.g., R 2 and R 3 together may be a bond or one or more CR 2 groups, an NR group, an O, or S wherein the S is optionally oxidized, or combinations thereof.
- the invention is also directed to methods to modulate calcium channel activity, preferably N-type and T-type channel activity, using the compounds of formula (1) and thus to treat certain undesirable physiological conditions; these conditions are associated with abnormal calcium channel activity.
- the invention is directed to pharmaceutical compositions containing these compounds, and to the use of these compounds for the preparation of medicaments for the treatment of conditions requiring modulation of calcium channel activity.
- Figure 1 shows illustrative compounds ofthe invention.
- Figure 2 is a graph showing the selectivity of compound PI 8 ofthe invention for N, PQ, T and L type channels.
- Figure 3 is a graph showing the selectivity of compound P36 ofthe invention for N, PQ, T and L type channels.
- Figure 4 is a graph showing the selectivity of compound P 104 of the invention for N, PQ, T and L type channels.
- the compounds of formula (1) useful in the methods ofthe invention exert their desirable effects through their ability to modulate the activity of N-type and/or T-type calcium channels. This makes them useful for treatment of certain conditions.
- conditions where antagonist activity is desired are stroke, anxiety, epilepsy, head trauma, migraine, inflammatory bowel disease, overactive bladder and chronic, neuropathic and acute pain.
- Calcium flux is also implicated in other neurological disorders such as schizophrenia, anxiety, depression, other psychoses, neural degenerative disorders and drug and alcohol addiction and withdrawal.
- Other treatable conditions include cardiovascular conditions such as hypertension and cardiac arrhythmias.
- T-type calcium channels have been implicated in certain types of cancer, diabetes infertility and sexual dysfunction.
- N-type and T-type channels are associated with particular conditions.
- the association of N-type and T-type channels in conditions associated with neural transmission would indicate that compounds ofthe invention which target N-type or T-type receptors are most useful in these conditions.
- these conditions are:
- the members ofthe genus of compounds of formula (1) exhibit high affinity for N-type channels and/or T-type channels. Thus, as described below, they are screened for their ability to interact with N-type and/or T-type channels as an initial indication of desirable function. It is desirable that the compounds exhibit IC 50 values of ⁇ 1 ⁇ M.
- the IC 50 is the concentration which inhibits 50% ofthe calcium, barium or other permeant divalent cation flux at a particular applied potential.
- open channel blockage is conveniently demonstrated when displayed calcium channels are maintained at an artificially negative resting potential of about -100 mV (as distinguished from the typical endogenous resting maintained potential. of about -70 mV).
- open channel blocking inhibitors diminish the current exhibited at the peak flow and can also accelerate the rate of current decay.
- activation inhibition This type of inhibition is distinguished from a second type of block, referred to herein as "inactivation inhibition.”
- inactivation inhibition When maintained at less negative resting potentials, such as the physiologically important potential of -70 mV, a certain percentage ofthe channels may undergo conformational change, rendering them incapable of being activated ⁇ i.e., opened ⁇ by the abrupt depolarization. Thus, the peak current due to calcium ion flow will be diminished not because the open channel is blocked, but because some ofthe channels are unavailable for opening (inactivated).
- “Inactivation” type inhibitors increase the percentage of receptors that are in an inactivated state.
- Resting channel block is the inhibition ofthe channel that occurs in the absence of membrane depolarization, that would normally lead to opening or inactivation. For example, resting channel blockers would diminish the peak current amplitude during the very first depolarization after drug application without additional inhibition during the depolarization.
- the compounds ofthe invention modulate the activity of calcium channels; in general, said modulation is the inhibition ofthe ability ofthe channel to transport calcium.
- modulation is the inhibition ofthe ability ofthe channel to transport calcium.
- the effect of a particular compound on calcium channel activity can readily be ascertained in a routine assay whereby the conditions are arranged so that the channel is activated, and the effect ofthe compound on this activation (either positive or negative) is assessed. Typical assays are described hereinbelow.
- alkyl straight-chain, branched-chain and cyclic monovalent substituents, containing only C and H when they are unsubstituted or unless otherwise noted. Examples include methyl, ethyl, isobutyl, cyclohexyl, cyclopentyl ethyl, 2- ⁇ ropenyl, 3-butynyl, and the like.
- the alkyl, alkenyl and alkynyl substituents contain 1-lOC (alkyl) or 2-10C (alkenyl or alkynyl). Preferably they contain 1-6C (lower alkyl) or 2-6C (lower alkenyl or lower alkynyl).
