CH542859A - Process for the preparation of new dihydro-1,4-benzodiazepines - Google Patents
Process for the preparation of new dihydro-1,4-benzodiazepinesInfo
- Publication number
- CH542859A CH542859A CH1749669A CH1749669A CH542859A CH 542859 A CH542859 A CH 542859A CH 1749669 A CH1749669 A CH 1749669A CH 1749669 A CH1749669 A CH 1749669A CH 542859 A CH542859 A CH 542859A
- Authority
- CH
- Switzerland
- Prior art keywords
- compound
- lower alkyl
- compounds
- general formula
- sep
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title claims description 9
- 229940049706 benzodiazepine Drugs 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 50
- 125000000217 alkyl group Chemical group 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 230000037396 body weight Effects 0.000 claims description 8
- -1 elixirs Substances 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 230000001419 dependent effect Effects 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical group 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000000932 sedative agent Substances 0.000 claims description 4
- 230000001624 sedative effect Effects 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 241000699670 Mus sp. Species 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 238000009833 condensation Methods 0.000 claims description 3
- 230000005494 condensation Effects 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 125000001624 naphthyl group Chemical class 0.000 claims description 3
- 125000001544 thienyl group Chemical class 0.000 claims description 3
- 241000282693 Cercopithecidae Species 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000006071 cream Substances 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- 239000005554 hypnotics and sedatives Substances 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 235000019359 magnesium stearate Nutrition 0.000 claims description 2
- 210000003205 muscle Anatomy 0.000 claims description 2
- 210000000653 nervous system Anatomy 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 238000007911 parenteral administration Methods 0.000 claims description 2
- 235000019271 petrolatum Nutrition 0.000 claims description 2
- 230000000704 physical effect Effects 0.000 claims description 2
- 230000002040 relaxant effect Effects 0.000 claims description 2
- 239000011347 resin Substances 0.000 claims description 2
- 229920005989 resin Polymers 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 239000000454 talc Substances 0.000 claims description 2
- 229910052623 talc Inorganic materials 0.000 claims description 2
- 235000012222 talc Nutrition 0.000 claims description 2
- 238000011200 topical administration Methods 0.000 claims description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 2
- 239000008158 vegetable oil Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 2
- 239000002249 anxiolytic agent Substances 0.000 claims 1
- 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 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 230000008485 antagonism Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 2
- WFVHUTAIJFEMAT-UHFFFAOYSA-N 7-chloro-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1,4-benzodiazepin-2-ol Chemical compound ClC=1C=CC2=C(C(=NCC(N2CC(F)(F)F)O)C2=CC=CC=C2)C1 WFVHUTAIJFEMAT-UHFFFAOYSA-N 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 208000012902 Nervous system disease Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical class N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- QKWWDTYDYOFRJL-UHFFFAOYSA-N 2,2-dimethoxyethanamine Chemical compound COC(CN)OC QKWWDTYDYOFRJL-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- UQUMJRFFSKGUSS-UHFFFAOYSA-N 7-chloro-2-methoxy-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1,4-benzodiazepine Chemical compound ClC=1C=CC2=C(C(=NCC(N2CC(F)(F)F)OC)C2=CC=CC=C2)C1 UQUMJRFFSKGUSS-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- 150000004753 Schiff bases Chemical class 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- MKBQTVZIYPYTSC-UHFFFAOYSA-N [5-chloro-2-(2,2,2-trifluoroethylamino)phenyl]-phenylmethanone Chemical compound FC(F)(F)CNC1=CC=C(Cl)C=C1C(=O)C1=CC=CC=C1 MKBQTVZIYPYTSC-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 230000002082 anti-convulsion Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 229960005152 pentetrazol Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
- B65B51/00—Devices for, or methods of, sealing or securing package folds or closures; Devices for gathering or twisting wrappers, or necks of bags
- B65B51/04—Applying separate sealing or securing members, e.g. clips
- B65B51/06—Applying adhesive tape
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Mechanical Engineering (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Die Erfindung bezieht sich auf ein Verfahren zur Herstellung von neuen 1 -substituierte-2-Oxy-2,3 -dihydro ,-aryl- iH-1,4-benzodiazepinen und deren pharmazeutisch annehmbaren Salzen.
