NO311938B1 - 1H-pyrido[3,4-b]indol-4-karboksamid-derivater, fremstilling derav, medikament og farmasöytisk preparat - Google Patents
1H-pyrido[3,4-b]indol-4-karboksamid-derivater, fremstilling derav, medikament og farmasöytisk preparat Download PDFInfo
- Publication number
- NO311938B1 NO311938B1 NO19991624A NO991624A NO311938B1 NO 311938 B1 NO311938 B1 NO 311938B1 NO 19991624 A NO19991624 A NO 19991624A NO 991624 A NO991624 A NO 991624A NO 311938 B1 NO311938 B1 NO 311938B1
- Authority
- NO
- Norway
- Prior art keywords
- general formula
- group
- compound
- mmol
- stated
- Prior art date
Links
- 239000003814 drug Substances 0.000 title claims description 5
- 229940079593 drug Drugs 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title description 6
- QLJUIXVDWIQWEV-UHFFFAOYSA-N 1h-pyrido[3,4-b]indole-4-carboxamide Chemical class C1=CC=C2C3=C(C(=O)N)C=NCC3=NC2=C1 QLJUIXVDWIQWEV-UHFFFAOYSA-N 0.000 title description 2
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 106
- 239000000203 mixture Substances 0.000 claims description 61
- 239000000243 solution Substances 0.000 claims description 52
- 239000002253 acid Substances 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 18
- -1 phenylmethoxy group Chemical group 0.000 claims description 18
- 150000001412 amines Chemical class 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 150000002148 esters Chemical class 0.000 claims description 12
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 11
- 150000005690 diesters Chemical class 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 150000003334 secondary amides Chemical class 0.000 claims description 9
- 150000003511 tertiary amides Chemical class 0.000 claims description 9
- XXRCUYVCPSWGCC-UHFFFAOYSA-N Ethyl pyruvate Chemical compound CCOC(=O)C(C)=O XXRCUYVCPSWGCC-UHFFFAOYSA-N 0.000 claims description 8
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 8
- 238000005804 alkylation reaction Methods 0.000 claims description 8
- 229940117360 ethyl pyruvate Drugs 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 230000007062 hydrolysis Effects 0.000 claims description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims description 8
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 claims description 6
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 6
- 230000002378 acidificating effect Effects 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- JBFYUZGYRGXSFL-UHFFFAOYSA-N imidazolide Chemical compound C1=C[N-]C=N1 JBFYUZGYRGXSFL-UHFFFAOYSA-N 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 150000003140 primary amides Chemical class 0.000 claims description 6
- 230000000949 anxiolytic effect Effects 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 claims description 3
- VRGCYEIGVVTZCC-UHFFFAOYSA-N 3,4,5,6-tetrachlorocyclohexa-3,5-diene-1,2-dione Chemical compound ClC1=C(Cl)C(=O)C(=O)C(Cl)=C1Cl VRGCYEIGVVTZCC-UHFFFAOYSA-N 0.000 claims description 3
- 230000001476 alcoholic effect Effects 0.000 claims description 3
- 150000008064 anhydrides Chemical class 0.000 claims description 3
- 230000001773 anti-convulsant effect Effects 0.000 claims description 3
- 229940049706 benzodiazepine Drugs 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 230000000147 hypnotic effect Effects 0.000 claims description 3
- 230000003287 optical effect Effects 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 125000001984 thiazolidinyl group Chemical group 0.000 claims description 3
