CH545302A - Triazolobenzodiazepine derivs - with anticonvulsant, cns depressant and muscle-relaxant activity - Google Patents
Triazolobenzodiazepine derivs - with anticonvulsant, cns depressant and muscle-relaxant activityInfo
- Publication number
- CH545302A CH545302A CH1212973A CH1212973A CH545302A CH 545302 A CH545302 A CH 545302A CH 1212973 A CH1212973 A CH 1212973A CH 1212973 A CH1212973 A CH 1212973A CH 545302 A CH545302 A CH 545302A
- Authority
- CH
- Switzerland
- Prior art keywords
- acid
- benzodiazepine
- phenyl
- chloro
- triazolo
- Prior art date
Links
- KYTREVLPRJOBEM-UHFFFAOYSA-N triazolo[4,5-i][1,2]benzodiazepine Chemical compound C1=CC2=CC=CN=NC2=C2C1=NN=N2 KYTREVLPRJOBEM-UHFFFAOYSA-N 0.000 title claims description 4
- 239000001961 anticonvulsive agent Substances 0.000 title abstract 2
- 229960003965 antiepileptics Drugs 0.000 title abstract 2
- 239000003158 myorelaxant agent Substances 0.000 title abstract 2
- 230000000694 effects Effects 0.000 title description 2
- 230000001773 anti-convulsant effect Effects 0.000 title 1
- 239000003874 central nervous system depressant Substances 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 239000002253 acid Substances 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 6
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 4
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 4
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- -1 MerckQ Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 150000007522 mineralic acids Chemical class 0.000 claims description 8
- 150000007524 organic acids Chemical class 0.000 claims description 8
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- ZGTBVQNRHXJPFO-UHFFFAOYSA-N 8-chloro-1-(diethoxymethyl)-6-phenyl-4h-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine Chemical compound C12=CC(Cl)=CC=C2N2C(C(OCC)OCC)=NN=C2CN=C1C1=CC=CC=C1 ZGTBVQNRHXJPFO-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 235000005985 organic acids Nutrition 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- ZVSQZAUNTZRFLP-UHFFFAOYSA-N 8-chloro-6-phenyl-4h-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-carbaldehyde Chemical compound C=1C(Cl)=CC=C(N2C(C=O)=NN=C2CN=2)C=1C=2C1=CC=CC=C1 ZVSQZAUNTZRFLP-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 claims description 4
- 239000000155 melt Substances 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- GWSXDWFXNVOIIC-UHFFFAOYSA-N (7-chloro-5-phenyl-3h-1,4-benzodiazepin-2-yl)hydrazine Chemical compound N=1CC(NN)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 GWSXDWFXNVOIIC-UHFFFAOYSA-N 0.000 claims description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 150000004965 peroxy acids Chemical class 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- GYHCTCSLYWTWJC-UHFFFAOYSA-N 1,4-benzodiazepine-1-carbaldehyde Chemical compound O=CN1C=CN=CC2=CC=CC=C12 GYHCTCSLYWTWJC-UHFFFAOYSA-N 0.000 claims description 2
- PHELOKYCCWVWFE-UHFFFAOYSA-N 2,2-dimethoxyacetic acid Chemical compound COC(OC)C(O)=O PHELOKYCCWVWFE-UHFFFAOYSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- DERAXXGTLFTNJF-UHFFFAOYSA-N 8-chloro-1-(dimethoxymethyl)-6-phenyl-4h-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine Chemical compound C12=CC(Cl)=CC=C2N2C(C(OC)OC)=NN=C2CN=C1C1=CC=CC=C1 DERAXXGTLFTNJF-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- 241001465754 Metazoa Species 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 238000004587 chromatography analysis Methods 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- 239000013078 crystal Substances 0.000 claims description 2
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000008298 dragée Substances 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 238000010828 elution Methods 0.000 claims description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 2
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 claims description 2
