AU661527B2 - Antimigraine 4-pyrimidinyl and pyridinyl derivatives of indol-3yl-alkyl piperazines - Google Patents
Antimigraine 4-pyrimidinyl and pyridinyl derivatives of indol-3yl-alkyl piperazines Download PDFInfo
- Publication number
- AU661527B2 AU661527B2 AU30034/92A AU3003492A AU661527B2 AU 661527 B2 AU661527 B2 AU 661527B2 AU 30034/92 A AU30034/92 A AU 30034/92A AU 3003492 A AU3003492 A AU 3003492A AU 661527 B2 AU661527 B2 AU 661527B2
- Authority
- AU
- Australia
- Prior art keywords
- indol
- methoxy
- propyl
- pyrimidinyl
- piperazine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 title claims description 4
- 230000002460 anti-migrenic effect Effects 0.000 title description 9
- 125000004076 pyridyl group Chemical group 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 95
- 239000000203 mixture Substances 0.000 claims description 94
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 90
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 67
- -1 cyano, hydroxy Chemical group 0.000 claims description 64
- 238000000034 method Methods 0.000 claims description 48
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 46
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 27
- 208000019695 Migraine disease Diseases 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- IDMFVGRBITWGLW-UHFFFAOYSA-N 5-methoxy-4-piperazin-1-ylpyrimidine Chemical compound COC1=CN=CN=C1N1CCNCC1 IDMFVGRBITWGLW-UHFFFAOYSA-N 0.000 claims description 15
- 208000001407 Vascular Headaches Diseases 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical group 0.000 claims description 7
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 7
- GLNLORIMKOOXGK-UHFFFAOYSA-N 5-methoxy-4-(2-methylpiperazin-1-yl)pyrimidine Chemical compound COC1=CN=CN=C1N1C(C)CNCC1 GLNLORIMKOOXGK-UHFFFAOYSA-N 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 150000002431 hydrogen Chemical group 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- HEJJUDZBNTVHQV-UHFFFAOYSA-N 5-methoxy-4-(3-methylpiperazin-1-yl)pyrimidine Chemical compound COC1=CN=CN=C1N1CC(C)NCC1 HEJJUDZBNTVHQV-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 208000006561 Cluster Headache Diseases 0.000 claims description 4
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 206010027603 Migraine headaches Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 238000007910 systemic administration Methods 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims 3
- RVRZXBHPVKUANA-UHFFFAOYSA-N C(#N)COC=1NC2=CC=CC=C2C=1 Chemical compound C(#N)COC=1NC2=CC=CC=C2C=1 RVRZXBHPVKUANA-UHFFFAOYSA-N 0.000 claims 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims 1
- 239000002552 dosage form Substances 0.000 claims 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims 1
- HXDRKCWISZTWQP-UHFFFAOYSA-N n-[3-[3-[4-(5-methoxypyrimidin-4-yl)-2-methylpiperazin-1-yl]propyl]-1h-indol-5-yl]-n-methylethanesulfonamide Chemical compound C12=CC(N(C)S(=O)(=O)CC)=CC=C2NC=C1CCCN(C(C1)C)CCN1C1=NC=NC=C1OC HXDRKCWISZTWQP-UHFFFAOYSA-N 0.000 claims 1
- 125000002004 n-butylamino group Chemical group [H]N(*)C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 192
- 239000000243 solution Substances 0.000 description 185
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 122
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 111
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 88
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 75
- 238000006243 chemical reaction Methods 0.000 description 68
- 235000019439 ethyl acetate Nutrition 0.000 description 66
