JP2781661B2 - Ｃｒｆアンタゴニストとしての置換ピラゾール - Google Patents
Ｃｒｆアンタゴニストとしての置換ピラゾールInfo
- Publication number
- JP2781661B2 JP2781661B2 JP6506653A JP50665394A JP2781661B2 JP 2781661 B2 JP2781661 B2 JP 2781661B2 JP 6506653 A JP6506653 A JP 6506653A JP 50665394 A JP50665394 A JP 50665394A JP 2781661 B2 JP2781661 B2 JP 2781661B2
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- ylmethyl
- methyl
- phenyl
- compound according
- 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.)
- Expired - Fee Related
Links
- 239000005557 antagonist Substances 0.000 title abstract description 7
- 150000003217 pyrazoles Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 109
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 14
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 5
- 230000036506 anxiety Effects 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 112
- -1 bromo, hydroxy Chemical group 0.000 claims description 82
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 31
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 28
- 229910052757 nitrogen Inorganic materials 0.000 claims description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
- 125000003342 alkenyl group Chemical group 0.000 claims description 24
- 229910052760 oxygen Inorganic materials 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 19
- 150000002431 hydrogen Chemical class 0.000 claims description 19
- 125000001153 fluoro group Chemical group F* 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- 229910052717 sulfur Inorganic materials 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- 125000001544 thienyl group Chemical group 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 11
- 125000001246 bromo group Chemical group Br* 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 239000001301 oxygen Substances 0.000 claims description 11
- 125000002883 imidazolyl group Chemical group 0.000 claims description 10
- 125000001041 indolyl group Chemical group 0.000 claims description 10
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 10
- 125000004076 pyridyl group Chemical group 0.000 claims description 10
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 10
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 10
- 125000001425 triazolyl group Chemical group 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 claims description 8
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 8
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 8
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 8
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 8
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 8
- 125000002541 furyl group Chemical group 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 8
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 8
- 125000002757 morpholinyl group Chemical group 0.000 claims description 8
- 125000002971 oxazolyl group Chemical group 0.000 claims description 8
- 125000003386 piperidinyl group Chemical group 0.000 claims description 8
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 8
- 125000005493 quinolyl group Chemical group 0.000 claims description 8
- 125000001984 thiazolidinyl group Chemical group 0.000 claims description 8
- 125000000335 thiazolyl group Chemical group 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 claims description 6
- 125000002346 iodo group Chemical group I* 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- 208000000103 Anorexia Nervosa Diseases 0.000 claims description 5
- 208000018522 Gastrointestinal disease Diseases 0.000 claims description 5
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 claims description 5
- 208000029650 alcohol withdrawal Diseases 0.000 claims description 5
- 208000035475 disorder Diseases 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 230000002008 hemorrhagic effect Effects 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 208000024891 symptom Diseases 0.000 claims description 5
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 4