- XTLNYNMNUCLWEZ-UHFFFAOYSA-N ethanol;propan-2-one Chemical compound CCO.CC(C)=O XTLNYNMNUCLWEZ-UHFFFAOYSA-N 0.000 claims description 2
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 claims description 2
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 claims description 2
- XCLBIKIQSCTANZ-UHFFFAOYSA-N ethyl 2,2-diethoxyacetate Chemical compound CCOC(OCC)C(=O)OCC XCLBIKIQSCTANZ-UHFFFAOYSA-N 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 239000012458 free base Substances 0.000 claims description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 2
- 239000003049 inorganic solvent Substances 0.000 claims description 2
- 229910001867 inorganic solvent Inorganic materials 0.000 claims description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims description 2
- 238000002844 melting Methods 0.000 claims description 2
- 230000008018 melting Effects 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 239000002245 particle Substances 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 2
- 235000011152 sodium sulphate Nutrition 0.000 claims description 2
- 241000894007 species Species 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 238000010257 thawing Methods 0.000 claims description 2
- 231100000331 toxic Toxicity 0.000 claims description 2
- 230000002588 toxic effect Effects 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims 3
- 238000007254 oxidation reaction Methods 0.000 claims 3
- 230000001419 dependent effect Effects 0.000 claims 1
- 125000001931 aliphatic group Chemical group 0.000 abstract 1
- 125000004414 alkyl thio group Chemical group 0.000 abstract 1
- 230000003556 anti-epileptic effect Effects 0.000 abstract 1
- 229940035363 muscle relaxants Drugs 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- 229940125723 sedative agent Drugs 0.000 abstract 1
- 239000000932 sedative agent Substances 0.000 abstract 1
- 125000001424 substituent group Chemical group 0.000 abstract 1
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000013016 damping Methods 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000005919 1,2,2-trimethylpropyl group Chemical group 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 206010052904 Musculoskeletal stiffness Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000002539 anti-aggressive effect Effects 0.000 description 1
- 230000002082 anti-convulsion Effects 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 239000008096 xylene 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
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)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
Title cpds. of formula (I): (where R1 is H or 1-3C alkyl; R2 is 1-4C alkyl or R2--R2 is a satd. divalent 2-5C aliphatic hydrocarbon residue, and rings A and B can be substd. by F, Cl, Br, CF3, NO2 or 1-6C alkyl or alkoxy) and their 5-oxides and acid addn. salts, can be used as tranquillisers, sedatives, muscle relaxants and anti-epileptics; the 5-oxides are also of use as inters. for further pharmacologically active cpds. Cpds. (I) are e.g. prepd. by (a) reacting a 2-X-3-R1-5-phenyl-3H-1,4-benzodiazepine (where X is SH, lower alkoxy or alkylthio opt. activated by a substituent, or opt. mono- or disubstd. amino) with (R2O)2CHCONHNH2. The 5-oxides are obtd. by oxidn.
Description
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von neuen Triazolo-benzodiazepin-derivaten der allgemeinen Formel I,
EMI1.1
in welcher R1 und R2 Wasserstoff, Fluor, Chlor, Brom, Alkyl- oder Alkoxygruppen mit je 1 bis 6 Kohlenstoffatomen, Trifluormethyl- oder Nitrogruppen bedeuten, und R3 eine Alkylgruppe mit 1 bis 4 Kohlenstoffatomen oder -R3.R3- einen zweiwertigen gesättigten aliphatischen Kohlenwasserstoffrest mit 2 bis 5 Kohlenstoffatomen bedeutet, und der Additionssalze solcher Verbindungen mit anorganischen oder organischen Säuren. Diese Verbindungen der allgemeinen Formel I können zur Herstellung ihrer 5-Oxide verwendet werden.