Die neuen 1,4-Benzodiazepine sind Verbindungen der allgemeinen Formel I
EMI1.1
worin X Wasserstoff, Halogen, Trifluormethyl, Nitro, Hydroxy, niedriges Alkyl oder niedriges Alkoxy; R1 Polyfluorniedriges Alkyl, Phenyl-niedriges Alkyl, niedriges Cycloalkyl, niedriges Cycloalkyl-niedriges Alkyl, niedriges Alkenyl oder Amino-niedriges Alkyl, wobei die Aminogruppe durch niedrige Alkylgruppen mono- oder di-substituiert sein kann; R2 Wasserstoff, niedriges Alkyl, Hydroxy oder niedriges Alka novloxy; R3 Phenyl. durch X substituiertes Phenyl, Naphthyl, Thienyl oder Pyrryl und R4 Wasserstoff, niedriges Alkyl oder
EMI1.2
worin n 0 oder 1 und Rs und R6 Wasserstoff oder niedriges Alkyl sind, bedeuten, und Salze dieser Verbindungen.
Der Ausdruck niedriges Alkyl umfasst sowohl geradkettige wie verzweigte gesättigte Kohlenwasserstoffreste, die bis zu 6 Kohlenstoffatome enthalten. Bevorzugt sind Gruppen wie Diethyl, Äthyl, Propyl, Isopropyl, n-Butyl und t-Butyl.
Der Ausdruck niedriges Alkenyl bezieht sich auf geradkettige und verzweigte Olefinreste, die bis zu 6 Kohlenstoffatome enthalten. Als Beispiele können 1-Propenyl, 2-Isopropenyl, 2-Butenyl, 3-Butenyl und 2-Isopentenyl genannt werden. Unter niedriges Cycloalkyl und niedriges Cycloalkylniedriges Alkyl versteht man ebenso Kohlenwasserstoffreste mit bis zu 6 Kohlenstoffatomen; als Beispiele sollen angeführt werden Cyclopropylmethyl, Cyclopentyl und Cyclohexyl.
Typische Beispiele für Phenyl-niedriges Alkyl sind Phen äthyl und Benzyl. Niedriges Alkoxy umfasst Äthergruppen, in denen die niedrige Alkylgruppe bis zu 6 Kohlenstoffatome enthält, wie z.B. Methoxy, Athoxy, Propoxy etc. Niedriges Alkanoyloxy umfasst solche Säurereste, die von aliphatischen Karbonsäuren mit bis zu 6 Kohlenstoffatomen erhalten worden sind, wie z.B. Formyl, Azetyl, Propionyl, Butyryl, Valeryl, Hexanoyl und die verzweigten Isomeren davon. Der Ausdruck Halogen umfasst alle vier Halogene, obwohl Chlor der bevorzugte Repräsentant ist. Besonders bevorzugt sind Verbindungen, die einen 7-Chlor-Substituenten enthalten.
Der Ausdruck Polyfluor-niedriges Alkyl bezieht sich auf niedrige Alkylradikale, die mit mehr als einem Fluoratom substituiert sind, wie z.B. 2,2,2-Trifluoräthyl, Trifluormethyl.
2,2,3,3,3-Pentafluorpropyl usw. Bevorzugt werden Polyfluorniedrige Alkylreste, die zwei a-Wasserstoffatome enthalten, d.h. Reste der allgemeinen Formel RfCH3, worin Rf den Polyfluoralkylrest bedeutet. Bevorzugt sind Verbindungen, in denen Rf Trifluormethyl ist, wie z.B. in den 1-(2,2,2-Trifluor äthyl)-substituierten Verbindungen.
Die pharmazeutisch annehmbaren Salze umfassen solche, die sowohl mit anorganischen wie auch organischen Säuren erhalten worden sind, wie z.B. Chlorwasserstoffsäure, Bromwasserstoffsäure, Salpetersäure, Schwefelsäure, Essigsäure.
Ameisensäure, Bernsteinsäure, Maleinsäure, p-Toluolsulfonsäure usw.
In gelöstem Zustand können die erfindungsgemäss hergestellten 2-Hydroxyverbindungen am besten durch Formel II charakterisiert werden, obwohl Gleichgewicht zwischen der Hydroxy-Form und der 2,5-Oxy-Brückenform der Formel III existiert.
EMI1.3
Im festen Zustand scheint das Gleichgewicht mehr auf der Seite der 2,5-Oxy-Brückenform zu liegen. Im folgenden werden unter dem Ausdruck 2-Hydroxyverbindungen sowohl die Verbindungen der Formel II als auch die Verbindungen der Formel III verstanden.
Das erfindungsgemässe Verfahren besteht darin, dass man eine Verbindung der allgemeinen Formel IV (siehe unten), worin X, Rl, R2 und R3 wie oben definiert sind, einer intramolekularen Kondensation unterwirft wobei der Ringschluss erfolgt und eine Verbindung der allgemeinen Formel II erhalten wird. Vorzugsweise setzt man die Verbindung der Formel IV mit einer Base um:
EMI2.1
<tb> <SEP> #·ÄH <SEP> N--Ci"
<tb> x¸ <SEP> II <SEP> ¯ <SEP> x <SEP> ·Nc$M
<tb> <SEP> C-"N <SEP> 2 <SEP> MC--NR
<tb> <SEP> 2 <SEP> 2
<tb> <SEP> 3 <SEP> 3
<tb> <SEP> (Iv) <SEP> (II)
<tb>
Für die Herstellung der Verbindungen, die eine verätherte 2-Hydroxygruppe enthalten, können die durch die obigen Reaktionen erhaltenen Verbindungen der allgemeinen Formel II mit dem entsprechenden Alkohol (R4OH) veräthert werden.
Diese Reaktion kann oft einfach durch Lösen der Hydroxyverbindung in dem entsprechenden Alkohol und Auskristallisierenlassen des Äthers durchgeführt werden.
Die Ausgangsverbindungen der allgemeinen Formel IV können nach dem folgenden Reaktionsschema hergestellt werden:
EMI2.2
R8 bedeutet hierin niedrig Alkyl und Ri, R2, R3 und X sind wie oben definiert.
Die Umwandlung der Schiffschen Base (V) in ein Aldehyd wird mit Hilfe einer Säure durchgeführt. Bevorzugte Säuren sind Lewissäuren, wie z.B. Bortrifluorid.
Eine weitere Möglichkeit, um die Ausgangsverbindungen der Formel IV herzustellen, besteht darin, dass man ein Benzophenon mit einem Aminoalkohol umsetzt und -das so erhaltene Produkt zu einer Verbindung der allgemeinen Formel IV oxydiert, wie im folgenden Reaktionsschema dargestellt ist:
EMI3.1
<tb> <SEP> 1
<tb> <SEP> rl
<tb> <SEP> H <SEP> + <SEP> O{{)2 <SEP> R2
<tb> xM
<tb> <SEP> 1 <SEP> 0
<tb> <SEP> NH2
<tb> <SEP> OH
<tb> <SEP> I1
<tb> <SEP> [4l <SEP> N <SEP> H <SEP> OH
<tb> <SEP> CH2 <SEP> M·dation <SEP> lv
<tb> <SEP> wN <SEP> - <SEP> CHR
<tb> <SEP> R3
<tb>
Beispiel 1
Herstellung von 7-Chlor- 1 -(2,2,2-trifluoräthyl)- 2-hydroxy-2,3-dihydro-5-phenyl- 1H- 1,4-benzodiazepin
Eine Mischung von 3,1 g (0,01 Mol) 2-(2,2,2-Trifluoräthylamino)-5-chlorbenzophenon und 25 ml
Aminoacetaldehyddimethylacetal wird 3 Stunden unter Rückfluss gekocht. Die Mischung wird abgekühlt, in Wasser gegossen, und der sich absetzende Niederschlag wird abgetrennt. Der Niederschlag wird zu 50 ml 0,IN Chlorwasserstoffsäure hinzugefügt, die Mischung wird durch Zugabe einer wässrigen Lösung von Natriumbikarbonat basisch gemacht und mit Chloroform extrahiert. Die Chloroformschicht wird mit Natriumsulfat getrocknet und fast bis zur Trockene eingedampft. Der Rest wird mit einer kleinen Menge Hexan behandelt, und man erhält die erwünschte Verbindung.
Schmelzpunkt 130-1310C.
Beispiel 2
Herstellung von 7-Chlor- 1 -(2,2,2-trifluoräthyl)- 2-methoxy-2,3-dihydro-5-phenyl- 1H- 1,4-benzodiazepin
2,5 g (0,0071 Mol) 7-Chlor- 1 -(2,2,2-trifluoräthyl)-2 hydroxy-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin werden in 10 ml Methanol gelöst und bei OoC bis zur Auskristallisierung stehen gelassen. 2,2 g der erwünschten Verbindung mit einem Schmelzpunkt von 145-1460C werden erhalten.
Ersetzt man in dem oben beschriebenen Verfahren das Methanol durch Äthanol, so erhält man die entsprechende 2 Äthoxyverbindung, die einen Schmelzpunkt von 135-1360C hat.