- ZSKDXMLMMQFHGW-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinolin-3-ylmethanol Chemical compound C1=CC=C2CNC(CO)CC2=C1 ZSKDXMLMMQFHGW-UHFFFAOYSA-N 0.000 claims description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims description 4
- 206010019233 Headaches Diseases 0.000 claims description 4
- 206010062016 Immunosuppression Diseases 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 230000003187 abdominal effect Effects 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 206010013663 drug dependence Diseases 0.000 claims description 4
- 231100000869 headache Toxicity 0.000 claims description 4
- 230000001506 immunosuppresive effect Effects 0.000 claims description 4
- 208000027866 inflammatory disease Diseases 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 230000035935 pregnancy Effects 0.000 claims description 4
- 208000011117 substance-related disease Diseases 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- 208000011580 syndromic disease Diseases 0.000 claims description 4
- LVQFITNVUVNNAD-UHFFFAOYSA-N 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-3,5-diethyl-4-[(2-methoxynaphthalen-1-yl)methyl]pyrazole Chemical compound CCC1=C(CC=2C3=CC=CC=C3C=CC=2OC)C(CC)=NN1C1=C(Cl)C=C(C(F)(F)F)C=C1Cl LVQFITNVUVNNAD-UHFFFAOYSA-N 0.000 claims description 3
- BSHDHDUEEISGRV-UHFFFAOYSA-N 2-[[1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-3,5-diethylpyrazol-4-yl]methyl]-3-(methoxymethyl)-3,4-dihydro-1h-isoquinoline Chemical compound CCC1=C(CN2C(CC3=CC=CC=C3C2)COC)C(CC)=NN1C1=C(Cl)C=C(C(F)(F)F)C=C1Cl BSHDHDUEEISGRV-UHFFFAOYSA-N 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- BFLRFUSUDUTDGP-GOSISDBHSA-N (3r)-3-(methoxymethyl)-2-[[5-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)pyrazol-4-yl]methyl]-3,4-dihydro-1h-isoquinoline Chemical compound C([C@@H]1COC)C2=CC=CC=C2CN1CC(C(=N1)SC)=C(C)N1C1=C(Cl)C=C(Cl)C=C1Cl BFLRFUSUDUTDGP-GOSISDBHSA-N 0.000 claims description 2
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 2
- WNUHFWGXMKMGLB-UHFFFAOYSA-N 2-[8-[[1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-3,5-diethylpyrazol-4-yl]methyl]quinolin-7-yl]oxyethanol Chemical compound CCC1=C(CC=2C3=NC=CC=C3C=CC=2OCCO)C(CC)=NN1C1=C(Cl)C=C(C(F)(F)F)C=C1Cl WNUHFWGXMKMGLB-UHFFFAOYSA-N 0.000 claims description 2
- PMNGXDYSRCIJKS-UHFFFAOYSA-N 2-[[1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-methyl-3-methylsulfanylpyrazol-4-yl]methyl]-3-(methoxymethyl)-3,4-dihydro-1h-isoquinoline Chemical compound COCC1CC2=CC=CC=C2CN1CC(C(=N1)SC)=C(C)N1C1=C(Cl)C=C(C(F)(F)F)C=C1Cl PMNGXDYSRCIJKS-UHFFFAOYSA-N 0.000 claims description 2
- MWPDOWUQTJTCRU-UHFFFAOYSA-N 2-[[3,5-diethyl-1-(2,4,6-trichlorophenyl)pyrazol-4-yl]methyl]-3-(methoxymethyl)-3,4-dihydro-1h-isoquinoline Chemical compound CCC1=C(CN2C(CC3=CC=CC=C3C2)COC)C(CC)=NN1C1=C(Cl)C=C(Cl)C=C1Cl MWPDOWUQTJTCRU-UHFFFAOYSA-N 0.000 claims description 2
- WPBWAPRNKZZQTQ-UHFFFAOYSA-N 2-[[3,5-diethyl-1-(2,4,6-trimethylphenyl)pyrazol-4-yl]methyl]-3-(methoxymethyl)-3,4-dihydro-1h-isoquinoline Chemical compound CCC1=C(CN2C(CC3=CC=CC=C3C2)COC)C(CC)=NN1C1=C(C)C=C(C)C=C1C WPBWAPRNKZZQTQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
- BFLRFUSUDUTDGP-UHFFFAOYSA-N 3-(methoxymethyl)-2-[[5-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)pyrazol-4-yl]methyl]-3,4-dihydro-1h-isoquinoline Chemical compound COCC1CC2=CC=CC=C2CN1CC(C(=N1)SC)=C(C)N1C1=C(Cl)C=C(Cl)C=C1Cl BFLRFUSUDUTDGP-UHFFFAOYSA-N 0.000 claims description 2
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 2
- 208000031886 HIV Infections Diseases 0.000 claims description 2
- 208000037357 HIV infectious disease Diseases 0.000 claims description 2
- 125000005605 benzo group Chemical group 0.000 claims description 2
- 150000001602 bicycloalkyls Chemical group 0.000 claims description 2
- 229910052796 boron Inorganic materials 0.000 claims description 2
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- 239000003488 releasing hormone Substances 0.000 claims description 2
- 150000003573 thiols Chemical class 0.000 claims description 2
