KR20120081973A - 질소-함유 화합물 및 심방 세동의 치료를 위한 그의 제약 조성물 - Google Patents
질소-함유 화합물 및 심방 세동의 치료를 위한 그의 제약 조성물 Download PDFInfo
- Publication number
- KR20120081973A KR20120081973A KR1020127004471A KR20127004471A KR20120081973A KR 20120081973 A KR20120081973 A KR 20120081973A KR 1020127004471 A KR1020127004471 A KR 1020127004471A KR 20127004471 A KR20127004471 A KR 20127004471A KR 20120081973 A KR20120081973 A KR 20120081973A
- Authority
- KR
- South Korea
- Prior art keywords
- optionally substituted
- lower alkyl
- group
- oxo
- pyridyl
- 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
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 41
- 206010003658 Atrial Fibrillation Diseases 0.000 title description 12
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 title description 8
- -1 diazepine compound Chemical class 0.000 claims abstract description 684
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 527
- 125000001424 substituent group Chemical group 0.000 claims abstract description 278
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 142
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 126
- 150000003839 salts Chemical class 0.000 claims abstract description 62
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 53
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 41
- 239000001257 hydrogen Substances 0.000 claims abstract description 41
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 28
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 13
- 125000002576 diazepinyl group Chemical class N1N=C(C=CC=C1)* 0.000 claims abstract description 8
- 125000000962 organic group Chemical group 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 355
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 147
- 125000004043 oxo group Chemical group O=* 0.000 claims description 142
- 229910052736 halogen Inorganic materials 0.000 claims description 125
- 150000002367 halogens Chemical class 0.000 claims description 121
- 125000001589 carboacyl group Chemical group 0.000 claims description 65
- 125000000623 heterocyclic group Chemical group 0.000 claims description 62
- 238000000034 method Methods 0.000 claims description 57
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 55
- 125000004076 pyridyl group Chemical group 0.000 claims description 48
- 125000002541 furyl group Chemical group 0.000 claims description 44
- 125000002883 imidazolyl group Chemical group 0.000 claims description 42
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 41
- 229910052757 nitrogen Inorganic materials 0.000 claims description 41
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 34
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 34
- 125000001544 thienyl group Chemical group 0.000 claims description 33
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 30
- 125000003282 alkyl amino group Chemical group 0.000 claims description 29
- 125000002757 morpholinyl group Chemical group 0.000 claims description 29
- 125000003118 aryl group Chemical group 0.000 claims description 26
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 26
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 26
- 125000004450 alkenylene group Chemical group 0.000 claims description 25
- 206010003119 arrhythmia Diseases 0.000 claims description 25
- 230000006793 arrhythmia Effects 0.000 claims description 25
- 125000001425 triazolyl group Chemical group 0.000 claims description 24
- 125000002971 oxazolyl group Chemical group 0.000 claims description 23
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 23
- 229920006395 saturated elastomer Polymers 0.000 claims description 23
- 125000005843 halogen group Chemical group 0.000 claims description 21
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 21
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 20
- 125000000335 thiazolyl group Chemical group 0.000 claims description 20
- 125000005493 quinolyl group Chemical group 0.000 claims description 18
- 125000004414 alkyl thio group Chemical group 0.000 claims description 17
- 125000001041 indolyl group Chemical group 0.000 claims description 17
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 17
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 17
- 125000005936 piperidyl group Chemical group 0.000 claims description 17
- 229910052717 sulfur Inorganic materials 0.000 claims description 17
- 125000004193 piperazinyl group Chemical group 0.000 claims description 16
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 15
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 229940049706 benzodiazepine Drugs 0.000 claims description 14
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 14
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 14
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 13
- 125000005946 imidazo[1,2-a]pyridyl group Chemical group 0.000 claims description 12
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 11
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 11
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 11
- 125000005877 1,4-benzodioxanyl group Chemical group 0.000 claims description 10
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 10
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 10
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 10
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 10
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims description 10
- 125000003367 polycyclic group Chemical group 0.000 claims description 10
- 150000001204 N-oxides Chemical class 0.000 claims description 9
- 125000004423 acyloxy group Chemical group 0.000 claims description 7
- 125000005606 carbostyryl group Chemical group 0.000 claims description 7
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 7
- 125000002393 azetidinyl group Chemical group 0.000 claims description 6
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 239000011593 sulfur Substances 0.000 claims description 5
- HBSZBMCPARLGST-UHFFFAOYSA-N 1-ethyl-3,3,5-trimethyl-7-[2-[2-(2-methyl-4-oxofuro[3,2-c]pyridin-5-yl)ethyl-[(4-methylpyridin-3-yl)methyl]amino]ethyl]-1,5-benzodiazepine-2,4-dione Chemical compound C1=C2N(C)C(=O)C(C)(C)C(=O)N(CC)C2=CC=C1CCN(CCN1C(C=2C=C(C)OC=2C=C1)=O)CC1=CN=CC=C1C HBSZBMCPARLGST-UHFFFAOYSA-N 0.000 claims description 4
- PIVIBAWPEWMUGA-UHFFFAOYSA-N 1-ethyl-7-[[[2-(methoxymethyl)pyridin-3-yl]methyl-[2-(2-methyl-4-oxofuro[3,2-c]pyridin-5-yl)ethyl]amino]methyl]-3,3,5-trimethyl-1,5-benzodiazepine-2,4-dione Chemical compound C1=C2N(C)C(=O)C(C)(C)C(=O)N(CC)C2=CC=C1CN(CCN1C(C=2C=C(C)OC=2C=C1)=O)CC1=CC=CN=C1COC PIVIBAWPEWMUGA-UHFFFAOYSA-N 0.000 claims description 4
- DIWJUIXPQZRWDB-UHFFFAOYSA-N 1-ethyl-7-[[[2-(methoxymethyl)pyridin-3-yl]methyl-[2-(7-methyl-4-oxofuro[3,2-c]pyridin-5-yl)ethyl]amino]methyl]-3,3,5-trimethyl-1,5-benzodiazepine-2,4-dione Chemical compound C1=C2N(C)C(=O)C(C)(C)C(=O)N(CC)C2=CC=C1CN(CCN1C(C=2C=COC=2C(C)=C1)=O)CC1=CC=CN=C1COC DIWJUIXPQZRWDB-UHFFFAOYSA-N 0.000 claims description 4
- XKVLXGCOQTXISM-UHFFFAOYSA-N 7-[[2-(2,7-dimethyl-4-oxofuro[3,2-c]pyridin-5-yl)ethyl-[(2,5-dimethylpyrazol-3-yl)methyl]amino]methyl]-1-ethyl-3,3,5-trimethyl-1,5-benzodiazepine-2,4-dione Chemical compound C1=C2N(C)C(=O)C(C)(C)C(=O)N(CC)C2=CC=C1CN(CCN1C(C=2C=C(C)OC=2C(C)=C1)=O)CC1=CC(C)=NN1C XKVLXGCOQTXISM-UHFFFAOYSA-N 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000003725 azepanyl group Chemical group 0.000 claims description 4
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 claims description 4
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 3
- 125000005873 benzo[d]thiazolyl group Chemical group 0.000 claims description 3
- BFTZNPALLKWPGM-UHFFFAOYSA-N 1-ethyl-3,3,5-trimethyl-7-[2-[(2-methylpyridin-3-yl)methyl-[2-(4-oxofuro[3,2-c]pyridin-5-yl)ethyl]amino]ethyl]-1,5-benzodiazepine-2,4-dione Chemical compound C1=C2N(C)C(=O)C(C)(C)C(=O)N(CC)C2=CC=C1CCN(CCN1C(C=2C=COC=2C=C1)=O)CC1=CC=CN=C1C BFTZNPALLKWPGM-UHFFFAOYSA-N 0.000 claims description 2
- JMBXCBLUFALXFQ-UHFFFAOYSA-N 1-ethyl-3,3,5-trimethyl-7-[2-[(2-methylpyridin-3-yl)methyl-[2-(4-oxofuro[3,2-c]pyridin-5-yl)ethyl]amino]ethyl]-1,5-benzodiazepine-2,4-dione;dihydrochloride Chemical compound Cl.Cl.C1=C2N(C)C(=O)C(C)(C)C(=O)N(CC)C2=CC=C1CCN(CCN1C(C=2C=COC=2C=C1)=O)CC1=CC=CN=C1C JMBXCBLUFALXFQ-UHFFFAOYSA-N 0.000 claims description 2
- BZSOVJGYIPHHPI-UHFFFAOYSA-N 1-ethyl-3,3,5-trimethyl-7-[2-[2-(2-methyl-4-oxofuro[3,2-c]pyridin-5-yl)ethyl-(pyridin-4-ylmethyl)amino]ethyl]-1,5-benzodiazepine-2,4-dione Chemical compound C1=C2N(C)C(=O)C(C)(C)C(=O)N(CC)C2=CC=C1CCN(CCN1C(C=2C=C(C)OC=2C=C1)=O)CC1=CC=NC=C1 BZSOVJGYIPHHPI-UHFFFAOYSA-N 0.000 claims description 2
- HRBFRCQPTYGPCU-UHFFFAOYSA-N 1-ethyl-3,3,5-trimethyl-7-[2-[2-(2-methyl-4-oxofuro[3,2-c]pyridin-5-yl)ethyl-(pyridin-4-ylmethyl)amino]ethyl]-1,5-benzodiazepine-2,4-dione;dihydrochloride Chemical compound Cl.Cl.C1=C2N(C)C(=O)C(C)(C)C(=O)N(CC)C2=CC=C1CCN(CCN1C(C=2C=C(C)OC=2C=C1)=O)CC1=CC=NC=C1 HRBFRCQPTYGPCU-UHFFFAOYSA-N 0.000 claims description 2
- VTTMYHZFIVNFDO-UHFFFAOYSA-N 1-ethyl-3,3,5-trimethyl-7-[3-[2-(2-methyl-4-oxofuro[3,2-c]pyridin-5-yl)ethyl-(pyridin-4-ylmethyl)amino]propyl]-1,5-benzodiazepine-2,4-dione Chemical compound C1=C2N(C)C(=O)C(C)(C)C(=O)N(CC)C2=CC=C1CCCN(CCN1C(C=2C=C(C)OC=2C=C1)=O)CC1=CC=NC=C1 VTTMYHZFIVNFDO-UHFFFAOYSA-N 0.000 claims description 2
- CTBHRNOKFGKHNG-UHFFFAOYSA-N 1-ethyl-3,3,5-trimethyl-7-[3-[2-(2-methyl-4-oxofuro[3,2-c]pyridin-5-yl)ethyl-(pyridin-4-ylmethyl)amino]propyl]-1,5-benzodiazepine-2,4-dione;dihydrochloride Chemical compound Cl.Cl.C1=C2N(C)C(=O)C(C)(C)C(=O)N(CC)C2=CC=C1CCCN(CCN1C(C=2C=C(C)OC=2C=C1)=O)CC1=CC=NC=C1 CTBHRNOKFGKHNG-UHFFFAOYSA-N 0.000 claims description 2
- HBQOOAUBDGHDPR-UHFFFAOYSA-N 1-ethyl-3,3,5-trimethyl-7-[[(2-methylpyridin-3-yl)methyl-[2-(1-oxoisoquinolin-2-yl)ethyl]amino]methyl]-1,5-benzodiazepine-2,4-dione Chemical compound C1=C2N(C)C(=O)C(C)(C)C(=O)N(CC)C2=CC=C1CN(CCN1C(C2=CC=CC=C2C=C1)=O)CC1=CC=CN=C1C HBQOOAUBDGHDPR-UHFFFAOYSA-N 0.000 claims description 2
- JTJBXYGORBJNJY-UHFFFAOYSA-N 1-ethyl-3,3,5-trimethyl-7-[[(2-methylpyridin-3-yl)methyl-[2-(1-oxoisoquinolin-2-yl)ethyl]amino]methyl]-1,5-benzodiazepine-2,4-dione;dihydrochloride Chemical compound Cl.Cl.C1=C2N(C)C(=O)C(C)(C)C(=O)N(CC)C2=CC=C1CN(CCN1C(C2=CC=CC=C2C=C1)=O)CC1=CC=CN=C1C JTJBXYGORBJNJY-UHFFFAOYSA-N 0.000 claims description 2
- ZOXIUAGKZYYSTB-UHFFFAOYSA-N 7-[[benzyl(2-pyridin-3-ylethyl)amino]methyl]-1-ethyl-3,3,5-trimethyl-1,5-benzodiazepine-2,4-dione Chemical compound C1=C2N(C)C(=O)C(C)(C)C(=O)N(CC)C2=CC=C1CN(CC=1C=CC=CC=1)CCC1=CC=CN=C1 ZOXIUAGKZYYSTB-UHFFFAOYSA-N 0.000 claims description 2
- SLBVAPAORNWYJR-UHFFFAOYSA-N 7-[[benzyl(2-pyridin-3-ylethyl)amino]methyl]-1-ethyl-3,3,5-trimethyl-1,5-benzodiazepine-2,4-dione;hydrochloride Chemical compound Cl.C1=C2N(C)C(=O)C(C)(C)C(=O)N(CC)C2=CC=C1CN(CC=1C=CC=CC=1)CCC1=CC=CN=C1 SLBVAPAORNWYJR-UHFFFAOYSA-N 0.000 claims description 2
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- FJMRKRIGYBJJQV-UHFFFAOYSA-N n-[2-[[(1-ethyl-3,3,5-trimethyl-2,4-dioxo-1,5-benzodiazepin-7-yl)methyl-(2-pyridin-3-ylethyl)amino]methyl]phenyl]methanesulfonamide Chemical compound C1=C2N(C)C(=O)C(C)(C)C(=O)N(CC)C2=CC=C1CN(CC=1C(=CC=CC=1)NS(C)(=O)=O)CCC1=CC=CN=C1 FJMRKRIGYBJJQV-UHFFFAOYSA-N 0.000 claims description 2
- PMDVTBUXNKNCNA-UHFFFAOYSA-N n-[2-[[(1-ethyl-3,3,5-trimethyl-2,4-dioxo-1,5-benzodiazepin-7-yl)methyl-(2-pyridin-3-ylethyl)amino]methyl]phenyl]methanesulfonamide;dihydrochloride Chemical compound Cl.Cl.C1=C2N(C)C(=O)C(C)(C)C(=O)N(CC)C2=CC=C1CN(CC=1C(=CC=CC=1)NS(C)(=O)=O)CCC1=CC=CN=C1 PMDVTBUXNKNCNA-UHFFFAOYSA-N 0.000 claims description 2
- 240000000662 Anethum graveolens Species 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 claims 1
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 claims 1
- 108091006146 Channels Proteins 0.000 abstract description 22
- 101001026214 Homo sapiens Potassium voltage-gated channel subfamily A member 5 Proteins 0.000 abstract description 12
- 238000006243 chemical reaction Methods 0.000 description 224
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 104
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 81
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 78
- 239000002904 solvent Substances 0.000 description 75
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
- 150000007514 bases Chemical class 0.000 description 65
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 64
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 60
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 54
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 48
- 125000004432 carbon atom Chemical group C* 0.000 description 48
- 239000003638 chemical reducing agent Substances 0.000 description 47
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 44
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 42
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 42
- 239000002253 acid Substances 0.000 description 42
- 239000000203 mixture Substances 0.000 description 41
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 40
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 40
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 38
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 32
- 125000001931 aliphatic group Chemical group 0.000 description 31
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 30
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 30
- 150000001412 amines Chemical class 0.000 description 30
- 150000002148 esters Chemical class 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- 150000002170 ethers Chemical class 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 26
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 26
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 24
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 24
- 150000008282 halocarbons Chemical class 0.000 description 21
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 21
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 20
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 20
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 20
- 239000003814 drug Substances 0.000 description 20
- 235000019253 formic acid Nutrition 0.000 description 20
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 19
- 150000007513 acids Chemical class 0.000 description 19
- 239000003054 catalyst Substances 0.000 description 19
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 19
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- 238000006192 iodination reaction Methods 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- GUWHRJQTTVADPB-UHFFFAOYSA-N lithium azide Chemical compound [Li+].[N-]=[N+]=[N-] GUWHRJQTTVADPB-UHFFFAOYSA-N 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000003328 mesylation reaction Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000003551 muscarinic effect Effects 0.000 description 1
- OQJBFFCUFALWQL-UHFFFAOYSA-N n-(piperidine-1-carbonylimino)piperidine-1-carboxamide Chemical compound C1CCCCN1C(=O)N=NC(=O)N1CCCCC1 OQJBFFCUFALWQL-UHFFFAOYSA-N 0.000 description 1
- YTCLURCISMZCOA-UHFFFAOYSA-N n-diaminophosphoryl-n-phenylaniline Chemical compound C=1C=CC=CC=1N(P(N)(=O)N)C1=CC=CC=C1 YTCLURCISMZCOA-UHFFFAOYSA-N 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 229910000480 nickel oxide Inorganic materials 0.000 description 1
- GNRSAWUEBMWBQH-UHFFFAOYSA-N oxonickel Chemical compound [Ni]=O GNRSAWUEBMWBQH-UHFFFAOYSA-N 0.000 description 1
- HBEQXAKJSGXAIQ-UHFFFAOYSA-N oxopalladium Chemical compound [Pd]=O HBEQXAKJSGXAIQ-UHFFFAOYSA-N 0.000 description 1
- 229910003445 palladium oxide Inorganic materials 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- LFAGQMCIGQNPJG-UHFFFAOYSA-N silver cyanide Chemical compound [Ag+].N#[C-] LFAGQMCIGQNPJG-UHFFFAOYSA-N 0.000 description 1
- 229940098221 silver cyanide Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- QKSQWQOAUQFORH-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical compound CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C QKSQWQOAUQFORH-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000005942 tetrahydropyridyl group Chemical group 0.000 description 1
- 150000003623 transition metal compounds Chemical class 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- REDSKZBUUUQMSK-UHFFFAOYSA-N tributyltin Chemical compound CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC REDSKZBUUUQMSK-UHFFFAOYSA-N 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 150000003732 xanthenes Chemical class 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- 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
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/12—1,5-Benzodiazepines; Hydrogenated 1,5-benzodiazepines
-
- 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
-
- 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
-
- 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
-
- 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
- C07D403/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Heart & Thoracic Surgery (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Quinoline Compounds (AREA)
- Pyridine Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Peptides Or Proteins (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Applications Claiming Priority (8)
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP5649577B2 (ja) * | 2009-08-21 | 2015-01-07 | 大塚製薬株式会社 | ベンゾ[b][1,4]ジアゼピン−2,4−ジオン化合物の製造方法 |
| WO2012162818A1 (en) * | 2011-06-03 | 2012-12-06 | Queen's University At Kingston | Substituted diarylamines and use of same as antioxidants |
| US8940742B2 (en) | 2012-04-10 | 2015-01-27 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| CN102627597B (zh) * | 2012-04-25 | 2013-10-23 | 山东轻工业学院 | 吲哚-3-甲醛异丁酰腙类衍生物及其制备方法 |
| WO2014184272A2 (en) * | 2013-05-14 | 2014-11-20 | Medizinische Hochschule Hannover | Means and methods for treating cancer |
| US9751888B2 (en) | 2013-10-04 | 2017-09-05 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| MX389256B (es) | 2013-10-04 | 2025-03-20 | Infinity Pharmaceuticals Inc | Compuestos heterociclicos y usos de los mismos. |
| EA201691872A1 (ru) | 2014-03-19 | 2017-04-28 | Инфинити Фармасьютикалз, Инк. | Гетероциклические соединения для применения в лечении pi3k-гамма-опосредованных расстройств |
| WO2016054491A1 (en) | 2014-10-03 | 2016-04-07 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| CN108349985A (zh) | 2015-09-14 | 2018-07-31 | 无限药品股份有限公司 | 异喹啉酮的固体形式、其制备方法、包含其的组合物及其使用方法 |
| WO2017161116A1 (en) | 2016-03-17 | 2017-09-21 | Infinity Pharmaceuticals, Inc. | Isotopologues of isoquinolinone and quinazolinone compounds and uses thereof as pi3k kinase inhibitors |
| WO2017214269A1 (en) | 2016-06-08 | 2017-12-14 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| WO2018112843A1 (en) | 2016-12-22 | 2018-06-28 | Merck Sharp & Dohme Corp. | Heteroaryl piperidine ether allosteric modulators of the m4 muscarinic acetylcholine receptor |
Family Cites Families (33)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US3133056A (en) * | 1961-05-15 | 1964-05-12 | May & Baker Ltd | N-phenylpiperazine derivatives of tetrahydrobenzodiazepines |
| US3984398A (en) | 1966-12-14 | 1976-10-05 | Roussel-Uclaf | 1,5-Benzodiazepine-2,4-diones |
| US4001408A (en) | 1966-12-14 | 1977-01-04 | Roussel-Uclaf | Substituted heterocyclic compounds, processes and composition including those |
| BE707667A (enExample) | 1966-12-14 | 1968-06-07 | ||
| GB1460936A (en) | 1974-10-01 | 1977-01-06 | Beecham Group Ltd | Benzodiazepines |
| JPS545981A (en) * | 1977-06-10 | 1979-01-17 | Otsuka Pharmaceut Co Ltd | Carbostyryl derivatives |
| IE46852B1 (en) | 1977-06-10 | 1983-10-05 | Otsuka Pharma Co Ltd | Novel carbostyril derivatives |
| JPS54163825A (en) * | 1978-06-15 | 1979-12-26 | Otsuka Pharma Co Ltd | Phosphoesterase inhibitor |
| JPS5579372A (en) * | 1978-12-08 | 1980-06-14 | Otsuka Pharmaceut Co Ltd | Preparation of carbostyril derivative |
| JPS56122356A (en) * | 1980-02-29 | 1981-09-25 | Otsuka Pharmaceut Co Ltd | Carbostyril derivative |
| JPS5780322A (en) * | 1980-11-05 | 1982-05-19 | Otsuka Pharmaceut Co Ltd | Cardiotonic agent |
| JPS6010008B2 (ja) * | 1982-07-12 | 1985-03-14 | 大塚製薬株式会社 | 血小板凝集抑制剤 |
| JP2753622B2 (ja) * | 1988-05-02 | 1998-05-20 | 大塚製薬株式会社 | カルボスチリル誘導体 |
| DE68920797T2 (de) * | 1988-08-10 | 1995-06-29 | Otsuka Pharma Co Ltd | Herzmittel. |
| JPH0296133A (ja) | 1988-10-01 | 1990-04-06 | Fuji Photo Film Co Ltd | ハロゲン化銀カラー写真感光材料 |
| JPH03148223A (ja) * | 1989-11-02 | 1991-06-25 | Otsuka Pharmaceut Co Ltd | 血小板凝集抑制剤 |
| BR9200951A (pt) * | 1991-03-21 | 1992-11-17 | Hoffmann La Roche | Compostos, processo para sua producao,preparacoes farmaceuticas e uso |
| JPH05194405A (ja) * | 1991-08-23 | 1993-08-03 | Otsuka Pharmaceut Co Ltd | カルボスチリル誘導体及び血小板凝集抑制剤 |
| CA2093633A1 (en) * | 1991-08-23 | 1993-02-24 | Seiji Sato | Carbostyril derivative and platelets aggregation inhibitory agent |
| PE27497A1 (es) | 1994-04-15 | 1997-08-07 | Glaxo Inc | Derivados de 1,5 benzodiazepina |
| US5700797A (en) | 1995-06-07 | 1997-12-23 | Merck & Co, Inc. | N-(2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl)-3-amides |
| US5691331A (en) * | 1995-06-07 | 1997-11-25 | Merck & Co., Inc. | N-(2,4-Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3yl) -3- amides |
| TW338037B (en) | 1995-10-05 | 1998-08-11 | Otsuka Pharma Co Ltd | Carbostyril derivatives possessing platelet aggregation inhibitory activity, antithrombotic activity, intima thinkening, inhibitory activity and phosphoriesterase inhibitory activity, their preparation and pharmaceutical composition |
| JP2964029B2 (ja) * | 1995-10-05 | 1999-10-18 | 大塚製薬株式会社 | カルボスチリル誘導体 |
| GB0008179D0 (en) | 2000-04-05 | 2000-05-24 | Glaxo Group Ltd | Chemical process |
| WO2001010216A1 (en) * | 1999-08-09 | 2001-02-15 | Merck & Co., Inc. | Antiarrhythmic compounds |
| US6949542B2 (en) | 2002-02-06 | 2005-09-27 | Hoffman-La Roche Inc. | Dihydro-benzo[b][1,4]diazepin-2-one derivatives |
| US7772433B2 (en) | 2002-02-28 | 2010-08-10 | University Of Tennessee Research Foundation | SARMS and method of use thereof |
| MXPA05006701A (es) * | 2002-12-20 | 2006-03-30 | Amgen Inc | Moduladores de asma y de inflacion alergica. |
| TWI329641B (en) * | 2005-08-31 | 2010-09-01 | Otsuka Pharma Co Ltd | (benzo[b]thiophen-4-yl)piperazine compounds, pharmaceutical compositions comprising the same, uses of the same and processes for preparing the same |
| JP2007290984A (ja) * | 2006-04-21 | 2007-11-08 | Kowa Co | コフィリン結合剤、及びコフィリン結合剤を有効成分とする抗癌剤 |
| JP4785881B2 (ja) | 2007-02-27 | 2011-10-05 | 大塚製薬株式会社 | 医薬 |
| MY156226A (en) * | 2008-02-22 | 2016-01-29 | Otsuka Pharma Co Ltd | Benzodiazepine compound and pharmaceutical composition |
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