- Heteroalkyl, heteroalkenyl and heteroalkynyl are similarly defined but may contain one or more O, S or N heteroatoms or combinations thereof within the backbone residue.
- acyl encompasses the definitions of alkyl, alkenyl, alkynyl, each of which is coupled to an additional residue through a carbonyl group. Heteroacyl includes the related heteroforms.
- Aromatic moiety or "aryl” moiety refers to a monocyclic or fused bicyclic moiety such as phenyl or naphthyl; “heteroaromatic” also refers to monocyclic or fused bicyclic ring systems containing one or more heteroatoms selected from O, S and N. The inclusion of a heteroatom permits inclusion of 5-membered rings as well as 6-membered rings.
- aromatic/heteroaromatic systems include pyridyl, pyrimidyl, indolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl and the like. Because tautomers are theoretically possible, phthalimido is also considered aromatic. Any monocyclic or fused ring bicyclic system which has the characteristics of aromaticity in terms of electron distribution throughout the ring system is included in this definition. Typically, the ring systems contain 5-12 ring member atoms.
- arylalkyl and heteroarylalkyl refer to aromatic and heteroaromatic systems which are coupled to another residue through a carbon chain, including substituted or unsubstituted, saturated or unsaturated, carbon chains, typically of 1-8C, or the hetero forms thereof. These carbon chains may also include a carbonyl group, thus making them able to provide substituents as an acyl or heteroacyl moiety.
- any alkyl, alkenyl, alkynyl, acyl, or aryl group contained in a substituent may itself optionally be substituted by additional substituents.
- the nature of these substituents is similar to those recited with regard to the primary substituents themselves.
- this alkyl may optionally be substituted by the remaining substituents listed as substituents where this makes chemical sense, and where this does not underaiine the size limit of alkyl per se; e.g., alkyl substituted by alkyl or by alkenyl would simply extend the upper limit of carbon atoms for these embodiments.
- alkyl substituted by aryl, amino, alkoxy, and the like would be included.
- Ar is preferably optionally substituted phenyl, 2-, 3- or 4-pyridyl, indolyl, 2- or 4-pyrimidyl, pyridazinyl, benzotriazolyl or benzimidazolyl. More preferably Ar is phenyl, pyridyl, or pyrimidyl. Most preferably Ar is phenyl.
- Each of these embodiments may optionally be substituted with a group defined above such as alkyl, alkenyl, alkynyl, aryl, O-aryl, O-alkylaryl, O-aroyl, NR-aryl, N-alkylaryl, NR-aroyl, halo, OR, NR 2 , SR, -OOCR, -NROCR, RCO, -COOR, -CONR 2 , and/or S0 2 NR , wherein each R is independently H or alkyl (1-8C), and/or by -CN, -CF 3 , and/or N0 2 . Alkyl, alkenyl, alkynyl and aryl portions of these may be further substituted by similar substituents.
- R 1 0 and carboxy.
- Preferred embodiments of R and R include alkoxy, halo, and alkyl.
- the compounds ofthe invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts.
- These salts maybe acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms ofthe compounds ofthe invention be prepared from inorganic or organic bases.
- Suitable pharmaceutically acceptable acids and bases are well-known in the art, such as hydrochloric, sulphuric, citric, acidic, or tartaric acids and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, and the like. Methods for preparation ofthe appropriate salts are well-established in the art.
- the compounds ofthe invention contain one or more chiral centers.
- the invention includes the isolated stereoisomeric forms as well as mixtures of stereoisomers in varying degrees of chiral purity.
- Reaction Scheme 2 is used to prepare compounds ofthe invention within the embodiment of formula (2). Variations in R, and substitutions for the fluoro substituents in compound 6 will result in variants having corresponding variations in the compounds shown as 8 above.
- compounds PI, P2, P3, P4, P5, P6, P7, P8, P39, P9, P10, P11, P12, P13, P14 and PI 5 may be synthesized using this approach.
- Reaction Scheme 3 shows synthesis of compounds ofthe invention which comprise tertiary butyl substituents in Ar.
- Reaction Scheme 4 shows synthesis of compounds ofthe invention which comprise a keto substitution on the piperazine ring, such as in compounds P48-P57.
- Reaction Scheme 5 shows synthesis of compounds ofthe invention which comprise a various substitutions on the piperazine ring, such as in compounds P36 and P47.