- NDUVLNGCQJZGRJ-UHFFFAOYSA-N 2-[[1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-3,5-diethylpyrazol-4-yl]methyl]-3-(ethoxymethyl)-3,4-dihydro-1h-isoquinoline Chemical compound CCOCC1CC2=CC=CC=C2CN1CC(=C1CC)C(CC)=NN1C1=C(Cl)C=C(C(F)(F)F)C=C1Cl NDUVLNGCQJZGRJ-UHFFFAOYSA-N 0.000 claims 1
- 239000000275 Adrenocorticotropic Hormone Substances 0.000 claims 1
- GNBIGTRLEXKQFM-UHFFFAOYSA-N C1(CC1)C=C=COC Chemical group C1(CC1)C=C=COC GNBIGTRLEXKQFM-UHFFFAOYSA-N 0.000 claims 1
- 101800000414 Corticotropin Proteins 0.000 claims 1
- IMROMDMJAWUWLK-UHFFFAOYSA-N Ethenol Chemical group OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 claims 1
- 102100027467 Pro-opiomelanocortin Human genes 0.000 claims 1
- 125000004799 bromophenyl group Chemical group 0.000 claims 1
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 claims 1
- 229960000258 corticotropin Drugs 0.000 claims 1
- 102000012289 Corticotropin-Releasing Hormone Human genes 0.000 abstract description 5
- 108010022152 Corticotropin-Releasing Hormone Proteins 0.000 abstract description 5
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 78
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 33
- 239000000047 product Substances 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- 239000011541 reaction mixture Substances 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 239000012312 sodium hydride Substances 0.000 description 10
- 229910000104 sodium hydride Inorganic materials 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000000284 extract Substances 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 235000019198 oils Nutrition 0.000 description 9
- 239000012267 brine Substances 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 6
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000004817 gas chromatography Methods 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
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- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
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- 239000011591 potassium Substances 0.000 description 1
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- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
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- AJXVJQAPXVDFBT-UHFFFAOYSA-M sodium;naphthalen-2-olate Chemical compound [Na+].C1=CC=CC2=CC([O-])=CC=C21 AJXVJQAPXVDFBT-UHFFFAOYSA-M 0.000 description 1
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- 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
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Classifications
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- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
- C07D231/18—One oxygen or sulfur atom
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- 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
- C07D401/06—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 carbon chain containing only aliphatic carbon atoms
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Transplantation (AREA)
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- AIDS & HIV (AREA)
- Toxicology (AREA)
- Anesthesiology (AREA)
- Hematology (AREA)
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- Rheumatology (AREA)
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- Pregnancy & Childbirth (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US99222892A | 1992-12-17 | 1992-12-17 | |
| US992,228 | 1992-12-17 | ||
| PCT/US1993/009170 WO1994013661A1 (en) | 1992-12-17 | 1993-09-30 | Substituted pyrazoles as crf antagonists |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH08500121A JPH08500121A (ja) | 1996-01-09 |
| JP2781661B2 true JP2781661B2 (ja) | 1998-07-30 |
Family
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| JP6506653A Expired - Fee Related JP2781661B2 (ja) | 1992-12-17 | 1993-09-30 | Ｃｒｆアンタゴニストとしての置換ピラゾール |
Country Status (26)
Families Citing this family (78)
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| GB9222253D0 (en) * | 1992-10-23 | 1992-12-09 | Celltech Ltd | Chemical compounds |
| GB9304920D0 (en) * | 1993-03-10 | 1993-04-28 | Celltech Ltd | Chemical compounds |
| GB9304919D0 (en) * | 1993-03-10 | 1993-04-28 | Celltech Ltd | Chemical compounds |
| SK47096A3 (en) * | 1993-10-12 | 1996-10-02 | Du Pont Merck Pharma | 1n-alkyl-n-arylpyrimidinamines and derivatives thereof |
| GB9326699D0 (en) * | 1993-12-22 | 1994-03-02 | Celltech Ltd | Chemical compounds |
| ATE260911T1 (de) * | 1993-12-22 | 2004-03-15 | Celltech R&D Ltd | Trisubstituierte phenyl-derivate, verfahren zu deren herstellung und deren verwendung als phosphodiesterase (typ iv) hemmstoffe |
| US5968944A (en) * | 1994-06-06 | 1999-10-19 | Pfizer Inc. | Substituted pyrazoles as corticotropin-releasing factor (CRF) antagonists |
| AU719558B2 (en) * | 1994-06-06 | 2000-05-11 | Pfizer Inc. | Substituted pyrazoles having corticotropin-releasing factor (CRF) antagonist activity |
| US5786354A (en) * | 1994-06-21 | 1998-07-28 | Celltech Therapeutics, Limited | Tri-substituted phenyl derivatives and processes for their preparation |
| US6245774B1 (en) | 1994-06-21 | 2001-06-12 | Celltech Therapeutics Limited | Tri-substituted phenyl or pyridine derivatives |
| GB9412571D0 (en) | 1994-06-22 | 1994-08-10 | Celltech Ltd | Chemical compounds |
| GB9412573D0 (en) | 1994-06-22 | 1994-08-10 | Celltech Ltd | Chemical compounds |
| US7125880B1 (en) | 1995-06-06 | 2006-10-24 | Pfizer Inc. | Corticotropin releasing factor antagonists |
| US6403599B1 (en) | 1995-11-08 | 2002-06-11 | Pfizer Inc | Corticotropin releasing factor antagonists |
| GB9523675D0 (en) | 1995-11-20 | 1996-01-24 | Celltech Therapeutics Ltd | Chemical compounds |
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| GB9608435D0 (en) * | 1996-04-24 | 1996-06-26 | Celltech Therapeutics Ltd | Chemical compounds |
| US6011052A (en) * | 1996-04-30 | 2000-01-04 | Warner-Lambert Company | Pyrazolone derivatives as MCP-1 antagonists |
| US6060478A (en) * | 1996-07-24 | 2000-05-09 | Dupont Pharmaceuticals | Azolo triazines and pyrimidines |
| US7094782B1 (en) | 1996-07-24 | 2006-08-22 | Bristol-Myers Squibb Company | Azolo triazines and pyrimidines |
| US6124289A (en) * | 1996-07-24 | 2000-09-26 | Dupont Pharmaceuticals Co. | Azolo triazines and pyrimidines |
| US6313124B1 (en) | 1997-07-23 | 2001-11-06 | Dupont Pharmaceuticals Company | Tetrazine bicyclic compounds |
| US6191131B1 (en) | 1997-07-23 | 2001-02-20 | Dupont Pharmaceuticals Company | Azolo triazines and pyrimidines |
| US5861398A (en) * | 1996-08-26 | 1999-01-19 | Alanex Corporation | Benzoperimidine-carboxylic acids and derivatives thereof |
| DE69710594T2 (de) * | 1996-09-16 | 2002-08-29 | Du Pont Pharmaceuticals Co., Wilmington | Eine resorbierbare röntgenopake markierung enthaltendes chirurgisches implantat und verfahren zum verriegeln desselben in einem körper |
| GB9619284D0 (en) * | 1996-09-16 | 1996-10-30 | Celltech Therapeutics Ltd | Chemical compounds |
| GB9622363D0 (en) | 1996-10-28 | 1997-01-08 | Celltech Therapeutics Ltd | Chemical compounds |
| US5760225A (en) * | 1996-11-15 | 1998-06-02 | Neurogen Corporation | Certain pyrazole derivatives as corticotropin-releasing factor receptor CRF1 specific ligands |
| GB9625184D0 (en) * | 1996-12-04 | 1997-01-22 | Celltech Therapeutics Ltd | Chemical compounds |
| AU5330698A (en) * | 1996-12-23 | 1998-07-17 | Celltech Therapeutics Limited | Fused polycyclic 2-aminopyrimidine derivatives, their preparation and their use as protein tyrosine kinase inhibitors |
| US5723608A (en) | 1996-12-31 | 1998-03-03 | Neurogen Corporation | 3-aryl substituted pyrazolo 4,3-d!pyrimidine derivatives; corticotropin-releasing factor receptor (CRF1) specific ligands |
| GB9705361D0 (en) | 1997-03-14 | 1997-04-30 | Celltech Therapeutics Ltd | Chemical compounds |
| US6187781B1 (en) | 1997-03-26 | 2001-02-13 | Taisho Pharmaceutical Co., Ltd. | 4-Tetrahydropyridylpyrimidine derivatives |
| GB9713087D0 (en) * | 1997-06-20 | 1997-08-27 | Celltech Therapeutics Ltd | Chemical compounds |
| US5955471A (en) * | 1998-01-13 | 1999-09-21 | Sk Corporation | Tetrahydroisoquinolinealkanol derivatives and pharmaceutical compositions containing same |
