NO144885B - Analogifremgangsmaate ved fremstilling av terapeutisk aktive benzodiazepinderivater - Google Patents
Analogifremgangsmaate ved fremstilling av terapeutisk aktive benzodiazepinderivater Download PDFInfo
- Publication number
- NO144885B NO144885B NO793013A NO793013A NO144885B NO 144885 B NO144885 B NO 144885B NO 793013 A NO793013 A NO 793013A NO 793013 A NO793013 A NO 793013A NO 144885 B NO144885 B NO 144885B
- Authority
- NO
- Norway
- Prior art keywords
- compound
- methyl
- general formula
- dihydro
- indicated above
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 12
- 229940053197 benzodiazepine derivative antiepileptics Drugs 0.000 title claims description 3
- 238000002360 preparation method Methods 0.000 title claims description 3
- 150000001557 benzodiazepines Chemical class 0.000 title description 2
- 230000001225 therapeutic effect Effects 0.000 title description 2
- -1 cyano, carboxy, amino, carbamoyl Chemical group 0.000 claims description 34
- 150000001875 compounds Chemical class 0.000 claims description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 10
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 5
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 3
- 239000012458 free base Substances 0.000 claims description 3
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical group CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 claims description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 5
- 125000003545 alkoxy group Chemical group 0.000 claims 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical class CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 2
- 125000000217 alkyl group Chemical group 0.000 claims 2
- 229910021529 ammonia Inorganic materials 0.000 claims 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 2
- 229910052794 bromium Inorganic materials 0.000 claims 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 2
- 229910052801 chlorine Inorganic materials 0.000 claims 2
- 239000000460 chlorine Substances 0.000 claims 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 2
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 claims 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 2
- BTJMOXDWIPVCRO-UHFFFAOYSA-N 2,3,4-trimethoxybenzamide Chemical class 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
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical class N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims 1
- DXNQLZJOTVNBOZ-UHFFFAOYSA-N [O]C(=O)Nc1ccccc1 Chemical group [O]C(=O)Nc1ccccc1 DXNQLZJOTVNBOZ-UHFFFAOYSA-N 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- 150000001447 alkali salts Chemical class 0.000 claims 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims 1
- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 claims 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical class OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 125000006627 ethoxycarbonylamino group Chemical group 0.000 claims 1
- 239000007789 gas Substances 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical group 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 239000012442 inert solvent Substances 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 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
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical class C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims 1
- 125000005544 phthalimido group Chemical group 0.000 claims 1
- 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 1
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
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- 238000010992 reflux Methods 0.000 description 7
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- 239000002026 chloroform extract Substances 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 206010010904 Convulsion Diseases 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical group N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 description 2
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- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
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- UYXAWHWODHRRMR-UHFFFAOYSA-N hexobarbital Chemical compound O=C1N(C)C(=O)NC(=O)C1(C)C1=CCCCC1 UYXAWHWODHRRMR-UHFFFAOYSA-N 0.000 description 2
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- 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
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- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Description
Foreliggende oppfinnelse angår fremstilling av terapeutisk aktive benzodiazepinderivater som angitt i innledningen til kravet ved en fremgangsmåte som angitt i kravets karakteristikk.
For fremstilling av ikke-giftige syreaddisjonssalter er f.eks. hydrogenklorid, eddiksyre, propionsyre, diethyleddiksyre, malonsyre, ravsyre/ fumarsyre, maleinsyre, melkesyre, vinsyre, eplesyre, citronsyre, svovelsyre, hydrobromsyre eller orthofosfor-syre egnet. Disse syreaddisjonsforbindelser anvendes farmasøyt-isk likesom den frie base og har særlig den fordel at de er opp-løselige i vann.
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.
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 méd formel I er ikke tid-ligere kjent. De nye forbindelser oppviser eh verdifull innflyt-else på sentralnervesystemet. Forbindelsene har ant ikonvulsiv., 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 forlikelighet (terapeutisk bredde) sammenlignet med handelspreparater.
Undersøkelsene strekker seg til bestemmelsene av følgende aktiviteter:
1. Prøving av antikonvulsive egenskaper:
a) Elektrosjokkanfall:
Metode:
Undersøkelsesforbindelsene ble prøvet efter perorål administrasjon til grupper på 5 mus hver i logaritmiske doseringsav^ stander på 0,l673 (Hackenberg, u. og H. Bartling, Naun<y>n-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 ekstensoranfall 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,l673) til grupper hver på 10 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. Beskyttelsesvirkningen mot konvulsjon og død ble bestemt ved sammenligning med samtidig utførte kontrollforsøk. Den effek-tive dose ED^0 mot konvulsjoner ble beregnet fra probit/log. dos-. eringskurveri. 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 0,1673. 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. E^^o = ^° n,inu1;'ters ligging på siden.
4• Akutt toksisitet:
Den akutte toksisitet ble bestemt efter en gangs administrasjon pr. os til hvite fastende NMRl-mus. Beregningen skjedde ifølge metoden til Litchfield, J. T. og F. Wilcoxbn (J. Pharmacol. Exptl. Therap. 96, 99 (1949).
Utgangsmaterialene som anvendes ved foreliggende fremgangsmåte, kan fremstilles som angitt i NO-paterit 142 866.
Forbindelsene med formel I som kan fremstilles, er angitt i
tabellen nedenfor.
Eksempel 1
70 g 7-klor-l-methyl-2-klormethyl-5-fenyl-2,3-dihydro-lH-1,4-benzodiazepin-hydroklorid i 1 liter vann og 1 liter dioxan ble oppvarmet under tilbakeløp med 500 ml 20%-ig natronlut i 1 time. Derefter ble dioxanet avdestillert i vakuum, den vandige oppløsning ble ekstrahert med kloroform, og kloroformekstraktet ble inndampet i vakuum. Det oljeaktige residuum ble opptatt i isopropanol og tilsatt etherisk saltsyre. Man fikk 7-klor-l-methyl-2-hydroxymethyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin-hydroklorid med smp. 22 7 - 235°C.
Eksempel 2
7-klor-l-ethyl-2-klormethyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin taes opp i 200 ml dioxan og kokes derpå under til-bakeløp i 1 time med 100 ml 20%-ig natriumhydroxydoppløsning. Efter fjernelse av dioxanet i vakuum ekstraheres den vandige opp-løsning méd kloroform, og dette kloroformekstrakt inndampes i vakuum. Det oljeaktige residuum taes opp i isopropanol og til-settes etherisk saltsyre. Man får 7-klor-l-ethyl-2-hydroxymethyl-5-fenyl-lH-2,3-dihydro-l,4-benzodiazepin-hydroklorid med smp.
196 - 202°C.
Eksempel 3
7,5 g 7-klor-l-methyl-2-klormethyl-5-fenyl-2,3-dihydro-lH-1,4-benzodiazepin-hydroklorid ble oppvarmet med en oppløsning av 2 g natrium i 100 ml methanol i 24 timer under tilbakeløp. Derefter ble en del av methanolen avdestillert, reaksjonsblandingen tilsatt vann og ekstrahert med kloroform. Kloroformekstraktene ble inndampet i vakuum, residuet tatt opp i benzen og filtrert over aluminiumoxyd (aktivitetstrinn II) med benzen. Benzen-eluatet ble oppsamlet og inndampet. Den erholdte olje ble oppløst i isopropanol og tilsatt etherisk saltsyre. Man fikk 3,4 g 7-klor-l-methyl-2-methoxymethyl-2,3-dihydro-5-fenyl-lH-1,4-benzodiazepin-hydroklorid med smp. 198 - 210°C.
På analogt vis ble følgende forbindelser med formel I fremstilt:
Eksempel 4
10 g 7-klor-l-methyl-2-klormethyl-5-fenyl-2,3-dihydro-lH-1,4-benzodiazepin-hydroklorid-isopropanol ble oppvarmet med 100 ml piperidin i 14 timer under tilbakeløp. Derpå ble over-skudd av piperidin avdestillert, residuet tilsatt vann og ekstrahert med kloroform. Kloroformekstraktene ble inndampet i vakuum og residuet krystallisert fra ether. Man fikk 6,8 g
(77% av det teoretiske beregnet på klormethylforbindelsen) 7-klor-l-methyl-2-piperidinomethyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin i form av svakt gulfarvede krystaller med smp. 143 - 145°C.