- the compounds ofthe invention can be synthesized individually using methods known in the artj ⁇ er.s'e, or as members of a combinatorial library. [0053] Synthesis of combinatorial libraries is now commonplace in the art. Suitable descriptions of such syntheses are found, for example, in Wentworth, Jr., P., et al, Current Opinion in Biol. (1993) 9:109-115; Salemme, F.R., et al, Structure (1997) 5:319-324.
- the libraries contain compounds with various substituents and various degrees of unsaturation, as well as different chain lengths.
- the libraries which contain, as few as 10, but typically several hundred members to several thousand members, may then be screened for compounds which are particularly effective against a specific subtype of calcium channel, i.e., the N-type channel.
- the libraries may be screened for compounds which block additional channels or receptors such as sodium channels, potassium channels and the like.
- Methods of performing these screening functions are well known in the art. These methods can also be used for individually ascertaining the ability of a compound to agonize or antagonize the channel.
- the channel to be targeted is expressed at the surface of a recombinant host cell such as human embryonic kidney cells.
- the ability of the members ofthe library to bind the channel to be tested is measured, for example, by the ability ofthe compound in the library to displace a labeled binding ligand such as the ligand normally associated with the channel or an antibody to the channel. More typically, ability to antagonize the channel is measured in the presence of calcium, barium or other permeant divalent cation and the ability ofthe compound to interfere with the signal generated is measured using standard techniques.
- one method involves the binding of radiolabeled agents that interact with the calcium channel and subsequent analysis of equilibrium binding measurements including, but not limited to, on rates, off rates, Kd values and competitive binding by other molecules.
- Another method involves the screening for the effects of compounds by electrophysiological assay whereby individual cells are impaled with a microelectrode and currents through the calcium channel are recorded before and after application ofthe compound of interest.
- Another method, high-throughput spectrophotometric assay utilizes loading of the cell lines with a fluorescent dye sensitive to intracellular calcium concentration and subsequent examination ofthe effects of compounds on the ability of depolarization by potassium chloride or other means to alter intracellular calcium levels.
- a more definitive assay can be used to distinguish inhibitors of calcium flow which operate as open channel blockers, as opposed to those that operate by promoting inactivation ofthe channel or as resting channel blockers. The methods to distinguish these types of inhibition are more particularly described in the examples below.
- open-channel blockers are assessed by measuring the level of peak current when depolarization is imposed on a background resting potential of about -100 mV in the presence and absence ofthe candidate compound.
- Successful open-channel blockers will reduce the peak current observed and may accelerate the decay of this current.
- Compounds that are inactivated channel blockers are generally determined by their ability to shift the voltage dependence of inactivation towards more negative potentials. This is also reflected in their ability to reduce peak currents at more depolarized holding potentials (e.g., -70 mV) and at higher frequencies of stimulation, e.g., 0.2 Hz vs. 0.03 Hz. Finally, resting channel blockers would diminish the peak current amplitude during the very first depolarization after drug application without additional inhibition during the depolarization.
- the compounds ofthe invention can be formulated as pharmaceutical of veterinary compositions.
- the mode of administration, and the type of treatment desired e.g., prevention, prophylaxis, therapy; the compounds are formulated in ways consonant with these parameters.
- a summary of such techniques is found in Remington's Pharmaceutical Sciences, latest edition, Mack Publishing Co., Easton, PA, incorporated herein by reference.
- the compounds of formula (1) may be used alone, as mixtures of two or more compounds of fonnula (1) or in combination with other pharmaceuticals. Depending on the mode of administration, the compounds will be formulated into suitable compositions to permit facile delivery.
- Formulations may be prepared in a manner suitable for systemic administration or topical or local administration.
- Systemic formulations include those designed for injection (e.g., intramuscular, intravenous or subcutaneous injection) or may be prepared for transdermal, transmucosal, or oral administration.
- the formulation will generally include a diluent as well as, in some cases, adjuvants, buffers, preservatives and the like.
- the compounds can be administered also in liposomal compositions or as microemulsions.
- formulations can be prepared in conventional forms as liquid solutions or suspensions or as solid forms suitable for solution or suspension in liquid prior to injection or as emulsions.
- Suitable excipients include, for example, water, saline, dextrose, glycerol and the like.
- Such compositions may also contain amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as, for example, sodium acetate, sorbitan monolaurate, and so forth.
- Systemic administration may also include relatively noninvasive methods such as the use of suppositories, transdermal patches, transmucosal delivery and intranasal administration.
- Oral administration is also suitable for compounds ofthe invention. Suitable forms include syrups, capsules, tablets, as is understood in the art.
