BG107817A - Бензодиазепинови производни като gaba a рецепторни модулатори - Google Patents

Бензодиазепинови производни като gaba a рецепторни модулатори Download PDF

Info

Publication number: BG107817A
Authority: BG; Bulgaria
Prior art keywords: triazolo; imidazo; benzodiazepine; ethyl; oxadiazol
Prior art date: 2000-11-16

Application number

BG107817A

Other languages

Bulgarian (bg)

English (en)

Inventor

Raffaello Masciadri

William A. Thomas

Juergen Wichmann

Original Assignee

F. Hoffmann- La Roche Ag

Priority date (The priority date 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 date listed.)

2000-11-16

Filing date

2003-05-16

Publication date

2004-07-30

2003-05-16 Application filed by F. Hoffmann- La Roche Ag filed Critical F. Hoffmann- La Roche Ag

2004-07-30 Publication of BG107817A publication Critical patent/BG107817A/bg

Links

102000004300 GABA-A Receptors Human genes 0.000 title description 17
108090000839 GABA-A Receptors Proteins 0.000 title description 17
229940053197 benzodiazepine derivative antiepileptics Drugs 0.000 title 1
125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 title 1
150000001875 compounds Chemical class 0.000 claims abstract description 151
-1 -SO2CH3 Chemical group 0.000 claims abstract description 146
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 108
GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical compound N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 claims abstract description 45
125000000217 alkyl group Chemical group 0.000 claims abstract description 26
BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims abstract description 24
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 20
239000001257 hydrogen Substances 0.000 claims abstract description 20
150000003839 salts Chemical class 0.000 claims abstract description 19
229910052736 halogen Inorganic materials 0.000 claims abstract description 17
229960003692 gamma aminobutyric acid Drugs 0.000 claims abstract description 13
150000002367 halogens Chemical group 0.000 claims abstract description 13
239000002253 acid Substances 0.000 claims abstract description 12
125000003545 alkoxy group Chemical group 0.000 claims abstract description 12
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 9
125000001424 substituent group Chemical group 0.000 claims abstract description 9
201000010099 disease Diseases 0.000 claims abstract description 8
125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 8
SFPHNARDXIEZPB-UHFFFAOYSA-N C1=NNN2C=CN=C3C(=C21)C=C(C=C3)C(=O)O Chemical compound C1=NNN2C=CN=C3C(=C21)C=C(C=C3)C(=O)O SFPHNARDXIEZPB-UHFFFAOYSA-N 0.000 claims abstract description 7
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 7
125000001766 1,2,4-oxadiazol-3-yl group Chemical group [H]C1=NC(*)=NO1 0.000 claims abstract description 4
125000004414 alkyl thio group Chemical group 0.000 claims abstract description 4
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 4
NKWDDGCMDWGDLU-UHFFFAOYSA-N 3H-[1,2,4]triazolo[4,3-d][1,4]benzodiazepine Chemical compound N1=NCN2C=CN=C3C(=C21)C=CC=C3 NKWDDGCMDWGDLU-UHFFFAOYSA-N 0.000 claims abstract description 3
125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 3
125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 3
238000000034 method Methods 0.000 claims description 34
NZTCFMPWFGWRBN-UHFFFAOYSA-N 3H-[1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid Chemical compound N1=NCN2C=CN=C3C(=C21)C=C(C=C3)C(=O)O NZTCFMPWFGWRBN-UHFFFAOYSA-N 0.000 claims description 22
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
RKJGFHGUMFXDDX-UHFFFAOYSA-N N1N=CC2=CN=C3C(=CN21)C=CC=C3 Chemical compound N1N=CC2=CN=C3C(=CN21)C=CC=C3 RKJGFHGUMFXDDX-UHFFFAOYSA-N 0.000 claims description 11
125000000980 1H-indol-3-ylmethyl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C(C([H])([H])[*])C2=C1[H] 0.000 claims description 10
150000002431 hydrogen Chemical class 0.000 claims description 10
238000002360 preparation method Methods 0.000 claims description 10
125000006497 3-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 claims description 7
125000001309 chloro group Chemical group Cl* 0.000 claims description 6
239000003814 drug Substances 0.000 claims description 6
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
125000001246 bromo group Chemical group Br* 0.000 claims description 5
239000000546 pharmaceutical excipient Substances 0.000 claims description 5
125000004505 1,2,4-oxadiazol-5-yl group Chemical group O1N=CN=C1* 0.000 claims description 3
125000000173 4-trifluoromethoxy benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC(F)(F)F)C([H])([H])* 0.000 claims description 3
125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 3
125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 3
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
208000035475 disorder Diseases 0.000 claims description 2
125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims 2
125000006701 (C1-C7) alkyl group Chemical group 0.000 claims 1
FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 claims 1
125000005605 benzo group Chemical group 0.000 claims 1
230000003930 cognitive ability Effects 0.000 claims 1
229940079593 drug Drugs 0.000 claims 1
230000001131 transforming effect Effects 0.000 claims 1
SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical class N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 abstract description 4
125000000753 cycloalkyl group Chemical group 0.000 abstract description 3
125000004503 1,2,3-oxadiazol-5-yl group Chemical group O1N=NC=C1* 0.000 abstract 1
AXLOCHLTNQDFFS-BESJYZOMSA-N azastene Chemical compound C([C@H]1[C@@H]2CC[C@@]([C@]2(CC[C@@H]1[C@@]1(C)C2)C)(O)C)C=C1C(C)(C)C1=C2C=NO1 AXLOCHLTNQDFFS-BESJYZOMSA-N 0.000 abstract 1
239000000203 mixture Substances 0.000 description 91
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 73
239000000243 solution Substances 0.000 description 70
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 46
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
239000000460 chlorine Substances 0.000 description 34
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 32
235000019439 ethyl acetate Nutrition 0.000 description 31
238000010992 reflux Methods 0.000 description 31
239000007787 solid Substances 0.000 description 31
MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 30
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 28
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 28
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 27
239000000741 silica gel Substances 0.000 description 27
229910002027 silica gel Inorganic materials 0.000 description 27
238000001816 cooling Methods 0.000 description 26
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 24
URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 22
