NO144386B - Fremgangsmaate ved fremstilling av benzodiazepinderivater - Google Patents
Fremgangsmaate ved fremstilling av benzodiazepinderivater Download PDFInfo
- Publication number
- NO144386B NO144386B NO793012A NO793012A NO144386B NO 144386 B NO144386 B NO 144386B NO 793012 A NO793012 A NO 793012A NO 793012 A NO793012 A NO 793012A NO 144386 B NO144386 B NO 144386B
- Authority
- NO
- Norway
- Prior art keywords
- carbon atoms
- acid addition
- addition salt
- benzodiazepine
- substituted
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 13
- 229940053197 benzodiazepine derivative antiepileptics Drugs 0.000 title claims description 4
- 150000001557 benzodiazepines Chemical class 0.000 title description 3
- -1 cyano, amino, acetylamino, phenoxy, chlorophenoxy, benzoyloxy, phenylthio, benzylamino, trimethoxybenzoylamino, phthalimido, methylpiperazino, morpholino Chemical group 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims 2
- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 claims 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims 2
- 239000012458 free base Substances 0.000 claims 2
- KZNXKMJGYSECTN-UHFFFAOYSA-N 1,2-benzodiazocine Chemical class N1=NC=CC=CC2=CC=CC=C21 KZNXKMJGYSECTN-UHFFFAOYSA-N 0.000 claims 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims 1
- BTJMOXDWIPVCRO-UHFFFAOYSA-N 2,3,4-trimethoxybenzamide Chemical compound COC1=CC=C(C(N)=O)C(OC)=C1OC BTJMOXDWIPVCRO-UHFFFAOYSA-N 0.000 claims 1
- ISPYQTSUDJAMAB-UHFFFAOYSA-N 2-chlorophenol Chemical compound OC1=CC=CC=C1Cl ISPYQTSUDJAMAB-UHFFFAOYSA-N 0.000 claims 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims 1
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 239000012442 inert solvent Substances 0.000 claims 1
- 239000012434 nucleophilic reagent Substances 0.000 claims 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-M phenolate Chemical compound [O-]C1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-M 0.000 claims 1
- 229940031826 phenolate Drugs 0.000 claims 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 206010010904 Convulsion Diseases 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- ANZXBICBBBRTPL-UHFFFAOYSA-N 3,8-dichloro-1-methyl-6-phenyl-3,4-dihydro-2h-1,5-benzodiazocine;hydrochloride Chemical compound Cl.C12=CC(Cl)=CC=C2N(C)CC(Cl)CN=C1C1=CC=CC=C1 ANZXBICBBBRTPL-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical group N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 230000001773 anti-convulsant effect Effects 0.000 description 2
- 239000002026 chloroform extract Substances 0.000 description 2
- 230000036461 convulsion Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- UYXAWHWODHRRMR-UHFFFAOYSA-N hexobarbital Chemical compound O=C1N(C)C(=O)NC(=O)C1(C)C1=CCCCC1 UYXAWHWODHRRMR-UHFFFAOYSA-N 0.000 description 2
- 229960002456 hexobarbital Drugs 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- LNSSSNFABNPARN-UHFFFAOYSA-N (7-chloro-1-methyl-5-phenyl-2,3-dihydro-1,4-benzodiazepin-2-yl)methanol hydrochloride Chemical compound Cl.C12=CC(Cl)=CC=C2N(C)C(CO)CN=C1C1=CC=CC=C1 LNSSSNFABNPARN-UHFFFAOYSA-N 0.000 description 1
- SXEGXQZVRAZGQR-UHFFFAOYSA-N 3,8-dichloro-1-methyl-6-phenyl-3,4-dihydro-2h-1,5-benzodiazocine Chemical compound C12=CC(Cl)=CC=C2N(C)CC(Cl)CN=C1C1=CC=CC=C1 SXEGXQZVRAZGQR-UHFFFAOYSA-N 0.000 description 1
- ZNCTZFTUAXQUHQ-UHFFFAOYSA-N 7-chloro-1-methyl-5-phenyl-2-(piperidin-1-ylmethyl)-2,3-dihydro-1,4-benzodiazepine Chemical compound C1N=C(C=2C=CC=CC=2)C2=CC(Cl)=CC=C2N(C)C1CN1CCCCC1 ZNCTZFTUAXQUHQ-UHFFFAOYSA-N 0.000 description 1
- HTTLCBVCGWYRQH-UHFFFAOYSA-N 7-chloro-2-(methoxymethyl)-1-methyl-5-phenyl-2,3-dihydro-1,4-benzodiazepine;hydrochloride Chemical compound Cl.C12=CC(Cl)=CC=C2N(C)C(COC)CN=C1C1=CC=CC=C1 HTTLCBVCGWYRQH-UHFFFAOYSA-N 0.000 description 1
- 206010053398 Clonic convulsion Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 238000011785 NMRI mouse Methods 0.000 description 1
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 1
- PQUGCKBLVKJMNT-UHFFFAOYSA-N SC560 Chemical compound C1=CC(OC)=CC=C1N1C(C=2C=CC(Cl)=CC=2)=CC(C(F)(F)F)=N1 PQUGCKBLVKJMNT-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
- 241000906446 Theraps Species 0.000 description 1
- 206010043994 Tonic convulsion Diseases 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000002539 anti-aggressive effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000002566 clonic effect Effects 0.000 description 1
- 239000012043 crude product Substances 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
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 235000015220 hamburgers Nutrition 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
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000003170 musculotropic effect Effects 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229940103091 potassium benzoate Drugs 0.000 description 1
- 235000010235 potassium benzoate Nutrition 0.000 description 1
- 239000004300 potassium benzoate Substances 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 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
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 238000005245 sintering Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000638 stimulation Effects 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
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/5545—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having eight-membered rings not containing additional condensed or non-condensed nitrogen-containing 3-7 membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D245/00—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms
- C07D245/04—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
- C07D245/06—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Epidemiology (AREA)
- Anesthesiology (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
Foreliggende oppfinnelse angår en ny fremgangsmåte ved fremstillingen av nye benzodiazepinderivater med den generelle formel:
hvor R^ er hydrogen, lavere alkyl eller benzyl,
1*2 er hydroxy, rettkjedet eller forgrenet alkoxy med 1-5 carbonatomer, cyano, amino, acetylamino, fenoxy, klorfenoxy, benzoyloxy, fenylthio, benzylamino, trimethoxybenzoylamino, fthalimido, methylpiperazino, morfolino eller piperidino, og ;A og B er benzenringer som kan være substituert med 1—3 sub-stituenter fra gruppen bestående av halogen, alkyl med 1-4 carbonatomer, alkoxy med 1 - 4 carbonatomer, eller nitro, eller A kan være substituert med methylthio eller ethylendioxy; ;såvel som syreaddisjonssalter derav. ;Som lavere alkyl, representert ved R^, kommer f.eks. methyl, ethyl, propyl, isopropyl, butyl, sek-butyl, t-butyl, amyl, hexyl, cyclopentyl, cyclohexyl eller cyclopropylmethyl på tale. ;Fra litteraturen er det kjent at forbindelsene med benzo-1,4-diazepin-strukturen er verdifulle legemidler (se Burger, Medicinal Chemistry, (1970), 3. opplag). ;Benzo-1,4-diazepin-forbindelsene med formel I er ikke tid-ligere kjent. De nye forbindelser oppviser en verdifull innflyt-else på sentralnervesystemet. Forbindelsene har antikonvulsiv, sedativ, muskelavslappende såvel som psykosedativ virkning. Dette kan vises ved farmakologiske standardforsøk på små forsøksdyr. ;De nye forbindelser skiller seg overraskende ganske spesielt ut ved god forlikelighe.t (terapeutisk bredde) sammenlignet med handelspreparater. ;Undersøkelsene strekker seg til bestemmelsene av følgende aktivitéter: ;1. <p>røving av antikonvulsive egenskaper: ;a) Elektrosjokkanfall: ;Metode: ;Undersøkelsesforbindelsene ble prøvet efter peroral administrasjon til grupper på 5 mus hver i logaritmiske doseringsav-stander på 0,1673 (Hackenberg, U. og H. Bartling, Naunyn-Schmiede-berg<*>s Arch.exp.Path. u. Pharmak. 235, 437-463 (1959). 1 time efter administrasjon ble 2 elektroder heftet ved ørene på dyrene, og den elektriske stimulering ble utløst. Opptredelsen eller uteblivelsen av toniske ekst ensoranf all ble registrert, og den prosentuelle be-skyttelsesvirkning mot anfall ble beregnet.
b) Pent et ra zolkrampe:
Metode:
Undersøkelsesforbindelsene ble likeledes administrert pr. os i logaritmiske doseringer (avstand 0,1673) til grupper hver på IO mus. 6o minutter efter administrasjon av forsøksforbindelsene ble pentetrazol injisert subkutant i en dose på 100 mg/kg. Opptredelsen av kloniske og toniske konvulsjoner og død ble iakttatt i løpet av 45 minutter. Totalobservasjonstiden ble utstrakt til 3 timer. Beskytt eisesvirkningen mot konvulsjon og død ble bestemt ved sammenligning med samtidig utførte kontrollforsøk. Den effek-tive dose ED^q mot konvulsjoner ble beregnet fra probit/log. dos-eringskurven. 2. Undersøkelse på antiaggressive egenskaper hos de elektrisk opphissede kampmus :
Metode:
Tedeschi, R. E. et al. J. Pharmacol. Exptl. Therap. 125, 28
(1959) . 1 time efter administrasjon pr. os av undersøkelsesforbind-elsen ble 8 muspar pr. dose prøvet i kampprøven efter den ovenfor angitte metode. Den logaritmiske doseringsavstand utgjorde likeledes 0,l673. Opphisselsestiden utgjorde 3 minutter. 3. Undersøkelse av narkosepotensierende egenskaper efter administrasjon av hexobarbital:
Metode:
Undersøkelsesforbindelsene ble administrert pr. os logarit-misk i doseavstander på 0,3324- 30 minutter efter administrasjon ble hexobarbital administrert i en dose på 65 mg/kg intravenøst. Tiden av søvnen ble målt. ed^q = ^° minutters ligging på siden.
4. Akutt toksisitet:
Den akutte toksisitet ble bestemt efter en gangs administrasjon pr. os til hvite fastende NMRI-mus. Beregningen skjedde ifølge metoden til Litchfield, J. T. og F. Wilcoxon (J. Pharmacol. Exptl. Therap. 96, 99 (1949).
Utgangsmaterialene for anvendelse ved foreliggende fremgangsmåte kan fremstilles som angitt i norsk patentansøkning 751349.
Ifølge foreliggende nye fremgangsmåte fremstilles benzodiaze-pinderivatene med formel I som angitt i kravets karakteristikk.
Fremgangsmåteforbindelsene kan anvendes i form av vanlige farmasøytiske preparater som psykosedative midler med ringe muskulotrope egenskaper til behandling av psykisk syke mennesker. Forbindelsene kan administreres såvel pr. os som parenteralt.
Eksempel 1
100 mg 3,8-diklor-l-methyl-6-fenyl-l,2,3,4-tetrahydro-l,5-benzodiazocin-hydroklorid ble oppvarmet i 3 ml vann og 4 ml dioxan med 0,5 ml 20%-ig natronlut i 3 timer under tilbakeløp. Derpå
ble dioxanet avdestillert under vakuum, råproduktet ekstrahert med kloroform og kloroformekstraktet inndampet i vakuum. Det fra isopropanol under tilsetning av etherisk saltsyre erholdte hydroklorid ble omkrystallisert fra isopropanol. Man fikk 7-klor-l-methyl-2-hydroxymethyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin-hydroklorid med smp. 22 7 - 2 35°C.
Eksempel 2
500 mg 3,8-diklor-l-methyl-6-fenyl-1,2,3,4-tetrahydro-l,5-benzodiazocin-hydroklorid ble oppvarmet i en oppløsning av 110 mg natrium i 70 ml methanol i 12 timer under tilbakeløp. Efter fordampning av methanolen i vakuum ble der opparbeidet med vann/kloroform, og kloroformoppløsningen ble inndampet i vakuum. Residuet ble opptatt i isopropanol og tilsatt etherisk saltsyre.
Man fikk 7-klor-l-methyl-2-methoxymethyl-5-fenyl-2,3-dihydro-lH-1,4-benzodiazepin-hydroklorid med smp. 198-210°C.
På analogt vis fåes ved å gå ut fra 3-klor-8-nitro-6-fenyl-1,2,3,4-tetrahydro-l,5-benzodiazocin med smp. 221-223°C, 7-nitro-2-methoxymethyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin-maleinat med smp. 189-194°C.
Eksempel 3
100 mg 3,8-diklor-l-methyl-6-fenyl-l,2,3,4-tetrahydro-l,5-benzodiazocin-hydroklorid ble oppvarmet i 10 ml piperidin i 24 timer under tilbakeløp. Til opparbeidelse ble reaksjonsbland-ingen helt i vann, ekstrahert med kloroform og derpå ble kloro-formen avdestillert i vakuum. Fra ether krystalliserte 7-klor-l-methyl-2-piperidinomethyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin med smp. 143 - 146°C.
Eksempel 4
5 g 3,8-diklor-l-methyl-6-fenyl-1,2,3,4-tetrahydro-l,5-benzodiazocih-hydroklorid oppløses i 100 ml dimethylformamid og oppvarmes med 3 g kaliumbenzoat i 20 timer under tilbakeløp. Efter vanlig opparbeidelse av reaksjonsblåndingen får man 7-klor-l-methyl-2-benzoyloxymethyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin, hvis hydroklorid har et smeltepunkt ved 175°C efter sintring ved 160°C.
Eksempel 5
88 g 3,8-diklor-l-methyl-6-fenyl-1,2,3,4-tetrahydro-l,5-benzodiazocin ble oppløst i 1000 ml methanol og oppvarmet med 19,8 g kaliumcyanid og 2 g kaliumjodid i 24 timer under tilbakeløp. Derpå ble oppløsningsmidlet avdestillert i vakuum, residuet ble tilsatt vann og ekstrahert med kloroform. De forenede kloroform-ekstrakter ble vasket med vann, tørret over natriumsulfat og
inndampet i vakuum. Residuet ble oppløst i isopropanol og tilsatt etherisk hydrogenklorid. Man fikk 7-klor-l-methyl-2-cyano-methyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin-hydroklorid med smeltepunkt 213-215°C.
Ifølge foreliggende fremgangsmåte ble dessuten følgende forbindelser fremstilt:
Claims (1)
- Fremgangsmåte ved fremstilling av benzodiazepinderivater med den generelle formel:hvor R er hydrogen, lavere alkyl eller benzyl;R2 er hydroxy, rettkjedet eller forgrenet alkoxy med 1-5 carbonatomer, cyano, amino, acetylamino, fenoxy, klorfenoxy, benzoyloxy, fenylthio, benzylamino, trimethoxybenzoylamino, fthalimido, methylpiperazino, morfolino eller piperidino, og A og B er benzenringer som kan være substituert med 1-3 subst ituenter fra gruppen bestående av halogen, alkyl med 1-4 carbonatomer, alkoxy med 1-4 carbonatomer, trifluor-methyl, eller nitro, eller A kan være substituert med methylthio eller ethylendioxy;såvel som syreaddisjonssalter derav,karakterisert ved at et benzodiazocin-derivat med den generelle formel:hvor R^, A og B er som ovenfor angitt, og R 7 er klor eller brom, eller et syreaddisjonssalt derav, omsettes med et nucleofilt reagens av gruppen bestående av ammoniakk, benzylamin, morfolin, methylpiperazin, piperidin, fthalimid, trimethoxybenzamid, acet-amid, benzoat, cyanid, alkoholat med 1-5 carbonatomer, fenolat, klorfenolat eller thiofenolat, ved forhøyet temperatur i et inert oppløsningsmiddel; eller underkastes en alkalisk hydrolyse hvorved der direkte dannes et benzodiazepinderivat med formel I, hvor R^, A og B er som ovenfor angitt, hvor R2 er hydroxy,og at en dannet fri base eventuelt overføres til et syreaddisjonssalt derav, eller et dannet syreaddisjonssalt eventuelt overføres til den frie base.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2221558A DE2221558C2 (de) | 1972-05-03 | 1972-05-03 | 5-Phenyl-2,3-dihydro-1H-1,4-benzodiazepine und ihre Säureadditionssalze, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO793012L NO793012L (no) | 1973-11-06 |
| NO144386B true NO144386B (no) | 1981-05-11 |
| NO144386C NO144386C (no) | 1981-08-19 |
Family
ID=5843904
Family Applications (6)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO1797/73A NO142866C (no) | 1972-05-03 | 1973-05-02 | Nye benzodiazepinderivater for anvendelse som ugangsmateriale og fremgangsmaate ved fremstilling derav |
| NO75751349A NO145761C (no) | 1972-05-03 | 1975-04-16 | Benzodiazocinderivater for anvendelse som utgangsmaterialer ved fremstilling av benzodiazepinderivater, og en ny fremgangsmaate for fremstilling av disse benzodiazocinderivater |
| NO76761580A NO143347C (no) | 1972-05-03 | 1976-05-07 | Utgangsmateriale for fremstilling av benzodiazepinderivater |
| NO780402A NO142476C (no) | 1972-05-03 | 1978-02-06 | Fremgangsmaate ved fremstilling av benzodiazepinderivater |
| NO793013A NO144885C (no) | 1972-05-03 | 1979-09-19 | Analogifremgangsmaate ved fremstilling av terapeutisk aktive benzodiazepinderivater |
| NO793012A NO144386C (no) | 1972-05-03 | 1979-09-19 | Fremgangsmaate ved fremstilling av benzodiazepinderivater |
Family Applications Before (5)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO1797/73A NO142866C (no) | 1972-05-03 | 1973-05-02 | Nye benzodiazepinderivater for anvendelse som ugangsmateriale og fremgangsmaate ved fremstilling derav |
| NO75751349A NO145761C (no) | 1972-05-03 | 1975-04-16 | Benzodiazocinderivater for anvendelse som utgangsmaterialer ved fremstilling av benzodiazepinderivater, og en ny fremgangsmaate for fremstilling av disse benzodiazocinderivater |
| NO76761580A NO143347C (no) | 1972-05-03 | 1976-05-07 | Utgangsmateriale for fremstilling av benzodiazepinderivater |
| NO780402A NO142476C (no) | 1972-05-03 | 1978-02-06 | Fremgangsmaate ved fremstilling av benzodiazepinderivater |
| NO793013A NO144885C (no) | 1972-05-03 | 1979-09-19 | Analogifremgangsmaate ved fremstilling av terapeutisk aktive benzodiazepinderivater |
Country Status (18)
| Country | Link |
|---|---|
| US (6) | US3998809A (no) |
| JP (3) | JPS5541231B2 (no) |
| AT (3) | AT327919B (no) |
| BE (1) | BE799001A (no) |
| CA (3) | CA984388A (no) |
| CH (5) | CH611607A5 (no) |
| DD (1) | DD105222A5 (no) |
| DE (3) | DE2265370C2 (no) |
| DK (3) | DK147050C (no) |
| ES (1) | ES414279A1 (no) |
| FR (3) | FR2183735B1 (no) |
| GB (3) | GB1429667A (no) |
| IL (5) | IL47693A (no) |
| NL (1) | NL179111C (no) |
| NO (6) | NO142866C (no) |
| SE (3) | SE409709B (no) |
| SU (2) | SU625607A3 (no) |
| ZA (1) | ZA733013B (no) |
Families Citing this family (45)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2520937C3 (de) * | 1975-05-10 | 1978-10-12 | Kali-Chemie Ag, 3000 Hannover | 7-Brom-1 -methyl^-alkoxymethyl-S-(2-halogenphenyl)-lH-23-dihydro-l,4benzodiazepinderivate, deren Säureadditionssalze und pharmazeutische Präparate |
| US4244869A (en) * | 1972-05-03 | 1981-01-13 | Kali-Chemie A.G. | Benzodiazepine derivatives and process of making them |
| DE2265370C2 (de) * | 1972-05-03 | 1982-12-02 | Kali-Chemie Ag, 3000 Hannover | 6-Phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocinderivate |
| ES469020A1 (es) * | 1977-05-10 | 1979-09-01 | Kali Chemie Pharma Gmbh | Procedimiento para la preparacion de nuevos 1-acil-2-hidroxi-1,3-diaminopropanos |
| DE2720968C2 (de) * | 1977-05-10 | 1986-05-07 | Kali-Chemie Pharma Gmbh, 3000 Hannover | N↓1↓-Acyl-2-hydroxy-1,3-diaminopropane und Arzneimittel |
| DE2720908A1 (de) * | 1977-05-10 | 1978-11-23 | Kali Chemie Pharma Gmbh | Arzneimittel mit ulkustherapeutischem effekt |
| US4123430A (en) * | 1977-11-10 | 1978-10-31 | G. D. Searle & Co. | 2-Aryl-4-(1-piperazinyl)-3H-1,5-benzodiazepines |
| DE2754112A1 (de) * | 1977-12-05 | 1979-06-13 | Kali Chemie Pharma Gmbh | 1,4-benzodiazepinderivate, ihre salze und diese verbindungen enthaltende arzneipraeparate |
| DE2810349A1 (de) * | 1978-03-10 | 1979-09-20 | Kali Chemie Pharma Gmbh | Verfahren zur herstellung von 3-hydroxy-6-phenyl-1,2,3,4-tetrahydro- 1,5-benzodiazocinen |
| US4371468A (en) * | 1978-05-15 | 1983-02-01 | Hoffmann-La Roche Inc. | Intermediates to produce imidazodiazepines |
| US4368157A (en) * | 1978-05-15 | 1983-01-11 | Hoffmann-La Roche Inc. | Intermediates to produce imidazodiazepines |
| US4368158A (en) * | 1978-05-15 | 1983-01-11 | Hoffmann-La Roche Inc. | Intermediates to produce imidazodiazepines |
| US4368159A (en) * | 1978-05-15 | 1983-01-11 | Hoffmann-La Roche Inc. | Intermediates to produce imidazodiazepines |
| DE2827801A1 (de) * | 1978-06-24 | 1980-01-10 | Kali Chemie Pharma Gmbh | Neue n tief 1 -benzoyl-n tief 2 -phenyl-1,3-diaminopropan-2-ole, verfahren zu deren herstellung und arzneimittel |
| DE2835708A1 (de) * | 1978-08-16 | 1980-03-06 | Kali Chemie Pharma Gmbh | Neue eckige klammer auf 1,2 eckige klammer zu-anellierte 7-phenyl-1,4-benzodiazepinderivate, verfahren zu deren herstellung und arzneimittel |
| JPS5775313A (en) * | 1980-10-30 | 1982-05-11 | Fanuc Ltd | Numerical controller of machine tool |
| DE3048264A1 (de) * | 1980-12-20 | 1982-09-09 | Kali-Chemie Pharma Gmbh, 3000 Hannover | 2-acylaminomethyl-1,4-benzodiazepine und deren salze sowie verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
| DE3124013A1 (de) * | 1981-06-19 | 1982-12-30 | Kali-Chemie Pharma Gmbh, 3000 Hannover | 2-acylaminomethyl-1,4-benzodiazepin-verbindungen sowie verfahren und zwischenprodukte zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
| DE3138769A1 (de) * | 1981-09-30 | 1983-04-14 | Kali-Chemie Pharma Gmbh, 3000 Hannover | 7-brom-5-(2-halogenphenyl)-1h-2,3-dihydro-1,4- benzodiazepin-verbindungen sowie verfahren und zwischenprodukte zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
| DE3151597A1 (de) * | 1981-12-28 | 1983-07-07 | Kali-Chemie Pharma Gmbh, 3000 Hannover | (1,2)-anellierte 1,4-benzodiazepin-verbindungen sowie verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
| DE3221402A1 (de) * | 1982-06-05 | 1983-12-08 | Kali-Chemie Pharma Gmbh, 3000 Hannover | 5-phenyl-1,4-benzodiazepine enthaltende analgetisch wirksame pharmazeutische zubereitungen |
| US4493168A (en) * | 1983-06-16 | 1985-01-15 | Coburn Optical Industries, Inc. | Calibration gauge for computer-controlled lens generator, or the like |
| US4602886A (en) * | 1983-12-28 | 1986-07-29 | Smit Adrianus J | Multi-color marking implement |
| US4786449A (en) * | 1983-12-28 | 1988-11-22 | Clowny Corporation | Method for manufacture of multi-color marking implements |
| US4724237A (en) * | 1984-06-26 | 1988-02-09 | Merck & Co., Inc. | 2-substituted-aminomethyl-1,4-benzodiazepines |
| EP0170024A3 (en) * | 1984-06-26 | 1990-01-31 | Merck & Co. Inc. | Use of 2-acylaminomethyl-1,4-benzodiazepine derivatives for the production of pharmaceutical compositions and process for the preparation for pharmaceutical compositions |
| US4684646A (en) * | 1984-06-26 | 1987-08-04 | Merck & Co., Inc. | 2-acylaminomethyl-1,4-benzodiazepine derivatives as CCK-antagonists |
| JPS61114933A (ja) * | 1984-11-12 | 1986-06-02 | Tokyo Electric Co Ltd | 事務機の給紙装置 |
| JPH0618794Y2 (ja) * | 1987-06-17 | 1994-05-18 | 株式会社スギノマシン | ウォータジェット加工機 |
| JPH0418564Y2 (no) * | 1988-01-08 | 1992-04-24 | ||
| US5856497A (en) * | 1995-12-11 | 1999-01-05 | Boehringer Ingelheim Pharmaceuticals, Inc. | Asymmetric synthesis of α-cycloalkylalkyl substituted methanamines |
| US5670640A (en) * | 1996-02-02 | 1997-09-23 | Hoffmann-La Roche Inc. | Process for the manufacture of imidazodiazepine derivatives |
| AU3207297A (en) * | 1996-07-01 | 1998-01-21 | Pharmacia & Upjohn Company | Process for the production of 8-chloro-6-(2-fluorophenyl)-1-methyl-4h-imidazo{1,5-a}benzod iazepine |
| CN1384867A (zh) | 1999-08-27 | 2002-12-11 | 宝洁公司 | 稳定性提高的配制组分、使用该组分的组合物和洗衣方法 |
| US7109156B1 (en) | 1999-08-27 | 2006-09-19 | Procter & Gamble Company | Controlled availability of formulation components, compositions and laundry methods employing same |
| US6821935B1 (en) | 1999-08-27 | 2004-11-23 | Procter & Gamble Company | Color safe laundry methods employing zwitterionic formulation components |
| US6818607B1 (en) * | 1999-08-27 | 2004-11-16 | Procter & Gamble Company | Bleach boosting components, compositions and laundry methods |
| US6825160B1 (en) | 1999-08-27 | 2004-11-30 | Procter & Gamble Company | Color safe laundry methods employing cationic formulation components |
| BR0014153A (pt) * | 1999-08-27 | 2002-05-07 | Procter & Gamble | Componentes de intensificação de branqueamento, composições e métodos de lavagem |
| US6903060B1 (en) | 1999-08-27 | 2005-06-07 | Procter & Gamble Company | Stable formulation components, compositions and laundry methods employing same |
| BR0013610A (pt) * | 1999-08-27 | 2002-07-16 | Procter & Gamble | Componentes de formulções de ação rápida,composições e métodos para lavar roupa empregando os mesmos |
| US7169744B2 (en) * | 2002-06-06 | 2007-01-30 | Procter & Gamble Company | Organic catalyst with enhanced solubility |
| US7557076B2 (en) * | 2002-06-06 | 2009-07-07 | The Procter & Gamble Company | Organic catalyst with enhanced enzyme compatibility |
| US20050113246A1 (en) * | 2003-11-06 | 2005-05-26 | The Procter & Gamble Company | Process of producing an organic catalyst |
| AR051659A1 (es) * | 2005-06-17 | 2007-01-31 | Procter & Gamble | Una composicion que comprende un catalizador organico con compatibilidada enzimatica mejorada |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2721215A (en) * | 1952-06-12 | 1955-10-18 | Hoffmann La Rache Inc | Diphenylacetyl diamines |
| US2785200A (en) * | 1953-06-08 | 1957-03-12 | Abbott Lab | Dichlorobenzoyl-ethylenediamine |
| US2721214A (en) * | 1953-06-09 | 1955-10-18 | Parke Davis & Co | Process for producing acylamido diols |
| US3576868A (en) * | 1966-06-03 | 1971-04-27 | Hoffmann La Roche | Benzoyl amino ethyl aniline derivatives |
| US3501460A (en) * | 1966-06-03 | 1970-03-17 | Hoffmann La Roche | Dehydration process for forming benzodiazepines |
| US3577557A (en) * | 1966-12-09 | 1971-05-04 | Sandoz Ag | Benzo(1,5)diazocinones |
| US3723414A (en) * | 1970-02-13 | 1973-03-27 | Schering Corp | 1-polyfluoroalkyl benzodiazepines |
| DE2166116A1 (de) * | 1970-04-24 | 1973-02-15 | Teikoku Hormone Mfg Co Ltd | Verfahren zur herstellung von n-(dialkylaminoalkylen)-2-alkoxy(oder -alkenyloxy)4-amino-5-halogenbenzamiden |
| DK137857B (da) * | 1970-09-03 | 1978-05-22 | Takeda Chemical Industries Ltd | Analogifremgangsmåde til fremstilling af 2-amino-1,5-benzodiazocinderivater eller farmaceutisk acceptable salte deraf. |
| JPS4728284Y1 (no) * | 1970-09-14 | 1972-08-26 | ||
| US4021224A (en) * | 1971-12-09 | 1977-05-03 | Stauffer Chemical Company | Herbicide compositions |
| DE2265370C2 (de) * | 1972-05-03 | 1982-12-02 | Kali-Chemie Ag, 3000 Hannover | 6-Phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocinderivate |
| US3975443A (en) * | 1972-06-06 | 1976-08-17 | Allen & Hanburys Limited | 1-(3,4-dichlorobenzamidomethyl)-cyclohexyldimethylamine |
| GB1374366A (en) * | 1972-07-21 | 1974-11-20 | Science Union & Cie | Propanol derivatives and a process for their preparation |
| US3957870A (en) * | 1973-07-19 | 1976-05-18 | Imperial Chemical Industries Limited | Organic compounds |
-
1972
- 1972-05-03 DE DE2265370A patent/DE2265370C2/de not_active Expired
- 1972-05-03 DE DE2221558A patent/DE2221558C2/de not_active Expired
- 1972-05-03 DE DE2265371A patent/DE2265371C3/de not_active Expired
-
1973
- 1973-04-16 DD DD170247A patent/DD105222A5/xx unknown
- 1973-04-19 NL NLAANVRAGE7305570,A patent/NL179111C/xx not_active IP Right Cessation
- 1973-04-25 GB GB3581775A patent/GB1429667A/en not_active Expired
- 1973-04-25 GB GB2491075A patent/GB1429666A/en not_active Expired
- 1973-04-25 GB GB1974173A patent/GB1429665A/en not_active Expired
- 1973-04-26 CH CH1605577A patent/CH611607A5/xx not_active IP Right Cessation
- 1973-04-26 CH CH1605777A patent/CH611609A5/xx not_active IP Right Cessation
- 1973-04-26 CH CH598873A patent/CH605834A5/xx not_active IP Right Cessation
- 1973-04-26 CH CH1605677A patent/CH611608A5/xx not_active IP Right Cessation
- 1973-04-30 CA CA169,890A patent/CA984388A/en not_active Expired
- 1973-04-30 CA CA169,889A patent/CA1009232A/en not_active Expired
- 1973-05-01 IL IL47693A patent/IL47693A/xx unknown
- 1973-05-01 IL IL42158A patent/IL42158A/xx unknown
- 1973-05-01 IL IL48141A patent/IL48141A/xx unknown
- 1973-05-01 US US05/355,986 patent/US3998809A/en not_active Expired - Lifetime
- 1973-05-01 JP JP4900373A patent/JPS5541231B2/ja not_active Expired
- 1973-05-02 SE SE7306128A patent/SE409709B/sv unknown
- 1973-05-02 FR FR7315752A patent/FR2183735B1/fr not_active Expired
- 1973-05-02 NO NO1797/73A patent/NO142866C/no unknown
- 1973-05-02 DK DK238573A patent/DK147050C/da not_active IP Right Cessation
- 1973-05-02 ES ES414279A patent/ES414279A1/es not_active Expired
- 1973-05-02 BE BE130663A patent/BE799001A/xx not_active IP Right Cessation
- 1973-05-03 SU SU731918571A patent/SU625607A3/ru active
- 1973-05-03 SU SU1920527A patent/SU526290A3/ru active
- 1973-05-03 AT AT389873A patent/AT327919B/de not_active IP Right Cessation
- 1973-05-03 AT AT143875*1A patent/AT327927B/de not_active IP Right Cessation
- 1973-05-03 AT AT389973A patent/AT327920B/de not_active IP Right Cessation
- 1973-05-03 ZA ZA733013A patent/ZA733013B/xx unknown
-
1974
- 1974-12-19 FR FR7442122A patent/FR2248278B1/fr not_active Expired
-
1975
- 1975-04-16 NO NO75751349A patent/NO145761C/no unknown
- 1975-07-11 IL IL47693A patent/IL47693A0/xx unknown
- 1975-09-19 IL IL48141A patent/IL48141A0/xx unknown
-
1976
- 1976-04-02 FR FR7609742A patent/FR2296616A1/fr active Granted
- 1976-05-07 NO NO76761580A patent/NO143347C/no unknown
- 1976-05-12 US US05/685,537 patent/US4096141A/en not_active Expired - Lifetime
- 1976-09-02 CA CA260,433A patent/CA1020570A/en not_active Expired
- 1976-09-23 US US05/725,989 patent/US4098786A/en not_active Expired - Lifetime
- 1976-10-04 US US05/729,142 patent/US4216167A/en not_active Expired - Lifetime
- 1976-12-29 SE SE7614681A patent/SE7614681L/xx not_active Application Discontinuation
- 1976-12-29 SE SE7614680A patent/SE422460B/xx unknown
-
1977
- 1977-05-20 DK DK222977A patent/DK144969C/da not_active IP Right Cessation
- 1977-05-20 DK DK223077A patent/DK223077A/da unknown
- 1977-12-09 JP JP52148667A patent/JPS5813535B2/ja not_active Expired
- 1977-12-09 JP JP52148666A patent/JPS589101B2/ja not_active Expired
-
1978
- 1978-01-01 CH CH1605877A patent/CH620423A5/de not_active IP Right Cessation
- 1978-01-23 US US05/871,741 patent/US4243585A/en not_active Expired - Lifetime
- 1978-02-06 NO NO780402A patent/NO142476C/no unknown
-
1979
- 1979-09-19 NO NO793013A patent/NO144885C/no unknown
- 1979-09-19 NO NO793012A patent/NO144386C/no unknown
-
1984
- 1984-04-24 US US06/602,279 patent/US4595531A/en not_active Expired - Fee Related
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