- the dosage ofthe compounds of the invention is typically 0.1-15 mg/kg, preferably 0.1-1 mg/kg.
- dosage levels are highly dependent on the nature ofthe condition, drug efficacy, the condition ofthe patient, the judgment of the practitioner, and the frequency and mode of administration.
- K 2 CO 3 (1.07g, 7.78 mmol) was added to a solution of 3,4,dimethoxyphenol (l.Og, 6.48 mmol) in dry DMF (15 ml). 2-Bromoethanol (0.8 lg, 6.48 mmol) was added, and the mixture was heated overnight at 120°C. The mixture was cooled, taken up in EtOAc, extracted with water (20 ml), saturated NaCl (4x 20 ml), dried over MgSO 4 , and evaporated under reduced pressure. The product was purified by column chromatography on silica (Hexane:EtOAc 3:1) to give the desired product in 60% yield.
- Antagonist activity was measured using whole cell patch recordings on human embryonic kidney cells either stably or transiently expressing rat N-type channels ( ⁇ XI B + ⁇ 2 b+ ⁇ ib subunits) with 5 mM barium as a charge carrier.
- cells either stably or transiently expressing rat L-type channels ( ⁇ ]C + ⁇ 2 ⁇ + Si b cDNA subunits) and P/Q-type channels ( ⁇ A + ⁇ 2 s + ⁇ b cDNA subunits)
- HEK 293 For transient expression, host cells, such as human embryonic kidney cells, HEK 293 (ATCC# CRL 1573) were grown in standard DMEM medium supplemented with 2 mM glutamine and 10% fetal bovine serum. HEK 293 cells were transfected by a standard calcium-phosphate-DNA coprecipitation method using the rat ⁇ i B + ⁇ i b + ⁇ 2 ⁇ N-type calcium channel subunits in a vertebrate expression vector (for example, see Current Protocols in Molecular Biology).
- Example 10 The methods of Example 10 were followed with slight modifications as will be apparent from the description below.
- ⁇ -type calcium channel blocking activity was assayed in human embryonic kidney cells, HEK 293, stably transfected with the rat brain ⁇ -type calcium channel subunits ( i ⁇ + ⁇ _ ⁇ +/3ib cD ⁇ A subunits).
- ⁇ -type calcium channels i B + 0_s + ⁇ b cD ⁇ A subunits
- L-type channels ⁇ ic + 2 ⁇ + ⁇ . b cD ⁇ A subunits
- P/Q-type channels a JA + ckt, + ⁇ b cD ⁇ A subunits
- DMEM Dulbecco's modified eagle medium
- Standard patch-clamp techniques were employed to identify blockers of T-type currents. Briefly, previously described HEK cell lines stably expressing human ⁇ io subunits were used for all the recordings (passage #: 4-20, 37° C, 5% CO 2 ). To obtain T- type currents, plastic dishes containing semi-confluent cells were positioned on the stage of a ZEISS AXIOVERT SI 00 microscope after replacing the culture medium with external solution (see below). Whole-cell patches were obtained using pipettes (borosilicate glass with filament, O.D.: 1.5 mm, I.D.: 0.86 mm, 10 cm length), fabricated on a SUTTER P-97 puller with resistance values of ⁇ 5 M ⁇ (see below for internal medium).
- T-type currents are reliably obtained by using two voltage protocols: “non-inactivating", and “inactivating"
- the holding potential is set at -110 mV and with a pre-pulse at -100 mV for 1 second prior to the test pulse at -40 mV for 50 ms.
- the pre-pulse is at approximately -85 mV for 1 second, which inactivates about 15% ofthe T-type channels, as shown below.
- test pulse - 40 mV, 50 ms 0.067 HH
- Vholding ⁇ -IO rnV non-inactivating pre-pulse -100 mV, 1 second u
- Test compounds were dissolved in external solution, 0.1-0.01 % DMSO. After -10 min rest, they were applied by gravity close to the cell using a WPI microfil tubing. The "non-inactivating" pre-pulse was used to examine the resting block of a compound. The “inactivating” protocol was employed to study voltage-dependent block. However, the initial data were obtained using the non-inactivating protocol. IC 50 value of PI 8 was found to be 0.022 ⁇ M under this protocol.
- Results are shown in Table 5 for some ofthe invention compounds.