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000002393 azetidinyl group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 125000006513 pyridinyl methyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 2
- 239000003193 general anesthetic agent Substances 0.000 claims 2
- 208000007848 Alcoholism Diseases 0.000 claims 1
- 206010002091 Anaesthesia Diseases 0.000 claims 1
- 208000019901 Anxiety disease Diseases 0.000 claims 1
- 108010062745 Chloride Channels Proteins 0.000 claims 1
- 102000011045 Chloride Channels Human genes 0.000 claims 1
- 208000027776 Extrapyramidal disease Diseases 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 208000008238 Muscle Spasticity Diseases 0.000 claims 1
- 206010062575 Muscle contracture Diseases 0.000 claims 1
- 241000208125 Nicotiana Species 0.000 claims 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 claims 1
- 208000018737 Parkinson disease Diseases 0.000 claims 1
- 239000013543 active substance Substances 0.000 claims 1
- 201000007930 alcohol dependence Diseases 0.000 claims 1
- 230000037005 anaesthesia Effects 0.000 claims 1
- 229940035676 analgesics Drugs 0.000 claims 1
- 229940035674 anesthetics Drugs 0.000 claims 1
- 239000000730 antalgic agent Substances 0.000 claims 1
- 230000036506 anxiety Effects 0.000 claims 1
- 239000002249 anxiolytic agent Substances 0.000 claims 1
- 239000002775 capsule Substances 0.000 claims 1
- 208000010877 cognitive disease Diseases 0.000 claims 1
- 208000006111 contracture Diseases 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 208000035475 disorder Diseases 0.000 claims 1
- 239000002552 dosage form Substances 0.000 claims 1
- 239000008298 dragée Substances 0.000 claims 1
- 206010015037 epilepsy Diseases 0.000 claims 1
- 239000007903 gelatin capsule Substances 0.000 claims 1
- 229940005494 general anesthetics Drugs 0.000 claims 1
- 238000001727 in vivo Methods 0.000 claims 1
- 230000006698 induction Effects 0.000 claims 1
- 239000003589 local anesthetic agent Substances 0.000 claims 1
- 229960005015 local anesthetics Drugs 0.000 claims 1
- 238000012423 maintenance Methods 0.000 claims 1
- 229940035363 muscle relaxants Drugs 0.000 claims 1
- 239000003158 myorelaxant agent Substances 0.000 claims 1
- 238000007911 parenteral administration Methods 0.000 claims 1
- 239000004031 partial agonist Substances 0.000 claims 1
- 238000009101 premedication Methods 0.000 claims 1
- 208000019116 sleep disease Diseases 0.000 claims 1
- 208000018198 spasticity Diseases 0.000 claims 1
- 239000000829 suppository Substances 0.000 claims 1
- 230000007428 synaptic transmission, GABAergic Effects 0.000 claims 1
- 239000003826 tablet Substances 0.000 claims 1
- 208000016153 withdrawal disease Diseases 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 135
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 93
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 62
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 51
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 39
- 239000002904 solvent Substances 0.000 description 38
- 238000010992 reflux Methods 0.000 description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 239000000047 product Substances 0.000 description 30
- 239000012074 organic phase Substances 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 23
- 229910052938 sodium sulfate Inorganic materials 0.000 description 19
- 235000011152 sodium sulphate Nutrition 0.000 description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 238000004587 chromatography analysis Methods 0.000 description 15
- 238000010828 elution Methods 0.000 description 15
- 239000012265 solid product Substances 0.000 description 15
