CH544764A - 1-aminoalkyl-6-phenyl-4h-s-triazolo (4,3-a)(1,4) - benzodiazepines - with cns depressant activity - Google Patents
1-aminoalkyl-6-phenyl-4h-s-triazolo (4,3-a)(1,4) - benzodiazepines - with cns depressant activityInfo
- Publication number
- CH544764A CH544764A CH1206173A CH1206173A CH544764A CH 544764 A CH544764 A CH 544764A CH 1206173 A CH1206173 A CH 1206173A CH 1206173 A CH1206173 A CH 1206173A CH 544764 A CH544764 A CH 544764A
- Authority
- CH
- Switzerland
- Prior art keywords
- carbon atoms
- alkyl
- group
- hydrolysis
- general formula
- Prior art date
Links
- 239000003874 central nervous system depressant Substances 0.000 title abstract 2
- 229940049706 benzodiazepine Drugs 0.000 title description 4
- 230000000694 effects Effects 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 230000007062 hydrolysis Effects 0.000 claims abstract description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 7
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 6
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 7
- 150000007522 mineralic acids Chemical class 0.000 claims description 7
- 150000007524 organic acids Chemical class 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 5
- 229940093915 gynecological organic acid Drugs 0.000 claims description 5
- 235000005985 organic acids Nutrition 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 229960000583 acetic acid Drugs 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- KYTREVLPRJOBEM-UHFFFAOYSA-N triazolo[4,5-i][1,2]benzodiazepine Chemical class C1=CC2=CC=CN=NC2=C2C1=NN=N2 KYTREVLPRJOBEM-UHFFFAOYSA-N 0.000 claims description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 239000012458 free base Substances 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 230000001419 dependent effect Effects 0.000 claims 2
- -1 polymethyleneimino Polymers 0.000 abstract description 18
- 239000002253 acid Substances 0.000 abstract description 5
- 238000006243 chemical reaction Methods 0.000 abstract description 5
- 125000002252 acyl group Chemical group 0.000 abstract description 2
- 125000004414 alkyl thio group Chemical group 0.000 abstract description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 2
- 229910052783 alkali metal Inorganic materials 0.000 abstract 1
- 150000001340 alkali metals Chemical class 0.000 abstract 1
- 150000002148 esters Chemical class 0.000 abstract 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 abstract 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 abstract 1
- 125000005544 phthalimido group Chemical group 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 4
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 4
- GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical compound N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- YOHJKBKLWJAEHF-UHFFFAOYSA-N 7-chloro-2-methylsulfanyl-5-phenyl-3h-1,4-benzodiazepine Chemical compound N=1CC(SC)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 YOHJKBKLWJAEHF-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ZMJBYMUCKBYSCP-UHFFFAOYSA-N (+)-Erythro-hydroxycitric acid Natural products OC(=O)C(O)C(O)(C(O)=O)CC(O)=O ZMJBYMUCKBYSCP-UHFFFAOYSA-N 0.000 description 1
- 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
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 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
- LZANARFQFSEWHV-UHFFFAOYSA-N 5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-thione Chemical class C12=CC=CC=C2NC(=S)CN=C1C1=CC=CC=C1 LZANARFQFSEWHV-UHFFFAOYSA-N 0.000 description 1
- FPZAMNOXVVYEPG-UHFFFAOYSA-N 7-chloro-2-methyl-5-phenyl-3H-1,4-benzodiazepin-3-amine Chemical compound CC1=NC2=C(C(=NC1N)C1=CC=CC=C1)C=C(C=C2)Cl FPZAMNOXVVYEPG-UHFFFAOYSA-N 0.000 description 1