239000000725 suspension Substances 0.000 description 19
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
239000012044 organic layer Substances 0.000 description 18
XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 18
229910052786 argon Inorganic materials 0.000 description 16
FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 16
OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 15
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
239000013078 crystal Substances 0.000 description 15
238000003756 stirring Methods 0.000 description 15
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 13
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
GYVGXEWAOAAJEU-UHFFFAOYSA-N n,n,4-trimethylaniline Chemical compound CN(C)C1=CC=C(C)C=C1 GYVGXEWAOAAJEU-UHFFFAOYSA-N 0.000 description 12
229910052938 sodium sulfate Inorganic materials 0.000 description 12
235000011152 sodium sulphate Nutrition 0.000 description 12
OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 11
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
230000027455 binding Effects 0.000 description 10
238000004587 chromatography analysis Methods 0.000 description 10
239000006260 foam Substances 0.000 description 10
238000006243 chemical reaction Methods 0.000 description 9
230000000694 effects Effects 0.000 description 8
102000005962 receptors Human genes 0.000 description 8
108020003175 receptors Proteins 0.000 description 8
239000000829 suppository Substances 0.000 description 8
GYHLCXMCGCVVCG-UHFFFAOYSA-N 2-(1h-indol-3-yl)acetohydrazide Chemical compound C1=CC=C2C(CC(=O)NN)=CNC2=C1 GYHLCXMCGCVVCG-UHFFFAOYSA-N 0.000 description 7
230000015572 biosynthetic process Effects 0.000 description 7
239000012043 crude product Substances 0.000 description 7
XZBIXDPGRMLSTC-UHFFFAOYSA-N formohydrazide Chemical compound NNC=O XZBIXDPGRMLSTC-UHFFFAOYSA-N 0.000 description 7
125000000623 heterocyclic group Chemical group 0.000 description 7
239000000047 product Substances 0.000 description 7
239000011734 sodium Substances 0.000 description 7
ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 7
AJVOIZUSHCYQHZ-UHFFFAOYSA-N 2-[(2,4-dimethoxyphenyl)methylazaniumyl]acetate Chemical compound COC1=CC=C(CNCC(O)=O)C(OC)=C1 AJVOIZUSHCYQHZ-UHFFFAOYSA-N 0.000 description 6
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
238000000354 decomposition reaction Methods 0.000 description 6
238000010438 heat treatment Methods 0.000 description 6
239000007858 starting material Substances 0.000 description 6
NEZWLDSUVYAJED-UHFFFAOYSA-N 2-[4-(dimethylamino)phenyl]acetohydrazide Chemical compound CN(C)C1=CC=C(CC(=O)NN)C=C1 NEZWLDSUVYAJED-UHFFFAOYSA-N 0.000 description 5
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
210000004027 cell Anatomy 0.000 description 5
JXVAFPULGWAWJD-UHFFFAOYSA-N ethyl 2-(dimethylaminomethylideneamino)acetate Chemical compound CCOC(=O)CN=CN(C)C JXVAFPULGWAWJD-UHFFFAOYSA-N 0.000 description 5
239000007903 gelatin capsule Substances 0.000 description 5
239000007788 liquid Substances 0.000 description 5
DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 5
229910052757 nitrogen Inorganic materials 0.000 description 5
239000002244 precipitate Substances 0.000 description 5
238000003786 synthesis reaction Methods 0.000 description 5
GUMZPHOQHLZJOY-UHFFFAOYSA-N 1,3-oxazine-2,4-dione Chemical compound O=C1C=COC(=O)N1 GUMZPHOQHLZJOY-UHFFFAOYSA-N 0.000 description 4
FPTCVTJCJMVIDV-UHFFFAOYSA-N 2-phenylacetohydrazide Chemical compound NNC(=O)CC1=CC=CC=C1 FPTCVTJCJMVIDV-UHFFFAOYSA-N 0.000 description 4
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
239000007983 Tris buffer Substances 0.000 description 4
YBGJZYCWGNYUMA-UHFFFAOYSA-M [Cl-].[P+]=O Chemical compound [Cl-].[P+]=O YBGJZYCWGNYUMA-UHFFFAOYSA-M 0.000 description 4
239000013543 active substance Substances 0.000 description 4
125000004494 ethyl ester group Chemical group 0.000 description 4
238000002474 experimental method Methods 0.000 description 4
ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
239000011541 reaction mixture Substances 0.000 description 4
230000001953 sensory effect Effects 0.000 description 4
235000017557 sodium bicarbonate Nutrition 0.000 description 4
229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
239000002904 solvent Substances 0.000 description 4
GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 4
LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
HRMXYTRKEOUMNG-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)acetohydrazide Chemical compound COC1=CC=C(CC(=O)NN)C=C1OC HRMXYTRKEOUMNG-UHFFFAOYSA-N 0.000 description 3
XEALVGVRTCEVES-UHFFFAOYSA-N 2-(3-methoxyphenyl)acetohydrazide Chemical compound COC1=CC=CC(CC(=O)NN)=C1 XEALVGVRTCEVES-UHFFFAOYSA-N 0.000 description 3
AKHLSIQEYPSGKE-UHFFFAOYSA-N 2-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)methyl]isoindole-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1CC(ON=1)=NC=1C1CC1 AKHLSIQEYPSGKE-UHFFFAOYSA-N 0.000 description 3
125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 3
ARDQOKBQXMKAJW-UHFFFAOYSA-N 5h-azulen-6-one Chemical compound C1=CC(=O)CC=C2C=CC=C21 ARDQOKBQXMKAJW-UHFFFAOYSA-N 0.000 description 3
MNPWKUXZCUMLFU-UHFFFAOYSA-N 7-bromo-4-[(2,4-dimethoxyphenyl)methyl]-1,3-dihydro-1,4-benzodiazepine-2,5-dione Chemical compound COC1=CC(OC)=CC=C1CN1C(=O)C2=CC(Br)=CC=C2NC(=O)C1 MNPWKUXZCUMLFU-UHFFFAOYSA-N 0.000 description 3
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
229920002261 Corn starch Polymers 0.000 description 3
239000004471 Glycine Substances 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
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 3
239000012346 acetyl chloride Substances 0.000 description 3
229940049706 benzodiazepine Drugs 0.000 description 3
239000002775 capsule Substances 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
239000008120 corn starch Substances 0.000 description 3
ZGLDQGIONSGJCN-UHFFFAOYSA-N diazepin-5-one Chemical compound O=C1C=CN=NC=C1 ZGLDQGIONSGJCN-UHFFFAOYSA-N 0.000 description 3
239000008298 dragée Substances 0.000 description 3
NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 3
JGYPIGSWFPYDMC-UHFFFAOYSA-N ethyl 6-chloro-8-methoxy-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound C1N=C(Cl)C2=CC(OC)=CC=C2N2C=NC(C(=O)OCC)=C21 JGYPIGSWFPYDMC-UHFFFAOYSA-N 0.000 description 3
RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 3
239000000706 filtrate Substances 0.000 description 3
OFBIFZUFASYYRE-UHFFFAOYSA-N flumazenil Chemical compound C1N(C)C(=O)C2=CC(F)=CC=C2N2C=NC(C(=O)OCC)=C21 OFBIFZUFASYYRE-UHFFFAOYSA-N 0.000 description 3
229960004381 flumazenil Drugs 0.000 description 3
239000008101 lactose Substances 0.000 description 3
239000012528 membrane Substances 0.000 description 3
239000000825 pharmaceutical preparation Substances 0.000 description 3
UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 3
229920005862 polyol Polymers 0.000 description 3
150000003077 polyols Chemical class 0.000 description 3
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 3
239000001993 wax Substances 0.000 description 3
QHJGIQJGUODHCU-UHFFFAOYSA-N (3-cyclopropyl-5h-1,2,4-oxadiazol-4-yl)methanamine Chemical compound NCN1CON=C1C1CC1 QHJGIQJGUODHCU-UHFFFAOYSA-N 0.000 description 2
BWKAYBPLDRWMCJ-UHFFFAOYSA-N 1,1-diethoxy-n,n-dimethylmethanamine Chemical compound CCOC(N(C)C)OCC BWKAYBPLDRWMCJ-UHFFFAOYSA-N 0.000 description 2
LWRSYTXEQUUTKW-UHFFFAOYSA-N 2,4-dimethoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C(OC)=C1 LWRSYTXEQUUTKW-UHFFFAOYSA-N 0.000 description 2
WQINSVOOIJDOLJ-UHFFFAOYSA-N 2-(1,3-dioxoisoindol-2-yl)acetic acid Chemical compound C1=CC=C2C(=O)N(CC(=O)O)C(=O)C2=C1 WQINSVOOIJDOLJ-UHFFFAOYSA-N 0.000 description 2
BCHPFJXZQWWCCZ-UHFFFAOYSA-N 2-(4-methoxyphenyl)acetohydrazide Chemical compound COC1=CC=C(CC(=O)NN)C=C1 BCHPFJXZQWWCCZ-UHFFFAOYSA-N 0.000 description 2
HRPIIQAHTMPUAF-UHFFFAOYSA-N 2-(5-methyl-1h-indol-3-yl)acetohydrazide Chemical compound CC1=CC=C2NC=C(CC(=O)NN)C2=C1 HRPIIQAHTMPUAF-UHFFFAOYSA-N 0.000 description 2
NBUUUJWWOARGNW-UHFFFAOYSA-N 2-amino-5-methylbenzoic acid Chemical compound CC1=CC=C(N)C(C(O)=O)=C1 NBUUUJWWOARGNW-UHFFFAOYSA-N 0.000 description 2
FEXJFVKXGYXIRT-UHFFFAOYSA-N 2-chloro-4-[(2,4-dimethoxyphenyl)methyl]-7-methoxy-3h-1,4-benzodiazepin-5-one Chemical compound COC1=CC(OC)=CC=C1CN1C(=O)C2=CC(OC)=CC=C2N=C(Cl)C1 FEXJFVKXGYXIRT-UHFFFAOYSA-N 0.000 description 2
GOZGQVRUDSZIBP-UHFFFAOYSA-N 2-chloro-4-[(2,4-dimethoxyphenyl)methyl]-7-methylsulfanyl-3h-1,4-benzodiazepin-5-one Chemical compound COC1=CC(OC)=CC=C1CN1C(=O)C2=CC(SC)=CC=C2N=C(Cl)C1 GOZGQVRUDSZIBP-UHFFFAOYSA-N 0.000 description 2
LJTHYSSOGSSWGL-UHFFFAOYSA-N 4-[(2,4-dimethoxyphenyl)methyl]-7-methoxy-1,3-dihydro-1,4-benzodiazepine-2,5-dione Chemical compound COC1=CC(OC)=CC=C1CN1C(=O)C2=CC(OC)=CC=C2NC(=O)C1 LJTHYSSOGSSWGL-UHFFFAOYSA-N 0.000 description 2
NPLCIHFPCPIHPP-UHFFFAOYSA-N 4-[(2,4-dimethoxyphenyl)methyl]-7-methyl-1,3-dihydro-1,4-benzodiazepine-2,5-dione Chemical compound COC1=CC(OC)=CC=C1CN1C(=O)C2=CC(C)=CC=C2NC(=O)C1 NPLCIHFPCPIHPP-UHFFFAOYSA-N 0.000 description 2
125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 2
HWAOHWIPJLMOAB-UHFFFAOYSA-N 5-(8-bromo-6-chloro-4h-imidazo[1,5-a][1,4]benzodiazepin-3-yl)-3-cyclopropyl-1,2,4-oxadiazole Chemical compound N1=CN2C3=CC=C(Br)C=C3C(Cl)=NCC2=C1C(ON=1)=NC=1C1CC1 HWAOHWIPJLMOAB-UHFFFAOYSA-N 0.000 description 2
JFAFNQOODJCVGT-UHFFFAOYSA-N 6-methoxy-1h-3,1-benzoxazine-2,4-dione Chemical compound N1C(=O)OC(=O)C2=CC(OC)=CC=C21 JFAFNQOODJCVGT-UHFFFAOYSA-N 0.000 description 2
IIXZSGIPOINDJO-UHFFFAOYSA-N 6-methyl-1h-3,1-benzoxazine-2,4-dione Chemical compound N1C(=O)OC(=O)C2=CC(C)=CC=C21 IIXZSGIPOINDJO-UHFFFAOYSA-N 0.000 description 2
UKHFPVCOXBJPIN-UHFFFAOYSA-N 9H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester Chemical compound N1C2=CC=CC=C2C2=C1C=NC(C(=O)OC)=C2 UKHFPVCOXBJPIN-UHFFFAOYSA-N 0.000 description 2
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
208000024827 Alzheimer disease Diseases 0.000 description 2
VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
102000004310 Ion Channels Human genes 0.000 description 2
108090000862 Ion Channels Proteins 0.000 description 2
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
241000700159 Rattus Species 0.000 description 2
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
239000000556 agonist Substances 0.000 description 2
RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
125000004124 azulen-6-yl group Chemical group [H]C1=C([H])C2=C([H])C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 2
239000002585 base Substances 0.000 description 2
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
229910052794 bromium Inorganic materials 0.000 description 2
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
125000004432 carbon atom Chemical group C* 0.000 description 2
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
239000003795 chemical substances by application Substances 0.000 description 2
229910052801 chlorine Inorganic materials 0.000 description 2
125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
RRUMLROPBAZIDM-UHFFFAOYSA-N ethyl 6,8-dibromo-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound C1N=C(Br)C2=CC(Br)=CC=C2N2C=NC(C(=O)OCC)=C21 RRUMLROPBAZIDM-UHFFFAOYSA-N 0.000 description 2
BDXRIFYLHNNJNV-UHFFFAOYSA-N ethyl 6-chloro-8-methyl-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound C1N=C(Cl)C2=CC(C)=CC=C2N2C=NC(C(=O)OCC)=C21 BDXRIFYLHNNJNV-UHFFFAOYSA-N 0.000 description 2
AKTDYUGXMFZUGI-UHFFFAOYSA-N ethyl 8-bromo-6-oxo-4,5-dihydroimidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound C1NC(=O)C2=CC(Br)=CC=C2N2C=NC(C(=O)OCC)=C21 AKTDYUGXMFZUGI-UHFFFAOYSA-N 0.000 description 2
CWKQABFGMDNHJK-UHFFFAOYSA-N ethyl 8-methoxy-6-oxo-4,5-dihydroimidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound C1NC(=O)C2=CC(OC)=CC=C2N2C=NC(C(=O)OCC)=C21 CWKQABFGMDNHJK-UHFFFAOYSA-N 0.000 description 2
VMCLHHXSXIJYAP-UHFFFAOYSA-N ethyl 8-methyl-6-oxo-4,5-dihydroimidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound C1NC(=O)C2=CC(C)=CC=C2N2C=NC(C(=O)OCC)=C21 VMCLHHXSXIJYAP-UHFFFAOYSA-N 0.000 description 2
239000003925 fat Substances 0.000 description 2
239000003446 ligand Substances 0.000 description 2
ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
150000007522 mineralic acids Chemical class 0.000 description 2
OMCUPXRCMTUDHI-UHFFFAOYSA-N n'-hydroxycyclopropanecarboximidamide Chemical compound ON=C(N)C1CC1 OMCUPXRCMTUDHI-UHFFFAOYSA-N 0.000 description 2
150000007524 organic acids Chemical class 0.000 description 2
239000008188 pellet Substances 0.000 description 2
230000000144 pharmacologic effect Effects 0.000 description 2
102000004169 proteins and genes Human genes 0.000 description 2
108090000623 proteins and genes Proteins 0.000 description 2
239000000018 receptor agonist Substances 0.000 description 2
229940044601 receptor agonist Drugs 0.000 description 2
239000011780 sodium chloride Substances 0.000 description 2
239000000454 talc Substances 0.000 description 2
229910052623 talc Inorganic materials 0.000 description 2
FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
239000008096 xylene Substances 0.000 description 2
FGWYWKIOMUZSQF-UHFFFAOYSA-N 1,1,1-triethoxypropane Chemical compound CCOC(CC)(OCC)OCC FGWYWKIOMUZSQF-UHFFFAOYSA-N 0.000 description 1
DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical compound CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
RAXBGBHBUFGWPG-UHFFFAOYSA-N 1,3-benzodioxole-5-carbohydrazide Chemical compound NNC(=O)C1=CC=C2OCOC2=C1 RAXBGBHBUFGWPG-UHFFFAOYSA-N 0.000 description 1