- 238000001914 filtration Methods 0.000 description 14
- 239000002244 precipitate Substances 0.000 description 14
- 238000012360 testing method Methods 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- JOSUREOWSQOZKH-UHFFFAOYSA-N 2-benzyl-6-fluoro-n,n,9-trimethyl-1-oxo-3,4-dihydropyrido[3,4-b]indole-4-carboxamide Chemical compound O=C1C(N(C2=CC=C(F)C=C22)C)=C2C(C(=O)N(C)C)CN1CC1=CC=CC=C1 JOSUREOWSQOZKH-UHFFFAOYSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- VQSDZYIVUYKURT-UHFFFAOYSA-N 2-benzyl-6-fluoro-9-methyl-1-oxo-3,4-dihydropyrido[3,4-b]indole-4-carboxylic acid Chemical compound C12=CC(F)=CC=C2N(C)C(C2=O)=C1C(C(O)=O)CN2CC1=CC=CC=C1 VQSDZYIVUYKURT-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 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 5
- 229960004381 flumazenil Drugs 0.000 description 5
- 238000011835 investigation Methods 0.000 description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000007912 intraperitoneal administration Methods 0.000 description 4
- 239000003586 protic polar solvent Substances 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- XWMRIWGDBMHDLE-UHFFFAOYSA-N 6-fluoro-9-methyl-1-oxo-2-phenylpyrido[3,4-b]indole-4-carboxylic acid Chemical compound O=C1C=2N(C)C3=CC=C(F)C=C3C=2C(C(O)=O)=CN1C1=CC=CC=C1 XWMRIWGDBMHDLE-UHFFFAOYSA-N 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 3
- 239000001961 anticonvulsive agent Substances 0.000 description 3
- 210000001638 cerebellum Anatomy 0.000 description 3
- IPTQYVUACAXQMA-UHFFFAOYSA-N ethyl 3-(2-ethoxy-2-oxoethyl)-5-fluoro-1h-indole-2-carboxylate Chemical compound C1=C(F)C=C2C(CC(=O)OCC)=C(C(=O)OCC)NC2=C1 IPTQYVUACAXQMA-UHFFFAOYSA-N 0.000 description 3
- QIZYMGRKSHRZEY-UHFFFAOYSA-N ethyl 5-fluoro-1-methylindole-2-carboxylate Chemical compound FC1=CC=C2N(C)C(C(=O)OCC)=CC2=C1 QIZYMGRKSHRZEY-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 3
- 230000020477 pH reduction Effects 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 210000000278 spinal cord Anatomy 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- FEKUXLUOKFSMRO-UHFFFAOYSA-N (4-fluorophenyl)hydrazine;hydron;chloride Chemical compound Cl.NNC1=CC=C(F)C=C1 FEKUXLUOKFSMRO-UHFFFAOYSA-N 0.000 description 2
- UXPXJMKDQRRSDB-UHFFFAOYSA-N 1-oxo-2-phenyl-4,9-dihydro-3h-pyrido[3,4-b]indole-4-carboxylic acid Chemical compound O=C1C=2NC3=CC=CC=C3C=2C(C(=O)O)CN1C1=CC=CC=C1 UXPXJMKDQRRSDB-UHFFFAOYSA-N 0.000 description 2
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
- XICVSOJBZNERDS-UHFFFAOYSA-N 3-(carboxymethyl)-5-fluoro-1h-indole-2-carboxylic acid Chemical compound C1=C(F)C=C2C(CC(=O)O)=C(C(O)=O)NC2=C1 XICVSOJBZNERDS-UHFFFAOYSA-N 0.000 description 2
- DUDOUJBRFAEDFV-UHFFFAOYSA-N 5-fluoro-3-(2-oxo-2-pyrrolidin-1-ylethyl)-1h-indole-2-carboxylic acid Chemical compound OC(=O)C=1NC2=CC=C(F)C=C2C=1CC(=O)N1CCCC1 DUDOUJBRFAEDFV-UHFFFAOYSA-N 0.000 description 2
- JCQNUEOYUWWZSX-UHFFFAOYSA-N 6-chloro-2-(2-methoxyethyl)-9-methyl-1-oxo-3,4-dihydropyrido[3,4-b]indole-4-carboxylic acid Chemical compound CN1C2=CC=C(Cl)C=C2C2=C1C(=O)N(CCOC)CC2C(O)=O JCQNUEOYUWWZSX-UHFFFAOYSA-N 0.000 description 2
- ODZCMBRZZIMRGI-UHFFFAOYSA-N 6-chloro-2-(2-methoxyethyl)-n,n,9-trimethyl-1-oxo-3,4-dihydropyrido[3,4-b]indole-4-carboxamide Chemical compound CN1C2=CC=C(Cl)C=C2C2=C1C(=O)N(CCOC)CC2C(=O)N(C)C ODZCMBRZZIMRGI-UHFFFAOYSA-N 0.000 description 2
- NUPGUZPAQBESKS-UHFFFAOYSA-N 6-fluoro-1-oxo-2-phenyl-4,9-dihydro-3h-pyrido[3,4-b]indole-4-carboxylic acid Chemical compound O=C1C=2NC3=CC=C(F)C=C3C=2C(C(=O)O)CN1C1=CC=CC=C1 NUPGUZPAQBESKS-UHFFFAOYSA-N 0.000 description 2