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 48
- 239000007787 solid Substances 0.000 description 43
- 239000012044 organic layer Substances 0.000 description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 34
- 238000010992 reflux Methods 0.000 description 34
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- 239000000047 product Substances 0.000 description 33
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 31
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 27
- 239000012141 concentrate Substances 0.000 description 26
- 235000008504 concentrate Nutrition 0.000 description 26
- 238000010898 silica gel chromatography Methods 0.000 description 26
- 239000011541 reaction mixture Substances 0.000 description 25
- 239000000725 suspension Substances 0.000 description 25
- 229920006395 saturated elastomer Polymers 0.000 description 24
- 206010027599 migraine Diseases 0.000 description 23
- 206010019233 Headaches Diseases 0.000 description 22
- 231100000869 headache Toxicity 0.000 description 22
- 239000000741 silica gel Substances 0.000 description 22
- 229910002027 silica gel Inorganic materials 0.000 description 22
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 19
- 230000008569 process Effects 0.000 description 19
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 19
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 18
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 18
- 239000012267 brine Substances 0.000 description 17
- 239000000463 material Substances 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 17
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
- 239000011734 sodium Substances 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 15
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 15
- 239000000284 extract Substances 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- 238000004587 chromatography analysis Methods 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 238000000921 elemental analysis Methods 0.000 description 13
- 238000001914 filtration Methods 0.000 description 13
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 239000000908 ammonium hydroxide Substances 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 11
- 150000001412 amines Chemical class 0.000 description 11
- 238000004458 analytical method Methods 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 10
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 10
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 239000006260 foam Substances 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 8
- 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 8
- 239000008346 aqueous phase Substances 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 238000012986 modification Methods 0.000 description 7
- 230000004048 modification Effects 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 7
- 229940076279 serotonin Drugs 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- IJQIGKLDBGKSNT-UHFFFAOYSA-N 4,6-dichloro-5-methoxypyrimidine Chemical compound COC1=C(Cl)N=CN=C1Cl IJQIGKLDBGKSNT-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 230000002792 vascular Effects 0.000 description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 5
- 230000029936 alkylation Effects 0.000 description 5
- 238000005804 alkylation reaction Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 239000012458 free base Substances 0.000 description 5
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 5
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 5
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 5