SURVUDPNZQGEJD-UHFFFAOYSA-N 1,4-diazepin-5-one Chemical compound O=C1C=CN=CC=N1 SURVUDPNZQGEJD-UHFFFAOYSA-N 0.000 description 1
POXWDTQUDZUOGP-UHFFFAOYSA-N 1h-1,4-diazepine Chemical compound N1C=CC=NC=C1 POXWDTQUDZUOGP-UHFFFAOYSA-N 0.000 description 1
XPFSMDZLNJRDNP-UHFFFAOYSA-N 1h-azepine-2,5-dione Chemical compound O=C1C=CNC(=O)C=C1 XPFSMDZLNJRDNP-UHFFFAOYSA-N 0.000 description 1
LZOISVDTQDUWEU-UHFFFAOYSA-N 2,4,8,10,11-pentazatetracyclo[11.4.0.02,6.08,12]heptadeca-1(17),4,6,9,11,13,15-heptaene Chemical class C=1N2C=NN=C2C2=CC=CC=C2N2CN=CC2=1 LZOISVDTQDUWEU-UHFFFAOYSA-N 0.000 description 1
RUQXGTPXKXCQME-UHFFFAOYSA-N 2-(1,3-benzodioxol-5-yl)acetohydrazide Chemical compound NNC(=O)CC1=CC=C2OCOC2=C1 RUQXGTPXKXCQME-UHFFFAOYSA-N 0.000 description 1
ZIQDOYGGMLNUCE-UHFFFAOYSA-N 2-(2,4-dimethoxyphenyl)acetohydrazide Chemical compound COC1=CC=C(CC(=O)NN)C(OC)=C1 ZIQDOYGGMLNUCE-UHFFFAOYSA-N 0.000 description 1
WSKCRBSHOIAZBQ-UHFFFAOYSA-N 2-(2-chlorophenyl)acetohydrazide Chemical compound NNC(=O)CC1=CC=CC=C1Cl WSKCRBSHOIAZBQ-UHFFFAOYSA-N 0.000 description 1
XOJKKBKZYLQRMC-UHFFFAOYSA-N 2-(2-methoxyphenyl)acetohydrazide Chemical compound COC1=CC=CC=C1CC(=O)NN XOJKKBKZYLQRMC-UHFFFAOYSA-N 0.000 description 1
CCPXEEAPDKISAS-UHFFFAOYSA-N 2-(2-methyl-1h-indol-3-yl)acetohydrazide Chemical compound C1=CC=C2C(CC(=O)NN)=C(C)NC2=C1 CCPXEEAPDKISAS-UHFFFAOYSA-N 0.000 description 1
OQTVDJMTAGGYCY-UHFFFAOYSA-N 2-(4-methylsulfonylphenyl)acetohydrazide Chemical compound CS(=O)(=O)C1=CC=C(CC(=O)NN)C=C1 OQTVDJMTAGGYCY-UHFFFAOYSA-N 0.000 description 1
JFONGQRKKZPXLX-UHFFFAOYSA-N 2-(4-nitrophenyl)acetohydrazide Chemical compound NNC(=O)CC1=CC=C([N+]([O-])=O)C=C1 JFONGQRKKZPXLX-UHFFFAOYSA-N 0.000 description 1
MLSJQOUEHHYKAD-UHFFFAOYSA-N 2-(4-phenylphenyl)acetohydrazide Chemical compound C1=CC(CC(=O)NN)=CC=C1C1=CC=CC=C1 MLSJQOUEHHYKAD-UHFFFAOYSA-N 0.000 description 1
AVJDUEZEDGKGIV-UHFFFAOYSA-N 2-(5-methoxy-1h-indol-3-yl)acetohydrazide Chemical compound COC1=CC=C2NC=C(CC(=O)NN)C2=C1 AVJDUEZEDGKGIV-UHFFFAOYSA-N 0.000 description 1
HYNQTSZBTIOFKH-UHFFFAOYSA-N 2-Amino-5-hydroxybenzoic acid Chemical compound NC1=CC=C(O)C=C1C(O)=O HYNQTSZBTIOFKH-UHFFFAOYSA-N 0.000 description 1
UMKSAURFQFUULT-UHFFFAOYSA-N 2-Amino-5-methoxybenzoic acid Chemical compound COC1=CC=C(N)C(C(O)=O)=C1 UMKSAURFQFUULT-UHFFFAOYSA-N 0.000 description 1
HOBZDLZRQWTFBE-UHFFFAOYSA-N 2-[2-(trifluoromethyl)phenyl]acetohydrazide Chemical compound NNC(=O)CC1=CC=CC=C1C(F)(F)F HOBZDLZRQWTFBE-UHFFFAOYSA-N 0.000 description 1
JNALJBUPABHFKK-UHFFFAOYSA-N 2-[3-(trifluoromethyl)phenyl]acetohydrazide Chemical compound NNC(=O)CC1=CC=CC(C(F)(F)F)=C1 JNALJBUPABHFKK-UHFFFAOYSA-N 0.000 description 1
VYIDYFSEDRZNIM-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]acetohydrazide Chemical compound NNC(=O)CC1=CC=C(OC(F)(F)F)C=C1 VYIDYFSEDRZNIM-UHFFFAOYSA-N 0.000 description 1
QWDJAZKQUMSQPQ-UHFFFAOYSA-N 2-[4-(trifluoromethyl)phenyl]acetohydrazide Chemical compound NNC(=O)CC1=CC=C(C(F)(F)F)C=C1 QWDJAZKQUMSQPQ-UHFFFAOYSA-N 0.000 description 1
QWNMKHLBVHTPFW-UHFFFAOYSA-N 2-amino-5-propan-2-ylbenzoic acid Chemical compound CC(C)C1=CC=C(N)C(C(O)=O)=C1 QWNMKHLBVHTPFW-UHFFFAOYSA-N 0.000 description 1
NPEIUNVTLXEOLT-UHFFFAOYSA-N 2-chloro-1,1,1-trimethoxyethane Chemical compound COC(CCl)(OC)OC NPEIUNVTLXEOLT-UHFFFAOYSA-N 0.000 description 1
FBRCVJHCGWUFKT-UHFFFAOYSA-N 2-chloro-4-[(2,4-dimethoxyphenyl)methyl]-7-methyl-3h-1,4-benzodiazepin-5-one Chemical compound COC1=CC(OC)=CC=C1CN1C(=O)C2=CC(C)=CC=C2N=C(Cl)C1 FBRCVJHCGWUFKT-UHFFFAOYSA-N 0.000 description 1
KFXZLLZDQCLYTO-UHFFFAOYSA-N 2-chloro-4-[(2,4-dimethoxyphenyl)methyl]-7-propan-2-yl-3h-1,4-benzodiazepin-5-one Chemical compound COC1=CC(OC)=CC=C1CN1C(=O)C2=CC(C(C)C)=CC=C2N=C(Cl)C1 KFXZLLZDQCLYTO-UHFFFAOYSA-N 0.000 description 1
125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
GVPVKNZZLIICEQ-UHFFFAOYSA-N 2-cyclopropylacetohydrazide Chemical compound NNC(=O)CC1CC1 GVPVKNZZLIICEQ-UHFFFAOYSA-N 0.000 description 1
MOKRDWKSHLLYKM-UHFFFAOYSA-N 2-hydrazinyl-2-oxoacetamide Chemical compound NNC(=O)C(N)=O MOKRDWKSHLLYKM-UHFFFAOYSA-N 0.000 description 1
LIUCWHQVLKSECA-UHFFFAOYSA-N 2-hydroxyacetohydrazide Chemical compound NNC(=O)CO LIUCWHQVLKSECA-UHFFFAOYSA-N 0.000 description 1
125000002927 2-methoxybenzyl group Chemical group [H]C1=C([H])C([H])=C(C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 description 1
NZJBELWVJFYUBJ-UHFFFAOYSA-N 2-pyridin-4-ylacetic acid;dihydrochloride Chemical compound Cl.Cl.OC(=O)CC1=CC=NC=C1 NZJBELWVJFYUBJ-UHFFFAOYSA-N 0.000 description 1
125000006494 2-trifluoromethyl benzyl group Chemical group [H]C1=C([H])C([H])=C(C(=C1[H])C([H])([H])*)C(F)(F)F 0.000 description 1
GTYZDORKFFSTLS-UHFFFAOYSA-N 2h-3,1-benzoxazine Chemical class C1=CC=CC2=NCOC=C21 GTYZDORKFFSTLS-UHFFFAOYSA-N 0.000 description 1
XCDKQKNUUYBVBS-UHFFFAOYSA-N 3-(1,3-benzodioxol-5-yl)propanehydrazide Chemical compound NNC(=O)CCC1=CC=C2OCOC2=C1 XCDKQKNUUYBVBS-UHFFFAOYSA-N 0.000 description 1
CGFZALQDDSEJJF-UHFFFAOYSA-N 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5-[(2,4-dimethoxyphenyl)methyl]-8-methoxy-4h-imidazo[1,5-a][1,4]benzodiazepin-6-one Chemical compound COC1=CC(OC)=CC=C1CN1C(=O)C2=CC(OC)=CC=C2N2C=NC(C=3ON=C(N=3)C3CC3)=C2C1 CGFZALQDDSEJJF-UHFFFAOYSA-N 0.000 description 1
MGKAEYHAAAUNSX-UHFFFAOYSA-N 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5-[(2,4-dimethoxyphenyl)methyl]-8-methyl-4h-imidazo[1,5-a][1,4]benzodiazepin-6-one Chemical compound COC1=CC(OC)=CC=C1CN1C(=O)C2=CC(C)=CC=C2N2C=NC(C=3ON=C(N=3)C3CC3)=C2C1 MGKAEYHAAAUNSX-UHFFFAOYSA-N 0.000 description 1
ABWKONTVVZNLEU-UHFFFAOYSA-N 3-hydroxypropanehydrazide Chemical compound NNC(=O)CCO ABWKONTVVZNLEU-UHFFFAOYSA-N 0.000 description 1
RDVYNYHUUGFVQN-UHFFFAOYSA-N 3-methyl-2h-phthalazine-1,4-dione Chemical compound C1=CC=C2C(=O)N(C)NC(=O)C2=C1 RDVYNYHUUGFVQN-UHFFFAOYSA-N 0.000 description 1
125000006495 3-trifluoromethyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])*)C(F)(F)F 0.000 description 1
XHBHKHBUALFEOU-UHFFFAOYSA-N 4,5-dihydroimidazo[1,5-a][1,4]benzodiazepin-6-one Chemical compound O=C1NCC2=CN=CN2C2=CC=CC=C12 XHBHKHBUALFEOU-UHFFFAOYSA-N 0.000 description 1
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 1
FIFJQFDXXJYMLD-UHFFFAOYSA-N 4-[(2,4-dimethoxyphenyl)methyl]-7-methylsulfanyl-1,3-dihydro-1,4-benzodiazepine-2,5-dione Chemical compound COC1=CC(OC)=CC=C1CN1C(=O)C2=CC(SC)=CC=C2NC(=O)C1 FIFJQFDXXJYMLD-UHFFFAOYSA-N 0.000 description 1
SYGNOVJSWQWNRY-UHFFFAOYSA-N 4-[(2,4-dimethoxyphenyl)methyl]-7-propan-2-yl-1,3-dihydro-1,4-benzodiazepine-2,5-dione Chemical compound COC1=CC(OC)=CC=C1CN1C(=O)C2=CC(C(C)C)=CC=C2NC(=O)C1 SYGNOVJSWQWNRY-UHFFFAOYSA-N 0.000 description 1
AZRRZGIBBLWSSQ-UHFFFAOYSA-N 4-ethyl-7-phenyl-3,5-diazabicyclo[2.2.2]octane-2,6-dione Chemical compound N1C(=O)C2C(=O)NC1(CC)CC2C1=CC=CC=C1 AZRRZGIBBLWSSQ-UHFFFAOYSA-N 0.000 description 1
