NO873108L - Fremgangsmaate for fremstilling av terapeutisk aktive 1,4-benzodiazepiner. - Google Patents

Fremgangsmaate for fremstilling av terapeutisk aktive 1,4-benzodiazepiner.

Info

Publication number: NO873108L
Authority: NO; Norway
Prior art keywords: alkyl; formula; methyl; compound; hydrogen
Prior art date: 1986-07-25

Application number

NO873108A

Other languages

English (en)

Norwegian (no)

Other versions

NO873108D0 (no

Inventor

Gerhard Walther

Albrecht Harreus

Karl-Heinz Weber

Werner Stransky

Gojko Muacevic

Jorge Casals Stenzel

Bechtel Wolf-Dietrich

Original Assignee

Boehringer Ingelheim Kg

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.)

1986-07-25

Filing date

1987-07-24

Publication date

1988-01-26

1987-07-24 Application filed by Boehringer Ingelheim Kg filed Critical Boehringer Ingelheim Kg

1987-07-24 Publication of NO873108D0 publication Critical patent/NO873108D0/no

1988-01-26 Publication of NO873108L publication Critical patent/NO873108L/no

Links

238000000034 method Methods 0.000 title claims description 18
238000002360 preparation method Methods 0.000 title claims description 15
229940049706 benzodiazepine Drugs 0.000 title description 4
230000001225 therapeutic effect Effects 0.000 title description 3
150000001875 compounds Chemical class 0.000 claims description 97
125000003118 aryl group Chemical group 0.000 claims description 39
229910052739 hydrogen Inorganic materials 0.000 claims description 31
239000001257 hydrogen Substances 0.000 claims description 30
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 25
-1 imidoester hydrochloride Chemical class 0.000 claims description 25
239000002253 acid Substances 0.000 claims description 20
239000000203 mixture Substances 0.000 claims description 20
239000000460 chlorine Substances 0.000 claims description 12
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 11
229910052736 halogen Inorganic materials 0.000 claims description 11
150000002367 halogens Chemical class 0.000 claims description 11
229910052757 nitrogen Inorganic materials 0.000 claims description 11
150000001412 amines Chemical class 0.000 claims description 9
150000003839 salts Chemical class 0.000 claims description 8
125000000217 alkyl group Chemical group 0.000 claims description 7
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
125000003277 amino group Chemical group 0.000 claims description 6
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
229910052801 chlorine Inorganic materials 0.000 claims description 6
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
125000003710 aryl alkyl group Chemical group 0.000 claims description 5
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
229910052794 bromium Inorganic materials 0.000 claims description 5
150000002431 hydrogen Chemical class 0.000 claims description 5
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 4
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
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 claims description 4
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
125000006519 CCH3 Chemical group 0.000 claims description 4
150000004985 diamines Chemical class 0.000 claims description 4
230000002829 reductive effect Effects 0.000 claims description 4
238000007363 ring formation reaction Methods 0.000 claims description 4
239000007858 starting material Substances 0.000 claims description 4
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
229910052760 oxygen Inorganic materials 0.000 claims description 3
239000001301 oxygen Substances 0.000 claims description 3
125000005544 phthalimido group Chemical group 0.000 claims description 3
229910052717 sulfur Inorganic materials 0.000 claims description 3
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 2
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 2
239000005864 Sulphur Substances 0.000 claims description 2
229910021529 ammonia Inorganic materials 0.000 claims description 2
125000004122 cyclic group Chemical group 0.000 claims description 2
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
125000005842 heteroatom Chemical group 0.000 claims description 2
238000006698 hydrazinolysis reaction Methods 0.000 claims description 2
125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
239000000376 reactant Substances 0.000 claims description 2
229920006395 saturated elastomer Polymers 0.000 claims description 2
LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 2
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
150000001450 anions Chemical class 0.000 claims 1
239000003638 chemical reducing agent Substances 0.000 claims 1
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 72
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
108010003541 Platelet Activating Factor Proteins 0.000 description 29
HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 28
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
238000006243 chemical reaction Methods 0.000 description 19
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
239000012074 organic phase Substances 0.000 description 16
239000000243 solution Substances 0.000 description 16