- LLWRXQXPJMPHLR-UHFFFAOYSA-N methylazanium;iodide Chemical compound [I-].[NH3+]C LLWRXQXPJMPHLR-UHFFFAOYSA-N 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 4
- 229910004298 SiO 2 Inorganic materials 0.000 description 4
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 229940039748 oxalate Drugs 0.000 description 4
- 235000010288 sodium nitrite Nutrition 0.000 description 4
- 239000001119 stannous chloride Substances 0.000 description 4
- 235000011150 stannous chloride Nutrition 0.000 description 4
- 230000006103 sulfonylation Effects 0.000 description 4
- 238000005694 sulfonylation reaction Methods 0.000 description 4
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 4
- CAXRPEAFHWDFTD-UHFFFAOYSA-N (4-nitrophenyl)methanesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(CS(Cl)(=O)=O)C=C1 CAXRPEAFHWDFTD-UHFFFAOYSA-N 0.000 description 3
- JOMNTHCQHJPVAZ-UHFFFAOYSA-N 2-methylpiperazine Chemical compound CC1CNCCN1 JOMNTHCQHJPVAZ-UHFFFAOYSA-N 0.000 description 3
- JUQKCIKIKSPUKF-UHFFFAOYSA-N 3-(5-nitro-1h-indol-3-yl)propan-1-ol Chemical compound C1=C([N+]([O-])=O)C=C2C(CCCO)=CNC2=C1 JUQKCIKIKSPUKF-UHFFFAOYSA-N 0.000 description 3
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000000538 analytical sample Substances 0.000 description 3
- 150000003857 carboxamides Chemical class 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 239000012954 diazonium Substances 0.000 description 3
- 150000001989 diazonium salts Chemical class 0.000 description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 3
- 150000003840 hydrochlorides Chemical class 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 3
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- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 208000035824 paresthesia Diseases 0.000 description 1
- 208000007777 paroxysmal Hemicrania Diseases 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- CRWVOXFUXPYTRK-UHFFFAOYSA-N pent-4-yn-1-ol Chemical compound OCCCC#C CRWVOXFUXPYTRK-UHFFFAOYSA-N 0.000 description 1
- 229960002195 perazine Drugs 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- VKBJNABNNJYRTK-UHFFFAOYSA-N piperazine;hydrate;hydrochloride Chemical compound O.Cl.C1CNCCN1 VKBJNABNNJYRTK-UHFFFAOYSA-N 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000036515 potency Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- JTTWNTXHFYNETH-UHFFFAOYSA-N propyl 4-methylbenzenesulfonate Chemical compound CCCOS(=O)(=O)C1=CC=C(C)C=C1 JTTWNTXHFYNETH-UHFFFAOYSA-N 0.000 description 1
- DKORSYDQYFVQNS-UHFFFAOYSA-N propyl methanesulfonate Chemical compound CCCOS(C)(=O)=O DKORSYDQYFVQNS-UHFFFAOYSA-N 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- 239000003762 serotonin receptor affecting agent Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- FMLPQHJYUZTHQS-UHFFFAOYSA-N tert-butyl 3-methylpiperazine-1-carboxylate Chemical compound CC1CN(C(=O)OC(C)(C)C)CCN1 FMLPQHJYUZTHQS-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- UHUZMAHDOFEXQY-UHFFFAOYSA-N tert-butyl-dimethyl-(5-trimethylsilylpent-4-ynoxy)silane Chemical compound CC(C)(C)[Si](C)(C)OCCCC#C[Si](C)(C)C UHUZMAHDOFEXQY-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- UMFCIIBZHQXRCJ-NSCUHMNNSA-N trans-anol Chemical compound C\C=C\C1=CC=C(O)C=C1 UMFCIIBZHQXRCJ-NSCUHMNNSA-N 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- CIXRWXTXQKQWBW-UHFFFAOYSA-N trimethyl(pent-4-ynyl)silane Chemical compound C[Si](C)(C)CCCC#C CIXRWXTXQKQWBW-UHFFFAOYSA-N 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Pharmacology & Pharmacy (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)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US810661 | 1977-06-27 | ||