125000001318 4-trifluoromethylbenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])*)C(F)(F)F 0.000 description 1
NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
DXSMYDSFWCOSFM-UHFFFAOYSA-N 6-bromo-1h-3,1-benzoxazine-2,4-dione Chemical compound N1C(=O)OC(=O)C2=CC(Br)=CC=C21 DXSMYDSFWCOSFM-UHFFFAOYSA-N 0.000 description 1
LNEXPKRQROQPAP-UHFFFAOYSA-N 6-oxo-8-propan-2-yl-4,5-dihydroimidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid Chemical compound O=C1NCC2=C(C(O)=O)N=CN2C2=CC=C(C(C)C)C=C21 LNEXPKRQROQPAP-UHFFFAOYSA-N 0.000 description 1
QMTYHQGXRLSCQT-UHFFFAOYSA-N 8-chloro-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4,5-dihydroimidazo[1,5-a][1,4]benzodiazepin-6-one Chemical compound C=1C(Cl)=CC=C(N2C=N3)C=1C(=O)NCC2=C3C(N=1)=NOC=1C1CC1 QMTYHQGXRLSCQT-UHFFFAOYSA-N 0.000 description 1
ZOWAKJXFWINEIV-UHFFFAOYSA-N 8-chloro-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-[(2,4-dimethoxyphenyl)methyl]-4h-imidazo[1,5-a][1,4]benzodiazepin-6-one Chemical compound COC1=CC(OC)=CC=C1CN1C(=O)C2=CC(Cl)=CC=C2N2C=NC(C=3N=C(ON=3)C3CC3)=C2C1 ZOWAKJXFWINEIV-UHFFFAOYSA-N 0.000 description 1
RNDQUOVSTYXDCB-UHFFFAOYSA-N 8-chloro-5-[(2,4-dimethoxyphenyl)methyl]-6-oxo-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile Chemical compound COC1=CC(OC)=CC=C1CN1C(=O)C2=CC(Cl)=CC=C2N2C=NC(C#N)=C2C1 RNDQUOVSTYXDCB-UHFFFAOYSA-N 0.000 description 1
238000009010 Bradford assay Methods 0.000 description 1
CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
BOCKQRZBJRNIAZ-UHFFFAOYSA-N C1(CC1)C1=NOC(=N1)N=C(N(C)C)C Chemical compound C1(CC1)C1=NOC(=N1)N=C(N(C)C)C BOCKQRZBJRNIAZ-UHFFFAOYSA-N 0.000 description 1
HIYQVJJCBASKQC-UHFFFAOYSA-N C1=NC(=C2CNCC3=C(N12)C=CC=C3)C#N Chemical compound C1=NC(=C2CNCC3=C(N12)C=CC=C3)C#N HIYQVJJCBASKQC-UHFFFAOYSA-N 0.000 description 1
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
102000017934 GABA-B receptor Human genes 0.000 description 1
108060003377 GABA-B receptor Proteins 0.000 description 1
WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
229920000168 Microcrystalline cellulose Polymers 0.000 description 1
238000012347 Morris Water Maze Methods 0.000 description 1
FGJTVJHKCOEOKY-UHFFFAOYSA-N N,N-dimethyl-2-(oxadiazol-5-yl)ethanimidamide Chemical compound O1N=NC=C1CC(=N)N(C)C FGJTVJHKCOEOKY-UHFFFAOYSA-N 0.000 description 1
GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
235000021355 Stearic acid Nutrition 0.000 description 1
229910000831 Steel Inorganic materials 0.000 description 1
KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
229930006000 Sucrose Natural products 0.000 description 1
GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
BVYVVQWACMERMD-UHFFFAOYSA-N [3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-8-methoxy-4h-imidazo[1,5-a][1,4]benzodiazepin-6-yl]hydrazine Chemical compound C=1C(OC)=CC=C(N2C=N3)C=1C(NN)=NCC2=C3C(ON=1)=NC=1C1CC1 BVYVVQWACMERMD-UHFFFAOYSA-N 0.000 description 1
150000001242 acetic acid derivatives Chemical class 0.000 description 1
ZMQBBPRAZLACCW-UHFFFAOYSA-N acetic acid;dichloromethane Chemical compound ClCCl.CC(O)=O ZMQBBPRAZLACCW-UHFFFAOYSA-N 0.000 description 1
OFLXLNCGODUUOT-UHFFFAOYSA-N acetohydrazide Chemical compound C\C(O)=N\N OFLXLNCGODUUOT-UHFFFAOYSA-N 0.000 description 1
239000003513 alkali Substances 0.000 description 1
229910000147 aluminium phosphate Inorganic materials 0.000 description 1
150000001408 amides Chemical class 0.000 description 1
239000003963 antioxidant agent Substances 0.000 description 1
230000000949 anxiolytic effect Effects 0.000 description 1
239000007864 aqueous solution Substances 0.000 description 1
CUFNKYGDVFVPHO-UHFFFAOYSA-N azulene Chemical compound C1=CC=CC2=CC=CC2=C1 CUFNKYGDVFVPHO-UHFFFAOYSA-N 0.000 description 1
VNZBKOMHHNBFPS-UHFFFAOYSA-N azulene-1-carboximidamide Chemical compound C1=CC=CC=C2C(C(=N)N)=CC=C21 VNZBKOMHHNBFPS-UHFFFAOYSA-N 0.000 description 1
HGLFWLLFPGIKOT-UHFFFAOYSA-N azulene-1-carboxylic acid Chemical compound C1=CC=CC=C2C(C(=O)O)=CC=C21 HGLFWLLFPGIKOT-UHFFFAOYSA-N 0.000 description 1
239000012148 binding buffer Substances 0.000 description 1
239000000872 buffer Substances 0.000 description 1
KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
239000003990 capacitor Substances 0.000 description 1
150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
239000003054 catalyst Substances 0.000 description 1
239000003153 chemical reaction reagent Substances 0.000 description 1
150000001860 citric acid derivatives Chemical class 0.000 description 1
230000019771 cognition Effects 0.000 description 1
239000003086 colorant Substances 0.000 description 1
238000005056 compaction Methods 0.000 description 1
230000009137 competitive binding Effects 0.000 description 1
238000010276 construction Methods 0.000 description 1
238000007796 conventional method Methods 0.000 description 1
239000003179 convulsant agent Substances 0.000 description 1
238000002425 crystallisation Methods 0.000 description 1
230000008025 crystallization Effects 0.000 description 1
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 1
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
229960003529 diazepam Drugs 0.000 description 1
AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
RCJVRSBWZCNNQT-UHFFFAOYSA-N dichloridooxygen Chemical compound ClOCl RCJVRSBWZCNNQT-UHFFFAOYSA-N 0.000 description 1
238000006073 displacement reaction Methods 0.000 description 1
238000004821 distillation Methods 0.000 description 1
239000002552 dosage form Substances 0.000 description 1
238000001035 drying Methods 0.000 description 1
239000003995 emulsifying agent Substances 0.000 description 1
239000000839 emulsion Substances 0.000 description 1
230000002708 enhancing effect Effects 0.000 description 1
238000011067 equilibration Methods 0.000 description 1
PUSKHXMZPOMNTQ-UHFFFAOYSA-N ethyl 2,1,3-benzoselenadiazole-5-carboxylate Chemical compound CCOC(=O)C1=CC=C2N=[Se]=NC2=C1 PUSKHXMZPOMNTQ-UHFFFAOYSA-N 0.000 description 1
KLMCGBQPWCZXOH-UHFFFAOYSA-N ethyl 5-[(2,4-dimethoxyphenyl)methyl]-6-oxo-8-propan-2-yl-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound CCOC(=O)C=1N=CN(C2=CC=C(C=C2C2=O)C(C)C)C=1CN2CC1=CC=C(OC)C=C1OC KLMCGBQPWCZXOH-UHFFFAOYSA-N 0.000 description 1
NCJFITZMCOZJJG-UHFFFAOYSA-N ethyl 5-[(2,4-dimethoxyphenyl)methyl]-8-methoxy-6-oxo-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound CCOC(=O)C=1N=CN(C2=CC=C(OC)C=C2C2=O)C=1CN2CC1=CC=C(OC)C=C1OC NCJFITZMCOZJJG-UHFFFAOYSA-N 0.000 description 1
YNNJJFCTTLDJPE-UHFFFAOYSA-N ethyl 5-[(2,4-dimethoxyphenyl)methyl]-8-methyl-6-oxo-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound CCOC(=O)C=1N=CN(C2=CC=C(C)C=C2C2=O)C=1CN2CC1=CC=C(OC)C=C1OC YNNJJFCTTLDJPE-UHFFFAOYSA-N 0.000 description 1
FZHHPMNXLJQUOY-UHFFFAOYSA-N ethyl 6-chloro-8-propan-2-yl-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound C1N=C(Cl)C2=CC(C(C)C)=CC=C2N2C=NC(C(=O)OCC)=C21 FZHHPMNXLJQUOY-UHFFFAOYSA-N 0.000 description 1