Die neuen Verbindungen wie z. B. das 6-Phenyl-8-chlor-4H-s-triazolo[4,3-a][ 1 ,4]benzo diazepin-1-carboxaldehyd-dimethylacetal und das 6-Phenyl-8-chlor-4H-s-triazolo[4,3-a][1 ,4]benzo- diazepin- 1 -carboxaldehyd-diäthylacetal, ihre 5-Oxide sowie ihre Additionssalze mit anorganischen und organischen Säuren besitzen wertvolle pharmakologische Eigenschaften und einen hohen therapeutischen Index. Die neuen Verbindungen wirken insbesondere zentraldämpfend, z. B. antiaggressiv und antikonvulsiv, und hemmen polysynaptische Reflexe. Diese Wirkungsqualitäten, welche durch ausgewählte Standardversuche ([vgl. W. Theobald und H.A. Kunz, Arzneimittelforsch. 13, 122 (1963) sowie W.
Theobald et al., Arzneimittelforsch. 17, 561(1967) erfasst werden können, charakterisieren die Verbindungen der allgemeinen Formel I, ihre 5-Oxide sowie ihre Säureadditionssalze als zentraldämpfende Verbindungen, die zur Behandlung von Spannungs- und Erregungszuständen, der Epilepsie und von Muskelsteife geeignet sind.
In den Verbindungen der allgemeinen Formel I sind R, und R2 als Alkylgruppen mit je 1 bis 6 Kohlenstoffatomen beispielsweise die Methyl-, Athyl-, Propyl-, Isopropyl-, Butyl-, Isobutyl-, Sek.butyl-, Pentyl-, 2-Methyl-butyl-, Isopentyl-, Hexyl-, Isohexyl-, 1-Methyl-pentyl-, 1,2,2-Trimethyl-propyloder die 1 -Äthyl-2-methyl-propylgruppe und als Alkoxygruppen mit 1 bis 6 Kohlenstoffatomen z. B. die Methoxy-, Athoxy-, Propoxy-, Isopropoxy-, Butoxy-, Isobutoxy-, Pentyloxy-, Hexyloxy- oder Isohexyloxygruppe. Ferner ist R3 als Alkylgruppe z. B. die Methyl-, Athyl-, Propyl-, Isopropyl-, Butyl-, Isobutyl- oder Sek.butylgruppen, oder -R3.R3- ist als zweiwertiger gesättigter aliphatischer Kohlenwasserstoffrest mit 2 bis 5 Kohlenstoffatomen z.
B. die Äthylen-, Propylen-, Äthyläthylen-, Trimethylen-, Tetramethylen-, 2,2-Dimethyl-trimethylen- oder die 2-Äthyl-trimethylen-gruppe.
Das erfindungsgemässe Verfahren zur Herstellung der neuen Triazolo-benzodiazepine, und ihrer Säureadditionssalze ist dadurch gekennzeichnet, dass man eine Verbindung der allgemeinen Formel II,
EMI1.2
in welcher R und R2 die unter der Formel I angegebene Bedeutung haben, mit einem reaktionsfähigen Ester einer Verbindung der allgemeinen Formel III,
EMI1.3
in welcher R3 oder -R3.R3- die unter der Formel I angegebene Bedeutung hat, kondensiert und die erhaltene Verbindung als freie Base oder als Additionssalz mit einer anorganischen oder organischen Säure isoliert.
Als reaktionsfähige Ester einer Verbindung der allgemeinen Formel III können z. B. niedere Alkylester, insbesondere der Methyl- oder Äthylester, eingesetzt werden.
Die erfindungsgemässe Umsetzung wird vorzugsweise bei einer Reaktionstemperatur von ca. 80 bis 1600C in einem inerten Lösungsmittel vorgenommen. Als inerte Lösungsmittel elgnen sich beispielsweise Kohlenwasserstoffe, wie Toluol oder Xylol, Halogenkohlenwasserstoffe, wie Chlorbenzol, Alkanole, z. B. Butanol, ätherartige Flüssigkeiten, wie Diäthylenglykoldimethyläther oder Dioxan, und Amide, insbesondere N,N,N/,Nl,N,NX-Hexamethyl-phosphorsäuretriamid. Die Reaktionszeiten liegen zwischen ca. einer und 24 Stunden.