238000005160 1H NMR spectroscopy Methods 0.000 description 15
ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 15
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
239000002904 solvent Substances 0.000 description 14
230000000694 effects Effects 0.000 description 13
238000002844 melting Methods 0.000 description 13
230000008018 melting Effects 0.000 description 13
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 12
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
238000010992 reflux Methods 0.000 description 12
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
238000001816 cooling Methods 0.000 description 11
239000011541 reaction mixture Substances 0.000 description 11
235000011121 sodium hydroxide Nutrition 0.000 description 11
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
238000009835 boiling Methods 0.000 description 10
239000000725 suspension Substances 0.000 description 10
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
230000002776 aggregation Effects 0.000 description 9
238000004220 aggregation Methods 0.000 description 9
239000000741 silica gel Substances 0.000 description 9
229910002027 silica gel Inorganic materials 0.000 description 9
ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 7
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 7
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
230000004054 inflammatory process Effects 0.000 description 7
229910000027 potassium carbonate Inorganic materials 0.000 description 7
238000012360 testing method Methods 0.000 description 7
GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical class N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 description 6
POYYVKCNRLFOJX-UHFFFAOYSA-N 1-methyl-6-phenyl-4h-imidazo[1,2-a][1,4]benzodiazepin-8-ol Chemical compound C12=CC(O)=CC=C2N2C(C)=CN=C2CN=C1C1=CC=CC=C1 POYYVKCNRLFOJX-UHFFFAOYSA-N 0.000 description 6
206010061218 Inflammation Diseases 0.000 description 6
241001465754 Metazoa Species 0.000 description 6
239000002585 base Substances 0.000 description 6
230000036772 blood pressure Effects 0.000 description 6
150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
238000001704 evaporation Methods 0.000 description 6
230000008020 evaporation Effects 0.000 description 6
238000003756 stirring Methods 0.000 description 6
239000000126 substance Substances 0.000 description 6
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 5
210000004369 blood Anatomy 0.000 description 5
239000008280 blood Substances 0.000 description 5
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 5
239000003480 eluent Substances 0.000 description 5
238000001802 infusion Methods 0.000 description 5
238000001953 recrystallisation Methods 0.000 description 5
208000010110 spontaneous platelet aggregation Diseases 0.000 description 5
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
FTZBVKJTOVZCSB-UHFFFAOYSA-N 6-(2-chlorophenyl)-1-methyl-4h-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-ol Chemical compound C12=CC(O)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl FTZBVKJTOVZCSB-UHFFFAOYSA-N 0.000 description 4
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
206010006482 Bronchospasm Diseases 0.000 description 4
241000700198 Cavia Species 0.000 description 4
241000700159 Rattus Species 0.000 description 4
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
208000024780 Urticaria Diseases 0.000 description 4
150000008065 acid anhydrides Chemical class 0.000 description 4
235000011114 ammonium hydroxide Nutrition 0.000 description 4
230000008485 antagonism Effects 0.000 description 4
239000005557 antagonist Substances 0.000 description 4
230000007885 bronchoconstriction Effects 0.000 description 4
150000001735 carboxylic acids Chemical class 0.000 description 4
238000004440 column chromatography Methods 0.000 description 4
238000007796 conventional method Methods 0.000 description 4
239000012043 crude product Substances 0.000 description 4
239000013078 crystal Substances 0.000 description 4
230000005764 inhibitory process Effects 0.000 description 4
238000002347 injection Methods 0.000 description 4
239000007924 injection Substances 0.000 description 4
238000001990 intravenous administration Methods 0.000 description 4
239000003960 organic solvent Substances 0.000 description 4
XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 4
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
GRJVJGHDIGMMPX-UHFFFAOYSA-N 1-methyl-6-phenyl-4h-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-ol Chemical compound C12=CC(O)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 GRJVJGHDIGMMPX-UHFFFAOYSA-N 0.000 description 3
HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 3
GOWFRJLAGSAAOZ-UHFFFAOYSA-N 8-methoxy-1-methyl-6-phenyl-4h-imidazo[1,2-a][1,4]benzodiazepine Chemical compound C=1C(OC)=CC=C(N2C(C)=CN=C2CN=2)C=1C=2C1=CC=CC=C1 GOWFRJLAGSAAOZ-UHFFFAOYSA-N 0.000 description 3
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 3
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
230000009471 action Effects 0.000 description 3
125000002947 alkylene group Chemical group 0.000 description 3
208000006673 asthma Diseases 0.000 description 3
150000001557 benzodiazepines Chemical class 0.000 description 3
206010006451 bronchitis Diseases 0.000 description 3
150000001733 carboxylic acid esters Chemical class 0.000 description 3
210000003169 central nervous system Anatomy 0.000 description 3
201000010099 disease Diseases 0.000 description 3
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
150000004820 halides Chemical class 0.000 description 3
230000000147 hypnotic effect Effects 0.000 description 3
238000000338 in vitro Methods 0.000 description 3
239000012442 inert solvent Substances 0.000 description 3
239000003921 oil Substances 0.000 description 3
CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 3
NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
239000000523 sample Substances 0.000 description 3
230000001624 sedative effect Effects 0.000 description 3
210000001519 tissue Anatomy 0.000 description 3
238000005303 weighing Methods 0.000 description 3
SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
SDGHXWKVBZYHRR-UHFFFAOYSA-N 2-(1h-imidazol-2-ylsulfonyl)-1h-imidazole Chemical compound N=1C=CNC=1S(=O)(=O)C1=NC=CN1 SDGHXWKVBZYHRR-UHFFFAOYSA-N 0.000 description 2
ZXCIEWBDUAPBJF-MUUNZHRXSA-N 2-O-acetyl-1-O-octadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C ZXCIEWBDUAPBJF-MUUNZHRXSA-N 0.000 description 2
PQECODMSWJOUAT-UHFFFAOYSA-N 4-(3-chloropropyl)morpholine;hydrochloride Chemical compound [Cl-].ClCCC[NH+]1CCOCC1 PQECODMSWJOUAT-UHFFFAOYSA-N 0.000 description 2
FHSRIUJMNUUOLM-UHFFFAOYSA-N 4-[2-[[6-(2-chlorophenyl)-1-methyl-4h-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl]oxy]ethyl]morpholine Chemical compound C12=CC(OCCN3CCOCC3)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl FHSRIUJMNUUOLM-UHFFFAOYSA-N 0.000 description 2
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101150013553 CD40 gene Proteins 0.000 description 2
239000004215 Carbon black (E152) Substances 0.000 description 2
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
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206010028980 Neoplasm Diseases 0.000 description 2
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241000700157 Rattus norvegicus Species 0.000 description 2
206010040914 Skin reaction Diseases 0.000 description 2
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-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
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
241001061127 Thione Species 0.000 description 2
102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 2
229960000583 acetic acid Drugs 0.000 description 2
239000013543 active substance Substances 0.000 description 2
150000001408 amides Chemical class 0.000 description 2
CBTVGIZVANVGBH-UHFFFAOYSA-N aminomethyl propanol Chemical compound CC(C)(N)CO CBTVGIZVANVGBH-UHFFFAOYSA-N 0.000 description 2
230000002052 anaphylactic effect Effects 0.000 description 2
230000036783 anaphylactic response Effects 0.000 description 2
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230000001773 anti-convulsant effect Effects 0.000 description 2
239000008346 aqueous phase Substances 0.000 description 2
239000011230 binding agent Substances 0.000 description 2
210000001772 blood platelet Anatomy 0.000 description 2
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210000001715 carotid artery Anatomy 0.000 description 2
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238000002425 crystallisation Methods 0.000 description 2
230000008025 crystallization Effects 0.000 description 2
208000009190 disseminated intravascular coagulation Diseases 0.000 description 2
HHHXVYUIPKDTLJ-UHFFFAOYSA-N ethyl 2-[(1-methyl-6-phenyl-4h-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl)oxy]acetate Chemical compound C=1C(OCC(=O)OCC)=CC=C(N2C(C)=NN=C2CN=2)C=1C=2C1=CC=CC=C1 HHHXVYUIPKDTLJ-UHFFFAOYSA-N 0.000 description 2
238000002474 experimental method Methods 0.000 description 2
239000011737 fluorine Substances 0.000 description 2
229910052731 fluorine Inorganic materials 0.000 description 2
239000012362 glacial acetic acid Substances 0.000 description 2
229940088597 hormone Drugs 0.000 description 2
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230000001732 thrombotic effect Effects 0.000 description 1
238000012546 transfer Methods 0.000 description 1
JOFWLTCLBGQGBO-UHFFFAOYSA-N triazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl JOFWLTCLBGQGBO-UHFFFAOYSA-N 0.000 description 1
229960003386 triazolam Drugs 0.000 description 1
230000001960 triggered effect Effects 0.000 description 1
230000008728 vascular permeability Effects 0.000 description 1
239000003981 vehicle Substances 0.000 description 1
235000012431 wafers Nutrition 0.000 description 1
239000008096 xylene Substances 0.000 description 1
239000011701 zinc Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—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
- C07D487/04—Ortho-condensed systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Medicinal Chemistry (AREA)
Engineering & Computer Science (AREA)
Diabetes (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Bioinformatics & Cheminformatics (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Hematology (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)

NO873108A 1986-07-25 1987-07-24 Fremgangsmaate for fremstilling av terapeutisk aktive 1,4-benzodiazepiner. NO873108L (no)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
DE3625197		1986-07-25

Publications (2)

Publication Number	Publication Date
NO873108D0 NO873108D0 (no)	1987-07-24
NO873108L true NO873108L (no)	1988-01-26

Family

ID=6305976

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
NO873108A NO873108L (no)	1986-07-25	1987-07-24	Fremgangsmaate for fremstilling av terapeutisk aktive 1,4-benzodiazepiner.

Country Status (16)

Country	Link
EP (1)	EP0255028A3 (fi)
JP (1)	JPS6335574A (fi)
KR (1)	KR880001657A (fi)
AU (1)	AU603591B2 (fi)
DD (1)	DD266355A5 (fi)
DK (1)	DK387587A (fi)
FI (1)	FI873243A (fi)
HU (1)	HU197011B (fi)
IL (1)	IL83318A0 (fi)
NO (1)	NO873108L (fi)
NZ (1)	NZ221189A (fi)
PL (1)	PL266932A1 (fi)
PT (1)	PT85396B (fi)
SU (1)	SU1681729A3 (fi)
YU (1)	YU136287A (fi)
ZA (1)	ZA875446B (fi)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
GB8720414D0 (en) *	1987-08-28	1987-10-07	Roussel Lab Ltd	Chemical compounds
DE4244265C2 (de) *	1992-12-28	1999-08-12	Korth Ruth Maria	Verwendung von Paf-Antagonisten gegen die neue Ausbildung von Paf-Bindungsstellen auf endothelialen Zellen zur Behandlung oder Vorbeugung des Hyperinsulinismus
US5895785A (en) *	1987-10-20	1999-04-20	Ruth Korth	Treatment and prevention of disorders mediated by LA-paf or endothelial cells
DE3808283A1 (de) *	1988-03-12	1989-09-21	Boehringer Ingelheim Kg	Neue 3,4,5-substituierte 4h-1,2,4-triazole, ihre herstellung und verwendung
DE3810848A1 (de) *	1988-03-30	1989-10-19	Boehringer Ingelheim Kg	Neue 2,3,4-substituierte imidazole und 3,4,5-substituierte 1,2,4-triazole, ihre herstellung und verwendung
IL91386A0 (en) *	1988-08-24	1990-04-29	Boehringer Ingelheim Kg	Method for treating autoimmune diseases by using a paf antagonist and pharmaceutical compositions comprising it
GR900100619A (el) *	1989-08-19	1991-12-30	Boehringer Ingelheim Kg	Υποκατεστημενα ν-ετεροκυκλικα,παραγωγη και χρησις αυτων.
JP2733708B2 (ja) *	1990-09-22	1998-03-30	カースル産業株式会社	排気口のフィルター装置
JP2520577Y2 (ja) *	1991-05-28	1996-12-18	住友重機械工業株式会社	消石灰溶解注入装置
ES2181665T3 (es) *	1991-11-04	2003-03-01	Ruth-Maria Korth	Tratamiento y prevencion de enfermedades mentales, acompañadas por unos elevados niveles de liso paf, con los antagonistas de paf.
JP3719324B2 (ja)	1997-12-24	2005-11-24	豊田工機株式会社	冷風冷却を用いた機械加工方法
JPH11188570A (ja)	1997-12-24	1999-07-13	Toyoda Mach Works Ltd	冷風冷却を用いた機械加工装置及び機械加工方法
CN109689647B (zh) *	2016-07-14	2023-01-20	百时美施贵宝公司	二环杂芳基取代的化合物

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
GB1332766A (en) *	1971-06-18	1973-10-03	Upjohn Co	Triazolo-benzodiazepines
FR2183716A1 (en) *	1972-05-05	1973-12-21	Centre Etd Ind Pharma	Substd-6-phenyl-4h-imidazo (1,2-a)-1,4-benzo diazepines - - tranquillisers anxiolytics,sedatives and muscle-relaxants
US3880876A (en) *	1972-11-03	1975-04-29	American Home Prod	Process for the preparation of 6-aryl-4H-s-triazolo-{8 4,3-a{9 {8 1,4{9 benzodiazepines
US4663321A (en) *	1984-06-26	1987-05-05	Merck & Co., Inc.	Triazolobenzodiazepines and pharmaceutical use
DE3610848A1 (de) *	1986-04-01	1987-10-15	Boehringer Ingelheim Kg	Neue 1,4-diazepine
US4735941A (en) *	1986-12-23	1988-04-05	Merck & Co., Inc.	1,4-benzodiazepines with 5- and 6-membered heterocyclic rings, useful as gastrointestinal and CNS agents

1987
- 1987-07-20 SU SU874202929A patent/SU1681729A3/ru active
- 1987-07-20 YU YU01362/87A patent/YU136287A/xx unknown
- 1987-07-21 PL PL1987266932A patent/PL266932A1/xx unknown
- 1987-07-22 EP EP87110590A patent/EP0255028A3/de not_active Withdrawn
- 1987-07-23 DD DD87305296A patent/DD266355A5/de not_active IP Right Cessation
- 1987-07-24 IL IL83318A patent/IL83318A0/xx unknown
- 1987-07-24 JP JP62185347A patent/JPS6335574A/ja active Pending
- 1987-07-24 DK DK387587A patent/DK387587A/da not_active Application Discontinuation
- 1987-07-24 NZ NZ221189A patent/NZ221189A/xx unknown
- 1987-07-24 AU AU76103/87A patent/AU603591B2/en not_active Ceased
- 1987-07-24 HU HU873414A patent/HU197011B/hu not_active IP Right Cessation
- 1987-07-24 PT PT85396A patent/PT85396B/pt unknown
- 1987-07-24 FI FI873243A patent/FI873243A/fi not_active Application Discontinuation
- 1987-07-24 NO NO873108A patent/NO873108L/no unknown
- 1987-07-24 ZA ZA875446A patent/ZA875446B/xx unknown
- 1987-07-25 KR KR1019870008107A patent/KR880001657A/ko not_active Application Discontinuation

Also Published As

Publication number	Publication date
DD266355A5 (de)	1989-03-29
PL266932A1 (en)	1988-09-01
AU603591B2 (en)	1990-11-22
PT85396A (de)	1987-08-01
FI873243A (fi)	1988-01-26
JPS6335574A (ja)	1988-02-16
HUT44788A (en)	1988-04-28
DK387587D0 (da)	1987-07-24
IL83318A0 (en)	1987-12-31
HU197011B (en)	1989-02-28
PT85396B (de)	1989-10-26
EP0255028A3 (de)	1990-03-21
NZ221189A (en)	1990-09-26
ZA875446B (en)	1989-03-29
YU136287A (en)	1990-06-30
NO873108D0 (no)	1987-07-24
DK387587A (da)	1988-01-26
FI873243A0 (fi)	1987-07-24
KR880001657A (ko)	1988-04-25
AU7610387A (en)	1988-01-28
EP0255028A2 (de)	1988-02-03
SU1681729A3 (ru)	1991-09-30

Publication	Publication Date	Title
US3932407A (en)	1976-01-13	Optionally substituted 1,2,3,5-tetrahydroimidezo(2,1-b)-quinazolin-2-ones and 6(H)-1,2,3,4-tetrahydropyimido(2,1-b)quinazolin-2-ones
PL153970B1 (en)	1991-06-28	Process for manufacturing novel derivatives of thieno-/1,4/diazepins
NO166367B (no)	1991-04-02	Analogifremgangsmaate for fremstilling av terapeutisk aktive tieno-1,4-diazepiner.
CZ410791A3 (en)	1993-04-14	Amides of thieno-triazolo-1,4-diazepino-2-carboxylic acid, process of their preparation and pharmaceutical preparation based thereon
WO1996028429A1 (en)	1996-09-19	6-SUBSTITUTED PYRAZOLO [3,4-d] PYRIMIDIN-4-ONES AND COMPOSITIONS AND METHODS OF USE THEREOF
NO163406B (no)	1990-02-12	Analogifremgangsmaate for fremstilling av terapeutisk aktive imidazokinolinonderivater.
NO873108L (no)	1988-01-26	Fremgangsmaate for fremstilling av terapeutisk aktive 1,4-benzodiazepiner.
AU716008B2 (en)	2000-02-17	Bicyclic benzazepine derivatives as vasopressin antagonists
NO162073B (no)	1989-07-24	Analogifremgangsmaate for fremstilling av farmakologiske aktive heterocykliske forbindelser.
NO175151B (no)	1994-05-30	Analogifremgangsmåte til fremstilling av terapeutisk aktive diazepinderivater
DE3724031A1 (de)	1988-01-28	Neue hetrazepine und verfahren zu ihrer herstellung
US5753647A (en)	1998-05-19	Acylamino-substituted hetrazepines
NO151287B (no)	1984-12-03	Analogifremgangsmaate for fremstilling av terapeutisk aktive 9-hydrazono-6,7,8,9-tetrahydro-4h-pyrido(1,2-a)-pyrimidinderivater
DK160762B (da)	1991-04-15	Analogifremgangsmaade til fremstilling af 2-phenyl- eller 2-pyridyl-pyrazolooe4,3-caaquinolin-3(1 og 5h)-on-forbindelser eller de 3-hydroxytautomere eller salte deraf
US3957783A (en)	1976-05-18	Thieno[2,3-d]pyrimidine derivatives
US4053600A (en)	1977-10-11	Tricyclic 1,2,4-triazolo-quinazolines
US4608375A (en)	1986-08-26	Quinazolinone derivatives, processes for the preparation thereof and pharmaceutical composition comprising the same
US4539400A (en)	1985-09-03	Pyridin-3-yl substituted ortho-fused pyrrole derivatives
RU2057754C1 (ru)	1996-04-10	Гетероциклические соединения или их кислотно-аддитивные соли
US4372956A (en)	1983-02-08	5, 10-Dihydroimidazo[2,1-b]quinazolines and pharmaceutical compositions containing them
SU1355131A3 (ru)	1987-11-23	Способ получени замещенных производных карбокситиазоло[3,2-а]пиримидина или их фармацевтически приемлемых солей
US3329701A (en)	1967-07-04	Cyanobenzophenones
SU725564A1 (ru)	1980-03-30	Способ получени замещенных 1пиперазинил-4н- -триазоло/3,4-с/ тиено/2,3-е/-1,4-диазепинов или их солей
JPS59141580A (ja)	1984-08-14	インド−ル誘導体
JPH04502475A (ja)	1992-05-07	１，２―ジヒドロ―２―オキソキノキサリンの新規誘導体、その製造および治療への該化合物の適用