CUVDXJJLINNBDB-UHFFFAOYSA-N ethyl 8-[tert-butyl(diphenyl)silyl]oxy-6-oxo-4,5-dihydroimidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound CCOC(=O)C=1N=CN(C2=CC=3)C=1CNC(=O)C2=CC=3O[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 CUVDXJJLINNBDB-UHFFFAOYSA-N 0.000 description 1
MDMOGZSWJAFOBB-UHFFFAOYSA-N ethyl 8-bromo-5-[(2,4-dimethoxyphenyl)methyl]-6-oxo-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound CCOC(=O)C=1N=CN(C2=CC=C(Br)C=C2C2=O)C=1CN2CC1=CC=C(OC)C=C1OC MDMOGZSWJAFOBB-UHFFFAOYSA-N 0.000 description 1
HJDRCNIDFRVPMH-UHFFFAOYSA-N ethyl 8-bromo-6-chloro-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound C1N=C(Cl)C2=CC(Br)=CC=C2N2C=NC(C(=O)OCC)=C21 HJDRCNIDFRVPMH-UHFFFAOYSA-N 0.000 description 1
ADEACBHLBQTGPA-UHFFFAOYSA-N ethyl 8-bromo-6-hydrazinyl-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound C1N=C(NN)C2=CC(Br)=CC=C2N2C=NC(C(=O)OCC)=C21 ADEACBHLBQTGPA-UHFFFAOYSA-N 0.000 description 1
238000001704 evaporation Methods 0.000 description 1
230000008020 evaporation Effects 0.000 description 1
238000001914 filtration Methods 0.000 description 1
238000003818 flash chromatography Methods 0.000 description 1
239000000796 flavoring agent Substances 0.000 description 1
229910052731 fluorine Inorganic materials 0.000 description 1
239000011737 fluorine Substances 0.000 description 1
239000011888 foil Substances 0.000 description 1
235000013355 food flavoring agent Nutrition 0.000 description 1
235000003599 food sweetener Nutrition 0.000 description 1
235000019253 formic acid Nutrition 0.000 description 1
239000001530 fumaric acid Substances 0.000 description 1
230000006870 function Effects 0.000 description 1
239000011521 glass Substances 0.000 description 1
239000008103 glucose Substances 0.000 description 1
BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
150000003840 hydrochlorides Chemical class 0.000 description 1
239000005457 ice water Substances 0.000 description 1
230000002401 inhibitory effect Effects 0.000 description 1
238000002347 injection Methods 0.000 description 1
239000007924 injection Substances 0.000 description 1
239000008011 inorganic excipient Substances 0.000 description 1
229960004903 invert sugar Drugs 0.000 description 1
238000002955 isolation Methods 0.000 description 1
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
230000000670 limiting effect Effects 0.000 description 1
238000005567 liquid scintillation counting Methods 0.000 description 1
239000000395 magnesium oxide Substances 0.000 description 1
CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
235000019359 magnesium stearate Nutrition 0.000 description 1
AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
239000011976 maleic acid Substances 0.000 description 1
150000002688 maleic acid derivatives Chemical class 0.000 description 1
210000005171 mammalian brain Anatomy 0.000 description 1
238000004519 manufacturing process Methods 0.000 description 1
230000000873 masking effect Effects 0.000 description 1
229910052751 metal Inorganic materials 0.000 description 1
239000002184 metal Substances 0.000 description 1
AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
229940098779 methanesulfonic acid Drugs 0.000 description 1
235000019813 microcrystalline cellulose Nutrition 0.000 description 1
239000008108 microcrystalline cellulose Substances 0.000 description 1
229940016286 microcrystalline cellulose Drugs 0.000 description 1
230000003278 mimic effect Effects 0.000 description 1
238000002156 mixing Methods 0.000 description 1
HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
239000012452 mother liquor Substances 0.000 description 1
JDEJGVSZUIJWBM-UHFFFAOYSA-N n,n,2-trimethylaniline Chemical compound CN(C)C1=CC=CC=C1C JDEJGVSZUIJWBM-UHFFFAOYSA-N 0.000 description 1
DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 1
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
XWCCTMBMQUCLSI-UHFFFAOYSA-N n-ethyl-n-propylpropan-1-amine Chemical compound CCCN(CC)CCC XWCCTMBMQUCLSI-UHFFFAOYSA-N 0.000 description 1
239000002858 neurotransmitter agent Substances 0.000 description 1
150000002823 nitrates Chemical class 0.000 description 1
229910017604 nitric acid Inorganic materials 0.000 description 1
230000009871 nonspecific binding Effects 0.000 description 1
QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
239000003921 oil Substances 0.000 description 1
235000019198 oils Nutrition 0.000 description 1
235000005985 organic acids Nutrition 0.000 description 1
239000008012 organic excipient Substances 0.000 description 1
230000003204 osmotic effect Effects 0.000 description 1
125000004430 oxygen atom Chemical group O* 0.000 description 1
239000004031 partial agonist Substances 0.000 description 1
229920000642 polymer Polymers 0.000 description 1
238000001556 precipitation Methods 0.000 description 1
238000002953 preparative HPLC Methods 0.000 description 1
239000003755 preservative agent Substances 0.000 description 1
230000002265 prevention Effects 0.000 description 1
230000000216 proconvulsive effect Effects 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
238000000746 purification Methods 0.000 description 1
239000002287 radioligand Substances 0.000 description 1
230000035484 reaction time Effects 0.000 description 1
230000002829 reductive effect Effects 0.000 description 1
230000000717 retained effect Effects 0.000 description 1
230000002441 reversible effect Effects 0.000 description 1
229920006395 saturated elastomer Polymers 0.000 description 1
239000010802 sludge Substances 0.000 description 1
WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
229910000342 sodium bisulfate Inorganic materials 0.000 description 1
230000002269 spontaneous effect Effects 0.000 description 1
239000003381 stabilizer Substances 0.000 description 1
239000008117 stearic acid Substances 0.000 description 1
239000010959 steel Substances 0.000 description 1
239000000758 substrate Substances 0.000 description 1
KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
239000005720 sucrose Substances 0.000 description 1
150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
239000003765 sweetening agent Substances 0.000 description 1
239000006188 syrup Substances 0.000 description 1
235000020357 syrup Nutrition 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
MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
150000004992 toluidines Chemical class 0.000 description 1
238000001665 trituration Methods 0.000 description 1
235000015112 vegetable and seed oil Nutrition 0.000 description 1
239000008158 vegetable oil Substances 0.000 description 1
239000011534 wash buffer Substances 0.000 description 1
239000000080 wetting agent Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Landscapes