- XHPOCKMEDRRWDU-UHFFFAOYSA-N 6-fluoro-4,9-dihydropyrano[3,4-b]indole-1,3-dione Chemical compound C12=CC(F)=CC=C2NC2=C1CC(=O)OC2=O XHPOCKMEDRRWDU-UHFFFAOYSA-N 0.000 description 2
- MTGNOMPUVDRBBK-UHFFFAOYSA-N 6-fluoro-9-methyl-1-oxo-2-pyridin-2-ylpyrido[3,4-b]indole-4-carboxylic acid Chemical compound O=C1C=2N(C)C3=CC=C(F)C=C3C=2C(C(O)=O)=CN1C1=CC=CC=N1 MTGNOMPUVDRBBK-UHFFFAOYSA-N 0.000 description 2
- ZIKNBJJOKXCQKK-UHFFFAOYSA-N 6-fluoro-9-methyl-2-(5-methyl-1,3,4-thiadiazol-2-yl)-4-(pyrrolidine-1-carbonyl)pyrido[3,4-b]indol-1-one Chemical compound S1C(C)=NN=C1N1C(=O)C(N(C)C2=CC=C(F)C=C22)=C2C(C(=O)N2CCCC2)=C1 ZIKNBJJOKXCQKK-UHFFFAOYSA-N 0.000 description 2
- IKKOWLNPZBQJQE-UHFFFAOYSA-N 6-fluoro-n,9-dimethyl-1-oxo-2-phenylpyrido[3,4-b]indole-4-carboxamide Chemical compound O=C1C=2N(C)C3=CC=C(F)C=C3C=2C(C(=O)NC)=CN1C1=CC=CC=C1 IKKOWLNPZBQJQE-UHFFFAOYSA-N 0.000 description 2
- HLYYAUJJWOSGIQ-UHFFFAOYSA-N 6-fluoro-n,n,9-trimethyl-1-oxo-2-phenylpyrido[3,4-b]indole-4-carboxamide Chemical compound O=C1C=2N(C)C3=CC=C(F)C=C3C=2C(C(=O)N(C)C)=CN1C1=CC=CC=C1 HLYYAUJJWOSGIQ-UHFFFAOYSA-N 0.000 description 2
- JFJJIKXQMTWAAT-UHFFFAOYSA-N 6-fluoro-n,n,9-trimethyl-1-oxo-2-pyridin-2-ylpyrido[3,4-b]indole-4-carboxamide Chemical compound O=C1C=2N(C)C3=CC=C(F)C=C3C=2C(C(=O)N(C)C)=CN1C1=CC=CC=N1 JFJJIKXQMTWAAT-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- 206010053398 Clonic convulsion Diseases 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 229960003965 antiepileptics Drugs 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 230000027455 binding Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 230000036461 convulsion Effects 0.000 description 2
- 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 2
- 229960003529 diazepam Drugs 0.000 description 2
- MTAYAMJCNSTJEW-UHFFFAOYSA-N ethyl 2-benzyl-6-fluoro-9-methyl-1-oxo-3,4-dihydropyrido[3,4-b]indole-4-carboxylate Chemical compound O=C1C(N(C2=CC=C(F)C=C22)C)=C2C(C(=O)OCC)CN1CC1=CC=CC=C1 MTAYAMJCNSTJEW-UHFFFAOYSA-N 0.000 description 2
- WEHDJPPZEYXUHG-UHFFFAOYSA-N ethyl 3-(2-ethoxy-2-oxoethyl)-5-fluoro-1-methylindole-2-carboxylate Chemical compound C1=C(F)C=C2C(CC(=O)OCC)=C(C(=O)OCC)N(C)C2=C1 WEHDJPPZEYXUHG-UHFFFAOYSA-N 0.000 description 2
- WPITZTQLIZBAIX-UHFFFAOYSA-N ethyl 3-(3-ethoxy-3-oxoprop-1-en-2-yl)-5-fluoro-1-methylindole-2-carboxylate Chemical compound C1=C(F)C=C2C(C(=C)C(=O)OCC)=C(C(=O)OCC)N(C)C2=C1 WPITZTQLIZBAIX-UHFFFAOYSA-N 0.000 description 2
- QYKKURCHDGEGQC-UHFFFAOYSA-N ethyl 3-(3-ethoxy-3-oxoprop-1-en-2-yl)-5-fluoro-1h-indole-2-carboxylate Chemical compound C1=C(F)C=C2C(C(=C)C(=O)OCC)=C(C(=O)OCC)NC2=C1 QYKKURCHDGEGQC-UHFFFAOYSA-N 0.000 description 2
- GECRCAVZSPCTDM-UHFFFAOYSA-N ethyl 5-chloro-1-methylindole-2-carboxylate Chemical compound ClC1=CC=C2N(C)C(C(=O)OCC)=CC2=C1 GECRCAVZSPCTDM-UHFFFAOYSA-N 0.000 description 2
- VIKOQTQMWBKMNA-UHFFFAOYSA-N ethyl 5-fluoro-1h-indole-2-carboxylate Chemical compound FC1=CC=C2NC(C(=O)OCC)=CC2=C1 VIKOQTQMWBKMNA-UHFFFAOYSA-N 0.000 description 2
- QIEJMMCCHCYERZ-UHFFFAOYSA-N ethyl 6-chloro-2-(2-methoxyethyl)-9-methyl-1-oxo-3,4-dihydropyrido[3,4-b]indole-4-carboxylate Chemical compound ClC=1C=C2C3=C(N(C2=CC=1)C)C(N(CC3C(=O)OCC)CCOC)=O QIEJMMCCHCYERZ-UHFFFAOYSA-N 0.000 description 2
- GKPGDKSSJYODNT-UHFFFAOYSA-N ethyl 6-fluoro-9-methyl-1-oxo-2-phenylpyrido[3,4-b]indole-4-carboxylate Chemical compound O=C1C=2N(C)C3=CC=C(F)C=C3C=2C(C(=O)OCC)=CN1C1=CC=CC=C1 GKPGDKSSJYODNT-UHFFFAOYSA-N 0.000 description 2
- 150000007857 hydrazones Chemical class 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- 229960003350 isoniazid Drugs 0.000 description 2
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- QMRUXPAZMUKUAE-UHFFFAOYSA-N methyl 5-fluoro-3-(2-oxo-2-pyrrolidin-1-ylethyl)-1h-indole-2-carboxylate Chemical compound COC(=O)C=1NC2=CC=C(F)C=C2C=1CC(=O)N1CCCC1 QMRUXPAZMUKUAE-UHFFFAOYSA-N 0.000 description 2
- SJHMSCYYOHVLMN-UHFFFAOYSA-N methyl 6-fluoro-9-methyl-1-oxo-2-pyridin-2-ylpyrido[3,4-b]indole-4-carboxylate Chemical compound O=C1C=2N(C)C3=CC=C(F)C=C3C=2C(C(=O)OC)=CN1C1=CC=CC=N1 SJHMSCYYOHVLMN-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- VKSDKCWPBOHNRF-UHFFFAOYSA-N n,n,9-trimethyl-1-oxo-2-phenyl-3,4-dihydropyrido[3,4-b]indole-4-carboxamide Chemical compound O=C1C(N(C2=CC=CC=C22)C)=C2C(C(=O)N(C)C)CN1C1=CC=CC=C1 VKSDKCWPBOHNRF-UHFFFAOYSA-N 0.000 description 2
- YDUZQZMXLHFRMS-UHFFFAOYSA-N n,n-dimethyl-1-oxo-2-phenyl-4,9-dihydro-3h-pyrido[3,4-b]indole-4-carboxamide Chemical compound O=C1C=2NC3=CC=CC=C3C=2C(C(=O)N(C)C)CN1C1=CC=CC=C1 YDUZQZMXLHFRMS-UHFFFAOYSA-N 0.000 description 2
- BYSMNWNGVOGVDU-UHFFFAOYSA-N n-ethyl-6-fluoro-n,9-dimethyl-1-oxo-2-phenylpyrido[3,4-b]indole-4-carboxamide Chemical compound O=C1C=2N(C)C3=CC=C(F)C=C3C=2C(C(=O)N(C)CC)=CN1C1=CC=CC=C1 BYSMNWNGVOGVDU-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 230000009870 specific binding Effects 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- SBJKEJNTMGQMMF-UHFFFAOYSA-N 1-oxo-n,2-diphenyl-4,9-dihydro-3h-pyrido[3,4-b]indole-4-carboxamide Chemical compound C1N(C=2C=CC=CC=2)C(=O)C=2NC3=CC=CC=C3C=2C1C(=O)NC1=CC=CC=C1 SBJKEJNTMGQMMF-UHFFFAOYSA-N 0.000 description 1
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- ACRGIRLCXXEJCS-UHFFFAOYSA-N 1h-indole-4-carboxamide Chemical compound NC(=O)C1=CC=CC2=C1C=CN2 ACRGIRLCXXEJCS-UHFFFAOYSA-N 0.000 description 1
- ROGHUJUFCRFUSO-UHFFFAOYSA-N 1h-indole-4-carboxylic acid Chemical compound OC(=O)C1=CC=CC2=C1C=CN2 ROGHUJUFCRFUSO-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- AGACTDUHAFTMBY-UHFFFAOYSA-N 2-benzyl-6-fluoro-n,n,9-trimethyl-1-oxopyrido[3,4-b]indole-4-carboxamide Chemical compound O=C1C=2N(C)C3=CC=C(F)C=C3C=2C(C(=O)N(C)C)=CN1CC1=CC=CC=C1 AGACTDUHAFTMBY-UHFFFAOYSA-N 0.000 description 1
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- HMPUHXCGUHDVBI-UHFFFAOYSA-N 5-methyl-1,3,4-thiadiazol-2-amine Chemical compound CC1=NN=C(N)S1 HMPUHXCGUHDVBI-UHFFFAOYSA-N 0.000 description 1
- QQWHWWDIFGNCLV-UHFFFAOYSA-N 6-fluoro-9-methyl-2-phenyl-4-(pyrrolidine-1-carbonyl)pyrido[3,4-b]indol-1-one Chemical compound O=C1C=2N(C)C3=CC=C(F)C=C3C=2C(C(=O)N2CCCC2)=CN1C1=CC=CC=C1 QQWHWWDIFGNCLV-UHFFFAOYSA-N 0.000 description 1
- DNIXWWKLYSOXFA-UHFFFAOYSA-N 6-fluoro-n,n,9-trimethyl-1-oxo-2-phenyl-3,4-dihydropyrido[3,4-b]indole-4-carboxamide Chemical compound O=C1C(N(C2=CC=C(F)C=C22)C)=C2C(C(=O)N(C)C)CN1C1=CC=CC=C1 DNIXWWKLYSOXFA-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 241000557626 Corvus corax Species 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- XAXXTYXMWOFKLW-UHFFFAOYSA-N [C-]1=CC=[NH+]1 Chemical compound [C-]1=CC=[NH+]1 XAXXTYXMWOFKLW-UHFFFAOYSA-N 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- OTOAIVOHHUOJBK-UHFFFAOYSA-N ethyl 1-oxo-2-phenyl-4,9-dihydro-3h-pyrido[3,4-b]indole-4-carboxylate Chemical compound O=C1C=2NC3=CC=CC=C3C=2C(C(=O)OCC)CN1C1=CC=CC=C1 OTOAIVOHHUOJBK-UHFFFAOYSA-N 0.000 description 1
- QQXQAEWRSVZPJM-UHFFFAOYSA-N ethyl 1h-indole-2-carboxylate Chemical compound C1=CC=C2NC(C(=O)OCC)=CC2=C1 QQXQAEWRSVZPJM-UHFFFAOYSA-N 0.000 description 1
- BMPKMWPCRVZZIT-UHFFFAOYSA-N ethyl 3-(3-ethoxy-3-oxoprop-1-en-2-yl)-1h-indole-2-carboxylate Chemical compound C1=CC=C2C(C(=C)C(=O)OCC)=C(C(=O)OCC)NC2=C1 BMPKMWPCRVZZIT-UHFFFAOYSA-N 0.000 description 1
- LWKIFKYHCJAIAB-UHFFFAOYSA-N ethyl 5-chloro-1h-indole-2-carboxylate Chemical compound ClC1=CC=C2NC(C(=O)OCC)=CC2=C1 LWKIFKYHCJAIAB-UHFFFAOYSA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 230000026781 habituation Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- WEAXQUBYRSEBJD-UHFFFAOYSA-N methyl 1h-indole-4-carboxylate Chemical compound COC(=O)C1=CC=CC2=C1C=CN2 WEAXQUBYRSEBJD-UHFFFAOYSA-N 0.000 description 1
- BJEOPBKIFVXIAQ-UHFFFAOYSA-N methyl 3-[1-(dimethylamino)-3-oxo-3-pyrrolidin-1-ylprop-1-en-2-yl]-5-fluoro-1-methylindole-2-carboxylate Chemical compound C12=CC(F)=CC=C2N(C)C(C(=O)OC)=C1C(=CN(C)C)C(=O)N1CCCC1 BJEOPBKIFVXIAQ-UHFFFAOYSA-N 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 239000001120 potassium sulphate Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 210000004894 snout Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- 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
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- 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
- A61P25/22—Anxiolytics
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Public Health (AREA)
- Neurology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychology (AREA)
- Addiction (AREA)
- Psychiatry (AREA)
- Anesthesiology (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9612229A FR2754262B1 (fr) | 1996-10-08 | 1996-10-08 | Derives de 1h-pyrido[3,4-b]indole-4-carboxamide, leur preparation et leur application en therapeutique |
| PCT/FR1997/001750 WO1998015552A1 (fr) | 1996-10-08 | 1997-10-03 | DERIVES DE 1H-PYRIDO[3,4-b]INDOLE-4-CARBOXAMIDE, LEUR PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUE |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO991624D0 NO991624D0 (no) | 1999-04-06 |
| NO991624L NO991624L (no) | 1999-06-07 |
| NO311938B1 true NO311938B1 (no) | 2002-02-18 |
Family
ID=9496449
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO19991624A NO311938B1 (no) | 1996-10-08 | 1999-04-06 | 1H-pyrido[3,4-b]indol-4-karboksamid-derivater, fremstilling derav, medikament og farmasöytisk preparat |
Country Status (33)
| Country | Link |
|---|---|
| US (1) | US6075021A (et) |
| EP (1) | EP0934319B1 (et) |
| JP (1) | JP4227197B2 (et) |
| KR (1) | KR100488095B1 (et) |
| CN (1) | CN1089765C (et) |
| AR (1) | AR009112A1 (et) |
| AT (1) | ATE218567T1 (et) |
| AU (1) | AU721102B2 (et) |
| BG (1) | BG63751B1 (et) |
| BR (1) | BR9711879A (et) |
| CA (1) | CA2266376A1 (et) |
| CO (1) | CO4910141A1 (et) |
| CY (1) | CY2291B1 (et) |
| CZ (1) | CZ298906B6 (et) |
| DE (1) | DE69713124T2 (et) |
| DK (1) | DK0934319T3 (et) |
| EE (1) | EE03830B1 (et) |
| ES (1) | ES2178008T3 (et) |
| FR (1) | FR2754262B1 (et) |
| HK (1) | HK1023338A1 (et) |
| HU (1) | HUP9904623A3 (et) |
| IL (1) | IL129018A0 (et) |
| NO (1) | NO311938B1 (et) |
| NZ (1) | NZ334708A (et) |
| PL (1) | PL188244B1 (et) |
| PT (1) | PT934319E (et) |
| RU (1) | RU2180904C2 (et) |
| SK (1) | SK282970B6 (et) |
| TR (1) | TR199900712T2 (et) |
| TW (1) | TW461889B (et) |
| UA (1) | UA57037C2 (et) |
| WO (1) | WO1998015552A1 (et) |
| ZA (1) | ZA978970B (et) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2766823B1 (fr) * | 1997-07-30 | 1999-10-08 | Synthelabo | Derives de 4-oxo-3,5-dihydro-4h-pyridazino[4,5-b] indole-1-acetamide, leur preparation et leur application en therapeutique |
| FR2788696B1 (fr) * | 1999-01-26 | 2004-03-05 | Synthelabo | Utilisation de derives de pyridazino [4,5-b] indole-1-acetamide pour la preparation de medicaments destines aux maladies du systeme nerveux central |
