US3900466A - 6-aza-3h-1,4-benzodiazepines - Google Patents
6-aza-3h-1,4-benzodiazepines Download PDFInfo
- Publication number
- US3900466A US3900466A US468088A US46808874A US3900466A US 3900466 A US3900466 A US 3900466A US 468088 A US468088 A US 468088A US 46808874 A US46808874 A US 46808874A US 3900466 A US3900466 A US 3900466A
- Authority
- US
- United States
- Prior art keywords
- group
- carbon atoms
- phenyl
- hydrogen
- acid
- Prior art date
- 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 - Lifetime
Links
- BTQDZLVHRYXJDK-UHFFFAOYSA-N 3h-pyrido[3,2-e][1,4]diazepine Chemical class C1=NCC=NC2=CC=CN=C21 BTQDZLVHRYXJDK-UHFFFAOYSA-N 0.000 title 1
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 71
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 32
- 239000001257 hydrogen Substances 0.000 claims abstract description 32
- 125000000217 alkyl group Chemical group 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 26
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 23
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000000460 chlorine Substances 0.000 claims abstract description 18
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 18
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 18
- 239000001301 oxygen Substances 0.000 claims abstract description 18
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 16
- 239000011737 fluorine Substances 0.000 claims abstract description 16
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 15
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 11
- 125000003277 amino group Chemical group 0.000 claims abstract description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 7
- -1 hydroxy, methoxy, ethoxy propoxy Chemical group 0.000 claims description 47
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 5
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical group ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical class N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims 1
- 125000004360 trifluorophenyl group Chemical group 0.000 claims 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 18
- 125000005277 alkyl imino group Chemical group 0.000 abstract description 10
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 10
- 125000001841 imino group Chemical group [H]N=* 0.000 abstract description 9
- 229910052717 sulfur Inorganic materials 0.000 abstract description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract description 8
- 239000011593 sulfur Substances 0.000 abstract description 8
- 150000003839 salts Chemical class 0.000 abstract description 7
- 125000005530 alkylenedioxy group Chemical group 0.000 abstract description 6
- 239000002249 anxiolytic agent Substances 0.000 abstract description 3
- 230000000949 anxiolytic effect Effects 0.000 abstract description 3
- 230000001741 anti-phlogistic effect Effects 0.000 abstract description 2
- 230000000561 anti-psychotic effect Effects 0.000 abstract description 2
- 239000000812 cholinergic antagonist Substances 0.000 abstract description 2
- 230000002048 spasmolytic effect Effects 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 239000002253 acid Substances 0.000 description 29
- 235000019441 ethanol Nutrition 0.000 description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 22
- 239000000203 mixture Substances 0.000 description 22
- 239000000243 solution Substances 0.000 description 18
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 17
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 238000000034 method Methods 0.000 description 14
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 239000000463 material Substances 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 235000019198 oils Nutrition 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 10
- 239000003513 alkali Substances 0.000 description 9
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 150000001298 alcohols Chemical class 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000005804 alkylation reaction Methods 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 230000029936 alkylation Effects 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000012442 inert solvent Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000011149 active material Substances 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 238000009903 catalytic hydrogenation reaction 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
- 239000013078 crystal Substances 0.000 description 3
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
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- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
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- 241000282472 Canis lupus familiaris Species 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
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- 125000002252 acyl group Chemical group 0.000 description 2
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- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 235000019149 tocopherols Nutrition 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- VMPHSYLJUKZBJJ-UHFFFAOYSA-N trilaurin Chemical compound CCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCC)COC(=O)CCCCCCCCCCC VMPHSYLJUKZBJJ-UHFFFAOYSA-N 0.000 description 1
- OHSJPLSEQNCRLW-UHFFFAOYSA-N triphenylmethyl radical Chemical compound C1=CC=CC=C1[C](C=1C=CC=CC=1)C1=CC=CC=C1 OHSJPLSEQNCRLW-UHFFFAOYSA-N 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- QUEDXNHFTDJVIY-UHFFFAOYSA-N γ-tocopherol Chemical class OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- n is an integer from 1 to 4.