- Table 5 Block of otic T-type Channels
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2006504105A JP2006522742A (ja) | 2003-04-08 | 2004-04-08 | ピペラジンから距離をおいて配置したベンズヒドリル基から成る一群のカルシウムチャンネル阻害剤 |
EP04726395A EP1611116A2 (fr) | 2003-04-08 | 2004-04-08 | Inhibiteurs des canaux calciques comprenant du benzhydryle espace de la piperazine |
CA002521330A CA2521330A1 (fr) | 2003-04-08 | 2004-04-08 | Inhibiteurs des canaux calciques comprenant du benzhydryle espace de la piperazine |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/107,037 US6011035A (en) | 1998-06-30 | 1998-06-30 | Calcium channel blockers |
US09/401,699 US6294533B1 (en) | 1998-06-30 | 1999-09-23 | Calcium channel blockers |
US09/476,927 US6387897B1 (en) | 1998-06-30 | 1999-12-30 | Preferentially substituted calcium channel blockers |
US10/060,900 US6617322B2 (en) | 1998-06-30 | 2002-01-29 | Preferentially substituted calcium channel blockers |
US10/409,868 | 2003-04-08 | ||
US10/409,868 US6943168B2 (en) | 1998-06-30 | 2003-04-08 | Calcium channel inhibitors comprising benzhydril spaced from piperazine |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2004089922A2 true WO2004089922A2 (fr) | 2004-10-21 |
WO2004089922A3 WO2004089922A3 (fr) | 2005-03-24 |
Family
ID=56290540
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CA2004/000539 WO2004089922A2 (fr) | 1998-06-30 | 2004-04-08 | Inhibiteurs des canaux calciques comprenant du benzhydryle espace de la piperazine |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2004089922A2 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006084369A1 (fr) * | 2005-02-09 | 2006-08-17 | Neuromed Pharmaceuticals Ltd. | Agents bloquants de canal calcium de type diamine |
US7378420B2 (en) | 2004-08-30 | 2008-05-27 | Neuromed Pharmaceuticals Ltd. | Urea derivatives as calcium channel blockers |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB920416A (en) * | 1958-04-04 | 1963-03-06 | Lakeside Lab Inc | Piperazino compounds |
US5646149A (en) * | 1993-12-08 | 1997-07-08 | Alcon Laboratories, Inc. | Compounds having both potent calcium antagonist and antioxidant activity and use thereof as cytoprotective agents |
WO2001045709A1 (fr) * | 1999-12-20 | 2001-06-28 | Neuromed Technologies, Inc. | Inhibiteurs calciques a base de piperazine et de piperidine substituees |
WO2001049670A1 (fr) * | 1999-12-30 | 2001-07-12 | Neuromed Technologies, Inc. | 5,10-dihydroacridines utilisees comme inhibiteurs calciques |
US6294533B1 (en) * | 1998-06-30 | 2001-09-25 | Neuormed Technologies, Inc. | Calcium channel blockers |
US20010029258A1 (en) * | 1998-06-30 | 2001-10-11 | Snutch Terrance P. | Partially saturated calcium channel blockers |
WO2003068759A1 (fr) * | 2002-02-12 | 2003-08-21 | Glaxo Group Limited | Anti-inflammatoires a base de derives piperazine |
US20040034035A1 (en) * | 1998-06-30 | 2004-02-19 | Neuromed Technologies, Inc. | Calcium channel inhibitors comprising benzhydril spaced from piperazine |
-
2004
- 2004-04-08 WO PCT/CA2004/000539 patent/WO2004089922A2/fr active Search and Examination
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB920416A (en) * | 1958-04-04 | 1963-03-06 | Lakeside Lab Inc | Piperazino compounds |
US5646149A (en) * | 1993-12-08 | 1997-07-08 | Alcon Laboratories, Inc. | Compounds having both potent calcium antagonist and antioxidant activity and use thereof as cytoprotective agents |
US6294533B1 (en) * | 1998-06-30 | 2001-09-25 | Neuormed Technologies, Inc. | Calcium channel blockers |
US20010029258A1 (en) * | 1998-06-30 | 2001-10-11 | Snutch Terrance P. | Partially saturated calcium channel blockers |
US6387897B1 (en) * | 1998-06-30 | 2002-05-14 | Neuromed Technologies, Inc. | Preferentially substituted calcium channel blockers |
US20040034035A1 (en) * | 1998-06-30 | 2004-02-19 | Neuromed Technologies, Inc. | Calcium channel inhibitors comprising benzhydril spaced from piperazine |