Organic Chemistry (AREA)
Chemical & Material Sciences (AREA)
Health & Medical Sciences (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
General Health & Medical Sciences (AREA)
Veterinary Medicine (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Chemical & Material Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
Chemical Kinetics & Catalysis (AREA)
Public Health (AREA)
Medicinal Chemistry (AREA)
Biomedical Technology (AREA)
Neurology (AREA)
Neurosurgery (AREA)
Hospice & Palliative Care (AREA)
Psychiatry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Plural Heterocyclic Compounds (AREA)

BG107817A 2000-11-16 2003-05-16 Бензодиазепинови производни като gaba a рецепторни модулатори BG107817A (bg)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
EP00124332		2000-11-16
PCT/EP2001/012887 WO2002040487A2 (en)	2000-11-16	2001-11-08	Benzodiazepine derivatives as gaba a receptor modulators

Publications (1)

Publication Number	Publication Date
BG107817A true BG107817A (bg)	2004-07-30

Family

ID=8170315

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
BG107817A BG107817A (bg)	2000-11-16	2003-05-16	Бензодиазепинови производни като gaba a рецепторни модулатори

Country Status (40)

Country	Link
US (1)	US6743789B2 (es)
EP (1)	EP1337535B1 (es)
JP (1)	JP4088151B2 (es)
KR (1)	KR100504300B1 (es)
CN (1)	CN1191255C (es)
AR (1)	AR031345A1 (es)
AT (1)	ATE268776T1 (es)
AU (2)	AU2002217007B2 (es)
BG (1)	BG107817A (es)
BR (1)	BR0115393A (es)
CA (1)	CA2427576C (es)
CZ (1)	CZ295256B6 (es)
DE (1)	DE60103776T2 (es)
DK (1)	DK1337535T3 (es)
EC (1)	ECSP034607A (es)
ES (1)	ES2220831T3 (es)
GC (1)	GC0000375A (es)
GT (1)	GT200100230A (es)
HR (1)	HRP20030360A2 (es)
HU (1)	HUP0303281A3 (es)
IL (1)	IL155813A0 (es)
JO (1)	JO2359B1 (es)
MA (1)	MA26962A1 (es)
MX (1)	MXPA03004251A (es)
MY (1)	MY141675A (es)
NO (1)	NO324706B1 (es)
NZ (1)	NZ525413A (es)
PA (1)	PA8532401A1 (es)
PE (1)	PE20020583A1 (es)
PL (1)	PL362925A1 (es)
PT (1)	PT1337535E (es)
RU (1)	RU2278865C2 (es)
SI (1)	SI1337535T1 (es)
SK (1)	SK7232003A3 (es)
TR (1)	TR200402073T4 (es)
TW (1)	TWI239333B (es)
UY (1)	UY27026A1 (es)
WO (1)	WO2002040487A2 (es)
YU (1)	YU35603A (es)
ZA (1)	ZA200303435B (es)

Families Citing this family (30)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US6686352B2 (en) *	2001-05-18	2004-02-03	Hoffmann-La Roche Inc.	Substituted imidazo [1,5-a] pyrimido [5,4-d] [1] benzazepine derivatives
WO2004113321A1 (ja) *	2003-06-19	2004-12-29	Daiichi Pharmaceutical Co., Ltd.	選択的なアミノ置換基導入法
DK1691811T3 (da)	2003-12-11	2014-10-20	Sunovion Pharmaceuticals Inc	Kombination af et sedativ og en neurotransmittermodulator og fremgangsmåder til forbedring af søvnkvaliteten og behandling af depression
CA2577060A1 (en)	2004-08-13	2006-02-23	Amgen Inc.	Substituted benzofused heterocycles
MX2007004250A (es) *	2004-10-12	2007-06-12	Hoffmann La Roche	Derivados de imidazo[1,5-a]triazolo[1,5-d]benzodiazepina para el tratamiento de trastornos cognitivos.
MX2007004640A (es) *	2004-10-20	2007-06-08	Hoffmann La Roche	Derivados de benzodiazepina sustituidos con halogeno.
BRPI0519991A2 (pt)	2004-10-20	2009-04-07	Hoffmann La Roche	derivados de imidazo-benzodiazepina
BRPI0515800A (pt)	2004-12-14	2008-08-05	Hoffmann La Roche	imidazo-benzodiazepinas tetracìclicas como moduladores de receptores de gaba
US8510055B2 (en)	2005-08-03	2013-08-13	The Johns Hopkins University	Methods for characterizing and treating cognitive impairment in aging and disease
EP2682481A3 (en) *	2005-08-03	2014-09-17	The Johns-Hopkins University	Methods for characterizing and treating cognitive impairment in aging and disease
WO2007042421A1 (en)	2005-10-11	2007-04-19	F. Hoffmann-La Roche Ag	Imidazo benzodiazepine derivatives
EP2314289A1 (en)	2005-10-31	2011-04-27	Braincells, Inc.	Gaba receptor mediated modulation of neurogenesis
WO2009139916A1 (en) *	2008-05-16	2009-11-19	Synta Pharmaceuticals Corp.	Tricyclic triazole compounds that modulate hsp90 activity
PE20110590A1 (es) *	2008-11-18	2011-08-31	Hoffmann La Roche	Alquilciclohexileteres de dihidrotetraazabenzoazulenos
MY150837A (en) *	2008-11-28	2014-02-28	Hoffmann La Roche	Arylcyclohexylethers of dihydrotetraazabenzoazulenes for use as vasopressin via receptor antagonists
CU20090172A7 (es)	2009-10-09	2011-10-05	Ct De Investigación Y Desarrollo De Medicamentos	Sistemas tricíclicos y tetracíclicos con actividad sobre el sistema nervioso central y vascular
WO2012068161A1 (en)	2010-11-15	2012-05-24	Agenebio, Inc.	Pyridazine derivatives, compositions and methods for treating cognitive impairment
US20150374705A1 (en)	2012-02-14	2015-12-31	Shanghai Institues for Biological Sciences	Substances for treatment or relief of pain
JP2015529254A (ja) *	2012-09-21	2015-10-05	ユーダブリューエム・リサーチ・ファウンデーション，インコーポレーテッド	喘息における気道の過敏症及び炎症を制御するための新規なｇａｂａａアゴニスト及び使用方法
MX381561B (es) *	2013-12-20	2025-03-12	Agenebio Inc	Derivados de benzodiazepina, composiciones, y métodos para tratar el deterioro cognitivo.
CN113264939A (zh) *	2015-06-19	2021-08-17	艾吉因生物股份有限公司	用于治疗认知损害的苯并二氮杂环庚三烯衍生物、组合物和方法
US10059718B2 (en) *	2016-01-04	2018-08-28	Tabomedex Biosciences, LLC	Fused quadracyclic compounds, compositions and uses thereof
US10973479B2 (en)	2016-05-16	2021-04-13	Canon Medical Systems Corporation	X-ray diagnosis apparatus, X-ray diagnosis apparatus controlling method, and X-ray diagnosis system
BR112019012821A2 (pt)	2016-12-19	2019-11-26	Agenebio, Inc.	derivados de benzodiazepina, composições e métodos para o tratamento do comprometimento cognitivo
US20180170941A1 (en) *	2016-12-19	2018-06-21	Agenebio, Inc.	Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment
KR102512548B1 (ko)	2017-12-22	2023-03-22	삼성디스플레이 주식회사	유기 전계 발광 소자 및 유기 전계 발광 소자용 함질소 화합물
EA202190076A1 (ru) *	2018-06-19	2021-09-22	Эйджинбайо, Инк.	Производные бензодиазепина, композиции и способы лечения когнитивных нарушений
KR102151969B1 (ko) *	2019-12-11	2020-09-04	주식회사 지투비	투과도 가변창의 제조방법 및 그에 의해 제조된 투과도 가변창
CN112979658B (zh) *	2021-02-22	2022-05-31	南湖实验室	一种氟马西尼的制备方法
IL319072A (en)	2022-08-19	2025-04-01	Agenebio Inc	History of Benzazepine, Compositions and Methods for Treating Cognitive Impairment