| US81066191A | 1991-12-19 | 1991-12-19 | |
| US95959292A | 1992-10-13 | 1992-10-13 | |
| US959592 | 1992-10-13 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU3003492A AU3003492A (en) | 1994-03-24 |
| AU661527B2 true AU661527B2 (en) | 1995-07-27 |
Family
ID=27123378
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU30034/92A Ceased AU661527B2 (en) | 1991-12-19 | 1992-12-10 | Antimigraine 4-pyrimidinyl and pyridinyl derivatives of indol-3yl-alkyl piperazines |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US5434154A (cg-RX-API-DMAC7.html) |
| EP (1) | EP0548813A1 (cg-RX-API-DMAC7.html) |
| JP (1) | JPH05262762A (cg-RX-API-DMAC7.html) |
| CN (1) | CN1085556A (cg-RX-API-DMAC7.html) |
| AU (1) | AU661527B2 (cg-RX-API-DMAC7.html) |
| CA (1) | CA2084531A1 (cg-RX-API-DMAC7.html) |
| CZ (1) | CZ359292A3 (cg-RX-API-DMAC7.html) |
| FI (1) | FI925737L (cg-RX-API-DMAC7.html) |
| IL (1) | IL104024A (cg-RX-API-DMAC7.html) |
| MX (1) | MX9207114A (cg-RX-API-DMAC7.html) |
| NO (1) | NO302522B1 (cg-RX-API-DMAC7.html) |
| NZ (1) | NZ245439A (cg-RX-API-DMAC7.html) |
| PH (1) | PH30988A (cg-RX-API-DMAC7.html) |
| RU (1) | RU2114111C1 (cg-RX-API-DMAC7.html) |
| TW (1) | TW221420B (cg-RX-API-DMAC7.html) |
Families Citing this family (46)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5521188A (en) * | 1993-09-16 | 1996-05-28 | Bristol-Myers Squibb Company | Antimigraine cyclobutenedione derivatives of indolylalkyl-pyridinyl and pyrimidinylpiperazines |
| CA2130078A1 (en) * | 1993-09-16 | 1995-03-17 | Jonas A. Gylys | Antimigraine cyclobutenedione derivatives of indolylalkyl-pyridinyl and pyrimidinylpiperazines |
| US5468768A (en) * | 1994-01-06 | 1995-11-21 | Bristol-Myers Squibb Company | Antimigraine derivatives of indolylcycloalkanylamines |
| JPH10501212A (ja) * | 1994-05-19 | 1998-02-03 | メルク シヤープ エンド ドーム リミテツド | ５−ｈｔ▲下１ｄ▼−アルファ作働薬としてのインドール−３−イルアルキルのピペラジン、ピペリジンおよびテトラヒドロピリジン誘導体 |
| GB9410031D0 (en) * | 1994-05-19 | 1994-07-06 | Merck Sharp & Dohme | Therapeutic agents |
| US5552402A (en) * | 1994-05-19 | 1996-09-03 | Merck, Sharp & Dohme Ltd. | Five-membered heteroaromatic compounds as 5-HT receptor agonists |
| US5567824A (en) * | 1994-05-24 | 1996-10-22 | Merck & Co., Inc. | Palladium catalyzed ring closure of triazolyltryptamine |
| ES2079323B1 (es) * | 1994-06-21 | 1996-10-16 | Vita Invest Sa | Derivados de indol utiles para el tratamiento de la migraña, composicion y uso correspondientes. |
| GB9415575D0 (en) * | 1994-08-02 | 1994-09-21 | Merck Sharp & Dohme | Therapeutic agents |
| US5550239A (en) * | 1994-11-08 | 1996-08-27 | Bristol-Myers Squibb Company | Process for large-scale production of indolyl alkyl pyrimidinyl piperazine compounds |
| GB9423682D0 (en) * | 1994-11-23 | 1995-01-11 | Merck Sharp & Dohme | Therapeutic agents |
| GB9501865D0 (en) * | 1995-01-31 | 1995-03-22 | Merck Sharp & Dohme | Therapeutic agents |
| US5618816A (en) * | 1995-03-02 | 1997-04-08 | Bristol-Myers Squibb Company | Antimigraine 1,2,5-thiadiazole derivatives of indolylalkyl-pyridnyl and pyrimidinylpiperazines |
| US5889010A (en) * | 1995-05-18 | 1999-03-30 | Pfizer Inc. | Benzimidazole derivatives having dopaminergic activity |
| CA2228286A1 (en) * | 1995-08-07 | 1997-02-20 | Merck Sharp & Dohme Limited | Substituted 1-indolylpropyl-4-phenethylpiperazine derivatives |
| JPH09124643A (ja) * | 1995-08-14 | 1997-05-13 | Bristol Myers Squibb Co | 抗うつ作用を有する１−アリールアルキル−４−（アルコキシピリジニル）−又は４−（アルコキシピリミジニル）ピペラジン誘導体 |