WO2001045709A1 (fr) * | 1999-12-20 | 2001-06-28 | Neuromed Technologies, Inc. | Inhibiteurs calciques a base de piperazine et de piperidine substituees |
WO2001049670A1 (fr) * | 1999-12-30 | 2001-07-12 | Neuromed Technologies, Inc. | 5,10-dihydroacridines utilisees comme inhibiteurs calciques |
WO2003068759A1 (fr) * | 2002-02-12 | 2003-08-21 | Glaxo Group Limited | Anti-inflammatoires a base de derives piperazine |
Non-Patent Citations (4)
Title |
---|
BOGER, DALE L. ET AL: "Non-amide-based combinatorial libraries derived from N-BOC-iminodiacetic acid: solution-phase synthesis of piperazinone libraries with activity against LEF-1/.beta.-catenin-mediated transcription" HELVETICA CHIMICA ACTA , 83(8), 1825-1845 CODEN: HCACAV; ISSN: 0018-019X, 2000, XP002304006 * |
JAMIESON, CRAIG ET AL: "A rapid approach for the optimization of polymer supported reagents in synthesis" SYNLETT , (11), 1603-1607 CODEN: SYNLES; ISSN: 0936-5214, 2000, XP001056501 * |
TOLDY L ET AL: "VERSUCHE ZUR HERSTELLUNG VON PHENTIAZINEN SELEKTIVER CORONARDILATATORISCHER WIRKUNG" ACTA CHIMICA ACADEMIAE SCIENTIARUM HUNGARICA, BUDAPEST, HU, vol. 44, 1965, pages 301-325, XP000996141 ISSN: 0001-5407 * |
WEBSTER, KERRI L. ET AL: "Design and preparation of serine-threonine protein phosphatase inhibitors based upon the nodularin and microcystin toxin structures. Part 3" JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1 , (14), 1673-1695 CODEN: JCSPCE; ISSN: 1472-7781, 2001, XP002304005 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7378420B2 (en) | 2004-08-30 | 2008-05-27 | Neuromed Pharmaceuticals Ltd. | Urea derivatives as calcium channel blockers |
US7649092B2 (en) | 2004-08-30 | 2010-01-19 | Neuromed Pharmaceuticals Ltd. | Urea derivatives as calcium channel blockers |
US7659395B2 (en) | 2004-08-30 | 2010-02-09 | Neuromed Pharmaceuticals Ltd. | Urea derivatives as calcium channel blockers |
WO2006084369A1 (fr) * | 2005-02-09 | 2006-08-17 | Neuromed Pharmaceuticals Ltd. | Agents bloquants de canal calcium de type diamine |
US7511077B2 (en) | 2005-02-09 | 2009-03-31 | Neuromed Pharmaceuticals Ltd. | Diamine calcium channel blockers |
Also Published As
Publication number | Publication date |
---|---|
WO2004089922A3 (fr) | 2005-03-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6943168B2 (en) | Calcium channel inhibitors comprising benzhydril spaced from piperazine | |
EP1610792B1 (fr) | Inhibiteurs calciques comportant deux fractions de benzhydrile | |
US7186726B2 (en) | Preferentially substituted calcium channel blockers | |
US7244758B2 (en) | N-type calcium channel blockers | |
US20040266784A1 (en) | Calcium channel inhibitors comprising benzhydril spaced from piperazine | |
EP1244451B1 (fr) | Inhibiteurs calciques a base de piperazine et de piperidine substituees | |
US20060084660A1 (en) | Calcium channel blockers comprising two benzhydril moieties | |
US20040259866A1 (en) | Calcium channel blockers comprising two benzhydril moieties | |
WO2001049670A1 (fr) | 5,10-dihydroacridines utilisees comme inhibiteurs calciques | |
CA2397681C (fr) | Inhibiteurs calciques partiellement satures | |
AU2005231872A1 (en) | Diarylamine derivatives as calcium channel blockers | |
US20030199523A1 (en) | Heterocyclic calcium in channel blockers | |
US20050227999A1 (en) | Diarylamine derivatives as calcium channel blockers | |
WO2004089922A2 (fr) | Inhibiteurs des canaux calciques comprenant du benzhydryle espace de la piperazine | |
EP1611116A2 (fr) | Inhibiteurs des canaux calciques comprenant du benzhydryle espace de la piperazine | |
KR20070019639A (ko) | 칼슘 채널 차단제로서 사용되는 피페라진 치환된 화합물 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2521330 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004726395 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2006504105 Country of ref document: JP |
|
WWP | Wipo information: published in national office |
Ref document number: 2004726395 Country of ref document: EP |
|
DPEN | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101) |