- CJAYKFPAEBBMQF-UHFFFAOYSA-N 7-chloro-5-(2-chlorophenyl)-2-methylsulfanyl-3h-1,4-benzodiazepine Chemical compound N=1CC(SC)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1Cl CJAYKFPAEBBMQF-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010052904 Musculoskeletal stiffness Diseases 0.000 description 1
- CJUMAFVKTCBCJK-UHFFFAOYSA-N N-benzyloxycarbonylglycine Chemical compound OC(=O)CNC(=O)OCC1=CC=CC=C1 CJUMAFVKTCBCJK-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 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
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 150000001346 alkyl aryl ethers Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000002539 anti-aggressive effect Effects 0.000 description 1
- 230000002082 anti-convulsion Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 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
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- HDFRDWFLWVCOGP-UHFFFAOYSA-N carbonothioic O,S-acid Chemical compound OC(S)=O HDFRDWFLWVCOGP-UHFFFAOYSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940019778 diethylene glycol diethyl ether Drugs 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- XTLNYNMNUCLWEZ-UHFFFAOYSA-N ethanol;propan-2-one Chemical compound CCO.CC(C)=O XTLNYNMNUCLWEZ-UHFFFAOYSA-N 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 1
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 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
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 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)
Abstract
Cpds of formula (I): (where Q is NR2R3;R1 is H or 1-3C alkyl, R2 and R3 are H, 1-6C alkyl, 2-6C hydroxyalkyl or 7-9C aralkyl, or NR2R3 is 5- to 7- membered polymethyleneimino or morpholino, both opt. substd by lower alkyl and contg. =10C; A is 1-3C alkylene, rings B and C are opt substd by F,Cl,Br,CF3,NO2,1-6C alkyl or alkoxy) and their 5-oxides and acid addn salts are CNS depressants. They may be prepd. by reacting a reactive ester of (I;Q=OH) with R2R3NH or its alkali metal deriv; reacting a 2-X-3-R1-5-Ph-3H-1,4-benzodiazepine with R2R3NACONHNH2 (where X=SH lower alkoxy or alkylthio (opt. activated by a substd) or opt. substd amino); hydrolysis of (I;Q=R2R3'N) (where R3'=acyl) to give (I;Q=R2HN); reaction of (I;Q=phthalimido) with N2H4 and/or strong acid to give (I;Q=NH2); redn of (I;Q=N3) to give (I;Q=NH2); or reaction of (IfQ=R2HN) with a 1-6C satd aliphatic oxo cpd and reducing the product.
Description
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von neuen Triazolo-benzodiazepinderivaten der allgemeinen Formel 1,
EMI1.1
in welcher A eine Alkylengruppe mit 1-3 Kohlenstoffatomen, R und R2 Wasserstoff, Halogen bis Atomnummer 35, Alkyloder Alkoxygruppen mit je 16 Kohlenstoffatomen, die Trifluormethyl- oder die Nitrogruppe und R3 Wasserstoff, eine Alkylgruppe mit 16 Kohlenstoffatomen oder eine Arylalkylgruppe mit 7-9 Kohlenstoffatomen bedeutet, sowie der Additionssalze solcher Verbindungen mit anorganischen oder organischen Säuren.
Die Triazolo-benzodiazepine der allgemeinen Formel I sowie ihre Additionssalze mit anorganischen oder organischen Säuren besitzen wertvolle pharmakologische Eigenschaften und einen hohen therapeutischen Index. Die neuen Verbindungen wirken antiaggressiv, antikonvulsiv und muskelrelaxierend. Diese Wirkungsqualitäten, welche durch ausgewählte Standardversuche [vgl. W. Theobald und A. Kunz, Arzneimittelforsch. 13, 122 (1963) sowie W. Theobald et al., Arzneimittelforsch. 17, 561 (1967)1 erfasst werden können, charakterisieren die Verbindungen der allgemeinen Formel I und ihre Additionssalze als Verbindungen, die zur Behandlung von Angst- und Spannungszuständen, der Epilepsie und von Muskelsteife verschiedener Genese geeignet sind.