- R is alkyl of 1 to 6 carbon atoms, a hydroxy group, an amino group, an alkoxy group having 1 to 6 carbon atoms, a phenyl group or a phenyl group substituted with alkyl of l to 6 carbon atoms, an alkoxy group of l to 6 carbon atoms, trifluoromethyl, fluorine or chlorine;
- B is oxygen, sulfur, an imino group or an alkylimino group having I to 6 carbon atoms
- R is hydrogen, a hydroxy group, an alkyl group with 1 to 6 carbon atoms, an alkoxy group with 1 to 6 carbon atoms, or the group N,, is nitrogen or an NO group;
- R and R are the same or different and are hydrogen, chlorine, fluorine, the trifluoromethyl group, alkyl groups of l to 6 carbon atoms or alkoxy groups with l to 6 carbon atoms, the tautomeric forms thereof and pharmaceutically acceptable salts thereof.
- the compounds have psychosedative, anxiolytic, spasmolytic, antipsychotic and antiphlogistic activity.
- R is alkyl of l to 6 carbon atoms, a hydroxy group
- B is oxygen, sulfur, an imino group or an alkylimino group having 1 to 6 carbon atoms
- the alkyl group's alkoxy groups and alkylimino groups preferably have] to 4 carbon atoms.
- R ⁇ is asubstituted' phenyl group it can be mono or di substituted and the substitutents can be the same or different.
- A is an alkylenedioxy group preferably it is the ethylenedioxy group, i.e., A with the attached carbon atom forms the dioxolane ring.
- alkyl and ,alkoxy groups which can be present include methyLethyl, propyl, isopropyl, butyl, tert.buty
- alkylimino groups are methylimino, ethylimino, propylimino, butylimino,
- R and B are as defined above and Y is a hydroxy group, a halogenatom, an alkoxy group, a mercapto group, an alkyl mercapto group, an amino group or an alkylamino group, in a given case with addition of an acid binding agent, or
- Process (a') is carried out, in a given case with the addition of customary acid binding agents such as alkali carbonates,'e.g., sodium'carbonate or potassium carbonate, pyridine or other customary tertiary amines, e.g., triethyl amine, at temperatures between 0 and 150C. in inert solvents such as dioxane, dimethyl formamide, dimethyl sulfoxide, aromatic hydrocarbons such as benzene and toluene or acetone.
- customary acid binding agents such as alkali carbonates,'e.g., sodium'carbonate or potassium carbonate, pyridine or other customary tertiary amines, e.g., triethyl amine, at temperatures between 0 and 150C.
- inert solvents such as dioxane, dimethyl formamide, dimethyl sulfoxide, aromatic hydrocarbons such as benzene and toluene or acetone.
- Process (b) takes place in customary solvents or suspension media at temperatures between 0 and 200C., preferably to 150C.
- polar solvents for example, alcohols, e.g., methyl alcohol, ethylalcohol, propyl alcohol, isopropyl alcohol and butyl alcohol, dioxane, tetrahydrofurane, dimethyl sulfoxide, dimethyl formamide or imidazole, as well as media such as pyridine or quinoline.
- Y is a halogen atom itcan be advantageous (but otherewise there should not be added) to add basic materials', e.g.,-sodium hydroxide, which facilitate an acid splitting.
- Y is a hydroxy group it is suitable and,
- (dehydrating) agents such as dicyelohexylcarbodiimide or l-ethoxy-2-carbethoxy-l.2- dihydroquinoline.
- Y is alkylmercaptogroup, alkoxy group or alkylamino group these groups are preferably; of lower molecular weight and for example consist of l to 6 carbon atoms, e.g., methyl mcrcato, hexyl mercapto, methoxy, ethoxy, methylamino and hexyl ar'ninoj v
- protective groups are easily split off.
- acyl potash,v soda, aqueous alkali solutions, alcoholic alkali solutions, N a
- Hydrogenizably splittable groups such as the benzyl group or the carbobenzoxy radical are suitably split off by catalytic hydrogenation in the presence of customary hydrogenation catalysts, especially palladium catalysts, in'a solvent or suspension agent, in a given case under elevated pressure.
- solvents or suspension agent there can be used water, lower aliphatic alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol, butyl alcohol, cyclic ethers such as dioxane or tetrahydrofuran, aliphatic ethers, e.g., diethyl ether,
- protective groups for the amino group there can be used for example, the benzyl group, a-phenylethyl group, benzyl groups substituted in the benzene nucleus as for example, the p-bromo or p.-nitrobenzyl group, the carbobenzoxy group, the carbobenzthio group, the trifluroacetyl, the phthalyl radical, the trityl radical, the p-toluenesulfonyl radical and similar groups as well as simple acyl groups such as the acetyl group, formyl group, tert. butylcarboxy group, etc.
