DD292458A5 - Verfahren zur herstellung von 1,7-anellierten 1h-indol-2-carbonsaeure-n-(1,4-benzodiazepin-3-yl)amiden - Google Patents

Verfahren zur herstellung von 1,7-anellierten 1h-indol-2-carbonsaeure-n-(1,4-benzodiazepin-3-yl)amiden Download PDF

Info

Publication number: DD292458A5
Authority: DD; German Democratic Republic
Prior art keywords: hydrogen; formula; halogen; compounds; lower alkyl
Prior art date: 1989-03-08

Application number

DD90338440A

Other languages

German (de)

English (en)

Inventor

Harald Waldeck

Werner Benson

Horst Zeugner

Klaus-Ullrich Wolf

Peter-Colin Gregory

Derk Hamminga

Ineke Van Wijngaarden

Original Assignee

Kali-Chemie Pharma Gmbh,De

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

1990-03-06

Publication date

1991-08-01

1990-03-06 Application filed by Kali-Chemie Pharma Gmbh,De filed Critical Kali-Chemie Pharma Gmbh,De

1991-08-01 Publication of DD292458A5 publication Critical patent/DD292458A5/de

Links

238000000034 method Methods 0.000 title claims abstract description 36
HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 title claims description 10
-1 1,4-BENZODIAZEPIN-3-YL Chemical class 0.000 title description 30
150000001408 amides Chemical class 0.000 title description 9
150000001875 compounds Chemical class 0.000 claims abstract description 57
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 37
239000001257 hydrogen Substances 0.000 claims abstract description 37
125000000217 alkyl group Chemical group 0.000 claims abstract description 32
150000002367 halogens Chemical class 0.000 claims abstract description 28
229910052736 halogen Inorganic materials 0.000 claims abstract description 27
125000004432 carbon atom Chemical group C* 0.000 claims abstract description 23
125000003545 alkoxy group Chemical group 0.000 claims abstract description 19
238000002360 preparation method Methods 0.000 claims abstract description 14
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 12
230000008569 process Effects 0.000 claims abstract description 11
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 8
125000002947 alkylene group Chemical group 0.000 claims abstract description 7
YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims abstract description 6
125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 5
125000005530 alkylenedioxy group Chemical group 0.000 claims abstract description 3
125000001316 cycloalkyl alkyl group Chemical group 0.000 claims abstract description 3
229930192474 thiophene Natural products 0.000 claims abstract description 3
239000002253 acid Substances 0.000 claims description 46
150000002431 hydrogen Chemical class 0.000 claims description 20
150000003839 salts Chemical class 0.000 claims description 19
150000007513 acids Chemical class 0.000 claims description 13
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
239000000460 chlorine Substances 0.000 claims description 10
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
229910052801 chlorine Inorganic materials 0.000 claims description 9
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
239000011737 fluorine Substances 0.000 claims description 6
229910052731 fluorine Inorganic materials 0.000 claims description 6
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
125000001041 indolyl group Chemical group 0.000 claims description 2
UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 2
229910052760 oxygen Inorganic materials 0.000 claims description 2
239000001301 oxygen Substances 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
229910052717 sulfur Inorganic materials 0.000 claims description 2
239000011593 sulfur Substances 0.000 claims description 2
125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
239000003814 drug Substances 0.000 abstract description 2
125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 5
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 210
239000000243 solution Substances 0.000 description 102
239000011541 reaction mixture Substances 0.000 description 59
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 51
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
239000000203 mixture Substances 0.000 description 51
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
238000006243 chemical reaction Methods 0.000 description 32
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
239000000047 product Substances 0.000 description 27
238000002844 melting Methods 0.000 description 24
230000008018 melting Effects 0.000 description 24
239000012043 crude product Substances 0.000 description 22
235000002639 sodium chloride Nutrition 0.000 description 22
239000002904 solvent Substances 0.000 description 22
239000000126 substance Substances 0.000 description 21
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
238000012360 testing method Methods 0.000 description 19
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
238000010626 work up procedure Methods 0.000 description 17
230000000694 effects Effects 0.000 description 16
230000003287 optical effect Effects 0.000 description 16
230000002829 reductive effect Effects 0.000 description 16
QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 14
238000010609 cell counting kit-8 assay Methods 0.000 description 14
239000012074 organic phase Substances 0.000 description 14
241001465754 Metazoa Species 0.000 description 13
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
229960000583 acetic acid Drugs 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
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
239000003480 eluent Substances 0.000 description 12
238000003818 flash chromatography Methods 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
238000003756 stirring Methods 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
238000001816 cooling 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
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-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
238000000746 purification Methods 0.000 description 10
150000008064 anhydrides Chemical class 0.000 description 9
230000027455 binding Effects 0.000 description 9
239000012362 glacial acetic acid Substances 0.000 description 9
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
239000012071 phase Substances 0.000 description 8
239000003826 tablet Substances 0.000 description 8
150000001412 amines Chemical class 0.000 description 7
150000002148 esters Chemical class 0.000 description 7
230000030136 gastric emptying Effects 0.000 description 7
150000004820 halides Chemical class 0.000 description 7
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 7
239000007787 solid Substances 0.000 description 7
125000001424 substituent group Chemical group 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
239000012359 Methanesulfonyl chloride Substances 0.000 description 6
241000699670 Mus sp. Species 0.000 description 6
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
229940049706 benzodiazepine Drugs 0.000 description 6
210000001198 duodenum Anatomy 0.000 description 6
239000006260 foam Substances 0.000 description 6
XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
108090000765 processed proteins & peptides Proteins 0.000 description 6
239000011780 sodium chloride Substances 0.000 description 6
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
229920002261 Corn starch Polymers 0.000 description 5
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
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 5
UMGDCJDMYOKAJW-UHFFFAOYSA-N aminothiocarboxamide Natural products NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 5
239000002585 base Substances 0.000 description 5
238000004440 column chromatography Methods 0.000 description 5
239000008120 corn starch Substances 0.000 description 5
239000002027 dichloromethane extract Substances 0.000 description 5
230000005764 inhibitory process Effects 0.000 description 5
229940098779 methanesulfonic acid Drugs 0.000 description 5
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 5
230000002093 peripheral effect Effects 0.000 description 5
LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
230000009467 reduction Effects 0.000 description 5
238000010992 reflux Methods 0.000 description 5
239000011347 resin Substances 0.000 description 5
229920005989 resin Polymers 0.000 description 5
238000000926 separation method Methods 0.000 description 5
235000017557 sodium bicarbonate Nutrition 0.000 description 5
229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
239000000725 suspension Substances 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
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
230000010933 acylation Effects 0.000 description 4
238000005917 acylation reaction Methods 0.000 description 4
230000015572 biosynthetic process Effects 0.000 description 4
230000037396 body weight Effects 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
239000003795 chemical substances by application Substances 0.000 description 4
239000013078 crystal Substances 0.000 description 4
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
238000001704 evaporation Methods 0.000 description 4
230000002401 inhibitory effect Effects 0.000 description 4
239000000543 intermediate Substances 0.000 description 4
OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 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
239000003921 oil Substances 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
239000012286 potassium permanganate Substances 0.000 description 4
239000012264 purified product Substances 0.000 description 4
229910000029 sodium carbonate Inorganic materials 0.000 description 4
LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 3
125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 3
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 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
241000699666 Mus <mouse, genus> Species 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
XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
239000004480 active ingredient Substances 0.000 description 3
150000001413 amino acids Chemical class 0.000 description 3
SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 3
239000012267 brine Substances 0.000 description 3
239000007853 buffer solution 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
239000003245 coal Substances 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
230000034994 death Effects 0.000 description 3
231100000517 death Toxicity 0.000 description 3
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
230000008020 evaporation Effects 0.000 description 3
230000007717 exclusion Effects 0.000 description 3
230000002349 favourable effect Effects 0.000 description 3
239000008273 gelatin Substances 0.000 description 3
229920000159 gelatin Polymers 0.000 description 3
235000019322 gelatine Nutrition 0.000 description 3
235000011852 gelatine desserts Nutrition 0.000 description 3
150000008282 halocarbons Chemical class 0.000 description 3
150000002429 hydrazines Chemical class 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
238000006317 isomerization reaction Methods 0.000 description 3
239000008101 lactose Substances 0.000 description 3
239000007788 liquid Substances 0.000 description 3
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
239000003960 organic solvent Substances 0.000 description 3
239000007800 oxidant agent Substances 0.000 description 3
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
208000024891 symptom Diseases 0.000 description 3
238000003786 synthesis reaction Methods 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
238000005303 weighing Methods 0.000 description 3
239000011701 zinc Substances 0.000 description 3
229910052725 zinc Inorganic materials 0.000 description 3
MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-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
BQEOYSYVSOQDAJ-UHFFFAOYSA-N 1h-1,4-benzodiazepin-3-amine Chemical class C1=NC(N)=CNC2=CC=CC=C21 BQEOYSYVSOQDAJ-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
ABFPKTQEQNICFT-UHFFFAOYSA-M 2-chloro-1-methylpyridin-1-ium;iodide Chemical compound [I-].C[N+]1=CC=CC=C1Cl ABFPKTQEQNICFT-UHFFFAOYSA-M 0.000 description 2
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
JQJPBYFTQAANLE-UHFFFAOYSA-N Butyl nitrite Chemical compound CCCCON=O JQJPBYFTQAANLE-UHFFFAOYSA-N 0.000 description 2
FZUGQWJSEBEASU-UHFFFAOYSA-N CCCCC.[I] Chemical compound CCCCC.[I] FZUGQWJSEBEASU-UHFFFAOYSA-N 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
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
150000004008 N-nitroso compounds Chemical class 0.000 description 2
LCTONWCANYUPML-UHFFFAOYSA-N PYRUVIC-ACID Natural products CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
239000002202 Polyethylene glycol Substances 0.000 description 2
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
239000007868 Raney catalyst Substances 0.000 description 2
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
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238000012986 modification Methods 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
229910052757 nitrogen Inorganic materials 0.000 description 1
239000012299 nitrogen atmosphere Substances 0.000 description 1
230000009935 nitrosation Effects 0.000 description 1
238000007034 nitrosation reaction Methods 0.000 description 1
238000005580 one pot reaction Methods 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
150000002923 oximes Chemical class 0.000 description 1
125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
230000020477 pH reduction Effects 0.000 description 1
210000000496 pancreas Anatomy 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
229940124531 pharmaceutical excipient Drugs 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
229940068918 polyethylene glycol 400 Drugs 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
239000011591 potassium Substances 0.000 description 1
239000002244 precipitate Substances 0.000 description 1
239000003755 preservative agent Substances 0.000 description 1
238000012545 processing Methods 0.000 description 1
229940080818 propionamide Drugs 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
229910052895 riebeckite Inorganic materials 0.000 description 1
239000010802 sludge Substances 0.000 description 1
230000009870 specific binding Effects 0.000 description 1
238000001228 spectrum Methods 0.000 description 1
238000009987 spinning Methods 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
239000008107 starch Substances 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
210000002784 stomach Anatomy 0.000 description 1
125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
125000000542 sulfonic acid group Chemical group 0.000 description 1
FVIRGMIYFJWRGC-UHFFFAOYSA-N sulfurobromidic acid Chemical class OS(Br)(=O)=O FVIRGMIYFJWRGC-UHFFFAOYSA-N 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
239000012085 test solution Substances 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
231100001274 therapeutic index Toxicity 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
231100000419 toxicity Toxicity 0.000 description 1
230000001988 toxicity Effects 0.000 description 1
YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
229910052722 tritium Inorganic materials 0.000 description 1
239000002753 trypsin inhibitor Substances 0.000 description 1
230000004580 weight loss Effects 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)

DD90338440A 1989-03-08 1990-03-06 Verfahren zur herstellung von 1,7-anellierten 1h-indol-2-carbonsaeure-n-(1,4-benzodiazepin-3-yl)amiden DD292458A5 (de)

Applications Claiming Priority (1)

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

Publications (1)

Publication Number	Publication Date
DD292458A5 true DD292458A5 (de)	1991-08-01

Family

ID=6375778

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
DD90338440A DD292458A5 (de)	1989-03-08	1990-03-06	Verfahren zur herstellung von 1,7-anellierten 1h-indol-2-carbonsaeure-n-(1,4-benzodiazepin-3-yl)amiden

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
CA2011658C (fr)	2000-05-16
DE3907389A1 (de)	1990-09-13
CA2011658A1 (fr)	1990-09-08
ZA901671B (en)	1990-11-28

Legal Events

Date	Code	Title
1997-07-31	RPI	Change in the person, name or address of the patentee (searches according to art. 11 and 12 extension act)
1997-09-25	RPI	Change in the person, name or address of the patentee (searches according to art. 11 and 12 extension act)
2002-10-10	ENJ	Ceased due to non-payment of renewal fee

Publication	Publication Date	Title
EP0492485B1 (fr)	1997-11-19	Dérivés de N-acyl-2,3-benzodiazépine, compositions pharmaceutiques les contenant et procédé pour leur préparation
EP0031080B1 (fr)	1983-09-21	Acylaminométhyl-2 benzodiazépines-1,4, leurs sels, procédé pour leur préparation et médicaments contenant lesdits composés
EP0059391A1 (fr)	1982-09-08	Imidazodiazépines, procédé pour leur préparation et compositions pharmaceutiques les contenant
DE1810423A1 (de)	1969-10-09	1-Phenyl-4-alkyl-3H-1,4-benzodiazepin-2,5-[1H,4H]-dione und Verfahren zu ihrer Herstellung
EP0387618B1 (fr)	1994-07-27	N-(1,4-benzodiazépin-3-yl)amides 1H-indole-2-carboxyliques 1,7-pontés
EP0156191B1 (fr)	1989-07-19	Diazépinones condensées, procédé pour leur préparation et médicaments contenant les composés
DE2323149C3 (de)	1979-02-22	Thienopyrimidine, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneipräparate
DE69229461T2 (de)	1999-10-21	Isatinoximderivate, ihre Herstellung und Anwendung
EP0045451A2 (fr)	1982-02-10	Dérivés de benzodiazépine, produits intermédiaires, leur préparation et médicaments qui les contiennent
DE69528189T2 (de)	2003-01-09	Diazepinoindole inhibitoren von phosphodiesterase iv
DE2810476A1 (de)	1978-09-14	Benzodiazepin-derivate, verfahren zu ihrer herstellung und solche derivate enthaltende arzneimittel
DE3004381A1 (de)	1980-09-04	Benzazepin-derivate
DE3587556T2 (de)	1994-02-10	2-Substituierte Aminomethyl-1,4-benzodiazepine, Verfahren zu ihrer Herstellung und sie enthaltende pharmazeutische Zusammensetzungen.
EP0508370B1 (fr)	1996-07-03	Diazépinones condensées, procédé pour leur préparation et compositions les contenant pour le traitement de maladies du système nerveux central et pour augmenter la perfusion cérébrale
DD292458A5 (de)	1991-08-01	Verfahren zur herstellung von 1,7-anellierten 1h-indol-2-carbonsaeure-n-(1,4-benzodiazepin-3-yl)amiden
DE2809591A1 (de)	1978-09-14	Benzodiazepin-derivate, verfahren zu ihrer herstellung und solche derivate enthaltende arzneimittel
EP0054839B1 (fr)	1985-06-19	Acylaminométhyl-2 benzodiazépines-1,4, leurs sels, procédé pour leur préparation et médicaments contenant ces composés
EP0072029B1 (fr)	1986-10-22	Triazolobenzazépines, procédé et intermédiaires pour leur fabrication et médicaments les contenant
DE69319945T2 (de)	1999-03-11	1,5-Benzodiazepinderivate und deren Verwendung in Heilmittel
DE3907390A1 (de)	1990-09-13	Neue 1,7-anellierte 1h-indol-2-carbonsaeure-n-(5-phenyl-1,4-benzodiazepin-3-yl)amide
AT403580B (de)	1998-03-25	Neue benz(e)inden-derivate, verfahren zu ihrer herstellung und die diese verbindungen enthaltenden arzneimittelpräparate
AT395155B (de)	1992-10-12	Verfahren zur herstellung von neuen imidazo(1,5-a)(1,4)diazepinverbindungen
EP0045520B1 (fr)	1984-06-20	Pyrimido (4,5-d)(2) benzazépines, procédé pour leur préparation et compositions pharmaceutiques les contenant
DE2527901A1 (de)	1976-01-15	Verfahren zur herstellung von neuen benzodiazepinderivaten
EP0066303A1 (fr)	1982-12-08	Azidométhyl-2-benzodiazépines 1,4, leurs sels, leur procédé de préparation et produits pharmaceutiques qui les contiennent