| US6472402B1 (en) | 1998-04-02 | 2002-10-29 | Neurogen Corporation | Aminoalkyl substituted 5,6,7,8-Tetrahydro-9H-Pyridino [2,3-B]indole derivatives |
| JP2002510686A (ja) | 1998-04-02 | 2002-04-09 | ニューロゲン コーポレイション | アミノアルキルで置換された５，６，７，８−テトラヒドロ−９Ｈ−ピリジノ［２，３−ｂ］インドール及び５，６，７，８−テトラヒドロ−９Ｈピリミジノ［４，５−Ｂ］インドール誘導体：ＣＲＦ１特異的配位子 |
| CN1178941C (zh) | 1998-11-12 | 2004-12-08 | 纽罗克里恩生物科学有限公司 | Crf受体拮抗剂以及与其有关的方法 |
| WO2000027846A2 (en) | 1998-11-12 | 2000-05-18 | Neurocrine Biosciences, Inc. | Crf receptor antagonists and methods relating thereto |
| US6531475B1 (en) | 1998-11-12 | 2003-03-11 | Neurocrine Biosciences, Inc. | CRF receptor antagonists and methods relating thereto |
| GB9914258D0 (en) | 1999-06-18 | 1999-08-18 | Celltech Therapeutics Ltd | Chemical compounds |
| US6409988B1 (en) | 1999-07-01 | 2002-06-25 | 3-Dimensional Pharmaceuticals, Inc. | Radiolabeled 1-aryl pyrazoles, the synthesis thereof and the use thereof as pest GABA receptor ligands |
| US6506784B1 (en) | 1999-07-01 | 2003-01-14 | 3-Dimensional Pharmaceuticals, Inc. | Use of 1,3-substituted pyrazol-5-yl sulfonates as pesticides |
| US6518266B1 (en) | 1999-07-22 | 2003-02-11 | 3-Dimensional Pharmaceuticals | 1- Aryl-3-thioalkyl pyrazoles, the synthesis thereof and the use thereof as insecticides |
| WO2001025241A2 (en) | 1999-10-06 | 2001-04-12 | 3-Dimensional Pharmaceuticals, Inc. | Fused 1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazoles, the synthesis thereof and the use thereof as pesticides |
| GB9924862D0 (en) | 1999-10-20 | 1999-12-22 | Celltech Therapeutics Ltd | Chemical compounds |
| TWI271406B (en) | 1999-12-13 | 2007-01-21 | Eisai Co Ltd | Tricyclic condensed heterocyclic compounds, preparation method of the same and pharmaceuticals comprising the same |
| US6569885B1 (en) | 1999-12-23 | 2003-05-27 | Icos Corporation | Cyclic AMP-specific phosphodiesterase inhibitors |
| CA2398956A1 (en) * | 2000-02-14 | 2001-08-16 | Japan Tobacco Inc. | A pharmaceutical composition for prophylaxis or therapy of a postoperative stress |
| AU2001234180A1 (en) * | 2000-02-25 | 2001-09-03 | Japan Tobacco Inc. | Benzamide derivative and use thereof |
| GB0016453D0 (en) * | 2000-07-04 | 2000-08-23 | Hoffmann La Roche | Pyrrole derivatives |
| GB0016787D0 (en) | 2000-07-07 | 2000-08-30 | Pfizer Ltd | Compounds useful in therapy |
| GB0024795D0 (en) * | 2000-10-10 | 2000-11-22 | Hoffmann La Roche | Pyrazole derivatives for the treatment of viral diseases |
| US20060223824A1 (en) | 2000-11-28 | 2006-10-05 | Wyeth | Serotonergic agents |
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| TWI312347B (en) | 2001-02-08 | 2009-07-21 | Eisai R&D Man Co Ltd | Bicyclic nitrogen-containing condensed ring compounds |
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| BRPI0620464A2 (pt) * | 2005-12-23 | 2011-11-16 | Astrazeneca Ab | composto, composição farmacêutica, uso de um composto, e, método para o tratamento de uma doença |
| JP2009544626A (ja) * | 2006-07-21 | 2009-12-17 | アイアールエム・リミテッド・ライアビリティ・カンパニー | Ｉｔｐｋｂ阻害剤としての化合物および組成物 |
| CL2008000119A1 (es) | 2007-01-16 | 2008-05-16 | Wyeth Corp | Compuestos derivados de pirazol, antagonistas del receptor nicotinico de acetilcolina; composicion farmaceutica; y uso en el tratamiento de enfermedades tales como demencia senil, alzheimer y esquizofrenia. |
| PT2167498E (pt) | 2007-06-15 | 2010-11-29 | Irm Llc | Compostos e composições como inibidores de itpkb |
| WO2009104080A2 (en) | 2008-02-20 | 2009-08-27 | Targia Pharmaceuticals | Cns pharmaceutical compositions and methods of use |
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| SU1427781A1 (ru) * | 1987-02-13 | 1992-04-23 | Научно-исследовательский институт фармакологии АМН СССР | 4-Аминокарбонил- или 4-аминоэтил-5-метилпиразолы, обладающие способностью регулировать скорость выведени этанола |
| US5063245A (en) * | 1990-03-28 | 1991-11-05 | Nova Pharmaceutical Corporation | Corticotropin-releasing factor antagonism compounds |
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1993
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