- Process (b) can also be carried out under some circumstances so that before the true cyclization there is prevously isolated the intermediate product of the formula:
- azabenzodiazepinc 1 formula I can be reacted further or substituted in a suitable manner.
- compounds of formulal wherein R is an OH group can be esterified ina suitable manner.
- lower aliphatie alcohols e.g., of l to 6 carbon .atoms such as methyl alcohol, ethyl alcohol, isopropyl alcohol, propyl alcohol,--butyl alcohol,.sec.
- butyl alcohol, t-butyl alcohol, amylalcohol, or hexyl alcohol in the presence of-acid catalysts, e.g., hydrochloric acid, sulfuric acid or p-toluene sulfonic acid or there can be reacted diazoalkanes having l to'6 carbon atoms, e.g., diazomethane and .diazohexane, in the conventional manner in ethereal of dioxane solution at temperatures between and 50C.
- -acid catalysts e.g., hydrochloric acid, sulfuric acid or p-toluene sulfonic acid or there can be reacted diazoalkanes having l to'6 carbon atoms, e.g., diazomethane and .diazohexane
- the groups Aand B in compounds of formula I can be changed-by various procedures.
- a and B are oxygen
- theseatoms can be-replaced by a sulfur atom by means of phosphorus pentasulfide.
- This reaction takes place in inert solventssuch as-benzene, toluene, dioxane, pyridine,v of chlorohydrocarbons,.-e.g,, chloroform, at temperatures between 0 and 150C.
- Compounds in whichA and/or B- isoxygen; or sulfur can in turn be reacted in polar mediatsuch as those mentioned above, for example).
- alkylamines with' l to 6 carbon .atoms,- e.g,, methylamine, ethyl amine, propyl amine, isopropyl amine, butyl amine, amyl amine or hexyl amine to form compounds in which A and/or'B are imi'no or. alkylimno groups.
- the reactions are carried out for example in polar.solventssuch as methanol, ethanolor excess amine at temperatures. between 0-and 150 C. lg
- A is two alkoxy s or an alkylenedioxy group (inwhichR, isphenyl min a given case substituted phenyl) there can be obtained therefrom the ketone where A is 0 in a manner known in itself using acid conditions.
- This reaction is carried out for example in polar solvents or suspension media which contain some water, as well as in aqueous methanol, ethanol, dioxane or tetrahydrofurane with the addition of some aqueous hydrochloric acid, sulfuric acid, p-toluene sulfonic acid, etc., or it can also be carried out in aqueous media.
- the temperature is between 0 and 100C, prefer- :ably at 0 to C.
- the temperatue employed are between 0 and 160C, preferably 50 to C.
- alkyl group with l to 6 carbon atoms or the groups --.(CH C A) R
- examples are p-toluenesulfonic ac d ethyl, esters. e.g., methyLp-tolucnesulfonate', ethyl-p-toluenesulfonate, lower dialkyl sulfates, e.g., dimethyl sulfate and diethyl sulfate and the like.
- the alkylation reaction takes place, in a given case, with addition of customary acid potassium carbonate, pyridine or other customary tertiary amines at temperatures between 0 and C.
- inert solvents such as alcohols, e.g., methyl alcohol, ethyl alcohol or. propyl, alcohol, dioxane, dimethyl formamide, dimethyl sufloxide, aromtiehydrocarbons such as benzene or toluene or acetone as well as mixtures of such solvents, I I
- alkylation with alkyl halides- for example, iodides
- alkyl halides- for example, iodides
- the c0mpound of'formula -l.-in w hi ch R is H or OH.,can firstbe converted to an alkalicompound if it is treated with an alkali metal, alkali'hydride or, alkali amide (especially sodiumorsodium compounds such as sodiumhydride and sodamide) in an inert solvent such as dioxane, dimethylformamide, benzene or toluene at temperatures between 0 and-1509C. ,and then the alkylating agent added.