In den Verbindungen der allgemeinen Formel list A als Alkylengruppe mit 1-3 Kohlenstoffatomen z. B. Die Methylen-, Äthyliden-, Äthylen-, Propylen- oder die Trimethylengruppe. Rl, R2 und R3 sind als Alkylgruppen mit 16 Kohlenstoffatomen beispielsweise die Methyl-, Athyl-, Propyl-, Iso propyl- Butyl-, Isobutyl-, sek. Butyl-, Pentyl-, 2-Methyl-butyl Isopentyl-, Hexyl-, Isohexyl-, 1-Methyl-pentyl-, 1,2,2-Trimethyl-propyl- oder die l Athyl-2-methyl-propylgruppe und R sowie R2 als Alkoxygruppen z. B. die Methoxy-, Athoxy-, Propoxy-, Isopropoxy-, Butoxy-, Isobutoxy-, Pentyloxy-, Hexyloxy- oder Isohexyloxygruppe. Weiter ist R3 als Arylalkylgruppe mit 7-9 Kohlenstoffatomen z.
B. die Benzyl-, o-, moder p-Methylbenzyl-, die 2,4-Dimethyl-benzyl-, die o-, m- oder p-Äthylbenzyl-, die Phenäthyl- oder die o-, m- oder p Methylphenäthylgruppe. Rl und R2 nehmen vorzugsweise die 8-bzw. 2'-Stellung ein.
Das erfindungsgemässe Verfahren zur Herstellung der neuen Triazolo-benzodiazepinderivate der allgemeinen Formel I sowie der Additionssalze solcher Verbindungen mit anorganischen oder organischen Säuren ist dadurch gekennzeichnet, dass man eine Verbindung der allgemeinen Formel II,
EMI1.2
in welcher R4 einen Acylrest bedeutet, und A, RI, R2 und R3 die unter der Formel I angegebene Bedeutung haben, hydrolysiert und ein erhaltenes Reaktionsprodukt in Form der freien Base oder ihres Additionssalzes mit einer anorganischen oder organischen Säure isoliert.
Die Gruppe R4 ist z. B. die Formylgruppe, eine niedere Alkanoylgruppe wie die Acetylgruppe, ein Arylcarbonylrest wie die Benzoylgruppe, ein Rest eines monofunktionellen Derivates der Kohlensäure oder der Thiokohlensäure, wie z. B. die Methoxycarbonyl-, Äthoxycarbonyl-, Phenoxycarbonyl- oder die Benzoyloxycarbonylgruppe, oder eine entsprechende Thiocarbonylgruppe.
Die Hydrolyse kann mit Hilfe eines Alkalimetallhydroxides, z. B. Kalium- oder Natriumhydroxides, bei einer Temperatur von ca. 50-1200C, vorzugsweise in einem höher siedenden hydroxylgruppenhaltigen, organischen Lösungsmittel, wie z. B.
Athylenglykol oder Diäthylenglykol, oder in einem niederen Monoalkyläther eines solchen Glykols, ferner auch in einem niederen Alkanol, z. B. Methanol oder Äthanol, vorgenommen werden. Ferner kann die Hydrolyse auch in saurem Medium durchgeführt werden, z. B. mit Bromwasserstoff oder Chlorwasserstoff in Essigsäure oder in alkanolischer Salzsäure bei einer Temperatur von ca. 50-1200C.
Die Ausgangsstoffe des Verfahrens, die Verbindungen der allgemeinen Formel II, können ihrerseits hergestellt werden, indem man eine Verbindung der allgemeinen Formel III,
EMI1.3
in welcher Rl und R2 die unter der Formel I angegebene Bedeutung haben und X die Mercapto- oder die Aminogruppe oder eine niedere Alkylamino-, Alkoxy- oder Alkylthiogruppe, insbesondere die Methylthiogruppe bedeutet, mit einem Hydrazid der allgemeinen Formel IV,
EMI2.1
in welcher R3 die unter der Formel I und R4 die unter der Formel II angegebene Bedeutung hat, umsetzt.
Die vorgenannte Umsetzung wird vorzugsweise bei einer Reaktionstemperatur von ca. 80160oC in einem inerten Lösungsmittel vorgenommen. Als inerte Lösungsmittel eignen sich beispielsweise Kohlenwasserstoffe, wie Toluol oder Xylol, Halogenkohlenwasserstoffe, wie Chlorbenzol, ätherartige Flüssigkeiten, wie Diäthylenglykoldimethyläther, Diäthylenglykoldiäthyläther oder Dioxan, und Amide, insbesondere N,N,N ,N ,N!,N{ -Hexamethyl-phosphorsäuretriamid. Die Reaktionszeiten liegen zwischen ca. einer und 24 Stunden.
Verbindungen, die unter die allgemeine Formel III fallen, sind in der Literatur beschrieben, z. B. das 2-Methylthio-5 -phenyl-7-chlor-3H-1 ,4-benzodiazepin [vgl. G. A. Archer und L. H. Sternbach, J. Org. Chem. 29, 231 (1964)] und das 2 -Methyl-amino-5 -phenyl-7 -chlor-3H- 1 ,4-benzodiazepin.
[vgl. L.H. Sternbach und E. Reeder, J.Org.Chem. 26, 1111 (1961)]. Weitere Verbindungen der allgemeinen Formel III können analog hergestellt werden.
Die nach den erfindungsgemässen Verfahren erhaltenen Verbindungen der allgemeinen Formel I werden anschliessend gewünschtenfalls in üblicher Weise in ihre Additionssalze mit anorganischen und organischen Säuren übergeführt. Beispielsweise versetzt man eine Lösung einer Verbindung der allgemeinen Formel I in einem organischen 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 Citronensäure verwendet werden.
Die neuen Wirkstoffe werden, wie weiter vorne erwähnt, 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, oder von pharmazeutisch annehmbaren Salzen der freien Basen bewegen sich zwischen 1 mg/kg und 5 mg/kg für Warmblüter. Geeignete Doseneinheitsformen, wie Dragees, Tabletten, Suppositorien oder Ampullen, enthalten vorzugsweise 5-25 mg eines erfindungsgemässen Wirkstoffes
Das nachfolgende Beispiel erläutert die Herstellung der neuen Verbindungen der allgemeinen Formel I und von bisher nicht beschriebenen Zwischenprodukten näher, soll jedoch der Umfang der Erfindung in keiner Weise beschränken. Die Temperaturen sind in Celsiusgraden angegeben.
Beispiel
4,57 g 0,01 Mol) 1- [[(Benzyloxycarbonyl)-amino]-methyl]-6-phenyl- 8-chlor-4H-s-triazolo[4,3 -a] [1 ,4]benzodiazepin werden in 60 ml mit Bromwasserstoff gesättigtem Eisessig gelöst und eine Stunde bei 200C gerührt. Hierauf wird das Reaktionsgemisch im Rotationsverdampfer auf ca. das halbe Volumen eingeengt und mit Äther versetzt. Die ausgefallenen Kristalle des rohen Hydrobromids des Hydrolysenproduktes werden abfiltriert, in Methylenchlorid suspendiert und die Suspension mit 2-n. Natriumcarbonatlösung geschüttelt, bis die Base vollständig freigesetzt und im Methylenchlorid gelöst ist.
Die organische Phase wird nun abgetrennt, zweimal mit Was sergewaschen, über Magnesiumsulfat getrocknet und eingedampft. Das Rohprodukt wird aus Äthylacetat-Petroläther kristallisiert, wobei man das 1 -(Aminomethyl)-6-phenyl-8-chlor-4H-s- triazolo[4,3 -aj [1 ,4]benzodiazepin vom Smp. 1641660C erhält.
Analog erhält man das 1 -(Aminomethyl)-6-(o-chlorphenyl)-8-chlor 4H-s-triazolo [4,3-a][ 1 ,4]benzodiazepin aus 4,92 g (0,01 Mol) 1-[[(Benzyloxy-carbonyl)-amino]-methyl]-6- (o-chlorphenyl)-8 -chlor-4H-s- triazolo[4,3-a][1,4]benzodiazepin, und das 1 -(Aminomethyl)-6-(o-fluorphenyl)-8-chlor- 4H-s-triazolo[4,3-a[[1,4]benzodiazepin aus 4,75 g 1 - [[(Benzyloxycarbonyl)-amino]-methyl] -6- (o-fluorphenyl)-8-chlor-4H-s- triazolo[4,3-a][1,4]benzodiazepin.
Die Ausgangsstoffe werden wie folgt hergestellt: a) Man erhitzt eine Lösung von 10,0 g (0,003 Mol) 2 (Methylthio)-5-phenyl-7-chlor-3H-1,4-benzodiazepin [vgl.
G.A. Archer und L.H. Sternbach, J.Org.Chem. 29, 231 (1964)] und 8,47 g (0,038 Mol) N-(Benzyloxycarbonyl)-glycin-hydrazin (N-Carboxy-glycin-N-benzylester-hydrazid) in 70 ml Hexamethylphosphorsäuretriamid 7 Stunden auf 1400.
Dann destilliert man das Lösungsmittel im Vakuum ab und verteilt den Rückstand zwischen Methylenchlorid und Wasser.
Die organische Phase wird abgetrennt, mit gesättigter Natriumchloridlösung gewaschen, über Natriumsulfat getrocknet und eingedampft. Den Rückstand kristallisiert man aus Äthylacetat unter Zusatz von Äther und wenig Petroläther, wobei man das
1 -[[(Benzyloxycarbonyl)-amino]-methyl]-6-phenyl- 8-chlor-4H-s-triazolo[4,3-a][1,4]benzodiazepin vom Smp. 1751820 erhält.
Analog erhält man unter Verwendung von 11,18 g (0,033 Mol) 2-(Methylthio)-5-(o-chlorphenyl)-7chlor-3H-1,4-benzodiazepin das 1-[[(Benzyl-oxycarbonyl)-amino]-methyl]-6- (o-chlorphenyl-8-chlor-4H-s triazolo[4,3-a][1,4]benzodiazepin, und unter Verwendung von 10,62 g (0,033 Mol) 2-(Methylthio)-5-(o-fluorphenyl) -7-chlor 3H-1 4-benzodiazepin das 1-[[(Benzyl-oxycarbonyl)amino]-methyl]-6-(o-fluorphenyl)-8-chlor 4H-s-triazolo[4,3-a][1,4]benzodiazepin.
Die beiden zuletzt genannten 2-(Methylthio)-Verbindungen sind aus den entsprechenden, im J.Org.Chem. 29, (1964) beschriebenen, substituierten 1,3-Dihydro-5-phenyl-2H-1,4 benzodiazepin-2-thionen analog zu dem dort für das 2 (Methylthio)-5-phenyl-7-chlor-3H-1 4-benzodiazepin beschriebenen Verfahren herstellbar.
The present invention relates to a process for the preparation of new triazolo-benzodiazepine derivatives of the general formula 1,
EMI1.1
in which A is an alkylene group with 1-3 carbon atoms, R and R2 are hydrogen, halogen up to atomic number 35, alkyl or alkoxy groups with 16 carbon atoms each, the trifluoromethyl or nitro group and R3 is hydrogen, an alkyl group with 16 carbon atoms or an arylalkyl group with 7-9 Means carbon atoms, as well as the addition salts of such compounds with inorganic or organic acids.
The triazolo-benzodiazepines of the general formula I and their addition salts with inorganic or organic acids have valuable pharmacological properties and a high therapeutic index. The new compounds have an anti-aggressive, anti-convulsive and muscle-relaxing effect. These effectiveness qualities, which are determined by selected standard tests [cf. W. Theobald and A. Kunz, Pharmaceutical Research. 13, 122 (1963) and W. Theobald et al., Arzneimittelforsch. 17, 561 (1967) 1, characterize the compounds of general formula I and their addition salts as compounds which are suitable for the treatment of anxiety and tension states, epilepsy and muscle stiffness of various origins.
In the compounds of the general formula list A as an alkylene group with 1-3 carbon atoms z. B. The methylene, ethylidene, ethylene, propylene or trimethylene group. Rl, R2 and R3 are alkyl groups with 16 carbon atoms, for example, methyl, ethyl, propyl, iso propyl, 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 R as well R2 as alkoxy groups e.g. B. the methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, hexyloxy or isohexyloxy group. Further, R3 is an arylalkyl group with 7-9 carbon atoms, for.
B. the benzyl, o-, moder p-methylbenzyl-, the 2,4-dimethyl-benzyl-, the o-, m- or p-ethylbenzyl, the phenethyl or the o-, m- or p methylphenäthylgruppe . R1 and R2 preferably take the 8 or. 2 'position.
The process according to the invention for the preparation of the new triazolobenzodiazepine derivatives of the general formula I and the addition salts of such compounds with inorganic or organic acids is characterized in that a compound of the general formula II,
EMI1.2
in which R4 is an acyl radical, and A, RI, R2 and R3 have the meaning given under formula I, hydrolyzed and a reaction product obtained is isolated in the form of the free base or its addition salt with an inorganic or organic acid.
The group R4 is e.g. B. the formyl group, a lower alkanoyl group such as the acetyl group, an arylcarbonyl radical such as the benzoyl group, a radical of a monofunctional derivative of carbonic acid or thiocarbonic acid, such as. B. the methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl or the benzoyloxycarbonyl group, or a corresponding thiocarbonyl group.
The hydrolysis can be carried out using an alkali metal hydroxide, e.g. B. potassium or sodium hydroxide, at a temperature of about 50-1200C, preferably in a higher-boiling hydroxyl-containing organic solvent, such as. B.
Ethylene glycol or diethylene glycol, or in a lower monoalkyl ether of such a glycol, also in a lower alkanol, e.g. B. methanol or ethanol can be made. Furthermore, the hydrolysis can also be carried out in an acidic medium, e.g. B. with hydrogen bromide or hydrogen chloride in acetic acid or in alkanolic hydrochloric acid at a temperature of about 50-1200C.
The starting materials of the process, the compounds of general formula II, can in turn be prepared by adding a compound of general formula III,
EMI1.3
in which Rl and R2 have the meaning given under the formula I and X is the mercapto or amino group or a lower alkylamino, alkoxy or alkylthio group, in particular the methylthio group, with a hydrazide of the general formula IV,
EMI2.1
in which R3 has the meaning given under formula I and R4 has the meaning given under formula II.
The aforementioned reaction is preferably carried out at a reaction temperature of about 80-160 ° C. in an inert solvent. Suitable inert solvents are, for example, hydrocarbons such as toluene or xylene, halogenated hydrocarbons such as chlorobenzene, ethereal liquids such as diethylene glycol dimethyl ether, diethylene glycol diethyl ether or dioxane, and amides, especially N, N, N, N, N!, N {-hexamethyl-phosphoric acid triamide The reaction times are between about one and 24 hours.
Compounds falling under the general formula III are described in the literature, e.g. B. 2-methylthio-5-phenyl-7-chloro-3H-1, 4-benzodiazepine [cf. G. A. Archer and L. H. Sternbach, J. Org. Chem. 29, 231 (1964)] and the 2-methyl-amino-5-phenyl-7-chloro-3H-1,4-benzodiazepine.
[see. L.H. Sternbach and E. Reeder, J.Org.Chem. 26, 1111 (1961)]. Further compounds of the general formula III can be prepared analogously.
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 organic 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 citric acid can be used.
As mentioned above, the new active ingredients are administered orally, rectally or parenterally. The dosage depends on the mode of administration, the species, the age and the individual condition. The daily doses of the free bases, or pharmaceutically acceptable salts of the free bases, range between 1 mg / kg and 5 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 according to the invention
The following example explains the preparation of the new compounds of general formula I and of hitherto not described intermediates in more detail, but is not intended to restrict the scope of the invention in any way. The temperatures are given in degrees Celsius.
example
4.57 g (0.01 mol) of 1- [[(benzyloxycarbonyl) amino] methyl] -6-phenyl-8-chloro-4H-s-triazolo [4,3-a] [1,4] benzodiazepine dissolved in 60 ml of glacial acetic acid saturated with hydrogen bromide and stirred for one hour at 200C. The reaction mixture is then concentrated to about half its volume in a rotary evaporator and ether is added. The precipitated crystals of the crude hydrobromide of the hydrolysis product are filtered off, suspended in methylene chloride and the suspension with 2-n. Sodium carbonate solution shaken until the base is completely released and dissolved in the methylene chloride.
The organic phase is then separated off, washed twice with water, dried over magnesium sulfate and evaporated. The crude product is crystallized from ethyl acetate-petroleum ether, 1 - (aminomethyl) -6-phenyl-8-chloro-4H-s-triazolo [4,3-aj [1,4] benzodiazepine of melting point 1641660C being obtained.
1 - (aminomethyl) -6- (o-chlorophenyl) -8-chloro 4H-s-triazolo [4,3-a] [1,4] benzodiazepine is obtained analogously from 4.92 g (0.01 mol) 1 - [[(Benzyloxy-carbonyl) -amino] -methyl] -6- (o-chlorophenyl) -8-chloro-4H-s-triazolo [4,3-a] [1,4] benzodiazepine, and the 1 - (Aminomethyl) -6- (o-fluorophenyl) -8-chloro-4H-s-triazolo [4,3-a [[1,4] benzodiazepine from 4.75 g of 1 - [[(benzyloxycarbonyl) amino] -methyl] -6- (o-fluorophenyl) -8-chloro-4H-s-triazolo [4,3-a] [1,4] benzodiazepine.
The starting materials are prepared as follows: a) A solution of 10.0 g (0.003 mol) of 2 (methylthio) -5-phenyl-7-chloro-3H-1,4-benzodiazepine [cf.
G.A. Archer and L.H. Sternbach, J.Org.Chem. 29, 231 (1964)] and 8.47 g (0.038 mol) of N- (benzyloxycarbonyl) -glycine hydrazine (N-carboxy-glycine-N-benzyl ester hydrazide) in 70 ml of hexamethylphosphoric acid triamide for 7 hours to 1400.
The solvent is then distilled off in vacuo and the residue is partitioned between methylene chloride and water.
The organic phase is separated off, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue is crystallized from ethyl acetate with the addition of ether and a little petroleum ether, whereby the
1 - [[(Benzyloxycarbonyl) amino] methyl] -6-phenyl-8-chloro-4H-s-triazolo [4,3-a] [1,4] benzodiazepine of mp 1751820.
Using 11.18 g (0.033 mol) of 2- (methylthio) -5- (o-chlorophenyl) -7chlor-3H-1,4-benzodiazepine, 1 - [[(benzyl-oxycarbonyl) -amino] is obtained analogously. -methyl] -6- (o-chlorophenyl-8-chloro-4H-s triazolo [4,3-a] [1,4] benzodiazepine, and using 10.62 g (0.033 mol) 2- (methylthio) -5- (o-fluorophenyl) -7-chloro 3H-1 4-benzodiazepine the 1 - [[(benzyl-oxycarbonyl) amino] -methyl] -6- (o-fluorophenyl) -8-chloro 4H-s-triazolo [4,3-a] [1,4] benzodiazepine.
The two last-mentioned 2- (methylthio) compounds are derived from the corresponding, in J.Org.Chem. 29, (1964) described substituted 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thiones analogous to that there for the 2 (methylthio) -5-phenyl-7-chloro-3H-1 4-benzodiazepine described process can be prepared.