| GB9519563D0 (en) * | 1995-09-26 | 1995-11-29 | Merck Sharp & Dohme | Therapeutic agents |
| EP0854714A1 (en) * | 1995-09-28 | 1998-07-29 | MERCK SHARP & DOHME LTD. | Substituted indolylpropyl-piperazine derivatives as 5-ht 1dalpha? agonists |
| US5998415A (en) * | 1995-11-02 | 1999-12-07 | Merck Sharp & Dohme Ltd. | Bicyclic heteroaryl-alkylene-(homo)piperazinones and thione analogues thereof, their preparation, and their use of as selective agonists of 5-HT1 -like receptors |
| GB9523250D0 (en) * | 1995-11-14 | 1996-01-17 | Merck Sharp & Dohme | Therapeutic agents |
| GB9609374D0 (en) * | 1996-05-03 | 1996-07-10 | Merck Sharp & Dohme | Therapeutic agents |
| US5808064A (en) * | 1996-08-13 | 1998-09-15 | Merck & Co., Inc. | Palladium catalyzed indolization |
| US5877329A (en) * | 1996-08-13 | 1999-03-02 | Merck & Co., Inc. | Palladium catalyzed indolization |
| US5811551A (en) * | 1996-08-13 | 1998-09-22 | Merck & Co., Inc. | Palladium catalyzed indolization |
| US5891885A (en) * | 1996-10-09 | 1999-04-06 | Algos Pharmaceutical Corporation | Method for treating migraine |
| GB9714383D0 (en) * | 1997-07-08 | 1997-09-10 | Pfizer Ltd | Improved process |
| DE19756036A1 (de) | 1997-12-17 | 1999-06-24 | Merck Patent Gmbh | Amid- und Harnstoffderivate |
| JP2004517081A (ja) * | 2000-11-29 | 2004-06-10 | イーライ・リリー・アンド・カンパニー | １−（２−ｍ−メタンスルホンアミドフェニルエチル）−４−（ｍ−トリフルオロメチルフェニル）ピペラジンならびにその医薬的に許容しうる塩および溶媒和物 |
| DE10102944A1 (de) * | 2001-01-23 | 2002-07-25 | Merck Patent Gmbh | Verfahren zur Herstellung von (3-Cyan-1H-indol-7-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon und dessen Salzen |
| US6685951B2 (en) | 2001-07-05 | 2004-02-03 | R. T. Alamo Ventures I, Inc. | Administration of dihydroergotamine as a sublingual spray or aerosol for the treatment of migraine |
| US20030198669A1 (en) * | 2001-07-05 | 2003-10-23 | R.T. Alamo Ventures I, Llc | Compositions and methods for rapid dissolving formulations of dihydroergotamine and caffeine for the treatment of migraine |
| US20030017175A1 (en) * | 2001-07-05 | 2003-01-23 | R.T. Alamo Ventures I, Inc. | Sublingual administration of dihydroergotamine for the treatment of migraine |
| DE60233076D1 (de) | 2002-02-13 | 2009-09-03 | Meiji Dairies Corp | Indolderivate substituiert mit langkettigen alcoholen und sie enthaltende arzneimittel |
| DE102004047517A1 (de) * | 2004-09-28 | 2006-03-30 | Merck Patent Gmbh | Neuartige Kristallform von (3-Cyan-1H-indol-7-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon, Hydrochlorid |
| WO2006129190A1 (en) * | 2005-06-03 | 2006-12-07 | Glenmark Pharmaceuticals Limited | Process for the preparation of almotriptan |
| RU2461556C2 (ru) * | 2006-12-30 | 2012-09-20 | Эбботт Гмбх Унд Ко. Кг | Замещенные производные оксидола и их применение в качестве лигандов рецептора вазопрессина |
| ES2538082T3 (es) | 2007-02-11 | 2015-06-17 | Map Pharmaceuticals Inc | Método de administración terapéutica de DHE para permitir el rápido alivio de migraña mientras que se minimiza el perfil de efectos secundarios |
| EP2036888A1 (en) * | 2007-09-17 | 2009-03-18 | Laboratorios del Dr. Esteve S.A. | Naphthyl-substituted sulfonamides |
| ES2751388T3 (es) | 2011-07-22 | 2020-03-31 | Univ Chicago | IGF-1 para su uso en el tratamiento de la jaqueca |
| AU2013361337A1 (en) | 2012-12-21 | 2015-07-09 | Map Pharmaceuticals, Inc. | 8'-Hydroxy-Dihydroergotamine compounds and compositions |
| CN104163813B (zh) * | 2013-05-16 | 2017-02-01 | 广东东阳光药业有限公司 | 取代的吲哚化合物及其使用方法和用途 |
| CN104337812B (zh) | 2013-07-29 | 2018-09-14 | 广东东阳光药业有限公司 | 取代的杂芳基化合物及其使用方法和用途 |