Ausgangsstoffe der allgemeinen Formel II sind bekannt, z. B. das 2-Hydrazino-5-phenyl-7-chlor-3H- 1,4-benzodiazepin (vgl. Kanji Meguro und Yutaka Kuwada, Tetrahedron Letters 1970, 4039). Weitere Verbindungen dieses Typus können analog hergestellt werden.
Als Oxidationsmittel für die gewünschtenfalls anschliessende Umwandlung von Verbindungen der allgemeinen Formel I in ihre 5-Oxide eignen sich vorzugsweise Wasserstoffperoxid oder Persäuren bei einer Temperatur von ca. 0 bis 70t.
Geeignete Persäuren sind z. B. Peressigsäure oder Benzopersäuren, wie Benzopersäure oder insbesondere m-Chlor-benzopersäure. Die Oxidationsmittel werden vorzugsweise in einem Lösungsmittel eingesetzt, z. B. Peressigsäure in Essigsäure und Benzopersäure in Halogenkohlenwasserstoffen, wie Methylenchlorid oder Chloroform.
Die nach dem erfindungsgemässen Verfahren erhaltenen Verbindungen der allgemeinen Formel I werden anschliessend gewünschtenfalls in üblicher Weise in ihrer Additionssalze mit anorganischen und organischen Säuren übergeführt. Beispielsweise versetzt man eine Lösung einer Verbindung der allgemeinen Formel I in einem anorganischen Lösungsmittel mit der als Salzkomponente gewünschten Säure. Vorzugsweise wählt man für die Umsetzung organische Lösungsmittel, in denen das entstehende Salz schwer löslich ist, damit es durch Filtration abgetrennt werden kann. Solche Lösungsmittel sind z. B. Methanol, Äther, Aceton, Methyläthylketon, Aceton Äther, Aceton-Äthanol, Methanol-Äther oder Äthanol-Äther.
Zur Verwendung als Arzneistoffe können anstelle freier Basen pharmazeutisch annehmbare Säureadditionssalze eingesetzt werden, d. h. Salze mit solchen Säuren, deren Anionen bei den in Frage kommenden Dosierungen nicht toxisch sind.
Ferner ist es von Vorteil, wenn die als Arzneistoffe zu verwendenden Salze gut kristallisierbar und nicht oder wenig hygroskopisch sind. Zur Salzbildung mit Verbindungen der allgemeinen Formel I können z. B. die Chlorwasserstoffsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Methansulfonsäure, Äthansulfonsäure, 2-Hydroxy-äthansulfonsäure oder Perchlorsäure verwendet werden.
Die neuen Wirkstoffe werden peroral, rektal oder parenteral verabreicht. Die Dosierung hängt von der Applikationsweise der Spezies, dem Alter und von dem individuellen Zustand ab. Die täglichen Dosen der freien Basen, ihrer 5 Oxide oder von pharmazeutisch annehmbaren Salzen der freien Basen bewegen sich zwischen 0,2 mg/kg und 4 mg/kg für Warmblüter. Geeignete Doseneinheitsformen, wie Dragees, Tabletten, Suppositorien oder Ampullen, enthalten vorzugsweise 5-25 mg eines erfindungsgemäss herstellbaren Wirkstoffes.
Die nachfolgenden Beispiele erläutern die Herstellung der neuen Verbindungen der allgemeinen Formel I, sollen jedoch den Umfang der Erfindung in keiner Weise beschränken. Die Temperaturen sind in Celsiusgraden angegeben, und für die Elutionschromatographie wird Kieselgel, MerckQ, Korngrösse 0,05-0,2 mm, verwendet.
Beispiel 1
Eine Lösung von 5 g 2-Hydrazino-5-phenyl-7-chlor-3H-1,4-benzodiazepin [vgl. Kanji Meguro und Yutaka Kuwada, Tetrahedron Letters 1970, 4039(1970)] und 5 g Diäthoxy-essigsäureäthylester in 50 ml N,N,N ,N ,N ,N -Hexamethylphosphorsäuretriamid wird 5 Stunden auf 1000 erhitzt. Dann dampft man das Reaktionsgemisch im Vakuum ein und verteilt den Rückstand zwischen Methylenchlorid und Wasser. Die organische Phase wird mit Wasser und gesättigter Natriumchloridlösung gewaschen, über Natriumsulfat getrocknet und eingedampft.
Den Rückstand kristallisiert man aus Essigsäureäthylester-Äther-Petrol- äther um, wonach das reine 6-Phenyl-8-chlor-4H-s-triazolo[4,3-a][1 ,4]benzo- diazepin- 1 -carboxaldehyddiäthylacetal bei 1331350 schmilzt.
Beispiel 2
Analog Beispiel 1 erhält man unter Verwendung von 5 g Dimethoxyessigsäure-dimethylester das 6-Phenyl-8-chlor-4H-s-triazolo[4,3-a][1,4]benzo- diazepin- 1 -carboxaldehyddimethylacetat vom Smp. 1661720.
Beispiel 3
Zu einer Lösung von 0,5 g (0,00126 Mol) 6-Phenyl-8-chlor-4H-s-triazolo[4,3-a][1 ,4]benzodiazepin-1 - carboxaldehyd-diäthylacetat in je 3 ml Aceton und Methanol werden 0,13 g (0,0013 Mol) Perchlorsäure gegeben. Nach Zugabe von 5 ml Petroläther kristallisiert das Salz aus. Nach dem Absaugen erhält man 6-Phenyl-8-chlor-4H-s-triazolo[4,3-all 1 ,4lbenzo- diazepin- 1 -carboxaldehyd-diäthylacetal-perchlorat, das sich bei 2502650 zersetzt.
Beispiel 4
Eine Lösung von 7,64 g (0,024 Mol) m-Chlor-perbenzoesäure in 140 ml Methylenchlorid wird innerhalb 15 Minuten bei 0-5O unter Rühren zu einer Lösung von 9,0 g (0,0126 Mol) 6-Phenyl-8-chlor-4H-s-triazolo[4,3-a][1,4]benzo- diazepin- 1 -carboxaldehyd-diäthylacetal in 100 ml Methylenchlorid getropft. Im auftauenden Eisbad wird das Reaktionsgemisch weitere 16 Stunden gerührt. Dann engt man es im Vakuum ein und versetzt es mit Äther. Die ausgefallenen Kristalle werden abgesaugt und zweimal mit heissem Äthylacetat gewaschen. Das erhaltene 6-Phenyl-8-chlor-4H-s-triazolo[4,3-a][1 [1,4]benzo- diazepin- 1 -carboxaldehyd-diäthylacetal-5-oxid schmilzt bei 2002020.
PATENTANSPRUCH 1
Verfahren zur Herstellung von neuen Triazolobenzodiazepinderivaten der allgemeinen Formel I,
EMI2.1
in welcher Rl und R2 Wasserstoff, Fluor, Chlor, Brom, Alkyl- oder Alkoxygruppen mit je 1 bis 6 Kohlenstoffatomen, Trifluormethyloder Nitrogruppen bedeuten, und R3 eine Alkylgruppe mit 1 bis 4 Kohlenstoffatomen oder -R3.R3- einen zweiwertigen gesättigten aliphatischen Kohlenwasserstoffrest mit 2 bis 5 Kohlenstoffatomen bedeutet, sowie der Additionssalze solcher Verbindungen mit anorganischen oder organischen Säuren, dadurch gekennzeichnet, dass man eine Verbindung der allgemeinen Formel II,
**WARNUNG** Ende DESC Feld konnte Anfang CLMS uberlappen**.
The present invention relates to a process for the preparation of new triazolo-benzodiazepine derivatives of the general formula I,
EMI1.1
in which R1 and R2 are hydrogen, fluorine, chlorine, bromine, alkyl or alkoxy groups each with 1 to 6 carbon atoms, trifluoromethyl or nitro groups, and R3 is an alkyl group with 1 to 4 carbon atoms or -R3.R3- a divalent saturated aliphatic hydrocarbon radical with 2 to 5 carbon atoms, and the addition salts of such compounds with inorganic or organic acids. These compounds of the general formula I can be used to prepare their 5-oxides.