Claims (1)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1206173A CH544764A (en) | 1971-01-21 | 1971-01-21 | 1-aminoalkyl-6-phenyl-4h-s-triazolo (4,3-a)(1,4) - benzodiazepines - with cns depressant activity |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH89171 | 1971-01-21 | ||
| CH1206173A CH544764A (en) | 1971-01-21 | 1971-01-21 | 1-aminoalkyl-6-phenyl-4h-s-triazolo (4,3-a)(1,4) - benzodiazepines - with cns depressant activity |
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| CH89171A CH545803A (en) | 1971-01-21 | 1971-01-21 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2709842A1 (en) * | 1976-03-15 | 1977-09-22 | Upjohn Co | BENZODIAZEPINE, METHOD OF MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THEM |
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| GB1381158A (en) * | 1971-09-13 | 1975-01-22 | Upjohn Co | Benzodiazepines and the manufacture thereof |
| US3767661A (en) * | 1971-09-13 | 1973-10-23 | Upjohn Co | 4h-s-triazolo(4,3-a)(1,4)benzodiazepines |
| US3767660A (en) * | 1971-09-13 | 1973-10-23 | Upjohn Co | 4h-s-triazolo(4,3-a)(1,4)benzodiazepines |
| BE790838A (en) * | 1971-11-02 | 1973-04-30 | Upjohn Co | NEWS 1-AMINOPHENYL-6-PHENYL-S-TRIAZOLO (4,3-A) (1,4) - BENZODIAZEPINES, THEIR METHOD OF PREPARATION AND THE MEDICINAL PRODUCT CONTAINING THEM |
| DE2356369C2 (en) * | 1972-11-24 | 1984-08-23 | The Upjohn Co., Kalamazoo, Mich. | Pharmaceutical preparation containing one or more benzodiazepine compounds |
| US3842090A (en) * | 1973-02-14 | 1974-10-15 | Upjohn Co | Certain 1-aminomethyl-6-phenyl 4h-s-triazolo(4,3-a)(1,4)benzodiazepines |
| US4501698A (en) * | 1983-03-31 | 1985-02-26 | The Upjohn Company | Preparing 1-(hydroxymethyl)-triazolobenzodiazepines and 1-(aminomethyl)-triazolobenzodiazepines |
| CA1234810A (en) * | 1983-12-19 | 1988-04-05 | Steve Nichols | Non-hygroscopic adinazolam methanesulfonate salt and process therefor |
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| US3987052A (en) * | 1969-03-17 | 1976-10-19 | The Upjohn Company | 6-Phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines |
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1971
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- 1972-01-20 CS CS7500008670A patent/CS185640B2/en unknown
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| DE2709842A1 (en) * | 1976-03-15 | 1977-09-22 | Upjohn Co | BENZODIAZEPINE, METHOD OF MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THEM |
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| Publication number | Publication date |
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| IE35968B1 (en) | 1976-07-07 |
| AU475348B2 (en) | 1976-08-19 |
| SU444370A3 (en) | 1974-09-25 |
| FR2122485B1 (en) | 1975-02-07 |
| SU481156A3 (en) | 1975-08-15 |
| HU166550B (en) | 1975-04-28 |
| CA965786A (en) | 1975-04-08 |
| IE35968L (en) | 1972-07-21 |
| ES399064A1 (en) | 1975-06-01 |
| PL83109B1 (en) | 1975-12-31 |
| NL7200538A (en) | 1972-07-25 |
| AR192612A1 (en) | 1973-02-28 |
| ZA72253B (en) | 1972-09-27 |
| FR2122485A1 (en) | 1972-09-01 |
| GB1394568A (en) | 1975-05-21 |
| BE778215A (en) | 1972-07-19 |
| IL38553A (en) | 1975-02-10 |
| CH545803A (en) | 1974-02-15 |
| AT315862B (en) | 1974-06-10 |
| AT315848B (en) | 1974-06-10 |
| GB1393256A (en) | 1975-05-07 |
| AT315863B (en) | 1974-06-10 |
| PL86933B1 (en) | 1976-06-30 |
| IL38553A0 (en) | 1972-03-28 |
| DD95010A5 (en) | 1973-01-12 |
| CS185640B2 (en) | 1978-10-31 |
| CS185604B2 (en) | 1978-10-31 |
| DE2201210A1 (en) | 1972-08-03 |
| AU3804772A (en) | 1973-07-26 |
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