| CN104725363B (zh) * | 2013-12-20 | 2019-03-01 | 广东东阳光药业有限公司 | 取代的哌嗪化合物及其使用方法和用途 |
| US9714232B2 (en) * | 2013-12-20 | 2017-07-25 | Sunshine Lake Pharma Co., Ltd. | Substituted piperazine compounds and methods of use thereof |
| CN106243088B (zh) * | 2015-06-03 | 2019-01-04 | 广东东阳光药业有限公司 | 取代的哌嗪化合物及其使用方法和用途 |
| WO2019082143A1 (en) * | 2017-10-27 | 2019-05-02 | Fresenius Kabi Oncology Ltd. | IMPROVED PROCESS FOR THE PREPARATION OF RIBOCICLIB AND ITS SALTS |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU643038B2 (en) * | 1990-06-29 | 1993-11-04 | Bristol-Myers Squibb Company | Antimigraine alkoxypyrimidine derivatives |
| AU643765B2 (en) * | 1990-06-29 | 1993-11-25 | Bristol-Myers Squibb Company | 1-indolylalkyl-4-(alkoxypyprimidinyl)piperazines |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB944443A (cg-RX-API-DMAC7.html) * | 1959-09-25 | 1900-01-01 | ||
| GB1189064A (en) | 1967-05-01 | 1970-04-22 | Sterling Drug Inc | Indole Derivatives |
| GR79215B (cg-RX-API-DMAC7.html) | 1982-06-07 | 1984-10-22 | Glaxo Group Ltd | |
| GB2162522B (en) | 1984-08-01 | 1988-02-24 | Glaxo Group Ltd | An indole derivative |
| US4954502A (en) * | 1988-06-10 | 1990-09-04 | Bristol-Myers Squibb Company | 1-indolyalkyl-4-(substituted-pyridinyl)piperazines |
| FR2635104B1 (fr) | 1988-08-03 | 1992-04-30 | Synthelabo | Derives d'indolone, leur preparation et leur application en therapeutique |
| GB8830312D0 (en) | 1988-12-28 | 1989-02-22 | Lundbeck & Co As H | Heterocyclic compounds |
| JP2871811B2 (ja) | 1990-02-28 | 1999-03-17 | サントリー株式会社 | 縮合７員環系化合物 |
-
1992
- 1992-12-04 CA CA002084531A patent/CA2084531A1/en not_active Abandoned
- 1992-12-07 CZ CS923592A patent/CZ359292A3/cs unknown
- 1992-12-08 IL IL104024A patent/IL104024A/xx not_active IP Right Cessation
- 1992-12-09 MX MX9207114A patent/MX9207114A/es unknown
- 1992-12-10 NO NO924764A patent/NO302522B1/no unknown
- 1992-12-10 AU AU30034/92A patent/AU661527B2/en not_active Ceased
- 1992-12-11 NZ NZ245439A patent/NZ245439A/xx unknown
- 1992-12-14 TW TW081110009A patent/TW221420B/zh active
- 1992-12-15 PH PH45427A patent/PH30988A/en unknown
- 1992-12-17 EP EP92121519A patent/EP0548813A1/en not_active Ceased
- 1992-12-17 RU RU92016241A patent/RU2114111C1/ru active
- 1992-12-17 FI FI925737A patent/FI925737L/fi not_active Application Discontinuation
- 1992-12-18 JP JP4361763A patent/JPH05262762A/ja active Pending
-
1993
- 1993-01-02 CN CN93101186A patent/CN1085556A/zh active Pending
-
1994
- 1994-04-26 US US08/233,545 patent/US5434154A/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU643038B2 (en) * | 1990-06-29 | 1993-11-04 | Bristol-Myers Squibb Company | Antimigraine alkoxypyrimidine derivatives |
| AU643765B2 (en) * | 1990-06-29 | 1993-11-25 | Bristol-Myers Squibb Company | 1-indolylalkyl-4-(alkoxypyprimidinyl)piperazines |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1085556A (zh) | 1994-04-20 |
| JPH05262762A (ja) | 1993-10-12 |
| RU2114111C1 (ru) | 1998-06-27 |
| AU3003492A (en) | 1994-03-24 |
| NZ245439A (en) | 1995-07-26 |
| FI925737A0 (fi) | 1992-12-17 |
| CZ359292A3 (en) | 1994-01-19 |
| FI925737A7 (fi) | 1993-06-20 |
| FI925737L (fi) | 1993-06-20 |
| US5434154A (en) | 1995-07-18 |
| MX9207114A (es) | 1993-07-01 |
| IL104024A (en) | 1997-04-15 |
| CA2084531A1 (en) | 1993-06-20 |
| TW221420B (cg-RX-API-DMAC7.html) | 1994-03-01 |
| PH30988A (en) | 1997-12-23 |
| EP0548813A1 (en) | 1993-06-30 |
| NO924764L (no) | 1993-06-21 |
| NO302522B1 (no) | 1998-03-16 |
| NO924764D0 (no) | 1992-12-10 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |