FI68816C - Foerfarande foer framstaellning av nya terapeutiskt anvaendbara bensodiazepinderivat - Google Patents

Foerfarande foer framstaellning av nya terapeutiskt anvaendbara bensodiazepinderivat Download PDF

Info

Publication number: FI68816C
Authority: FI; Finland
Prior art keywords: formula; dihydro; fluorophenyl; methyl; benzodiazepin
Prior art date: 1978-08-11

Application number

FI792482A

Other languages

English (en)

Finnish (fi)

Other versions

FI792482A (fi

FI68816B (fi

Inventor

Albert Eduard Fischli

Andre Szente

Original Assignee

Hoffmann La Roche

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1978-08-11

Filing date

1979-08-09

Publication date

1985-11-11

1979-08-09 Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche

1980-02-12 Publication of FI792482A publication Critical patent/FI792482A/fi

1985-07-31 Application granted granted Critical

1985-07-31 Publication of FI68816B publication Critical patent/FI68816B/fi

1985-11-11 Publication of FI68816C publication Critical patent/FI68816C/fi

Links

238000000034 method Methods 0.000 title claims description 52
230000001225 therapeutic effect Effects 0.000 title claims 3
150000001875 compounds Chemical class 0.000 claims description 208
239000000203 mixture Substances 0.000 claims description 130
-1 amino compound Chemical class 0.000 claims description 88
125000000217 alkyl group Chemical group 0.000 claims description 48
125000006239 protecting group Chemical group 0.000 claims description 39
229910052739 hydrogen Inorganic materials 0.000 claims description 36
239000001257 hydrogen Substances 0.000 claims description 35
238000002360 preparation method Methods 0.000 claims description 35
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 28
239000012948 isocyanate Substances 0.000 claims description 23
150000002513 isocyanates Chemical class 0.000 claims description 23
229940053197 benzodiazepine derivative antiepileptics Drugs 0.000 claims description 21
239000002253 acid Substances 0.000 claims description 20
229910052736 halogen Inorganic materials 0.000 claims description 18
150000002367 halogens Chemical group 0.000 claims description 18
150000003839 salts Chemical class 0.000 claims description 14
125000003710 aryl alkyl group Chemical group 0.000 claims description 12
125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
125000000623 heterocyclic group Chemical group 0.000 claims description 11
125000005041 acyloxyalkyl group Chemical group 0.000 claims description 10
125000003118 aryl group Chemical group 0.000 claims description 10
229940049706 benzodiazepine Drugs 0.000 claims description 8
239000000460 chlorine Chemical group 0.000 claims description 8
150000004820 halides Chemical class 0.000 claims description 8
125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 7
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
229910052801 chlorine Chemical group 0.000 claims description 7
125000002768 hydroxyalkyl group Chemical group 0.000 claims description 7
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 claims description 5
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
125000004069 aziridinyl group Chemical group 0.000 claims description 5
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
229910052794 bromium Inorganic materials 0.000 claims description 5
229910052731 fluorine Inorganic materials 0.000 claims description 5
239000011737 fluorine Substances 0.000 claims description 5
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
229910052757 nitrogen Inorganic materials 0.000 claims description 5
229910052760 oxygen Inorganic materials 0.000 claims description 5
239000001301 oxygen Substances 0.000 claims description 5
229910052717 sulfur Inorganic materials 0.000 claims description 5
125000004432 carbon atom Chemical group C* 0.000 claims description 4
MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 3
125000002947 alkylene group Chemical group 0.000 claims description 3
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
125000001153 fluoro group Chemical group F* 0.000 claims description 3
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
125000004434 sulfur atom Chemical group 0.000 claims description 3
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
239000011593 sulfur Substances 0.000 claims description 2
125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 claims 10
125000004122 cyclic group Chemical group 0.000 claims 1
238000009472 formulation Methods 0.000 claims 1
125000001424 substituent group Chemical class 0.000 claims 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 360
239000000243 solution Substances 0.000 description 166
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 145
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RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 63
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 54
239000000741 silica gel Substances 0.000 description 54
229910002027 silica gel Inorganic materials 0.000 description 54
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 51
150000001557 benzodiazepines Chemical class 0.000 description 50
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 48
229910052938 sodium sulfate Inorganic materials 0.000 description 47
235000011152 sodium sulphate Nutrition 0.000 description 47
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 46
238000006243 chemical reaction Methods 0.000 description 40
125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 39
239000011541 reaction mixture Substances 0.000 description 36
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HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 25
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
229910000030 sodium bicarbonate Inorganic materials 0.000 description 22
235000017557 sodium bicarbonate Nutrition 0.000 description 22
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
241001465754 Metazoa Species 0.000 description 20
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 20
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 19
LTCDLGUFORGHGY-UHFFFAOYSA-N 7-Aminoflunitrazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(N)C=C2C=1C1=CC=CC=C1F LTCDLGUFORGHGY-UHFFFAOYSA-N 0.000 description 18
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
239000004202 carbamide Substances 0.000 description 16
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 14
235000012000 cholesterol Nutrition 0.000 description 13
239000000284 extract Substances 0.000 description 13
239000012074 organic phase Substances 0.000 description 13
238000003756 stirring Methods 0.000 description 13
NZOMAPGMBUKISS-UHFFFAOYSA-N 7-amino-6-chloro-5-(2-fluorophenyl)-1-methyl-3h-1,4-benzodiazepin-2-one Chemical compound N=1CC(=O)N(C)C2=CC=C(N)C(Cl)=C2C=1C1=CC=CC=C1F NZOMAPGMBUKISS-UHFFFAOYSA-N 0.000 description 12
229960000583 acetic acid Drugs 0.000 description 12
238000001816 cooling Methods 0.000 description 12
238000002425 crystallisation Methods 0.000 description 12
230000008025 crystallization Effects 0.000 description 12
KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 11
CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 11
239000007864 aqueous solution Substances 0.000 description 11
SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 11
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 10
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 10
239000003208 petroleum Substances 0.000 description 10
229910000027 potassium carbonate Inorganic materials 0.000 description 10
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 9
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229960002478 aldosterone Drugs 0.000 description 9
HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 9
239000012362 glacial acetic acid Substances 0.000 description 9
210000002700 urine Anatomy 0.000 description 9
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
125000002252 acyl group Chemical group 0.000 description 8
238000002329 infrared spectrum Methods 0.000 description 8
GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 8
239000003960 organic solvent Substances 0.000 description 8
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
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ZOEAIPZRKHTZAG-UHFFFAOYSA-N 1-[5-(2-fluorophenyl)-1-methyl-2-oxo-3h-1,4-benzodiazepin-7-yl]-3-(2-hydroxyethyl)urea Chemical compound N=1CC(=O)N(C)C2=CC=C(NC(=O)NCCO)C=C2C=1C1=CC=CC=C1F ZOEAIPZRKHTZAG-UHFFFAOYSA-N 0.000 description 6
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229910021626 Tin(II) chloride Inorganic materials 0.000 description 6
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230000002378 acidificating effect Effects 0.000 description 6
125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 6
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239000000126 substance Substances 0.000 description 6
TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 5
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125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 4
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238000002474 experimental method Methods 0.000 description 4
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239000001828 Gelatine Substances 0.000 description 3
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230000003042 antagnostic effect Effects 0.000 description 3
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239000012043 crude product Substances 0.000 description 3
NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 3
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239000000839 emulsion Substances 0.000 description 1
150000002170 ethers Chemical class 0.000 description 1
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229960003750 ethyl chloride Drugs 0.000 description 1
WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 description 1
238000001125 extrusion Methods 0.000 description 1
239000000945 filler Substances 0.000 description 1
239000000706 filtrate Substances 0.000 description 1
239000012467 final product Substances 0.000 description 1
239000000796 flavoring agent Substances 0.000 description 1
125000006332 fluoro benzoyl group Chemical group 0.000 description 1
235000013305 food Nutrition 0.000 description 1
235000013355 food flavoring agent Nutrition 0.000 description 1
235000003599 food sweetener Nutrition 0.000 description 1
239000007789 gas Substances 0.000 description 1
239000008103 glucose Substances 0.000 description 1
125000005843 halogen group Chemical group 0.000 description 1
230000002140 halogenating effect Effects 0.000 description 1
238000010438 heat treatment Methods 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
229930195733 hydrocarbon Natural products 0.000 description 1
150000002431 hydrogen Chemical class 0.000 description 1
229910000039 hydrogen halide Inorganic materials 0.000 description 1
239000012433 hydrogen halide Substances 0.000 description 1
XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
230000003301 hydrolyzing effect Effects 0.000 description 1
150000002440 hydroxy compounds Chemical class 0.000 description 1
239000012535 impurity Substances 0.000 description 1
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239000002198 insoluble material Substances 0.000 description 1
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IQPQWNKOIGAROB-UHFFFAOYSA-N isocyanate group Chemical group [N-]=C=O IQPQWNKOIGAROB-UHFFFAOYSA-N 0.000 description 1
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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239000008101 lactose Substances 0.000 description 1
229910052943 magnesium sulfate Inorganic materials 0.000 description 1
235000019341 magnesium sulphate Nutrition 0.000 description 1
238000005259 measurement Methods 0.000 description 1
239000002609 medium Substances 0.000 description 1
125000005905 mesyloxy group Chemical group 0.000 description 1
230000004060 metabolic process Effects 0.000 description 1
125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
150000007522 mineralic acids Chemical class 0.000 description 1
239000012452 mother liquor Substances 0.000 description 1
YNTOKMNHRPSGFU-UHFFFAOYSA-N n-Propyl carbamate Chemical compound CCCOC(N)=O YNTOKMNHRPSGFU-UHFFFAOYSA-N 0.000 description 1
RCKPQOQGGFHDHC-UHFFFAOYSA-N n-[5-(2-fluorophenyl)-1-methyl-2-oxo-3h-1,4-benzodiazepin-7-yl]-1,3-thiazolidine-3-carboxamide Chemical compound C1=C2C(C=3C(=CC=CC=3)F)=NCC(=O)N(C)C2=CC=C1NC(=O)N1CCSC1 RCKPQOQGGFHDHC-UHFFFAOYSA-N 0.000 description 1
WSDUPOSYTDCEIF-UHFFFAOYSA-N n-[5-(2-fluorophenyl)-1-methyl-2-oxo-3h-1,4-benzodiazepin-7-yl]aziridine-1-carboxamide Chemical compound C1=C2C(C=3C(=CC=CC=3)F)=NCC(=O)N(C)C2=CC=C1NC(=O)N1CC1 WSDUPOSYTDCEIF-UHFFFAOYSA-N 0.000 description 1
XJKXIYHHYJLJGD-UHFFFAOYSA-N n-[5-(2-fluorophenyl)-1-methyl-2-oxo-3h-1,4-benzodiazepin-7-yl]pyrrolidine-1-carboxamide Chemical compound C1=C2C(C=3C(=CC=CC=3)F)=NCC(=O)N(C)C2=CC=C1NC(=O)N1CCCC1 XJKXIYHHYJLJGD-UHFFFAOYSA-N 0.000 description 1
IDEFUHYYFDUQMY-UHFFFAOYSA-N n-[6-chloro-5-(2-fluorophenyl)-1-methyl-2-oxo-3h-1,4-benzodiazepin-7-yl]-4-methylpiperazine-1-carboxamide Chemical compound C1CN(C)CCN1C(=O)NC1=CC=C(N(C)C(=O)CN=C2C=3C(=CC=CC=3)F)C2=C1Cl IDEFUHYYFDUQMY-UHFFFAOYSA-N 0.000 description 1
SQKFWZPXZMZLSL-UHFFFAOYSA-N n-[6-chloro-5-(2-fluorophenyl)-1-methyl-2-oxo-3h-1,4-benzodiazepin-7-yl]morpholine-4-carboxamide Chemical compound ClC1=C2C(C=3C(=CC=CC=3)F)=NCC(=O)N(C)C2=CC=C1NC(=O)N1CCOCC1 SQKFWZPXZMZLSL-UHFFFAOYSA-N 0.000 description 1
TYRGLVWXHJRKMT-QMMMGPOBSA-N n-benzyloxycarbonyl-l-serine-betalactone Chemical compound OC(=O)[C@H](C)NC(=O)OCC1=CC=CC=C1 TYRGLVWXHJRKMT-QMMMGPOBSA-N 0.000 description 1
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
230000007935 neutral effect Effects 0.000 description 1
150000002828 nitro derivatives Chemical class 0.000 description 1
QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
150000004027 organic amino compounds Chemical group 0.000 description 1
150000007530 organic bases Chemical class 0.000 description 1
239000008012 organic excipient Substances 0.000 description 1
230000003204 osmotic effect Effects 0.000 description 1
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
229910052763 palladium Inorganic materials 0.000 description 1
239000003755 preservative agent Substances 0.000 description 1
230000002265 prevention Effects 0.000 description 1
230000002035 prolonged effect Effects 0.000 description 1
210000003689 pubic bone Anatomy 0.000 description 1
125000001453 quaternary ammonium group Chemical group 0.000 description 1
238000011084 recovery Methods 0.000 description 1
238000007142 ring opening reaction Methods 0.000 description 1
229930195734 saturated hydrocarbon Natural products 0.000 description 1
230000001624 sedative effect Effects 0.000 description 1
238000000926 separation method Methods 0.000 description 1
HUAUNKAZQWMVFY-UHFFFAOYSA-M sodium;oxocalcium;hydroxide Chemical compound [OH-].[Na+].[Ca]=O HUAUNKAZQWMVFY-UHFFFAOYSA-M 0.000 description 1
239000003381 stabilizer Substances 0.000 description 1
239000008117 stearic acid Substances 0.000 description 1
238000010254 subcutaneous injection Methods 0.000 description 1
239000007929 subcutaneous injection Substances 0.000 description 1
KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
239000005720 sucrose Substances 0.000 description 1
238000001356 surgical procedure Methods 0.000 description 1
239000003765 sweetening agent Substances 0.000 description 1
239000006188 syrup Substances 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
239000000454 talc Substances 0.000 description 1
229910052623 talc Inorganic materials 0.000 description 1
235000021195 test diet Nutrition 0.000 description 1
238000010998 test method Methods 0.000 description 1
JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
238000004809 thin layer chromatography Methods 0.000 description 1
BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical group C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
230000036325 urinary excretion Effects 0.000 description 1
238000005303 weighing Methods 0.000 description 1
229910052725 zinc Inorganic materials 0.000 description 1
239000011701 zinc Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)

FI792482A 1978-08-11 1979-08-09 Foerfarande foer framstaellning av nya terapeutiskt anvaendbara bensodiazepinderivat FI68816C (fi)

Applications Claiming Priority (6)

Application Number	Priority Date	Filing Date	Title
CH856378		1978-08-11
CH856378		1978-08-11
CH527079		1979-06-06
CH527079		1979-06-06
CH629679		1979-07-05
CH629679		1979-07-05

Publications (3)

Publication Number	Publication Date
FI792482A FI792482A (fi)	1980-02-12
FI68816B FI68816B (fi)	1985-07-31
FI68816C true FI68816C (fi)	1985-11-11

Family

ID=27175157

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
FI792482A FI68816C (fi)	1978-08-11	1979-08-09	Foerfarande foer framstaellning av nya terapeutiskt anvaendbara bensodiazepinderivat

Country Status (19)

Country	Link
US (3)	US4294758A (pt)
EP (1)	EP0008421B1 (pt)
AR (1)	AR226541A1 (pt)
AU (1)	AU528800B2 (pt)
BR (1)	BR7905173A (pt)
CA (1)	CA1114373A (pt)
CU (1)	CU21116A (pt)
DD (1)	DD145533A5 (pt)
DE (1)	DE2966639D1 (pt)
DK (1)	DK336379A (pt)
FI (1)	FI68816C (pt)
GR (1)	GR72263B (pt)
HU (1)	HU182499B (pt)
IL (1)	IL57989A (pt)
MC (1)	MC1279A1 (pt)
NO (1)	NO792615L (pt)
NZ (1)	NZ191224A (pt)
PH (1)	PH16128A (pt)
PT (1)	PT70056A (pt)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
CA1163266A (en) *	1980-07-31	1984-03-06	Albert E. Fischli	Benzodiazepine derivatives
CA1157855A (en) *	1980-07-31	1983-11-29	Albert E. Fischli	Benzodiazepine derivatives
CA1202023A (en) *	1982-01-19	1986-03-18	Jean-Marie Cassal	Benzodiazepines
US5432700A (en) *	1992-12-21	1995-07-11	Ford Motor Company	Adaptive active vehicle suspension system
WO2000034267A1 (fr) *	1998-12-04	2000-06-15	Takeda Chemical Industries, Ltd.	Procede de production d'un compose d'amide cyclique

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US3329701A (en) *	1962-06-14	1967-07-04	Hoffmann La Roche	Cyanobenzophenones
BE787117A (fr) *	1971-08-04	1973-02-05	Hoffmann La Roche	Derives de benzodiazepine
JPS5418269B2 (pt) *	1972-07-20	1979-07-06
JPS5084590A (pt) *	1973-11-28	1975-07-08
US4141895A (en) *	1977-06-16	1979-02-27	E. I. Du Pont De Nemours And Company	Hydroxyquinazolines and their use as intermediates for pharmaceutical agents

1979
- 1979-07-23 CA CA332,382A patent/CA1114373A/en not_active Expired
- 1979-08-03 AU AU49569/79A patent/AU528800B2/en not_active Ceased
- 1979-08-06 IL IL57989A patent/IL57989A/xx unknown
- 1979-08-06 NZ NZ191224A patent/NZ191224A/en unknown
- 1979-08-07 MC MC791399A patent/MC1279A1/xx unknown
- 1979-08-09 FI FI792482A patent/FI68816C/fi not_active IP Right Cessation
- 1979-08-09 GR GR59804A patent/GR72263B/el unknown
- 1979-08-10 NO NO792615A patent/NO792615L/no unknown
- 1979-08-10 DD DD79214920A patent/DD145533A5/de unknown
- 1979-08-10 AR AR277682A patent/AR226541A1/es active
- 1979-08-10 PT PT70056A patent/PT70056A/pt unknown
- 1979-08-10 PH PH22885A patent/PH16128A/en unknown
- 1979-08-10 EP EP79102899A patent/EP0008421B1/de not_active Expired
- 1979-08-10 DE DE7979102899T patent/DE2966639D1/de not_active Expired
- 1979-08-10 HU HU79HO2171A patent/HU182499B/hu unknown
- 1979-08-10 DK DK336379A patent/DK336379A/da not_active Application Discontinuation
- 1979-08-10 BR BR7905173A patent/BR7905173A/pt unknown
- 1979-08-11 CU CU7935123A patent/CU21116A/es unknown
1980
- 1980-09-11 US US06/186,094 patent/US4294758A/en not_active Expired - Lifetime
- 1980-09-11 US US06/186,061 patent/US4296031A/en not_active Expired - Lifetime
- 1980-09-11 US US06/186,051 patent/US4281188A/en not_active Expired - Lifetime

Also Published As

Publication number	Publication date
DD145533A5 (de)	1980-12-17
FI792482A (fi)	1980-02-12
AU528800B2 (en)	1983-05-12
NO792615L (no)	1980-02-12
HU182499B (en)	1984-01-30
EP0008421B1 (de)	1984-02-08
BR7905173A (pt)	1980-04-22
FI68816B (fi)	1985-07-31
GR72263B (pt)	1983-10-10
IL57989A (en)	1982-11-30
IL57989A0 (en)	1979-12-30
CU21116A (es)	1982-08-24
PT70056A (en)	1979-09-01
CA1114373A (en)	1981-12-15
EP0008421A3 (en)	1980-05-28
US4294758A (en)	1981-10-13
PH16128A (en)	1983-07-08
DK336379A (da)	1980-02-12
NZ191224A (en)	1984-07-06
DE2966639D1 (en)	1984-03-15
AR226541A1 (es)	1982-07-30
MC1279A1 (fr)	1980-05-23
US4281188A (en)	1981-07-28
US4296031A (en)	1981-10-20
EP0008421A2 (de)	1980-03-05
AU4956979A (en)	1980-02-14

Publication	Publication Date	Title
US5569654A (en)	1996-10-29	Benzodiazepinones
BG98881A (bg)	1995-03-31	Производни на 1,5-бензодиазепина
HU186584B (en)	1985-08-28	Process for producing new benzodiazepine derivatives
US4377522A (en)	1983-03-22	Benzodiazepine derivatives
US4327026A (en)	1982-04-27	Benzodiazepine derivatives
US4153789A (en)	1979-05-08	Phenylindolines
FI68816C (fi)	1985-11-11	Foerfarande foer framstaellning av nya terapeutiskt anvaendbara bensodiazepinderivat
CZ17396A3 (en)	1996-07-17	1,5-benzodiazepine derivatives, their use, process of their preparation and pharmaceutical compositions containing thereof
CA1152066A (en)	1983-08-16	Benzodiazepine derivatives
US4361511A (en)	1982-11-30	Benzodiazepine derivatives
AU688316B2 (en)	1998-03-12	1,5 benzodiazepine derivatives having CCK and/or gastrin antagonistic activity
US4251443A (en)	1981-02-17	Benzodiazepine derivatives
FI82454B (fi)	1990-11-30	Foerfarande foer framstaellning av terapeutiskt aktiva iminotiazolidinderivat.
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2004-08-31	MM	Patent lapsed	Owner name: F. HOFFMANN-LA ROCHE & CO.