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
DK174086D0 (da)	1986-04-16	1986-04-16	Ferrosan As	Nye benzodiazepinderivater samt fremgangsmaade til fremstilling af samme
TW201311B (es) *	1991-06-17	1993-03-01	Hoffmann La Roche

2001
- 2001-11-07 TW TW090127658A patent/TWI239333B/zh not_active IP Right Cessation
- 2001-11-08 AT AT01996541T patent/ATE268776T1/de not_active IP Right Cessation
- 2001-11-08 YU YU35603A patent/YU35603A/sh unknown
- 2001-11-08 CA CA002427576A patent/CA2427576C/en not_active Expired - Fee Related
- 2001-11-08 EP EP01996541A patent/EP1337535B1/en not_active Expired - Lifetime
- 2001-11-08 US US10/007,883 patent/US6743789B2/en not_active Expired - Fee Related
- 2001-11-08 DK DK01996541T patent/DK1337535T3/da active
- 2001-11-08 KR KR10-2003-7006609A patent/KR100504300B1/ko not_active Expired - Fee Related
- 2001-11-08 DE DE60103776T patent/DE60103776T2/de not_active Expired - Lifetime
- 2001-11-08 ES ES01996541T patent/ES2220831T3/es not_active Expired - Lifetime
- 2001-11-08 CZ CZ20031597A patent/CZ295256B6/cs not_active IP Right Cessation
- 2001-11-08 JP JP2002543495A patent/JP4088151B2/ja not_active Expired - Fee Related
- 2001-11-08 PL PL01362925A patent/PL362925A1/xx not_active Application Discontinuation
- 2001-11-08 HU HU0303281A patent/HUP0303281A3/hu unknown
- 2001-11-08 SK SK723-2003A patent/SK7232003A3/sk unknown
- 2001-11-08 SI SI200130125T patent/SI1337535T1/xx unknown
- 2001-11-08 WO PCT/EP2001/012887 patent/WO2002040487A2/en not_active Ceased
- 2001-11-08 BR BR0115393-5A patent/BR0115393A/pt not_active IP Right Cessation
- 2001-11-08 CN CNB018189415A patent/CN1191255C/zh not_active Expired - Fee Related
- 2001-11-08 TR TR2004/02073T patent/TR200402073T4/xx unknown
- 2001-11-08 RU RU2003116895/04A patent/RU2278865C2/ru not_active IP Right Cessation
- 2001-11-08 NZ NZ525413A patent/NZ525413A/en unknown
- 2001-11-08 IL IL15581301A patent/IL155813A0/xx unknown
- 2001-11-08 AU AU2002217007A patent/AU2002217007B2/en not_active Ceased
- 2001-11-08 AU AU1700702A patent/AU1700702A/xx active Pending
- 2001-11-08 HR HR20030360A patent/HRP20030360A2/hr not_active Application Discontinuation
- 2001-11-08 PT PT01996541T patent/PT1337535E/pt unknown
- 2001-11-08 MX MXPA03004251A patent/MXPA03004251A/es active IP Right Grant
- 2001-11-12 JO JO2001183A patent/JO2359B1/en active
- 2001-11-13 GC GCP20011724 patent/GC0000375A/en active
- 2001-11-14 PE PE2001001135A patent/PE20020583A1/es not_active Application Discontinuation
- 2001-11-15 MY MYPI20015253A patent/MY141675A/en unknown
- 2001-11-15 PA PA20018532401A patent/PA8532401A1/es unknown
- 2001-11-15 UY UY27026A patent/UY27026A1/es not_active Application Discontinuation
- 2001-11-15 GT GT200100230A patent/GT200100230A/es unknown
- 2001-11-15 AR ARP010105323A patent/AR031345A1/es not_active Application Discontinuation
2003
- 2003-05-05 ZA ZA200303435A patent/ZA200303435B/en unknown
- 2003-05-15 NO NO20032208A patent/NO324706B1/no unknown
- 2003-05-15 EC EC2003004607A patent/ECSP034607A/es unknown
- 2003-05-16 MA MA27163A patent/MA26962A1/fr unknown
- 2003-05-16 BG BG107817A patent/BG107817A/bg unknown

Also Published As

Publication number	Publication date
ES2220831T3 (es)	2004-12-16
GC0000375A (en)	2007-03-31
ATE268776T1 (de)	2004-06-15
CZ20031597A3 (cs)	2003-11-12
ECSP034607A (es)	2003-06-25
CA2427576C (en)	2007-11-06
DE60103776D1 (de)	2004-07-15
CA2427576A1 (en)	2002-05-23
AR031345A1 (es)	2003-09-17
WO2002040487A2 (en)	2002-05-23
CZ295256B6 (cs)	2005-06-15
AU1700702A (en)	2002-05-27
PL362925A1 (en)	2004-11-02
MY141675A (en)	2010-06-15
HK1062442A1 (en)	2004-11-05
KR100504300B1 (ko)	2005-07-28
DE60103776T2 (de)	2005-07-14
NZ525413A (en)	2005-02-25
TR200402073T4 (tr)	2004-10-21
HUP0303281A3 (en)	2005-05-30
HUP0303281A2 (hu)	2004-01-28
PT1337535E (pt)	2004-09-30
EP1337535B1 (en)	2004-06-09
JO2359B1 (en)	2006-12-12
GT200100230A (es)	2002-07-04
IL155813A0 (en)	2003-12-23
NO324706B1 (no)	2007-12-03
YU35603A (sh)	2006-05-25
JP2004517070A (ja)	2004-06-10
US6743789B2 (en)	2004-06-01
DK1337535T3 (da)	2004-10-25
MXPA03004251A (es)	2003-09-22
BR0115393A (pt)	2004-07-06
US20020103371A1 (en)	2002-08-01
PA8532401A1 (es)	2002-08-26
ZA200303435B (en)	2004-08-05
JP4088151B2 (ja)	2008-05-21
HRP20030360A2 (en)	2005-04-30
NO20032208L (no)	2003-05-15
CN1191255C (zh)	2005-03-02
CN1474820A (zh)	2004-02-11
RU2278865C2 (ru)	2006-06-27
EP1337535A2 (en)	2003-08-27
SI1337535T1 (en)	2004-10-31
TWI239333B (en)	2005-09-11
PE20020583A1 (es)	2002-07-06
MA26962A1 (fr)	2004-12-20
WO2002040487A3 (en)	2002-09-26
UY27026A1 (es)	2002-06-20
RU2003116895A (ru)	2005-02-20
NO20032208D0 (no)	2003-05-15
KR20030045192A (ko)	2003-06-09
AU2002217007B2 (en)	2006-11-30
SK7232003A3 (en)	2004-03-02

Publication	Publication Date	Title
BG107817A (bg)	2004-07-30	Бензодиазепинови производни като gaba a рецепторни модулатори
AU2002217007A1 (en)	2002-08-01	Benzodiazepine derivatives as GABA A receptor modulators
KR100533406B1 (ko)	2005-12-02	Ｇａｂａａ 수용체 조절제로서의이미다조[1,5-ａ]피리미도[5,4-ｄ]벤즈아제핀 유도체
US5387585A (en)	1995-02-07	Imidazodiazepine derivatives
JPH0657710B2 (ja)	1994-08-03	イミダゾジアゼピン誘導体
BG107750A (bg)	2004-01-30	ПИРОЛОТРИАЗИНОВИ СЪЕДИНЕНИЯ И ИЗПОЛЗВАНЕТО ИМ КАТО ИНХИБИТОРИ НА р38 КИНАЗА
BG99505A (en)	1996-01-31	Imidodiazepines, method for their preparation and application
JPH10500998A (ja)	1998-01-27	ヒドロキシメチル−イミダゾジアゼピン類及びそれらのエステル
KR940009784B1 (ko)	1994-10-17	벤조디아제핀 유도체의 제조방법
ES2399439T3 (es)	2013-04-01	Derivados de imidazo-benzodiazepina
ES2198146T3 (es)	2004-01-16	Derivados de triazolpiridazina para mejorar la cognicion.
BRPI0617204A2 (pt)	2011-07-19	derivados de imidazo benzodiazepina
NZ554556A (en)	2009-11-27	Halogen substituted imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepines