CA2011658C - Amides de 1h-indole-2-acide-carboxylique-n-(1,4-benzodiazepin-3-yl) cyclises en 1 et 7 - Google Patents

Amides de 1h-indole-2-acide-carboxylique-n-(1,4-benzodiazepin-3-yl) cyclises en 1 et 7 Download PDF

Info

Publication number: CA2011658C
Authority: CA; Canada
Prior art keywords: represents hydrogen; halogen; lower alkyl; formula; carbon atoms
Prior art date: 1989-03-08
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Expired - Fee Related

Application number

CA002011658A

Other languages

English (en)

Other versions

CA2011658A1 (fr

Inventor

Harald Waldeck

Werner Benson

Horst Zeugner

Klaus-Ullrich Wolf

Peter-Colin Gregory

Derk Hamminga

Ineke Van Wijngaarden

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Abbott Products GmbH

Original Assignee

Solvay Pharmaceuticals GmbH

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.)

1989-03-08

Filing date

1990-03-07

Publication date

2000-05-16

1990-03-07 Application filed by Solvay Pharmaceuticals GmbH filed Critical Solvay Pharmaceuticals GmbH

1990-09-08 Publication of CA2011658A1 publication Critical patent/CA2011658A1/fr

2000-05-16 Application granted granted Critical

2000-05-16 Publication of CA2011658C publication Critical patent/CA2011658C/fr

2010-03-07 Anticipated expiration legal-status Critical

Status Expired - Fee Related legal-status Critical Current

Links

150000001408 amides Chemical class 0.000 title description 11
HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 title description 5
150000001875 compounds Chemical class 0.000 claims abstract description 68
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 51
239000001257 hydrogen Substances 0.000 claims abstract description 51
125000000217 alkyl group Chemical group 0.000 claims abstract description 46
150000002367 halogens Chemical group 0.000 claims abstract description 42
229910052736 halogen Inorganic materials 0.000 claims abstract description 40
125000004432 carbon atom Chemical group C* 0.000 claims abstract description 33
125000003545 alkoxy group Chemical group 0.000 claims abstract description 30
125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 30
238000000034 method Methods 0.000 claims abstract description 29
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 14
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 14
YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims abstract description 10
125000002947 alkylene group Chemical group 0.000 claims abstract description 9
125000001316 cycloalkyl alkyl group Chemical group 0.000 claims abstract description 6
125000005530 alkylenedioxy group Chemical group 0.000 claims abstract description 5
125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 5
229930192474 thiophene Natural products 0.000 claims abstract description 5
239000002253 acid Substances 0.000 claims description 51
-1 methoxy, methyl Chemical group 0.000 claims description 35
150000003839 salts Chemical class 0.000 claims description 21
230000003287 optical effect Effects 0.000 claims description 16
239000000460 chlorine Chemical group 0.000 claims description 9
229910052801 chlorine Chemical group 0.000 claims description 9
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
230000008569 process Effects 0.000 claims description 7
229910052731 fluorine Chemical group 0.000 claims description 6
239000011737 fluorine Chemical group 0.000 claims description 6
125000001041 indolyl group Chemical group 0.000 claims description 5
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
229910052760 oxygen Inorganic materials 0.000 claims description 4
239000001301 oxygen Substances 0.000 claims description 4
239000008194 pharmaceutical composition Substances 0.000 claims description 4
239000000546 pharmaceutical excipient Substances 0.000 claims description 4
229910052717 sulfur Inorganic materials 0.000 claims description 4
239000011593 sulfur Substances 0.000 claims description 4
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
125000001153 fluoro group Chemical group F* 0.000 claims description 2
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
230000003042 antagnostic effect Effects 0.000 claims 1
239000003754 cholecystokinin receptor blocking agent Substances 0.000 claims 1
239000003937 drug carrier Substances 0.000 claims 1
238000004519 manufacturing process Methods 0.000 claims 1
125000001544 thienyl group Chemical group 0.000 claims 1
238000002360 preparation method Methods 0.000 abstract description 7
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 222
239000000243 solution Substances 0.000 description 110
239000011541 reaction mixture Substances 0.000 description 66
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 54
239000000203 mixture Substances 0.000 description 51
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 47
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
238000006243 chemical reaction Methods 0.000 description 35
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 28
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
239000000047 product Substances 0.000 description 27
239000002904 solvent Substances 0.000 description 27
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
238000002844 melting Methods 0.000 description 23
230000008018 melting Effects 0.000 description 23
239000012043 crude product Substances 0.000 description 22
239000000126 substance Substances 0.000 description 22
238000012360 testing method Methods 0.000 description 22
230000000694 effects Effects 0.000 description 19
230000002829 reductive effect Effects 0.000 description 19
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
238000003818 flash chromatography Methods 0.000 description 16
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
150000002431 hydrogen Chemical group 0.000 description 15
239000012074 organic phase Substances 0.000 description 15
QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 14
241001465754 Metazoa Species 0.000 description 14
150000007513 acids Chemical class 0.000 description 14
238000010609 cell counting kit-8 assay Methods 0.000 description 14
239000003480 eluent Substances 0.000 description 13
239000000741 silica gel Substances 0.000 description 13
229910002027 silica gel Inorganic materials 0.000 description 13
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 12
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
229960000583 acetic acid Drugs 0.000 description 12
210000000232 gallbladder Anatomy 0.000 description 12
IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 12
108010087230 Sincalide Proteins 0.000 description 11
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
150000008064 anhydrides Chemical class 0.000 description 11
150000002148 esters Chemical class 0.000 description 11
238000000746 purification Methods 0.000 description 11
238000010992 reflux Methods 0.000 description 11
229910052938 sodium sulfate Inorganic materials 0.000 description 11
235000011152 sodium sulphate Nutrition 0.000 description 11
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 10
HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 10
239000008346 aqueous phase Substances 0.000 description 10
238000001816 cooling Methods 0.000 description 10
XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 10
239000000725 suspension Substances 0.000 description 10
DFBJMGMQEPYFMB-UHFFFAOYSA-N 3-amino-8-methoxy-1-methyl-5-phenyl-3h-1,4-benzodiazepin-2-one Chemical compound C=1C(OC)=CC=C2C=1N(C)C(=O)C(N)N=C2C1=CC=CC=C1 DFBJMGMQEPYFMB-UHFFFAOYSA-N 0.000 description 9
238000001704 evaporation Methods 0.000 description 9
239000012071 phase Substances 0.000 description 9
238000003756 stirring Methods 0.000 description 9
210000002784 stomach Anatomy 0.000 description 9
239000003826 tablet Substances 0.000 description 9
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
238000004821 distillation Methods 0.000 description 8
239000012362 glacial acetic acid Substances 0.000 description 8
239000011780 sodium chloride Substances 0.000 description 8
238000005406 washing Methods 0.000 description 8
239000012359 Methanesulfonyl chloride Substances 0.000 description 7
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 7
150000001412 amines Chemical class 0.000 description 7
230000027455 binding Effects 0.000 description 7
230000037396 body weight Effects 0.000 description 7
239000006260 foam Substances 0.000 description 7
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 7
229910052700 potassium Inorganic materials 0.000 description 7
239000011591 potassium Substances 0.000 description 7
239000007787 solid Substances 0.000 description 7
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
102000004859 Cholecystokinin Receptors Human genes 0.000 description 6
108090001085 Cholecystokinin Receptors Proteins 0.000 description 6
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
239000002585 base Substances 0.000 description 6
239000003610 charcoal Substances 0.000 description 6
210000001198 duodenum Anatomy 0.000 description 6
150000004820 halides Chemical class 0.000 description 6
108090000765 processed proteins & peptides Proteins 0.000 description 6
235000017557 sodium bicarbonate Nutrition 0.000 description 6
229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
125000001424 substituent group Chemical group 0.000 description 6
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
MWASGDJOVNIDEM-UHFFFAOYSA-N 3-amino-1-methyl-5-phenyl-3h-1,4-benzodiazepin-2-one Chemical compound N=1C(N)C(=O)N(C)C2=CC=CC=C2C=1C1=CC=CC=C1 MWASGDJOVNIDEM-UHFFFAOYSA-N 0.000 description 5
229920002261 Corn starch Polymers 0.000 description 5
235000019759 Maize starch Nutrition 0.000 description 5
241000699670 Mus sp. Species 0.000 description 5
239000003795 chemical substances by application Substances 0.000 description 5
238000004440 column chromatography Methods 0.000 description 5
239000013078 crystal Substances 0.000 description 5
239000002027 dichloromethane extract Substances 0.000 description 5
238000001035 drying Methods 0.000 description 5
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
238000001914 filtration Methods 0.000 description 5
OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 5
229940098779 methanesulfonic acid Drugs 0.000 description 5
230000002093 peripheral effect Effects 0.000 description 5
239000012286 potassium permanganate Substances 0.000 description 5
208000024891 symptom Diseases 0.000 description 5
238000010626 work up procedure Methods 0.000 description 5
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
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 4
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
239000013543 active substance Substances 0.000 description 4
230000010933 acylation Effects 0.000 description 4
238000005917 acylation reaction Methods 0.000 description 4
SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 4
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
229910052794 bromium Inorganic materials 0.000 description 4
239000003153 chemical reaction reagent Substances 0.000 description 4
238000007865 diluting Methods 0.000 description 4
150000008282 halocarbons Chemical class 0.000 description 4
230000002401 inhibitory effect Effects 0.000 description 4
230000005764 inhibitory process Effects 0.000 description 4
239000000543 intermediate Substances 0.000 description 4
239000008101 lactose Substances 0.000 description 4
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
YLGXILFCIXHCMC-JHGZEJCSSA-N methyl cellulose Chemical compound COC1C(OC)C(OC)C(COC)O[C@H]1O[C@H]1C(OC)C(OC)C(OC)OC1COC YLGXILFCIXHCMC-JHGZEJCSSA-N 0.000 description 4
230000000144 pharmacologic effect Effects 0.000 description 4
QKFJKGMPGYROCL-UHFFFAOYSA-N phenyl isothiocyanate Chemical compound S=C=NC1=CC=CC=C1 QKFJKGMPGYROCL-UHFFFAOYSA-N 0.000 description 4
239000012264 purified product Substances 0.000 description 4
LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
KZNXKMJGYSECTN-UHFFFAOYSA-N 1,2-benzodiazocine Chemical compound N1=NC=CC=CC2=CC=CC=C21 KZNXKMJGYSECTN-UHFFFAOYSA-N 0.000 description 3
JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
108010010803 Gelatin Proteins 0.000 description 3
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 3
229910000564 Raney nickel Inorganic materials 0.000 description 3
FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
150000001413 amino acids Chemical class 0.000 description 3
125000003310 benzodiazepinyl group Chemical group N1N=C(C=CC2=C1C=CC=C2)* 0.000 description 3
230000015572 biosynthetic process Effects 0.000 description 3
239000007853 buffer solution Substances 0.000 description 3
238000004587 chromatography analysis Methods 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
230000008602 contraction Effects 0.000 description 3
230000008878 coupling Effects 0.000 description 3
238000010168 coupling process Methods 0.000 description 3
238000005859 coupling reaction Methods 0.000 description 3
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238000001640 fractional crystallisation Methods 0.000 description 3
238000005194 fractionation Methods 0.000 description 3
239000008273 gelatin Substances 0.000 description 3
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235000019322 gelatine Nutrition 0.000 description 3
235000011852 gelatine desserts Nutrition 0.000 description 3
OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 3
239000005457 ice water Substances 0.000 description 3
239000012535 impurity Substances 0.000 description 3
238000011065 in-situ storage Methods 0.000 description 3
150000002576 ketones Chemical class 0.000 description 3
239000007788 liquid Substances 0.000 description 3
ZDPSGFYSVVWKBE-UHFFFAOYSA-N n-(1h-1,4-benzodiazepin-3-yl)-1h-indole-2-carboxamide Chemical class N1C2=CC=CC=C2C=NC(NC(=O)C=2NC3=CC=CC=C3C=2)=C1 ZDPSGFYSVVWKBE-UHFFFAOYSA-N 0.000 description 3
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
150000002832 nitroso derivatives Chemical class 0.000 description 3
239000003960 organic solvent Substances 0.000 description 3
239000007800 oxidant agent Substances 0.000 description 3
210000000496 pancreas Anatomy 0.000 description 3
238000001953 recrystallisation Methods 0.000 description 3
229910000029 sodium carbonate Inorganic materials 0.000 description 3
239000000454 talc Substances 0.000 description 3
229910052623 talc Inorganic materials 0.000 description 3
239000011975 tartaric acid Substances 0.000 description 3
235000002906 tartaric acid Nutrition 0.000 description 3
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230000001988 toxicity Effects 0.000 description 3
239000011701 zinc Substances 0.000 description 3
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MWASGDJOVNIDEM-OAHLLOKOSA-N (3r)-3-amino-1-methyl-5-phenyl-3h-1,4-benzodiazepin-2-one Chemical compound O=C([C@H](N)N=1)N(C)C2=CC=CC=C2C=1C1=CC=CC=C1 MWASGDJOVNIDEM-OAHLLOKOSA-N 0.000 description 2
LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
UYBWIEGTWASWSR-UHFFFAOYSA-N 1,3-diaminopropan-2-ol Chemical class NCC(O)CN UYBWIEGTWASWSR-UHFFFAOYSA-N 0.000 description 2
BLXSFCHWMBESKV-UHFFFAOYSA-N 1-iodopentane Chemical compound CCCCCI BLXSFCHWMBESKV-UHFFFAOYSA-N 0.000 description 2
OQPXCSARTKLGNT-UHFFFAOYSA-N 2-(chloromethyl)-1,7-dimethyl-5-thiophen-2-yl-2,3-dihydro-1,4-benzodiazepine Chemical compound C12=CC(C)=CC=C2N(C)C(CCl)CN=C1C1=CC=CS1 OQPXCSARTKLGNT-UHFFFAOYSA-N 0.000 description 2
GYFVKJJXIPRLNO-UHFFFAOYSA-N 2-(chloromethyl)-8-methoxy-1-methyl-5-phenyl-2,3-dihydro-1,4-benzodiazepine Chemical compound C=1C(OC)=CC=C2C=1N(C)C(CCl)CN=C2C1=CC=CC=C1 GYFVKJJXIPRLNO-UHFFFAOYSA-N 0.000 description 2
KQHZWJVRONLUAJ-UHFFFAOYSA-N 2-amino-n-(8-methoxy-1-methyl-2-oxo-5-phenyl-3h-1,4-benzodiazepin-3-yl)-3-phenylpropanamide Chemical compound C=1C(OC)=CC=C(C(=N2)C=3C=CC=CC=3)C=1N(C)C(=O)C2NC(=O)C(N)CC1=CC=CC=C1 KQHZWJVRONLUAJ-UHFFFAOYSA-N 0.000 description 2
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HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 1
239000000391 magnesium silicate Substances 0.000 description 1
229910052919 magnesium silicate Inorganic materials 0.000 description 1
235000019792 magnesium silicate Nutrition 0.000 description 1
238000005259 measurement Methods 0.000 description 1
229910052751 metal Inorganic materials 0.000 description 1
239000002184 metal Substances 0.000 description 1
150000007522 mineralic acids Chemical class 0.000 description 1
230000004899 motility Effects 0.000 description 1
210000003205 muscle Anatomy 0.000 description 1
ODKLEQPZOCJQMT-UHFFFAOYSA-N n,n-diethylpyridin-4-amine Chemical compound CCN(CC)C1=CC=NC=C1 ODKLEQPZOCJQMT-UHFFFAOYSA-N 0.000 description 1
230000007935 neutral effect Effects 0.000 description 1
230000009935 nitrosation Effects 0.000 description 1
238000007034 nitrosation reaction Methods 0.000 description 1
230000009871 nonspecific binding Effects 0.000 description 1
238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
238000005580 one pot reaction Methods 0.000 description 1
239000013588 oral product Substances 0.000 description 1
150000007524 organic acids Chemical class 0.000 description 1
235000005985 organic acids Nutrition 0.000 description 1
230000003647 oxidation Effects 0.000 description 1
238000007254 oxidation reaction Methods 0.000 description 1
230000001590 oxidative effect Effects 0.000 description 1
150000002923 oximes Chemical class 0.000 description 1
239000008188 pellet Substances 0.000 description 1
239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
239000003208 petroleum Substances 0.000 description 1
COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
235000011007 phosphoric acid Nutrition 0.000 description 1
150000003016 phosphoric acids Chemical class 0.000 description 1
XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
125000005543 phthalimide group Chemical group 0.000 description 1
239000003755 preservative agent Substances 0.000 description 1
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
150000003222 pyridines Chemical class 0.000 description 1
230000009467 reduction Effects 0.000 description 1
229910052895 riebeckite Inorganic materials 0.000 description 1
238000000926 separation method Methods 0.000 description 1
239000000377 silicon dioxide Substances 0.000 description 1
239000002002 slurry Substances 0.000 description 1
230000009870 specific binding Effects 0.000 description 1
238000001228 spectrum Methods 0.000 description 1
239000008107 starch Substances 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
239000007858 starting material Substances 0.000 description 1
230000004936 stimulating effect Effects 0.000 description 1
239000011550 stock solution Substances 0.000 description 1
238000010254 subcutaneous injection Methods 0.000 description 1
239000007929 subcutaneous injection Substances 0.000 description 1
125000000542 sulfonic acid group Chemical group 0.000 description 1
239000000829 suppository Substances 0.000 description 1
FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
QIQITDHWZYEEPA-UHFFFAOYSA-N thiophene-2-carbonyl chloride Chemical compound ClC(=O)C1=CC=CS1 QIQITDHWZYEEPA-UHFFFAOYSA-N 0.000 description 1
125000005490 tosylate group Chemical group 0.000 description 1
231100000331 toxic Toxicity 0.000 description 1
230000002588 toxic effect Effects 0.000 description 1
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
239000002753 trypsin inhibitor Substances 0.000 description 1
239000003981 vehicle Substances 0.000 description 1
238000005303 weighing Methods 0.000 description 1

Classifications

- 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
- C07D471/06—Peri-condensed systems
- 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
- C07D487/02—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 two hetero rings
- C07D487/06—Peri-condensed systems
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/06—Peri-condensed systems

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

CA002011658A 1989-03-08 1990-03-07 Amides de 1h-indole-2-acide-carboxylique-n-(1,4-benzodiazepin-3-yl) cyclises en 1 et 7 Expired - Fee Related CA2011658C (fr)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
DE3907389A DE3907389A1 (de)	1989-03-08	1989-03-08	Neue 1,7-anellierte 1h-indol-carbonsaeure-n-(5-alkyl-1,4-benzodiazepin-3-yl)amide
DEP3907389.0		1989-03-08

Publications (2)

Publication Number	Publication Date
CA2011658A1 CA2011658A1 (fr)	1990-09-08
CA2011658C true CA2011658C (fr)	2000-05-16

Family

ID=6375778

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA002011658A Expired - Fee Related CA2011658C (fr)	1989-03-08	1990-03-07	Amides de 1h-indole-2-acide-carboxylique-n-(1,4-benzodiazepin-3-yl) cyclises en 1 et 7

Country Status (4)

Country	Link
CA (1)	CA2011658C (fr)
DD (1)	DD292458A5 (fr)
DE (1)	DE3907389A1 (fr)
ZA (1)	ZA901671B (fr)

1989
- 1989-03-08 DE DE3907389A patent/DE3907389A1/de not_active Withdrawn
1990
- 1990-03-05 ZA ZA901671A patent/ZA901671B/xx unknown
- 1990-03-06 DD DD90338440A patent/DD292458A5/de not_active IP Right Cessation
- 1990-03-07 CA CA002011658A patent/CA2011658C/fr not_active Expired - Fee Related

Also Published As

Publication number	Publication date
DE3907389A1 (de)	1990-09-13
CA2011658A1 (fr)	1990-09-08
ZA901671B (en)	1990-11-28
DD292458A5 (de)	1991-08-01

Legal Events

Date	Code	Title	Description
1997-02-21	EEER	Examination request
2007-03-07	MKLA	Lapsed

Publication	Publication Date	Title
US5536832A (en)	1996-07-16	N-acyl-2,3-benzodiazepine derivatives pharmaceutical compositions containing them and process for preparing same
EP1192165B1 (fr)	2004-09-22	Gamma-carbolines fusionnees a heterocycles substitues
DK167572B1 (da)	1993-11-22	6-substituerede 4-aminotetrahydrobenzoec,daaindoler, fremgangsmaade til fremstilling heraf samt farmaceutiske praeparater indeholdende saadanne indoler
US5618812A (en)	1997-04-08	Benzodiazepine derivatives
US5010076A (en)	1991-04-23	1,7-fused 1H-indole-2-carboxylic acid-N-(1,4-benzodiazepin-3-yl)amides
US4929614A (en)	1990-05-29	Benzodiazepines, process and intermediates for the preparation thereof and their application in therapy
US5798353A (en)	1998-08-25	Polysubstituted 3-acylamino-5-phenyl-1,4-benzodiazepin-2-one derivatives, process for their preparation and the pharmaceutical compositions containing them
HK1006570B (en)	1999-03-05	1,7-fused 1h-indole-2-carboxylic n-(1,4-benzodiazepin-3-yl)-amides
JPH09502428A (ja)	1997-03-11	Ｃｃｋまたはガストリン拮抗剤として有用な１，５−ベンゾジアゼピン誘導体
US4554272A (en)	1985-11-19	Substituted quinazolino-1,4-benzodiazepin-6,9-diones and their preparation
US3429874A (en)	1969-02-25	1-polyhalogenoalkyl-2-oxo-1,3-dihydro-2h-1,4-benzodiazepines
FI92205B (fi)	1994-06-30	Menetelmä terapeuttisesti käyttökelpoisten N-pyrrolo- ja pyrido /3,2,1,-j k/ /1,4/ bentsodiatsepinyyli-N'-aryyliurea ja tioureajohdannaisten valmistamiseksi
PT93673B (pt)	1996-08-30	Processo para a preparacao de derivados da piridina
Arán et al.	1997	Approaches to 1, 1-disubstituted cinnolin-3-ylio oxides: synthesis and reactivity of a new class of heterocyclic betaines
CA2011658C (fr)	2000-05-16	Amides de 1h-indole-2-acide-carboxylique-n-(1,4-benzodiazepin-3-yl) cyclises en 1 et 7
EP0166356B1 (fr)	1993-09-01	Aminométhyl-1,4-benzodiazépines substituées sur la position 2, procédé pour leur préparation et compositions pharmaceutiques les contenant
KR20010072262A (ko)	2001-07-31	삼환식 카르복스아미드
EP1532105B1 (fr)	2009-06-10	Derives d'anthranyle ayant une activite anticholecystokinine (anti-cck-1), leur procede de preparation et leur utilisation pharmaceutique
RU2142948C1 (ru)	1999-12-20	Замещенные производные 3-ациламино-5-фенил-1,4-бензодиазепин-2-она, способ их получения и промежуточный продукт
IE43762B1 (en)	1981-05-20	Diazepine derivatives
EP0272868A1 (fr)	1988-06-29	1,4-Benzodiazépines avec hétérocycles à 6 chaînons
US3968230A (en)	1976-07-06	Compositions containing benzodiazepindiones and method of use
CA1196634A (fr)	1985-11-12	7-bromo-5-(2-halophenyl)-1h-2,3-dihydro-1,4- benzodiazepines; preparation et compositions pharmaceutiques qui en renferment
HU198932B (en)	1989-12-28	Process for producing tetracyclic quinazolinones and pharmaceutical compositions comprising same as active ingredient
JPS6018656B2 (ja)	1985-05-11	置換されたフエニルケトンの製造方法