- g y I Compunds; of formula'l'wherein N is a nitrogen atom cambe convertedinto the corresponding N -oxide, For
- catalysts especially nob'le metal, catalysts (palladium/activated .carbom, platinum) or Raneynickel; as solvents there are preferably, employed lower alcohols, e,g., methanol, ethanol and isopropanol.
- temperatures employed. are between 0.and 200 C apreferablybetween 0 andJQOfC.
- process . can be carried outat pressures up to 5 0;atmospheres absolute.
- acids such as sulfuric,;acid,,phosphoric acid, hydrohalic'v acids, e.g., hy-
- drochloric acid or hydrobromic acid ethylenediamine tetraacetic acid, sulfamic,acid,.benzene sulfonic acid, p-toluene, sulfonic acid, ,camphor sulfonic ,acid, emthane sulfonic acid, guarazulenesulfonic acid, maleic 'acid, furnaric acid, oxalic, acid, tartaric acid, lactic acid,
- the compoupds of formula l contain acid groups they can be converted in customary manner into their alkali (e.g., sodium or potassium ammonium or subtreating a solution in an organic agent such as alcohols,
- the compounds of the invention are suitable for the production of pharmaceutical compositions.
- the pharmaceutical compositions or medicaments can contain one or more of the compounds of the invention or mixtures of the same with other pharmaceutically active materials.
- the customary pharmaceutical carriers and assistants can be used for the production of pharmaceutical preparations there can be used the customary pharmaceutical carriers and assistants.
- the medicines can be employed entcrally, parenterally, orally or perlingually.
- dispensing can take place in the form of tablets, capsules, pills, dragees, plugs, salves, jellies, cremes, powders, liquids, dusts or aerosols.
- n l to 3 A is oxygen;
- N is nitrogen
- R1 is methoxy, ethoxy, propoxy, phenyl, fluorophenyl or chlorophenyl; v
- R is hydrogen orhydroxy
- R is hydrogen, fluorine,,or chlorine, preferably ,in
- R is hydrogen. 3
- the starting compounds used in process (a) can' be prepared for example according to the process of German published Application No. 2,259,471 or von Bebenburg et al. U.S. application Ser.-No. 313,542, filed Dec. 8, l972 orin analogousmanner to those processes. The entire disclosure of the von Bebenburg et al. U.S. application is hereby incorporated by reference. These starting compounds are claimed as new compounds in said von Bebenburg et al. application.
- EXAMPLE 6 l-acetylmethyl-5-phenyl-6-aza-7-chloro-1,2-dihydro- 3H- l ,4-benzodiazepinone-( 2) CO CH To a mixture of 27 grams (0.1 mole) of -phenyl-6- aza-7-chlorol ,2-dihydro-3H- l benzodiazepinone- (Mi- 400 ml of dioxane and 40 ml of dimethyl formamide thcre were added under nitrogen with Stirring at EXAMPLE 7 l'-( 2-p-chlorophenyl-2-oxo-ethy l )-5 -phenyl-6-aza- 7- chlorol .Z-dihydrq-SH-l ',4-benzodiazepinone-( 2) To amixture of 27.2 grams (0.
- the crystals that formed were filtered off with suction and recrystallized from dimethyl formamid e/methanol.
- EXAMPLE 8 l-cyanom'ethyl-5-phenyl-6-aza-7-chlorol ,2-dihydro- 3H- 1 ,4-benzodiazepinonc-( 2) e11 CN v l3.5 grams (0.05 mole) of 5-phenyl-6-aza-7-chlorol,2-dihydro-3H-1,4-benzodiazepin0ne-(2) and 6 grams of chloroacetonitrile were reacted in a manner analogous to- Example 7. The reaction product was recrystal- Iize-d twice from acetone. Yield 6 grams; .M.P.
- Example 9 The starting'material in Example 9 was produced as follows.
- the precipitating crystals of the acid were filtc with suction and washed with water. Yield of 11,11 46 grams.
- the acid was esterified without further purification.
- the 46 -grams of'acid were dissolved in 500 m1 of ethanol and there was introduced with stirring at 60C hydrogen chloride until saturation occurred. Next the solution was concentrated to 200 ml and cooled while stirring.
- Theprecipitated crystals of the Z-benzoyl-3 carbethoxymethylamino-ochloropyridine were filtered off with suction and washed with'ethanol. Yield 35 grams; M.P. 88to 90C.
- compositions or drugs contain as the aetive material one or several of the compounds of the invention, in a given case in admixture with other" pharmacologicalllyor pharmaceutically effective materials.
- the production of the medicine can take place with the use of known and customary pharmaceutical assistants,carriers and diluents.
- Such carriers and assistants as set forth for example are thos recommended in the following literature as adjuvants for pharmacy, cosmetic and relatedfields su'ch as in Ullmans Encyklopadie' der intor Chemie,
- gelatin examples include gelatin, natural sugars such as sucrose or lactose, lecithin, pectin,
- l off starch for example corn starch
- tylose, talc, lycopocially of plant origin forexamplc. peanut oil, castor oil, olive oil, sesameoil, cottonseed oil, corn oil, monodiand triglycerides of saturated fatty acids (C H OL to C H O arid their mixtues, e.g., glyceryl 'monostearate, glyceryl distear'atej'glyceryl tristear'ate'; glyceryl trilaurate), pharmaceutically' compatible 'monoor polyvalent alcohols and polyglycols such as glycerine, mannitol, sorbitol, pentaeryth'ritol, ethyl 'alcohoL'diethylene glycol, triethylene glycol, ethylene glycol, ,pr'opy lene glycol.dipropylene'glycol, polyethylene glycol;- proylene
- unsaturated fatty acids (2 to 22 carbon atoms, especially lOto l8 carbon atoms),i'with monol to 20 carbon atoms alkanol s
- polyhydric alcohols such as glycols, glycerine, diethylene glycol, pentaerythritol, sorbitol, mannitol, eth
- esters of polyvalent alcohols can be gi en case also be etherified, benzyl benzoate, dioxolanedglycerine formal, glycol furfural, dimethyl ac'etamide, lactimide, lactates, e.g., ethyl lactate, ethyl carbonate, silicones (especially middle viscosity dimethyl polysioloane) and the like:
- water or physiologically compatible'organi 'solvents as for example, ethanol, l ,Z-prop yIene glycol, poly glycols, e.g., diethylene glycol, triethylene glycol and dipropylene glycol and their derivatives, dimethyl sulfox ide, fatty alcohols, e.g., stearyl alcohol, cetyl alcohol, lauryl alcohol and oleyl alcohol, triglycerides, e.g., glycoeryl acetate, partial estes of glycerine, e.g., monoacetic diacetin, glyceryl mo'nostearate, glyceryl distearate, glyceryl monopalrnitate, paraffins and the 1 i l '11.
- ethanol, l ,Z-prop yIene glycol poly glycols, e.g., diethylene glycol, triethylene glycol and dipropylene glycol and their derivatives, dimethyl s
- the productipn of th'epfepa'rations' thefe canbe used known and conventional solvent-aids.
- solvent aids there can bej used, for example, polyoxyethy'lated fats, e.g'., polyoxyethylated ol eotriglyceride;linoliaed oleotriglyceride.
- Examples 'of"oleotriglycerides olive oil, peanut oil, ca'stor oil, sesame oil, cottonseed oil,c'or n oil see @1186 Dr. H.
- materials qiues tion contain polyxyethylene chains whose degree of polymerization is generally between 2 and 40 and especially between lO and 20. Such materials can be obtained for example by reactionof thecorresponding glyceride with ethylene oxide (for example 40 moles of ethylene oxide per mole of glyceride).
- preservatives for example ethylenediamine tetraacetic acid
- buffers for example aqueous sulfate, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, arate, sulfate, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, ED
- alkyl gallates e.g., methyl gallate and ethyl gallate, butyl hydroxyanisole, nordihydroguararetic acid
- tocopherols such as tocopherol and 17 synergists (material which bind heavy metals by com plex formation. for example, lecithin, ascorbicv acid,
- preservatives there can be used for example sorbic acid, p-hydroxybenzoie acid esters (for example lower alkyl esters such as the methyl ester and the ethyl ester benzoic acid), sodium benzoate, trichloroisobutyl alco-
- sorbic acid for example lower alkyl esters such as the methyl ester and the ethyl ester benzoic acid
- sodium benzoate sodium benzoate
- the lowest effective dosage in the above-mentioned animal experiments for example is 0.5 mg/kg body weight orally, 0.1 mg/kg sublingually and 0.05 mg/kg intravenously.
- a general dosage range there can be used, for example, 0.5 to l mg/kg body weight orally, 0.1 to 2 mg/kg sublingually and 0.05 to 1 mg/kg intravenously.
- the compounds of the invention are useful in treating anxiety. stress and restlessness conditions, vegetative dystony, nervousness, irritability, moodiness, footlight fever (of actors), weather feelings, behaviour and adaptability problems of children, functional cardiovascular, gastrointestinal and respiratory complaints. They are also useful in' menstrual and climatic disturbances, aiding before operation and in assisting birth.
- the pharmaceutical preparations generally contain between 1 and I07: of the active component (or components) of the invention.
- the compounds can be delivered in the form of tablets, capsules, pills, dragees, suppositories, salves, gels, creams, powders, liquids, dusts or aerosols.
- liquids there can be used oily or aqueous solutions or suspensions, emulsions.
- the preferred forms of use are as tablets which contain between I and 50 mg of active material or solutions which contain between 0.1 and of active material.
- the amount of active component of the invention can be used for example in an amount of:
- parenteral dispensation for example, intravenously, intramuscularly between 0.1 and 5 mg;
- r 18 For example, there is recommended the use of l to 3 tablets containing 1 to 50 mg of active ingredient 3 times dailyor for example intravenouslythe injection 1 to 3- times daily or for example intravenously the injection l to 3 times daily of a l to 2 ml ampoule con taining 01 to 10 mg of active substances.
- the minimum daily dosage for example is 3 mg;
- the maximum daily dosage should not be over 200 mg.
- the oral individual dosage in general is between 0.5 and 50 ,mg/kg body weight; the parenteral individual dosage is between about 0.1 and 10 ing/kg body weight.
- the individual dosage orally is generally between 5 and I00 mg/kg; the parenteral individualdosge is between l and ZOmg/kg body weight.
- the acute toxicity of the co ounds ofthe invention inthe mouse is between 500 mg/kg 10,000fmg/kg (or .above 8000 mg/kg).
- the drugs can be used in human medicine in veterinary medicine ⁇ elgf, to treat cats, dogs,- horses, sheep, cattlegoats and pigs of in agriculture:
- the drugs can be used alone or'in admixture with otherpharmacologically active materials.
- the salts can also be usedias curing agents for melamine-formaldehyde resins.
- n is an integer from 1 to 4.
- R is alkyl of l to 6 carbon atoms, a hydroxy group
- B is oxygen, sulfur, an imino group or an alkylimino group having 1 to 6 carbon atoms
- R and R are hydrogen, chlorine, fluorine, the trifluoromethyl group, alkyl groups of l to 6 carbon atoms or alkoxy groups with l to 6 carbon atoms, the tautomeric forms thereof and pharmaceutically acceptable salts thereof.
- R is a hydroxy group, an amino group, an alkoxy group having 1 to 6 carbon atoms, a phenyl group or a phenyl group substituted with alkyl of l to 6 carbon atoms, an alkoxy group of l to 6 carbon atoms, trifluoromethyl, fluorine or chlorine.
- a compound according to claim 1 wherein the group C(R ) A is cyano, B is oxygen, R is hydrogen, hydroxy or alkoxy with l to 4 carbon atoms, R is hydrogen, chlorine or fluorine, and R is hydrogen.
- R2 is hydrogen, hydroxy, methoxy, ethoxy or propoxy.
- n is an integer from 1 to 3
- R is methyl, hydroxy, ethoxy, phenyl 'or chlorophenyl
- R2 is hydrogen
- R is hydrogen or chloro
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US05/576,112 US3972873A (en) | 1973-05-25 | 1975-05-09 | Certain pyrido[3,2-e]1,4-diazepinones and derivatives |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT462873A AT331251B (de) | 1973-05-25 | 1973-05-25 | Verfahren zur herstellung von neuen 6-aza-7-chlor-1,2-dihydro-3h-1,4-benzodiazepinen und deren salzen |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US05/576,112 Continuation-In-Part US3972873A (en) | 1973-05-25 | 1975-05-09 | Certain pyrido[3,2-e]1,4-diazepinones and derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
US3900466A true US3900466A (en) | 1975-08-19 |
Family
ID=3566375
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US468088A Expired - Lifetime US3900466A (en) | 1973-05-25 | 1974-05-08 | 6-aza-3h-1,4-benzodiazepines |
Country Status (17)
Country | Link |
---|---|
US (1) | US3900466A (xx) |
JP (1) | JPS5019767A (xx) |
AR (1) | AR200928A1 (xx) |
AT (1) | AT331251B (xx) |
BE (1) | BE815467A (xx) |
CA (1) | CA1035771A (xx) |
CH (1) | CH605942A5 (xx) |
DD (1) | DD111206A5 (xx) |
DE (1) | DE2425282A1 (xx) |
EG (1) | EG11352A (xx) |
ES (3) | ES426617A1 (xx) |
FR (1) | FR2230367B1 (xx) |
GB (1) | GB1410319A (xx) |
HU (1) | HU174561B (xx) |
NL (1) | NL7407015A (xx) |
RO (1) | RO63559A (xx) |
ZA (1) | ZA743348B (xx) |
Families Citing this family (1)
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DE19710449A1 (de) * | 1997-03-13 | 1998-09-17 | Basf Ag | Verfahren zur Aufreinigung von Natronlauge |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3314941A (en) * | 1964-06-23 | 1967-04-18 | American Cyanamid Co | Novel substituted pyridodiazepins |
-
1973
- 1973-05-25 AT AT462873A patent/AT331251B/de not_active IP Right Cessation
-
1974
- 1974-05-08 US US468088A patent/US3900466A/en not_active Expired - Lifetime
- 1974-05-22 AR AR253867A patent/AR200928A1/es active
- 1974-05-22 EG EG188A patent/EG11352A/xx active
- 1974-05-22 BE BE6044605A patent/BE815467A/xx unknown
- 1974-05-22 FR FR7417836A patent/FR2230367B1/fr not_active Expired
- 1974-05-23 CA CA200,670A patent/CA1035771A/en not_active Expired
- 1974-05-23 DD DD178713A patent/DD111206A5/xx unknown
- 1974-05-24 NL NL7407015A patent/NL7407015A/xx not_active Application Discontinuation
- 1974-05-24 CH CH714474A patent/CH605942A5/xx not_active IP Right Cessation
- 1974-05-24 DE DE19742425282 patent/DE2425282A1/de not_active Withdrawn
- 1974-05-24 ES ES426617A patent/ES426617A1/es not_active Expired
- 1974-05-24 ZA ZA00743348A patent/ZA743348B/xx unknown
- 1974-05-24 ES ES426618A patent/ES426618A1/es not_active Expired
- 1974-05-24 ES ES426619A patent/ES426619A1/es not_active Expired
- 1974-05-24 JP JP49058658A patent/JPS5019767A/ja active Pending
- 1974-05-24 HU HU74DE853A patent/HU174561B/hu unknown
- 1974-05-24 GB GB2330874A patent/GB1410319A/en not_active Expired
- 1974-05-24 RO RO7400078928A patent/RO63559A/ro unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3314941A (en) * | 1964-06-23 | 1967-04-18 | American Cyanamid Co | Novel substituted pyridodiazepins |
Also Published As
Publication number | Publication date |
---|---|
EG11352A (en) | 1977-11-30 |
CH605942A5 (xx) | 1978-10-13 |
DD111206A5 (xx) | 1975-02-05 |
ATA462873A (de) | 1975-11-15 |
FR2230367A1 (xx) | 1974-12-20 |
JPS5019767A (xx) | 1975-03-01 |
ES426619A1 (es) | 1977-01-01 |
AR200928A1 (es) | 1974-12-27 |
GB1410319A (en) | 1975-10-15 |
DE2425282A1 (de) | 1974-12-19 |
ZA743348B (en) | 1975-05-28 |
BE815467A (fr) | 1974-11-22 |
ES426618A1 (es) | 1976-07-01 |
ES426617A1 (es) | 1976-12-16 |
FR2230367B1 (xx) | 1978-03-24 |
RO63559A (fr) | 1978-07-15 |
HU174561B (hu) | 1980-02-28 |
AT331251B (de) | 1976-08-10 |
AU6932574A (en) | 1975-11-27 |
NL7407015A (xx) | 1974-11-27 |
CA1035771A (en) | 1978-08-01 |
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