The new connections such. B. 6-Phenyl-8-chloro-4H-s-triazolo [4,3-a] [1, 4] benzodiazepine-1-carboxaldehyde-dimethylacetal and 6-phenyl-8-chloro-4H-s- Triazolo [4,3-a] [1,4] benzodiazepine-1-carboxaldehyde diethyl acetal, their 5-oxides and their addition salts with inorganic and organic acids have valuable pharmacological properties and a high therapeutic index. The new compounds have a particular central damping effect, e.g. B. anti-aggressive and anti-convulsive, and inhibit polysynaptic reflexes. These qualities of action, which are determined by selected standard experiments ([cf. W. Theobald and H.A. Kunz, Arzneimittelforsch. 13, 122 (1963) and W.
Theobald et al., Arzneimittelforsch. 17, 561 (1967) characterize the compounds of general formula I, their 5-oxides and their acid addition salts as central damping compounds which are suitable for the treatment of states of tension and excitement, epilepsy and muscle stiffness.
In the compounds of the general formula I, R, and R2 as alkyl groups each having 1 to 6 carbon atoms are, for example, the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, 2- Methyl-butyl, isopentyl, hexyl, isohexyl, 1-methyl-pentyl, 1,2,2-trimethyl-propyl or the 1-ethyl-2-methyl-propyl group and as alkoxy groups with 1 to 6 carbon atoms, e.g. B. the methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, hexyloxy or isohexyloxy group. Furthermore, R3 is an alkyl group, for. B. the methyl, ethyl, propyl, isopropyl, butyl, isobutyl or sec.butyl groups, or -R3.R3- is a divalent saturated aliphatic hydrocarbon radical with 2 to 5 carbon atoms z.
B. the ethylene, propylene, ethylethylene, trimethylene, tetramethylene, 2,2-dimethyl-trimethylene or the 2-ethyl-trimethylene group.
The inventive method for the preparation of the new triazolo-benzodiazepines, and their acid addition salts is characterized in that a compound of the general formula II,
EMI1.2
in which R and R2 have the meaning given under formula I, with a reactive ester of a compound of general formula III,
EMI1.3
in which R3 or -R3.R3- has the meaning given under formula I, condenses and the compound obtained is isolated as a free base or as an addition salt with an inorganic or organic acid.
As a reactive ester of a compound of general formula III, for. B. lower alkyl esters, especially the methyl or ethyl ester, can be used.
The reaction according to the invention is preferably carried out at a reaction temperature of about 80 to 160 ° C. in an inert solvent. As inert solvents, for example, hydrocarbons such as toluene or xylene, halogenated hydrocarbons such as chlorobenzene, alkanols, eg. B. butanol, ethereal liquids such as diethylene glycol dimethyl ether or dioxane, and amides, especially N, N, N /, Nl, N, NX-hexamethyl-phosphoric acid triamide. The reaction times are between about one and 24 hours.
Starting materials of the general formula II are known, for. B. 2-hydrazino-5-phenyl-7-chloro-3H-1,4-benzodiazepine (cf. Kanji Meguro and Yutaka Kuwada, Tetrahedron Letters 1970, 4039). Other connections of this type can be made in the same way.
Hydrogen peroxide or peracids at a temperature of about 0 to 70% are preferably suitable as oxidizing agents for the subsequent conversion of compounds of the general formula I into their 5-oxides if desired.
Suitable peracids are e.g. B. peracetic acid or benzoperic acids, such as benzoperic acid or especially m-chloro-benzoperic acid. The oxidizing agents are preferably used in a solvent, e.g. B. peracetic acid in acetic acid and benzoperic acid in halogenated hydrocarbons, such as methylene chloride or chloroform.
The compounds of general formula I obtained by the process according to the invention are then, if desired, converted into their addition salts with inorganic and organic acids in the customary manner. For example, a solution of a compound of the general formula I in an inorganic solvent is mixed with the acid desired as the salt component. For the reaction, preference is given to choosing organic solvents in which the salt formed is sparingly soluble so that it can be separated off by filtration. Such solvents are e.g. B. methanol, ether, acetone, methyl ethyl ketone, acetone ether, acetone-ethanol, methanol-ether or ethanol-ether.
For use as drugs, pharmaceutically acceptable acid addition salts can be used in place of free bases; H. Salts with acids whose anions are not toxic at the dosages in question.
It is also advantageous if the salts to be used as medicinal substances are readily crystallizable and have little or no hygroscopic properties. For salt formation with compounds of general formula I, for. B. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid or perchloric acid can be used.
The new active ingredients are administered orally, rectally or parenterally. The dosage depends on the mode of administration of the species, the age and the individual condition. The daily doses of the free bases, their oxides or pharmaceutically acceptable salts of the free bases range between 0.2 mg / kg and 4 mg / kg for warm-blooded animals. Suitable dosage unit forms, such as dragees, tablets, suppositories or ampoules, preferably contain 5-25 mg of an active ingredient which can be prepared according to the invention.
The following examples illustrate the preparation of the new compounds of general formula I, but are not intended to restrict the scope of the invention in any way. The temperatures are given in degrees Celsius, and silica gel, MerckQ, particle size 0.05-0.2 mm is used for the elution chromatography.
example 1
A solution of 5 g of 2-hydrazino-5-phenyl-7-chloro-3H-1,4-benzodiazepine [cf. Kanji Meguro and Yutaka Kuwada, Tetrahedron Letters 1970, 4039 (1970)] and 5 g of diethoxyacetic acid ethyl ester in 50 ml of N, N, N, N, N, N -hexamethylphosphoric triamide is heated to 1000 for 5 hours. The reaction mixture is then evaporated in vacuo and the residue is partitioned between methylene chloride and water. The organic phase is washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated.
The residue is recrystallized from ethyl acetate-ether-petroleum ether, after which the pure 6-phenyl-8-chloro-4H-s-triazolo [4,3-a] [1,4] benzodiazepine-1-carboxaldehyde diethyl acetal is added 1331350 melts.
Example 2
Analogously to Example 1, using 5 g of dimethoxyacetic acid dimethyl ester, 6-phenyl-8-chloro-4H-s-triazolo [4,3-a] [1,4] benzodiazepine-1-carboxaldehyde dimethyl acetate with a melting point of 1661720 is obtained .
Example 3
To a solution of 0.5 g (0.00126 mol) of 6-phenyl-8-chloro-4H-s-triazolo [4,3-a] [1,4] benzodiazepine-1-carboxaldehyde diethyl acetate in 3 ml each Acetone and methanol are added to 0.13 g (0.0013 mol) of perchloric acid. After adding 5 ml of petroleum ether, the salt crystallizes out. After suctioning off, 6-phenyl-8-chloro-4H-s-triazolo [4,3-all 1,4-benzodiazepine-1-carboxaldehyde diethylacetal perchlorate which decomposes at 2502650 is obtained.
Example 4
A solution of 7.64 g (0.024 mol) of m-chloroperbenzoic acid in 140 ml of methylene chloride is stirred within 15 minutes at 0-5O to a solution of 9.0 g (0.0126 mol) of 6-phenyl-8- chloro-4H-s-triazolo [4,3-a] [1,4] benzodiazepine-1-carboxaldehyde diethyl acetal added dropwise to 100 ml of methylene chloride. The reaction mixture is stirred for a further 16 hours in a thawing ice bath. Then you concentrate it in a vacuum and add ether to it. The precipitated crystals are filtered off with suction and washed twice with hot ethyl acetate. The 6-phenyl-8-chloro-4H-s-triazolo [4,3-a] [1 [1,4] benzodiazepine-1-carboxaldehyde diethylacetal-5-oxide melts at 2002020.