Die erfindungsgemäss hergestellten Verbindungen üben einen Einfluss auf das zentrale Nervensystem aus, wie durch pharmakologische Standardmethoden festgestellt worden ist, und sind wertvolle Beruhigungsmittel bzw. Mittel zur Beseitigung von Angstzuständen. Ausserdem sind die neuen Verbindungen wertvolle Mittel gegen Konvulsionen und haben muskelerschlaffende Eigenschaften. Bei der pharmakologischen Untersuchung wurden erhebliche Unterschiede zwischen einer Beruhigungsdosis und einer Dosis, die eine neurologische Beeinträchtigung bewirkt, festgestellt.
Das therapeutische Verhältnis (Verhältnis der wirksamen Dosis, die erforderlich ist, um eine neurologische Beeinträchtigung zu verursachen, zur effektiven Dosis, die erforderlich ist, um eine beruhigende Wirkung zu erzielen) ist bei den erfindungsgemässen Verbindungen bedeutend höher als das bei zur Zeit bekannten analogen Verbindungen beobachtete Verhältnis. Als weiterer Vorteil wurde festgestellt, dass Versuchstiere bei wiederholter Behandlung für die Bewertung der Wirkung als Mittel gegen Konvulsionen keine Toleranz gegenüber den neuen Verbindungen entwickeln.
Die erfindungsgemäss hergestellten Verbindungen sind leichter wasserlöslich als die analogen 2-Oxo-verbindungen.
Sie haben auch eine günstigere Verteilungskonstante zwischen organischen und wässerigen Schichten, Dies ist ein wichtiger Faktor, da dadurch eine höhere Aufnahme der Verbindung in den Blutkreislauf gewährleistet ist, wenn die Verbindung oral verabreicht wird.
Durch verschiedene Standardlaboratoriumsuntersuchungen wie sie z.B. in Antagonism of Pentylene Tetrazole , Everett and Richard, J. Pharm. and Exp. Ther., Vol. 81, Seite 402 (1944); Antagonism of Maximal Electro-Shock-Induced seizures in Mice , Synward, E.A. et al, J. Pharm. and Exp.
Ther., Vol. 106, Seite 319 (1952); The Central Nervous System Activity and Acute Toxicity , Irwin, Science 136, Seite 123 (1962); Antagonism of Foot-Shock Induced Fighting in Mice , Tedeschi, et al., J. Pharm. and Exp. Ther., Vol. 125, Seite 28 (1949) und Taming Activity in Monkeys, Randall, Diseases of the Nervous System , Vol. 21, Seite 7 (1960) beschrieben sind, wurde festgestellt, dass, wenn die Verbindung als Mittel zur Beseitigung von Angstzuständen verwendet wird, die Dosierung etwa 0,1-5 mg pro kg Körpergewicht per Tag (aufgeteilt auf mehrere Dosen) betragen sollte; dass, wenn die Verbindung als Beruhigungsmittel verwendet wird, die bevorzugte Menge etwa 2 bis 30 mg pro kg Körpergewicht per Tag (aufgeteilt auf mehrere Dosen) zu sein scheint;
dass für muskelentspannende Wirkungen die erforderliche Dosis zwischen 0,1 und 1,5 mg per kg Körpergewicht und Tag liegt (aufgeteilt auf mehrere Dosen) und dass, wenn die Verbindung als sedativ-hypnotisches Mittel verwendet wird, die wirksame Dosis etwa 3-10 mg/kg Körpergewicht und Tag in einer Dosis beträgt. Orale Verabreichung ist in allen Fällen die bevorzugte Verabreichungsform.
Die erfindungsgemäss hergestellten Verbindungen können allein oder in Kombination mit anderen Medikamenten verabreicht werden. Normalerweise wird ein geeigneter pharmazeutischer Träger verwendet. Der Träger wird je nach Verabreichungsform, physikalischen Eigenschaften der Verbindungen und üblicher pharmazeutischer Praxis gewählt. Der Träger sollte nicht mit der aktiven Verbindung reagieren. Bevorzugt werden die Verbindungen oral verabreicht, obwohl parenterale und topische Verabreichungen auch möglich sind. Die pharmazeutischen Zusammensetzungen, die die aktiven Verbindungen enthalten, können in Form von Tabletten, Kapseln, Sirupen, Elixieren, Suspensionen, Salben und Cremen verwendet werden.
In der Herstellung der pharmazeutischen Zusammensetzungen können solche pharmazeutisch annehmbare Lösungsmittel wie z.B. Wasser, Gelatine, Laktose, Stärke, Magnesiumstearat, Talk, pflanzliche Öle, Harze und Vaseline verwendet werden.
PATENTANSPRUCH 1
Verfahren zur Herstellung von neuen Dihydro-1,4-benzodiazepinen der allgemeinen Formel II
EMI4.1
und deren pharmazeutisch annehmbaren Säureadditionssalzen, worin X Wasserstoff, Halogen, Trifluormethyl, Nitro, niedriges Alkyl, Hydroxy oder niedriges Alkoxy; Rl Polyfluor-niedriges Alkyl, Phenyl-niedriges Alkyl, niedriges Cycloalkyl, niedriges Cycloalkyl-niedriges Alkyl, niedriges Alkenyl oder Amino-niedriges Alkyl, wobei die Aminogruppe durch niedriges Alkyl mono- oder disubstituiert sein kann; R2 Wasserstoff, niedriges Alkyl, Hydroxy oder niedriges Alkanoyloxy; und Ri Phenyl, X-substituiertes Phenyl, Naphthyl, Thienyl oder Pyrryl bedeuten;
dadurch gekennzeichnet, dass man eine Verbindung der allgemeinen Formel
EMI4.2
worin X, Rl, R2 und R3 oben definiert sind, einer intramolekularen Kondensation unterwirft.
UNTERANSPRÜCHE
1. Verfahren nach Patentanspruch I, dadurch gekennzeichnet, dass man eine Verbindung der allgemeinen Formel IV mit einer Base behandelt.
2. Verfahren nach Patentanspruch I, dadurch gekennzeichnet, dass man eine solche Verbindung der Formel IV verwendet, in der Rl Polyfluor-niedriges Alkyl bedeutet.
3. Verfahren nach Patentanspruch I oder Unteranspruch 1 oder 2, dadurch gekennzeichnet, dass man eine so erhaltene Verbindung der Formel II zu der Verbindung der allgemeinen Formel
**WARNUNG** Ende DESC Feld konnte Anfang CLMS uberlappen**.
The invention relates to a process for the preparation of new 1-substituted-2-oxy-2,3-dihydro, -aryl-iH-1,4-benzodiazepines and their pharmaceutically acceptable salts.
The new 1,4-benzodiazepines are compounds of the general formula I.
EMI1.1
wherein X is hydrogen, halogen, trifluoromethyl, nitro, hydroxy, lower alkyl or lower alkoxy; R1 polyfluoro-lower alkyl, phenyl-lower alkyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, lower alkenyl or amino-lower alkyl, it being possible for the amino group to be mono- or di-substituted by lower alkyl groups; R2 is hydrogen, lower alkyl, hydroxy or lower alkanovloxy; R3 phenyl. phenyl, naphthyl, thienyl or pyrryl substituted by X and R4 hydrogen, lower alkyl or
EMI1.2
wherein n is 0 or 1 and Rs and R6 are hydrogen or lower alkyl, and salts of these compounds.
The term lower alkyl includes both straight-chain and branched saturated hydrocarbon radicals containing up to 6 carbon atoms. Groups such as diethyl, ethyl, propyl, isopropyl, n-butyl and t-butyl are preferred.
The term lower alkenyl refers to straight and branched chain olefin radicals containing up to 6 carbon atoms. Examples are 1-propenyl, 2-isopropenyl, 2-butenyl, 3-butenyl and 2-isopentenyl. Lower cycloalkyl and lower cycloalkyl-lower alkyl are also understood to mean hydrocarbon radicals having up to 6 carbon atoms; Cyclopropylmethyl, cyclopentyl and cyclohexyl should be cited as examples.
Typical examples of phenyl-lower alkyl are phenyl and benzyl. Lower alkoxy includes ether groups in which the lower alkyl group contains up to 6 carbon atoms, e.g. Methoxy, ethoxy, propoxy, etc. Lower alkanoyloxy includes those acid residues obtained from aliphatic carboxylic acids having up to 6 carbon atoms, e.g. Formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl and the branched isomers thereof. The term halogen encompasses all four halogens, although chlorine is the preferred representative. Compounds which contain a 7-chloro substituent are particularly preferred.
The term polyfluoro-lower alkyl refers to lower alkyl radicals substituted with more than one fluorine atom, e.g. 2,2,2-trifluoroethyl, trifluoromethyl.
2,2,3,3,3-pentafluoropropyl, etc. Preference is given to polyfluoro-lower alkyl radicals containing two α-hydrogen atoms, i. Radicals of the general formula RfCH3, in which Rf denotes the polyfluoroalkyl radical. Preferred are compounds in which Rf is trifluoromethyl, e.g. in the 1- (2,2,2-trifluoroethyl) -substituted compounds.
The pharmaceutically acceptable salts include those obtained with both inorganic and organic acids, e.g. Hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, acetic acid.
Formic acid, succinic acid, maleic acid, p-toluenesulfonic acid, etc.
In the dissolved state, the 2-hydroxy compounds prepared according to the invention can best be characterized by formula II, although there is an equilibrium between the hydroxy form and the 2,5-oxy bridge form of the formula III.
EMI1.3
In the solid state, the equilibrium appears to be more on the side of the 2,5-oxy bridge form. In the following, the term 2-hydroxy compounds is understood to mean both the compounds of the formula II and the compounds of the formula III.
The process according to the invention consists in that a compound of the general formula IV (see below), in which X, R1, R2 and R3 are defined as above, is subjected to an intramolecular condensation, the ring closure taking place and a compound of the general formula II being obtained. The compound of the formula IV is preferably reacted with a base:
EMI2.1
<tb> <SEP> # · ÄH <SEP> N - Ci "
<tb> x¸ <SEP> II <SEP> ¯ <SEP> x <SEP> · Nc $ M
<tb> <SEP> C- "N <SEP> 2 <SEP> MC - NR
<tb> <SEP> 2 <SEP> 2
<tb> <SEP> 3 <SEP> 3
<tb> <SEP> (Iv) <SEP> (II)
<tb>
For the preparation of the compounds which contain an etherified 2-hydroxy group, the compounds of the general formula II obtained by the above reactions can be etherified with the corresponding alcohol (R4OH).
This reaction can often be carried out simply by dissolving the hydroxy compound in the corresponding alcohol and letting the ether crystallize out.
The starting compounds of the general formula IV can be prepared according to the following reaction scheme:
EMI2.2
R8 herein denotes lower alkyl and Ri, R2, R3 and X are as defined above.
The conversion of the Schiff base (V) into an aldehyde is carried out with the aid of an acid. Preferred acids are Lewis acids, e.g. Boron trifluoride.
Another way of preparing the starting compounds of the formula IV is to react a benzophenone with an amino alcohol and the product thus obtained is oxidized to a compound of the general formula IV, as shown in the following reaction scheme:
EMI3.1
<tb> <SEP> 1
<tb> <SEP> rl
<tb> <SEP> H <SEP> + <SEP> O {{) 2 <SEP> R2
<tb> xM
<tb> <SEP> 1 <SEP> 0
<tb> <SEP> NH2
<tb> <SEP> OH
<tb> <SEP> I1
<tb> <SEP> [4l <SEP> N <SEP> H <SEP> OH
<tb> <SEP> CH2 <SEP> M · dation <SEP> lv
<tb> <SEP> wN <SEP> - <SEP> CHR
<tb> <SEP> R3
<tb>
example 1
Preparation of 7-chloro-1 - (2,2,2-trifluoroethyl) -2-hydroxy-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine
A mixture of 3.1 g (0.01 mol) of 2- (2,2,2-trifluoroethylamino) -5-chlorobenzophenone and 25 ml
Aminoacetaldehyde dimethyl acetal is refluxed for 3 hours. The mixture is cooled, poured into water, and the settling precipitate is separated off. The precipitate is added to 50 ml of 0.1N hydrochloric acid, the mixture is made basic by adding an aqueous solution of sodium bicarbonate and extracted with chloroform. The chloroform layer is dried with sodium sulfate and evaporated almost to dryness. The remainder is treated with a small amount of hexane and the desired compound is obtained.
Melting point 130-1310C.
Example 2
Preparation of 7-chloro-1 - (2,2,2-trifluoroethyl) -2-methoxy-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine
2.5 g (0.0071 mol) of 7-chloro-1 - (2,2,2-trifluoroethyl) -2 hydroxy-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine are in 10 ml Dissolved methanol and left to stand at OoC until crystallization. 2.2 g of the desired compound with a melting point of 145-1460C are obtained.
If the methanol is replaced by ethanol in the process described above, the corresponding 2 ethoxy compound is obtained, which has a melting point of 135-1360C.
The compounds prepared according to the invention exert an influence on the central nervous system, as has been established by standard pharmacological methods, and are valuable sedatives or agents for eliminating states of anxiety. In addition, the new compounds are valuable agents against convulsions and have muscle-slacking properties. The pharmacological examination revealed significant differences between a sedative dose and a dose that produced neurological impairment.
The therapeutic ratio (ratio of the effective dose required to cause neurological impairment to the effective dose required to achieve a sedative effect) is significantly higher for the compounds according to the invention than for the currently known analogous compounds observed ratio. Another advantage was found that test animals do not develop tolerance to the new compounds on repeated treatment for the evaluation of the anti-convulsive effect.
The compounds prepared according to the invention are more readily soluble in water than the analogous 2-oxo compounds.
They also have a more favorable constant of partition between organic and aqueous layers. This is an important factor as it ensures higher uptake of the compound into the bloodstream when the compound is administered orally.
Through various standard laboratory tests such as e.g. in Antagonism of Pentylene Tetrazole, Everett and Richard, J. Pharm. and Exp. Ther., Vol. 81, p. 402 (1944); Antagonism of Maximal Electro-Shock-Induced seizures in Mice, Synward, E.A. et al, J. Pharm. and Exp.
Ther., Vol. 106, p. 319 (1952); The Central Nervous System Activity and Acute Toxicity, Irwin, Science 136, p. 123 (1962); Antagonism of Foot-Shock Induced Fighting in Mice, Tedeschi, et al., J. Pharm. And Exp. Ther., Vol. 125, p. 28 (1949) and Taming Activity in Monkeys, Randall, Diseases of the Nervous System, Vol 21, page 7 (1960), it has been found that when the compound is used as an agent for relieving anxiety, the dosage should be about 0.1-5 mg per kg of body weight per day (divided into several doses) ; that when the compound is used as a sedative, the preferred amount appears to be about 2 to 30 mg per kg of body weight per day (divided into several doses);
that for muscle relaxing effects the dose required is between 0.1 and 1.5 mg per kg of body weight per day (divided into several doses) and that, when the compound is used as a sedative-hypnotic agent, the effective dose is about 3-10 mg / kg body weight and day in one dose. Oral administration is the preferred form of administration in all cases.
The compounds prepared according to the invention can be administered alone or in combination with other medicaments. A suitable pharmaceutical carrier will normally be used. The carrier will be chosen according to the mode of administration, physical properties of the compounds and common pharmaceutical practice. The wearer should not react with the active compound. Preferably the compounds are administered orally, although parenteral and topical administrations are also possible. The pharmaceutical compositions containing the active compounds can be used in the form of tablets, capsules, syrups, elixirs, suspensions, ointments and creams.
In the preparation of the pharmaceutical compositions, such pharmaceutically acceptable solvents as e.g. Water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, resins and petroleum jelly can be used.
PATENT CLAIM 1
Process for the preparation of new dihydro-1,4-benzodiazepines of the general formula II
EMI4.1
and their pharmaceutically acceptable acid addition salts, wherein X is hydrogen, halogen, trifluoromethyl, nitro, lower alkyl, hydroxy or lower alkoxy; Rl polyfluoro-lower alkyl, phenyl-lower alkyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, lower alkenyl or amino-lower alkyl, it being possible for the amino group to be mono- or di-substituted by lower alkyl; R2 is hydrogen, lower alkyl, hydroxy or lower alkanoyloxy; and Ri is phenyl, X-substituted phenyl, naphthyl, thienyl or pyrryl;
characterized in that a compound of the general formula
EMI4.2
wherein X, Rl, R2 and R3 are defined above, subjected to intramolecular condensation.
SUBCLAIMS
1. The method according to claim I, characterized in that a compound of the general formula IV is treated with a base.
2. The method according to claim I, characterized in that such a compound of the formula IV is used in which Rl is polyfluoro-lower alkyl.
3. The method according to claim I or dependent claim 1 or 2, characterized in that a compound of the formula II thus obtained is converted to the compound of the general formula
** WARNING ** End of DESC field could overlap beginning of CLMS **.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US77923768A | 1968-11-26 | 1968-11-26 | |
| US83664469A | 1969-06-25 | 1969-06-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH542859A true CH542859A (en) | 1973-10-15 |
Family
ID=27119557
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH60272A CH534169A (en) | 1968-11-26 | 1969-11-21 | Process for the preparation of new dihydro-1,4-benzodiazepines |
| CH1749669A CH542859A (en) | 1968-11-26 | 1969-11-21 | Process for the preparation of new dihydro-1,4-benzodiazepines |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH60272A CH534169A (en) | 1968-11-26 | 1969-11-21 | Process for the preparation of new dihydro-1,4-benzodiazepines |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPS5116432B1 (en) |
| AT (1) | AT314543B (en) |
| BE (1) | BE742124A (en) |
| CH (2) | CH534169A (en) |
| CY (1) | CY836A (en) |
| DE (1) | DE1958742A1 (en) |
| DK (1) | DK133299C (en) |
| ES (1) | ES398613A1 (en) |
| FI (1) | FI50710C (en) |
| FR (1) | FR2024239B1 (en) |
| GB (2) | GB1297630A (en) |
| HK (1) | HK13676A (en) |
| IL (1) | IL33394A (en) |
| KE (1) | KE2598A (en) |
| NL (1) | NL6917680A (en) |
| NO (1) | NO127302B (en) |
| PL (1) | PL80394B1 (en) |
| SE (1) | SE372767B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3723414A (en) * | 1970-02-13 | 1973-03-27 | Schering Corp | 1-polyfluoroalkyl benzodiazepines |
| US4056525A (en) * | 1975-06-02 | 1977-11-01 | American Home Products Corporation | 2,3-dialkoxy-3h-1,4-benzodiazepines |
| DE4025395A1 (en) * | 1990-08-10 | 1992-02-13 | Miele & Cie | Covering end edges of furniture plates - involves adhesive tape guide with contact pressure roller and cutter |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3481921A (en) * | 1965-10-22 | 1969-12-02 | Hoffmann La Roche | Benzodiazepines |
-
1969
- 1969-11-20 FR FR696939943A patent/FR2024239B1/fr not_active Expired
- 1969-11-21 SE SE6916040A patent/SE372767B/xx unknown
- 1969-11-21 CH CH60272A patent/CH534169A/en not_active IP Right Cessation
- 1969-11-21 IL IL33394A patent/IL33394A/en unknown
- 1969-11-21 GB GB1297630D patent/GB1297630A/en not_active Expired
- 1969-11-21 FI FI693383A patent/FI50710C/en active
- 1969-11-21 CY CY836A patent/CY836A/en unknown
- 1969-11-21 CH CH1749669A patent/CH542859A/en not_active IP Right Cessation
- 1969-11-21 NO NO04614/69A patent/NO127302B/no unknown
- 1969-11-21 GB GB1297629D patent/GB1297629A/en not_active Expired
- 1969-11-22 DE DE19691958742 patent/DE1958742A1/en active Pending
- 1969-11-24 JP JP44093668A patent/JPS5116432B1/ja active Pending
- 1969-11-24 DK DK622069A patent/DK133299C/en active
- 1969-11-24 NL NL6917680A patent/NL6917680A/xx unknown
- 1969-11-24 AT AT1027471A patent/AT314543B/en not_active IP Right Cessation
- 1969-11-24 BE BE742124D patent/BE742124A/xx unknown
- 1969-11-25 PL PL1969137110A patent/PL80394B1/pl unknown
-
1972
- 1972-01-05 ES ES398613A patent/ES398613A1/en not_active Expired
-
1976
- 1976-02-10 KE KE2598*UA patent/KE2598A/en unknown
- 1976-03-11 HK HK136/76*UA patent/HK13676A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5116432B1 (en) | 1976-05-24 |
| SE372767B (en) | 1975-01-13 |
| FR2024239A1 (en) | 1970-08-28 |
| NO127302B (en) | 1973-06-04 |
| ES398613A1 (en) | 1975-05-16 |
| IL33394A (en) | 1973-08-29 |
| AT314543B (en) | 1974-04-10 |
| FI50710C (en) | 1976-06-10 |
| FI50710B (en) | 1976-03-01 |
| CY836A (en) | 1976-09-10 |
| DK133299B (en) | 1976-04-26 |
| DE1958742A1 (en) | 1970-07-09 |
| NL6917680A (en) | 1970-05-28 |
| DK133299C (en) | 1976-09-20 |
| BE742124A (en) | 1970-05-25 |
| IL33394A0 (en) | 1970-01-29 |
| FR2024239B1 (en) | 1973-01-12 |
| HK13676A (en) | 1976-03-19 |
| PL80394B1 (en) | 1975-08-30 |
| CH534169A (en) | 1973-02-28 |
| GB1297630A (en) | 1972-11-29 |
| KE2598A (en) | 1976-02-27 |
| GB1297629A (en) | 1972-11-29 |
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