NO127302B - - Google Patents
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- Publication number
- NO127302B NO127302B NO04614/69A NO461469A NO127302B NO 127302 B NO127302 B NO 127302B NO 04614/69 A NO04614/69 A NO 04614/69A NO 461469 A NO461469 A NO 461469A NO 127302 B NO127302 B NO 127302B
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- Prior art keywords
- alkyl
- compound
- hydrogen
- lower alkyl
- phenyl
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 17
- 229940049706 benzodiazepine Drugs 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical group 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 229910052987 metal hydride Inorganic materials 0.000 claims description 3
- 150000004681 metal hydrides Chemical class 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 150000004678 hydrides Chemical class 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 125000000468 ketone group Chemical group 0.000 claims description 2
- 125000001624 naphthyl group Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 4
- 239000003513 alkali Substances 0.000 claims 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 claims 1
- 238000006266 etherification reaction Methods 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- -1 ethoxy, propoxy Chemical group 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 238000012360 testing method Methods 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 230000037396 body weight Effects 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000003158 myorelaxant agent Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 230000001773 anti-convulsant effect Effects 0.000 description 2
- 239000002249 anxiolytic agent Substances 0.000 description 2
- 230000000949 anxiolytic effect Effects 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000000932 sedative agent Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000379208 Latris Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229940005530 anxiolytics Drugs 0.000 description 1
- DXZDEAJXVCLRLE-UHFFFAOYSA-N azepin-2-one Chemical compound O=C1C=CC=CC=N1 DXZDEAJXVCLRLE-UHFFFAOYSA-N 0.000 description 1
- 150000001557 benzodiazepines Chemical class 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
- QLFNUXTWJGXNLH-UHFFFAOYSA-N bis(2-methoxyethoxy)alumane Chemical compound COCCO[AlH]OCCOC QLFNUXTWJGXNLH-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 239000005554 hypnotics and sedatives Substances 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229940035363 muscle relaxants Drugs 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229960005152 pentetrazol Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 230000004799 sedative–hypnotic effect Effects 0.000 description 1
- 206010040560 shock Diseases 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- MDDPTCUZZASZIQ-UHFFFAOYSA-N tris[(2-methylpropan-2-yl)oxy]alumane Chemical compound [Al+3].CC(C)(C)[O-].CC(C)(C)[O-].CC(C)(C)[O-] MDDPTCUZZASZIQ-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil 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
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
- B65B51/00—Devices for, or methods of, sealing or securing package folds or closures; Devices for gathering or twisting wrappers, or necks of bags
- B65B51/04—Applying separate sealing or securing members, e.g. clips
- B65B51/06—Applying adhesive tape
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Mechanical Engineering (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Fremgangsmåte ved fremstilling av terapeutisk virksomme Procedure for the production of therapeutically active
1-substituerte 2-oxy-2,3-dihydro-5-aryl-lH-l,4-benzodiazepiner.1-Substituted 2-oxy-2,3-dihydro-5-aryl-1H-1,4-benzodiazepines.
Foreliggende oppfinnelse angår en ny fremgangsmåte ved fremstilling av 1-substituer te 2-oxy-2,3-dihydro-5-aryl-lH-l ^-benzodiar.epiner. The present invention relates to a new process for the production of 1-substituted 2-oxy-2,3-dihydro-5-aryl-1H-1,2-benzodiar.epines.
Fra Chem. Rev. 68 side" 766 . (1968) er det kjent å redusere 1- From Chem. Fox. 68 page" 766 . (1968) it is known to reduce 1-
usubstituerte 5-aryl-lH-l,<1>+-benzodiazepin-2-oner til 1-usubsti tuer te 5-aryl-lH-l^-benzod.iazepiner eller et tilsvarende tetrahydroderivat. unsubstituted 5-aryl-1H-1,<1>+-benzodiazepine-2-ones to 1-unsubstituted 5-aryl-1H-1^-benzodiazepines or a corresponding tetrahydro derivative.
I motsetning til dette er det nå ganske overraskende funnet at 5-aryl-lH-l ,lf-benzodiazepin-2-oner med en substituent L I-stilling, In contrast, it has now been rather surprisingly found that 5-aryl-1H-1,1f-benzodiazepine-2-ones with a substituent L I position,
selektivt kan reduseres til de tilsvarende 2-hydroxyforbindelser. can be selectively reduced to the corresponding 2-hydroxy compounds.
De benzodiazepiher som erholdes Ifolge fremgangsmåten er forbindelser The benzodiazepines obtained according to the method are compounds
av den generelle formel of the general formula
og farmasøytisk: akseptable -salter derav, . and pharmaceutical: acceptable -salts thereof, .
hvor X er-.hydrogen, halogen, -'tri fluormethyl, ni tro,, hydroxyl, lavere-alkyl eller laverealkoxy,.- R-^ er lavere al kyl poi.yf lubr-lavere-alkyl-, f enyl-låvere-alkyl r lavere cycloalkyT,. layer.e-cyclo.alkyl-lavere-.aikyl, where X is -.hydrogen, halogen, -'trifluoromethyl, ni tro,, hydroxyl, lower-alkyl or lower alkoxy,.--^ is lower alkyl poly.yf lubr-lower-alkyl-, phenyl-lower- alkyl r lower cycloalkyT,. layer.e-cyclo.alkyl-lower-.aikyl,
lavere alkenyl eller amino-lavere-alkyl,idet. aminogruppen kan være lower alkenyl or amino-lower-alkyl, ie. the amino group can be
substituert, med en eller flere ...lavere alkylgrupper, er hydrogen, lavere alkyl,-hydroxyl eller lavere alkanoyloxy, R^ er fenyl, X-substituert fenyl, nafthyl," thienyl eller ..pyrryl,, ogVR^ er hydrogen, lavere alkyl e L i or.. substituted, with one or more ...lower alkyl groups, is hydrogen, lower alkyl, -hydroxyl or lower alkanoyloxy, R^ is phenyl, X-substituted phenyl, naphthyl," thienyl, or ..pyrryl,, and VR^ is hydrogen, lower alkyl e L i or..
hvor r. 6r 0 eller i og .R^ og R^ er hydrogen eller lavere alkyl, og hvor m er 0 eller 1. ..betegnelsen "lavere alkyl" referer seg både til rettkjedede og forgrenede mettede hydro.carbonradikaler med. inntil 6 carbonatomer. Foretrukne lavere alkylgrupper methyl, ethyl, propyl,' isopiropyl, n-butyl og i.bu ly i. where r. 6r 0 or i and .R^ and R^ are hydrogen or lower alkyl, and where m is 0 or 1. ..the term "lower alkyl" refers to both straight-chain and branched saturated hydrocarbon radicals with. up to 6 carbon atoms. Preferred lower alkyl groups methyl, ethyl, propyl,' isopyrropyl, n-butyl and i.bu ly i.
På tilsvarende rnå-te betegner "lavere alkenyl" rettkjedede og In the corresponding sense, "lower alkenyl" denotes straight-chain and
■ forgrenede olefiniske hydrocarbonradikaler med inntil.6 carbonatomer, såsom f.eks. 1-propenyl, 2-i sopropenyl., 2-butenyl, 3'-butenyl og 2-i. sopentenyl. letegne1 sene "lavere cycloalkyl" og "lavere-cycloalkyl-lavere-alkyl" er begrensede på tilsvarende måte og illu-r;trer';S f.oks. ved eyolopentyl, cycl ohexyl. og cyclopropylmethyi.. Tilsvarende illustreres betegnelsen "fenyl-lavere-alkyl" ved fen-et hyl og.benzyl. "Lavere -alkoxy" betegner etherradikaler i hvilke den la v.-r o a'! kyl gruppe er som definert for "lavere alkyl" ovenfor, såsom V. ek r.;, rnethoxy, ethoxy, propoxy og lignende. "Lavere alkanoyloxy" betegner de. syre rad i.kal er som er avledet fra alkansyrer med inntil. 6 car bon atom- r og omfatter således rad i kai er såsom f o-r myl, ■ branched olefinic hydrocarbon radicals with up to 6 carbon atoms, such as e.g. 1-propenyl, 2-i isopropenyl., 2-butenyl, 3'-butenyl and 2-i. sopentenyl. The figures "lower cycloalkyl" and "lower-cycloalkyl-lower-alkyl" are similarly limited and illustrate, e.g. by eylopentyl, cycl ohexyl. and cyclopropylmethyl.. Similarly, the term "phenyl-lower-alkyl" is illustrated by phen-et hyl and.benzyl. "Lower -Alkoxy" denotes ether radicals in which the la v.-r o a'! kyl group is as defined for "lower alkyl" above, such as V. ek r.;, rnethoxy, ethoxy, propoxy and the like. "Lower alkanoyloxy" they denote. acid rad i.kal is which is derived from alkanoic acids with up to. 6 carbon atoms and thus includes row i kai is such as f o-r myl,
•:/:':;.;/ : , propionyl, but.yry] , ■ valeryi, hexanoyl og de "forgrenede i so- •:/:':;.;/ : , propionyl, but.yry] , ■ valeryi, hexanoyl and the "branched in so-
mere av disse, .ietegnelsen "halogen" innbefatter samtlige fire halo-gener, enn skjont klor foretrekkes. I foretrukne forbindelser erholdt ved fremgangsmåten er X en 7-klorsubstituerit-.'- more of these, the term "halogen" includes all four halogens, although chlorine is preferred. In preferred compounds obtained by the process, X is a 7-chloro-substituted
Betegnelsen "polyfluor-lavere-alkyl" referer seg til lavere alkylradikaler som er substituert med flere enn ett fluoratom, og innbefatter radikaler såsom 2,2,2-trifluoretnyl, trifluormethyl, 2,2,3,3,3-pentafluorpropyi og lignende. I foretrukne forbindelser har polyfluor-laverealkyl-radikalet to a-hydrogenatomer, The term "polyfluoro-lower alkyl" refers to lower alkyl radicals substituted with more than one fluorine atom, and includes radicals such as 2,2,2-trifluoroethnyl, trifluoromethyl, 2,2,3,3,3-pentafluoropropyl and the like. In preferred compounds, the polyfluoro-lower alkyl radical has two α-hydrogen atoms,
og kan således illustreres ved R^CH^ hvor R^. er polyfluoralkyl. Aller helst e.r R^ trifluormethyl, såsom i de l-(2,2,2-trifluorethyl)-substituerte forbindelser. and can thus be illustrated by R^CH^ where R^. is polyfluoroalkyl. Most preferably, R 1 is trifluoromethyl, as in the 1-(2,2,2-trifluoroethyl)-substituted compounds.
De i farmasoytisk henseende aksepterbare salter innbefatter de som dannes med såvel uorganiske som organiske syrer, såsom f.eks._ saltsyre, bromhydrogehsyre, salpetersyre, svovelsyre, eddiksyre, maursyre, ravsyre, maleinsyre, p-toluensulfonsyre og lignende. The pharmaceutically acceptable salts include those formed with both inorganic and organic acids, such as, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, acetic acid, formic acid, succinic acid, maleic acid, p-toluenesulfonic acid and the like.
I opplosning kan 2-hydroxy-forbindelsene som fremstilles ved fremgangsmåten, ifolge oppfinnelsen, best representeres ved den ved formel II angitte struktur, idet det eksisterer en likevekt mellom denne 2-hydroxy-form og 2,5-oxy-formen (III) som inneholder en bro. In solution, the 2-hydroxy compounds produced by the method according to the invention can best be represented by the structure indicated by formula II, as there is an equilibrium between this 2-hydroxy form and the 2,5-oxy form (III) which contains a bridge.
Når' forbindelsen foreligger i fast tilstand, kan likevekten være forskjovet i retning av 2, 5- oxy-formen. Når det i det nedenstående refereres til 2-hydroxy-forbindelseneifolge oppfinnelsen, siktes det til forbindelser som kan ha enten formel II eller formel III. When the compound is in the solid state, the equilibrium may be shifted in the direction of the 2,5-oxy form. In the following, when reference is made to 2-hydroxy compounds according to the invention, this means compounds which can have either formula II or formula III.
Den nye fremgangsmåte ifolge oppfinnelsen for fremstilling av forbindelser av formel I er karakterisert ved en forbindelse av den generelle formel IV. The new process according to the invention for producing compounds of formula I is characterized by a compound of the general formula IV.
hvor X, , R^ i ^-z °S m er som ovenfor angitt, underkastes reduksjon av ketogruppen med et komplekst metall hydrid. Den derved erholdte forbindelse av formel I, som har'en fri hydroxylgruppe i 2-stillingen, kan deretter om onskes forethres til den tilsvarende forbindelse av formel I hvor R^ er lavere alkyl eller En foretrukken utforelsesform av denne fremgangsmåte går ut på at man tilsetter et lithiumaluminiumhydrid i et egnet inert opplosningsmiddel, såsom tetrahydrofuran eller ether,_til det tilsvarende 2,3-dihydro-2-oxo-5-aryl-lH-l ,>+-benzodiazepin ved lavere temperaturer,, f.eks.' ved temperaturer omkring 0°C. Reaksjonen kan illustreres ved den f51gende reaksjonsligning: where X, , R^ i ^-z °S m is as indicated above, is subjected to reduction of the keto group with a complex metal hydride. The thereby obtained compound of formula I, which has a free hydroxyl group in the 2-position, can then, if desired, be etherified to the corresponding compound of formula I where R^ is lower alkyl or A preferred embodiment of this method involves adding a lithium aluminum hydride in a suitable inert solvent, such as tetrahydrofuran or ether, to the corresponding 2,3-dihydro-2-oxo-5-aryl-1H-1,>+-benzodiazepine at lower temperatures, e.g. at temperatures around 0°C. The reaction can be illustrated by the following reaction equation:
hvor R1? R2, R^ og X er som ovenfor angitt,. R^ er lavere alkyl og s har verdien 0, 1, 2 eller 3. where R1? R 2 , R 1 and X are, as indicated above, R^ is lower alkyl and s has the value 0, 1, 2 or 3.
Dersom X betegner en nitrogruppe ved den ovenfor omtalte reaksjon, vil også denne gruppe, idet minste i noen utstrekning, angripes under reduksjonen. Derved reduseres utbyttet av den onskede forbindelse. If X denotes a nitro group in the above-mentioned reaction, this group, being the smallest to some extent, will also be attacked during the reduction. Thereby, the yield of the desired compound is reduced.
De tilsvarende 2-ethere kan lett fremstilles ved omsetning av de tilsvarende 2-hydroxy-forbindelser av formel II med den passende alkohol (R,0H), idet Rh betegner lavere alkyl eller gruppen The corresponding 2-ethers can be easily prepared by reacting the corresponding 2-hydroxy compounds of formula II with the appropriate alcohol (R,OH), Rh being lower alkyl or the group
1 hvor n, R^ og R^ er som ovenfor angitt. Utgangsmaterialene av den generelle formel IV er velkjente og kan fremstilles f.eks. ved hjelp av de fremgangsmåter som er beskrevet -i- osterriksk patentskrift nr. 2-75• 528 og belgisk patentskrift nr. 1 where n, R^ and R^ are as indicated above. The starting materials of the general formula IV are well known and can be prepared e.g. by means of the methods described -in- Austrian Patent Document No. 2-75 • 528 and Belgian Patent Document No.
692.621. 692,621.
De folgendé eksempler illustrer oppfinnelsen. The following examples illustrate the invention.
Eksempel 1 Example 1
Fremstilling av 7-klor-l-( 2, 2, 2- trifluorethyl)- 2- hydroxy- 2, 3- dihydro-5- fenyl- lH- 1,^- benz od iazepin Preparation of 7-chloro-1-(2,2,2-trifluoroethyl)-2-hydroxy-2,3-dihydro-5-phenyl-1H-1,^-benz odiazepine
0,6<!>+ g (0,017 mol) lithiumaluminiumhydrid settes til en omrort opplosning av 5,6 g (0,016. mol) 7-klor-l-(2,2.,2-trifluorethyl)-1,3-dihydro-2-oxo-5-fenyl-2H-l,If-benzodiazepin i 80 ml tort tetrahydrofuran aykjolt til 0°C. Etter fullfort tilsetning omrores blandingen i ytterligere 5 minutter, hvoretter den bråkjoles med våt ether. Opplosningen filtreres, tbrres over natri-umsulfat og konsentreres under redusert trykk. Opplosningen behandles deretter med en".liten mengde hexan. Det fåes 3,0 g av den onskede forbindelse i form av hvite nåler. (sm.p.: l-3.0-131°C). 0.6<!>+ g (0.017 mol) lithium aluminum hydride is added to a stirred solution of 5.6 g (0.016. mol) 7-chloro-1-(2,2,2-trifluoroethyl)-1,3-dihydro -2-oxo-5-phenyl-2H-1,If-benzodiazepine in 80 ml of dry tetrahydrofuran cooled to 0°C. After complete addition, the mixture is stirred for a further 5 minutes, after which it is quenched with wet ether. The solution is filtered, filtered over sodium sulphate and concentrated under reduced pressure. The solution is then treated with a small amount of hexane. 3.0 g of the desired compound are obtained in the form of white needles. (m.p.: 1-3.0-131°C).
Dersom man i dette eksempel anvender l-(2,2,2-trifluorethyl)-1,3-dihydro-2-oxo-5-f enyl-2H-l ,>+-benzodiazepin som utgangsmateriale, fåes l-(2,2,2-trifluorethyl)-2-hydroxy-2,3-dihydro-5-fenyl-lH-l,^-benzodiazepin. (Sm.p. 123°-125°C). If in this example 1-(2,2,2-trifluoroethyl)-1,3-dihydro-2-oxo-5-phenyl-2H-1,>+-benzodiazepine is used as starting material, 1-(2, 2,2-trifluoroethyl)-2-hydroxy-2,3-dihydro-5-phenyl-1H-1,3-benzodiazepine. (M.p. 123°-125°C).
Eksempel 2 Example 2
Fremstilling av 7- klor- l-( 2, 2T2- trifluorethyl)- 2- methoxy-2,3-dihydro-5- f enyl- lH- 1 T>+- benzodia zepin Preparation of 7-chloro-1-(2,2T2-trifluoroethyl)-2-methoxy-2,3-dihydro-5-phenyl-1H-1T>+- benzodiazepine
2,5 g (0,0071 mol) 7-klor-l-(2,2,2-trifluorethyl)-2-hydroxy-2,3-dihydro-5-fenyl-lH-l/f-benzodiazepin opploses i 10 ml methanbl, og blandingen tillates å stå ved 0°C inntil krystallisasjon finner sted. Det fåes 2,2 g av den onskede forbindelse. (Sm. p. : 1^5°-l<1>+6<0>). 2.5 g (0.0071 mol) of 7-chloro-1-(2,2,2-trifluoroethyl)-2-hydroxy-2,3-dihydro-5-phenyl-1H-1/f-benzodiazepine is dissolved in 10 ml of methanebl, and the mixture is allowed to stand at 0°C until crystallization takes place. 2.2 g of the desired compound are obtained. (Sm. p. : 1^5°-l<1>+6<0>).
Dersom ethanol,anvendes istedenfornethanol i dette eksempel, fåes den tilsvarende 2-ethoxyforbindelse, med smeltepunkt 135°-13l-",<0>C. If ethanol is used instead of ethanol in this example, the corresponding 2-ethoxy compound is obtained, with a melting point of 135°-13l-",<0>C.
Eks empel 3. Example 3.
Fremstilling av 7- klor- l- methyl- 2-hydroxy-2t.3-d ihydro-5- feny. l- lH- 1 , h ~ benzodiazepin Preparation of 7-chloro-1-methyl-2-hydroxy-2t.3-dihydro-5-phenyl. l- lH- 1 , h ~ benzodiazepine
1,2 g (0,032 mol) lithiumaluminiumhydrid"settes til.en omrort opplosning av 7,0 g (0,025 mol) 7-klor-l,3-dihydro-l-methyl-2-oxo-5~fenyl-2H-l^-benzodiazepin i 150 ml tort tetrahydrofuran aykjolt til.0°C. Etter fullfort tilsetning omrores blandingen i ytterligere 5 minutter. Den bråkjbles deretter med. våt ether. Opplosningen 1.2 g (0.032 mol) lithium aluminum hydride" is added to a stirred solution of 7.0 g (0.025 mol) 7-chloro-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1 ^-benzodiazepine in 150 ml of dry tetrahydrofuran cooled to 0°C. After complete addition, the mixture is stirred for a further 5 minutes. It is then triturated with wet ether. The solution
filtreres, torresover natriumsulfat og konsentreres uider redusert trykk...Blandingen tritureres deretter: med etherpetrolether. Det fåes 2,8 g av den onskede; forbindelse. Sm.p.: 125° - 126°C. filtered, dried over sodium sulfate and concentrated under reduced pressure...The mixture is then triturated: with etherpetroleum ether. 2.8 g of the desired product are obtained; connection. Melting point: 125° - 126°C.
Eksempel h Example h
l-(p.ptp-trifl uorethyl)- 7- klor- 2- hydro- xv-2. 3- dihydro- 5-( o- fluorfe-nvl) 1-(p.ptp-trifluoroethyl)-7-chloro-2-hydro-xv-2. 3- dihydro- 5-( o- fluorophen-nvl)
- 1H- 1 A-. benzodia zepin - 1H- 1 A-. benzodiazepine
Til en opplosning av 0,371 g (0,001 mol).7-klor-l,3-dihydro-l-(P ,p ,p-trifluorethyl )-5-(o-fluorfenyl)-2H-l ,1+-benzodiazepin-2-on To a solution of 0.371 g (0.001 mol).7-chloro-1,3-dihydro-1-(P,p,p-trifluoroethyl)-5-(o-fluorophenyl)-2H-1,1+-benzodiazepine- 2-Mon
i 20 ml benzen av 5°C ble tilsatt 0,2 ml.(0,001^ ekvivalenter) av in 20 ml of benzene at 5°C was added 0.2 ml. (0.001^ equivalents) of
en 70^-ig benzenlosning av latri .in. bi s(2-methoxyethoxy)al.uminium-hydrid. Etter omroring i 10 min., ble tilsatt 1,5 ml vann',, og blandingen fortynnet m d benzen,. filtrert, og torket over MgSO^.' Losningen bie konsentrert og" hexan tilsatt, hvorved det ble erholdt 0,l5<!>+g l-(p,p,p-trifluorethyl)-7-klor-2-hydroxy-2,3-dihydro-5-(o-fluorfenyl)-1H-1,^-benzodiazepin, ved smeltepunkt 119 - 120°C. „ a 70^-ig benzene solution of latri .in. bis(2-methoxyethoxy)aluminum hydride. After stirring for 10 min., 1.5 ml of water was added and the mixture diluted with benzene. filtered, and dried over MgSO^.' The solution was concentrated and hexane added, whereby 0.15<!>+g of 1-(p,p,p-trifluoroethyl)-7-chloro-2-hydroxy-2,3-dihydro-5-(o -fluorophenyl)-1H-1,^-benzodiazepine, at melting point 119 - 120°C.
Eks empel 5 Example 5
Fremstilling av 7-klor-2,3-dihydro- 2- hyd roxy- l-( p. p. p- triflu orethyl) Preparation of 7-chloro-2,3-dihydro-2-hydroxy-1-(p.p.p-trifluoroethyl)
-5-fe nyl- lH- 1A- benzodiazepin ^-- oxyd -5-fe nyl- lH- 1A- benzodiazepine ^-- oxyd
Til en opplosning av 2,0 g (0,005'+ mol) 7-klor-l, 3-d ihydro-1-(P,P,p-tri fluor et hy I) - 5-f enyl-2H-l - ben zod i azepin -2-on ^--oxyd i 50 ml torr tetrahydrofuran ble tilsatt under omroring 1,65 g (0,0065 mol) 11 thium(tri-t-butoxyaluminium)hydrid'. (Li[(CH^) C0]^A1H). Lesningen ble oyeb 1. i kkelig gul. Etter omroring over natten ved rom-temperatur ble 2 ml vann tilsatt sammen med . 25 ml. ehter. bunnfallet ble filtrert fra og filtratet torket over Mg SO, To a solution of 2.0 g (0.005'+ mol) 7-chloro-1,3-dihydro-1-(P,P,p-trifluoro et hy I)-5-phenyl-2H-1 - benzod in azepin-2-one 2-oxide in 50 ml dry tetrahydrofuran was added with stirring 1.65 g (0.0065 mol) 11 thium(tri-t-butoxyaluminum)hydride'. (Li[(CH^)CO]^AlH). The reading was oyeb 1. in yellow. After stirring overnight at room temperature, 2 ml of water was added together with . 25 ml. owns. the precipitate was filtered off and the filtrate dried over MgSO,
L6.sning.en ble filtrert og alt løsningsmiddel fjernet under redusert trykk. De resulterende krystaller ble omkrystallisert fra ether-hexan (benkull). The supernatant was filtered and all solvent removed under reduced pressure. The resulting crystals were recrystallized from ether-hexane (bone charcoal).
Forbindelsene som erholdes ved den nye fr mgangsmåte utover en The connections obtained by the new fr method beyond one
virkning på sentralnervesystemet hos pattedyr, som vist ved standard farmakologisk provning og er nyttige som beroligende midler eller som angstdempende'midler. Dertil oppviser de verdifulle krampehemmende og muskelavslappende egenskaper. Under den farmakologiske testing ble det observert betydelig forskjell-mellom beroligende og muskelavslappende doser og doser som forårsaker neurdlogisk svekkelse,, såsom .f.eks. ataxia. Det terapeutiske forhold er vanligvis hoyere for forbindelsen som erholdes ifolge fremgangsmåten, enn for analoge, kjente forbindelser..Som en ytterligere fordel har det vist seg at forsøks-dyrene ikke utvikler noen toleranse ved gjentatt behandling under testingen av de krampehemmende egenskaper. effect on the central nervous system in mammals, as shown by standard pharmacological testing and are useful as sedatives or as anxiolytics. In addition, they exhibit valuable antispasmodic and muscle-relaxing properties. During the pharmacological testing, significant differences were observed between sedative and muscle relaxant doses and doses that cause neurologic impairment, such as .e.g. ataxia. The therapeutic ratio is usually higher for the compound obtained according to the method than for analogous, known compounds. As a further advantage, it has been shown that the test animals do not develop any tolerance upon repeated treatment during the testing of the anticonvulsant properties.
Forbindelsene ifblge den nye fremgangsmåte er mer vannopplbselige enn The compounds according to the new method are more water-soluble than
de tilsvarende 2-oxo-utgangsmaterialer. De har en gunstigere fordelings-konstant mellom organiske og' vandige skikt. Denne faktor er av betydning, fordi deri indikerer stbrre absorbsjon i blodet hos patte- the corresponding 2-oxo starting materials. They have a more favorable distribution constant between organic and aqueous layers. This factor is important, because it indicates greater absorption in the blood of mammals.
dyr ved oral administrering. animals by oral administration.
Ved hjelp av standard laboratorie-testmetoder, såsom "Antagonism of Pentylene Tetrazole", Everett og Richard, J.Pharm, and Exp. Ther., Using standard laboratory test methods, such as "Antagonism of Pentylene Tetrazole", Everett and Richard, J. Pharm, and Exp. Ther.,
Vol. 81, s. h02 (19'+<*>+) og "Antagoni sm of Maximal Electro-Shock-Induced. aeizures in Mice", Synward, E.A. et al., J. Pharm, and Exp. Ther., Vol. 81, pp. h02 (19'+<*>+) and "Antagoni sm of Maximal Electro-Shock-Induced. aeizures in Mice", Synward, E.A. et al., J. Pharm, and Exp. Ther.,
Vol. 106, s. 319 (1952) for testing av den krampehemmende virkning, "Central Nervous System Activity and Acute Toxicity", Irwin, Seiince 136, s. 123 (1962) for testing av de muskelavsl appende og beroligende-hypnotiske virkninger, "Antagonism of Foot-Schock Induced Fighting in Mice", Tedeschi, et al., J.Pharm, and Exp. Ther., Vol. 125, s. 28 Vol. 106, p. 319 (1952) for testing the anticonvulsant effect, "Central Nervous System Activity and Acute Toxicity", Irwin, Seiince 136, p. 123 (1962) for testing the muscle relaxant and sedative-hypnotic effects, "Antagonism of Foot-Schock Induced Fighting in Mice", Tedeschi, et al., J.Pharm, and Exp. Ther., Vol. 125, p. 28
(1959) og "Tårning Activity in Monkeys", Randall, Diseasos of the Nervous System, Vol. 21, s. 7 (1960) for testing av den angstdempende virkning, har det vist seg at for anvendelse av forbindelsen som angstdempende midler er dosen ca. 0,1-5 mg/kg kroppsvekt, pr. dag, idet. forbindelsen fortrinnsvis administreres oralt i oppdelte doser. Ved anvendelse av forbindelsene som krampehemmende midler er doseområdet ca. 2-30 mg/kg kroppsvekt pr. dag, idet administreringen' fortrinnsvis skjer oralt i oppdelte doser. Ved anvendelse av forbindelsene som muskelavslappende midler er doseområdet ca. 0,1-1,5 mg/kg kroppsvekt pr. dag, idet også i dette- tilfelle administrer ingen fortrinnsvis skjer oralt- i oppdelte doser. Når forbindelsene skal anvendes som beroligende-hypnptiske midler, er doseområdet ca. 3_10 mg/kg kroppsvekt pr. dag, og administreringen skjer fortrinnsvis oralt i en enkelt dose. (1959) and "Tårning Activity in Monkeys", Randall, Diseasos of the Nervous System, Vol. 21, p. 7 (1960) for testing the anxiolytic effect, it has been found that for the use of the compound as anxiolytic agents the dose about. 0.1-5 mg/kg body weight, per day, in the the compound is preferably administered orally in divided doses. When using the compounds as anticonvulsants, the dose range is approx. 2-30 mg/kg body weight per day, the administration preferably taking place orally in divided doses. When using the compounds as muscle relaxants, the dose range is approx. 0.1-1.5 mg/kg body weight per day, as also in this case administer none preferably occurs orally - in divided doses. When the compounds are to be used as sedative-hypnotic agents, the dose range is approx. 3_10 mg/kg body weight per day, and the administration preferably takes place orally in a single dose.
Forbindelsene ifolge den nye fremgangsmåte kan administreres alene eller sammen med andre medikamenter. Enten de anvendes alene eller sammen med andre aktive forbindelser benyttes der vanligvis en egnet, i farmasoytisk henseende aksepterbar bærer.. ,3esreren velges etter administreringsmåten som skal benyttes, og også etter forbindelsenes fysikalske egenskaper og den vanlige farmasøytiske praksis. - Den må ikke reagere kjemisk med forbindelsen som skal administeres. Fortrinnsvis administreres forbindelsene oralt, enskjont også parenteral og lokal administrering kan være aktuell. Preparatene inneholdende de nye forbindelser kan ha form av tabletter, kapsler, siruper, eleksirer, suspensjoner,- salver, kremer og lignende. The compounds according to the new method can be administered alone or together with other drugs. Whether they are used alone or together with other active compounds, a suitable, pharmaceutically acceptable carrier is usually used. - It must not react chemically with the compound to be administered. Preferably, the compounds are administered orally, although parenteral and local administration may also be relevant. The preparations containing the new compounds can take the form of tablets, capsules, syrups, elixirs, suspensions, ointments, creams and the like.
I de farrnasoytiske preparater kan der benyttes i farmasoytisk In the farrnazoytic preparations there can be used in pharmazoytic
henseende aksepterbare fortynningsmidler, såsom f.eks. vann, gelatin,, lactose, stivelse, magnesiumtearat, talk, vegetabilske Oljer, gummier og petroleumgele. regarding acceptable diluents, such as e.g. water, gelatin, lactose, starch, magnesium tearate, talc, vegetable oils, gums and petroleum jelly.
Claims (3)
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US4056525A (en) * | 1975-06-02 | 1977-11-01 | American Home Products Corporation | 2,3-dialkoxy-3h-1,4-benzodiazepines |
DE4025395A1 (en) * | 1990-08-10 | 1992-02-13 | Miele & Cie | Covering end edges of furniture plates - involves adhesive tape guide with contact pressure roller and cutter |
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CY836A (en) | 1976-09-10 |
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JPS5116432B1 (en) | 1976-05-24 |
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BE742124A (en) | 1970-05-25 |
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FI50710C (en) | 1976-06-10 |
DE1958742A1 (en) | 1970-07-09 |
CH534169A (en) | 1973-02-28 |
SE372767B (en) | 1975-01-13 |
HK13676A (en) | 1976-03-19 |
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