PATENT CLAIM 1
Process for the preparation of new triazolobenzodiazepine derivatives of the general formula I,
EMI2.1
in which Rl and R2 denote hydrogen, fluorine, chlorine, bromine, alkyl or alkoxy groups each with 1 to 6 carbon atoms, trifluoromethyl or nitro groups, and R3 an alkyl group with 1 to 4 carbon atoms or -R3.R3- a divalent saturated aliphatic hydrocarbon radical with 2 up to 5 carbon atoms, as well as the addition salts of such compounds with inorganic or organic acids, characterized in that a compound of the general formula II,
** WARNING ** End of DESC field could overlap beginning of CLMS **.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1212973A CH545302A (en) | 1971-04-08 | 1971-04-08 | Triazolobenzodiazepine derivs - with anticonvulsant, cns depressant and muscle-relaxant activity |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1212973A CH545302A (en) | 1971-04-08 | 1971-04-08 | Triazolobenzodiazepine derivs - with anticonvulsant, cns depressant and muscle-relaxant activity |
| CH523371 | 1971-04-08 |
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| Publication Number | Publication Date |
|---|---|
| CH545302A true CH545302A (en) | 1974-01-13 |
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| Application Number | Title | Priority Date | Filing Date |
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| CH1212973A CH545302A (en) | 1971-04-08 | 1971-04-08 | Triazolobenzodiazepine derivs - with anticonvulsant, cns depressant and muscle-relaxant activity |
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| US (1) | US3867536A (en) |
| JP (1) | JPS5614671B1 (en) |
| AR (3) | AR193382A1 (en) |
| AT (2) | AT317230B (en) |
| AU (1) | AU472767B2 (en) |
| BE (1) | BE781816A (en) |
| CA (1) | CA991639A (en) |
| CH (1) | CH545302A (en) |
| CS (3) | CS178448B2 (en) |
| DD (1) | DD97655A5 (en) |
| DE (1) | DE2215939A1 (en) |
| DK (1) | DK141965B (en) |
| FI (1) | FI52583C (en) |
| FR (1) | FR2132767B1 (en) |
| GB (1) | GB1392327A (en) |
| HU (1) | HU165318B (en) |
| IE (1) | IE36231B1 (en) |
| IL (1) | IL39051A (en) |
| NL (1) | NL7204700A (en) |
| NO (1) | NO134839C (en) |
| PL (1) | PL83566B1 (en) |
| SE (1) | SE413408B (en) |
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| ZA (1) | ZA721896B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3987052A (en) * | 1969-03-17 | 1976-10-19 | The Upjohn Company | 6-Phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines |
| BE759099A (en) * | 1969-11-18 | 1971-04-30 | Takeda Chemical Industries Ltd | PROCESS FOR MANUFACTURING HETEROCYCLIC COMPOUNDS |
| US3681343A (en) * | 1971-05-11 | 1972-08-01 | Upjohn Co | 6-phenyl-s-triazolo{8 4,3-a{9 {8 1,4{9 {0 benzodiazepines |
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1971
- 1971-04-08 CH CH1212973A patent/CH545302A/en not_active IP Right Cessation
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1972
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- 1972-03-28 IE IE404/72A patent/IE36231B1/en unknown
- 1972-03-29 FI FI720882A patent/FI52583C/en active
- 1972-03-30 US US239780A patent/US3867536A/en not_active Expired - Lifetime
- 1972-03-30 CA CA138,606A patent/CA991639A/en not_active Expired
- 1972-04-01 DE DE19722215939 patent/DE2215939A1/en not_active Withdrawn
- 1972-04-05 GB GB1570272A patent/GB1392327A/en not_active Expired
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- 1972-04-06 NO NO1163/72A patent/NO134839C/no unknown
- 1972-04-07 AT AT781173A patent/AT317230B/en not_active IP Right Cessation
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