| FR2788776B1 (fr) * | 1999-01-26 | 2001-02-23 | Synthelabo | Derives de 4-oxo-3, 5-dihydro-4h-pyridazino [4,5-b] indole-1 -carboxamide, leur preparation et leur application en therapeutique |
| FR2811897A1 (fr) * | 2000-07-24 | 2002-01-25 | Sanofi Synthelabo | UTILISATION DE DERIVES DE PYRIDAZINO[4,5-b]INDOLE-1- ACETAMIDE POUR LA PREPARATION DE MEDICAMENTS DESTINES AU TRAITEMENT DES DYSFONCTIONNEMENTS DES RECEPTEURS DE TYPE PERIPHERIQUE AUX BENZODIAZEPINES |
| FR2811990A1 (fr) * | 2000-07-24 | 2002-01-25 | Sanofi Synthelabo | DERIVES DE 1-(4-OXO-3,5-DIHYDRO-4H-PYRIDAZINO[4,5-b]INDOLE-1 -CARBONYL)PIPERAZINE, LEUR PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUE |
| FR2833953B1 (fr) * | 2001-12-21 | 2004-12-03 | Sanofi Synthelabo | DERIVES DE 3-HETEROARYL-3,5-DIHYDRO-4-OXO-4H-PYRIDAZINO [4,5-b]INDOLE-1-CARBOXAMIDE, LEUR PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUE |
| FR2838124B1 (fr) | 2002-04-03 | 2004-05-28 | Sanofi Synthelabo | Derives de 3-heteroaryl-3,5-dihydro-4-oxo-4h-pyridazino [4,5-b]indole-1-acetamide, leur preparation et leur application en therapeutique |
| PA8586801A1 (es) * | 2002-10-31 | 2005-02-04 | Pfizer | Inhibidores de hiv-integrasa, composiciones farmaceuticas y metodos para su uso |
| BRPI0407052A (pt) * | 2003-01-27 | 2006-01-17 | Pfizer | Inibidores da hiv-integrase, composições farmacêuticas, e métodos para sua utilização |
| BRPI0510319A (pt) * | 2004-04-26 | 2007-10-16 | Pfizer | inibidores da enzima integrase de hiv |
| DE602005002746T2 (de) * | 2004-04-26 | 2008-02-07 | Pfizer Inc. | Inhibitoren des hiv-integrase-enzyms |
| JP5483874B2 (ja) * | 2005-05-05 | 2014-05-07 | サノフィ−アベンティス・ユー・エス・エルエルシー | 安定なナノ粒子処方物 |
| BRPI0616657A2 (pt) * | 2005-10-07 | 2011-06-28 | Pfizer Prod Inc | inibidores da enzima hiv integrase |
| UA95788C2 (en) | 2005-12-15 | 2011-09-12 | Ф. Хоффманн-Ля Рош Аг | Fused pyrrole derivatives |
| WO2007143597A2 (en) * | 2006-06-05 | 2007-12-13 | Novartis Ag | Organic compounds |
| CN1946120B (zh) * | 2006-10-20 | 2010-05-12 | 华为技术有限公司 | 实现话单关联的方法及系统 |
| KR100688448B1 (ko) * | 2006-12-06 | 2007-03-02 | (주)경진건축사사무소 | 건축물 내부 조적구조 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2724384B1 (fr) * | 1994-09-14 | 1999-04-16 | Cemaf | Nouveaux derives de la 3,4-dihydro beta-carboline agonistes de la melatonine, leur procede de preparation et leur utilisation a titre de medicament |
-
1996
- 1996-10-08 FR FR9612229A patent/FR2754262B1/fr not_active Expired - Fee Related
-
1997
- 1997-03-10 UA UA99041847A patent/UA57037C2/uk unknown
- 1997-10-03 JP JP51723798A patent/JP4227197B2/ja not_active Expired - Fee Related
- 1997-10-03 PT PT97943932T patent/PT934319E/pt unknown
- 1997-10-03 CZ CZ0119399A patent/CZ298906B6/cs not_active IP Right Cessation
- 1997-10-03 EE EEP199900155A patent/EE03830B1/et not_active IP Right Cessation
- 1997-10-03 IL IL12901897A patent/IL129018A0/xx not_active IP Right Cessation
- 1997-10-03 ES ES97943932T patent/ES2178008T3/es not_active Expired - Lifetime
- 1997-10-03 EP EP97943932A patent/EP0934319B1/fr not_active Expired - Lifetime
- 1997-10-03 SK SK451-99A patent/SK282970B6/sk not_active IP Right Cessation
- 1997-10-03 WO PCT/FR1997/001750 patent/WO1998015552A1/fr active IP Right Grant
- 1997-10-03 RU RU99108986/04A patent/RU2180904C2/ru not_active IP Right Cessation
- 1997-10-03 NZ NZ334708A patent/NZ334708A/xx not_active IP Right Cessation
- 1997-10-03 HU HU9904623A patent/HUP9904623A3/hu unknown
- 1997-10-03 TR TR1999/00712T patent/TR199900712T2/xx unknown
- 1997-10-03 DE DE69713124T patent/DE69713124T2/de not_active Expired - Lifetime
- 1997-10-03 CA CA002266376A patent/CA2266376A1/en not_active Abandoned
- 1997-10-03 AU AU45594/97A patent/AU721102B2/en not_active Ceased
- 1997-10-03 DK DK97943932T patent/DK0934319T3/da active
- 1997-10-03 BR BR9711879A patent/BR9711879A/pt not_active IP Right Cessation
- 1997-10-03 PL PL97332643A patent/PL188244B1/pl not_active IP Right Cessation
- 1997-10-03 CN CN97198661A patent/CN1089765C/zh not_active Expired - Fee Related
- 1997-10-03 KR KR10-1999-7003048A patent/KR100488095B1/ko not_active IP Right Cessation
- 1997-10-03 AT AT97943932T patent/ATE218567T1/de active
- 1997-10-06 CO CO97058251A patent/CO4910141A1/es unknown
- 1997-10-07 AR ARP970104610A patent/AR009112A1/es active IP Right Grant
- 1997-10-07 TW TW086114669A patent/TW461889B/zh not_active IP Right Cessation
- 1997-10-07 ZA ZA9708970A patent/ZA978970B/xx unknown
- 1997-10-08 US US09/284,070 patent/US6075021A/en not_active Expired - Lifetime
-
1999
- 1999-03-31 BG BG103301A patent/BG63751B1/bg unknown
- 1999-04-06 NO NO19991624A patent/NO311938B1/no not_active IP Right Cessation
-
2000
- 2000-03-08 HK HK00101436A patent/HK1023338A1/xx unknown
-
2002
- 2002-08-22 CY CY0200050A patent/CY2291B1/xx unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| NO311938B1 (no) | 1H-pyrido[3,4-b]indol-4-karboksamid-derivater, fremstilling derav, medikament og farmasöytisk preparat | |
| US4788191A (en) | 1,3-dithiolano-, 1,4-dithiino- and 1,4-dithiepino[2,3-C]pyrrole derivatives, their production and use | |
| DK174161B1 (da) | Anellerede indolderivater, fremgangsmåde til deres fremstilling og fremgangsmåde til fremstilling af farmaceutisk præparat indeholdende dem | |
| US20060128745A1 (en) | Chemical compounds | |
| AU2006271518B2 (en) | N(arylalkyl)-1h-pyrrolopyridine-2-carboxamide derivatives, preparation and therapeutic use thereof | |
| KR100497782B1 (ko) | 4-옥소-3,5-디히드로-4Ｈ-피리다지노[4,5-ｂ]인돌-1-아세트아미드 유도체, 그것의 제조 및 치료에서의 그것의 응용 | |
| SK27494A3 (en) | Benzoxazine derivatives, method of their preparation and pharmaceutical composition containing these derivatives | |
| MX2014003660A (es) | Derivados de 5-bencilaminometil-6-aminopirazolo [3,4-b] piridina como inhibidores de proteina de transferencia de ester de colesterilo (cetp) utiles para el tratamiento de aterosclerosis. | |
| JP2010515673A (ja) | ４−（ヘテロシクリル）アルキル−ｎ−（アリールスルホニル）インドール化合物および５−ｈｔ６リガンドとしてのその使用 | |
| EP1255734A1 (en) | Isatine derivatives with neurotrophic activity | |
| KR20000029564A (ko) | 5ＨＴ2ｃ길항제및Ｄ2길항제를함유하는약제학적조성물 | |
| SK12895A3 (en) | 3-(2-aminoethyl)-4-(3-trifluoromethyl-benzoyl)-3,4-dihydro-2h- -1,4-benzoxazine derivatives, method of their preparation and pharmaceutical composition containing of these derivatives | |
| EP0743946A1 (en) | 5ht2b receptor antagonists condensed indoles | |
| CA2728096C (en) | Substituted 2h-pyrrolo[3,4-c]quinoline compound with serotoninergic activity, processes to prepare and pharmaceutical compositions comprising the compound | |
| US6436954B1 (en) | Benzoquinolizidine and benzoindolizidine derivatives and therapeutic uses thereof | |
| MXPA99003254A (es) | Derivados de 1h-pirido(3-4-b)indol-4-carboxamida, preparacion y aplicacion de los mismos en terapeutica | |
| WO2006075619A1 (ja) | ２－（環状アミノカルボニル）インドリン誘導体及びそれを含有する医薬組成物 | |
| AU2006272049A1 (en) | Substituted piperidine derivatives as somatostatin SST1 receptor antagonists | |
| MXPA00001009A (en) | 4-OXO-3,5-DIHYDRO-4H-PYRIDAZINO[4,5-b |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM1K | Lapsed by not paying the annual fees |