Analogt med dette eksempel ble de følgende forbindelser fremstilt:
7-klor-l-methyl-2-morfolinomethyl-5-fenyl-2 ,.3-dihydro-lH-l, 4-
benzodiazepin i et utbytte på 45%. Smp. for dihydrokloridet: 237-245°C. 7-klor-l-methyl-2-(N-methyl)-piperazinomethyl-5-fenyl-2,3-dihydro-
1H-1,4-benzodiazepin i et utbytte på 46%. Smp. av trihydro-kloridet inneholdende 1 mol ethanol: 214-215°C. 7-klor-l-methyl-2-benzylaminomethyl-5-fenyl-2,3-dihydro-lH-l,4-
benzodiazepin. Utbytte: 40%. Smp. av dihydrokloridet: 165-168°C.
7-klor-l-methyl-2-aminomethyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin-dihydroklorid med smp. 206-209°C (inneholdende
0,5 mol isopropanol).
Eksempel 5
5 g l-methyl-2-klormethyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin-hydroklorid inneholdende 0,65 mol isopropanol og 0,5 mol H20 ble oppvarmet med 50 ml N-methylpiperazin i 10 timer under tilbakeløp. Efter avdestillering av overskuddet av N-methylpiperazin ble residuet tilsatt vann og ekstrahert med kloroform. Kloroformekstraktene ble inndampet i vakuum. Derved fikk man l-methyl-2-(N-methyl)-piperazinomethyl-5-fenyl-2,3-dihydro-1H-1,4-benzodiazepin som en olje i et utbytte på 78%. Eksempel 6 10 g 7-klor-l-methyl-2-klormethyl-5-(2 *-klorfenyl)-2,3-dihydro-lH-1,4-benzodiazepin-hydroklorid ble oppvarmet med 100 ml morfolin i 15 timer under tilbakeløp. Efter opparbeidelse av reaksjonsblandingen fikk man 7-klor-l-methyl-2-morfolinomethyl-5-(2<1->klorfenyl)-2,3-dihydro-lH-l,4-benzodiazepin med smp. 136-138°C.
Eksempel 7
127 g 7-klor-l-methyl-2-klormethyl-5-fenyl-2,3-dihydro-lH-1,4-benzodiazepin ble oppløst i 1000 ml methanol, tilsatt 70 g kaliumjodid og 78 g kaliumfthalimid og oppvarmet under tilbakeløp i 24 timer. Derpå ble oppløsningen filtrert varm og inndampet i vakuum: Det erholdte bunnfall ble frafiltrert og omkrystallisert fra methanol. Man fikk 7-klor-l-methyl-2-fthalimidomethyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin med smp. 151-152°C i 60% utbytte.
På lignende måte fikk man 7-klor-l-methyl-2-(3,4,5-tri-methoxy)-benzoylaminomethyl-5-fenyl-lH-2,3-dihydro-l,4-benzodiazepin-hydroklorid med smp. 180°C, og 7-klor-l-methyl-2-acetamidomethyl-5-fenyl-lH-2,3-dihydro-l,4-benzodiazepin-hydroklorid med smp. 184-186°C.
Ved fremgangsmåtene i eksempel 4-7 ble de følgende forbindelser med formel I fremstilt:
Eksempel 8
10 g 7-klor-l-methyl-2-aminomethyl-5-feriyl-2,3-dihydro-lH-1,4-benzodiazepin ble omsatt i 200 ml methylenklorid med 4,36 g fenolisocyanat. Ethanol ble så tilsatt efter 24 timer, og oppløs-ningen ble inndampet i vakuum. Residuet ble tatt opp med ether og omsatt med en isopropanoloppløsning av hydrogenklorid. Det dannede bunnfall ble fjernet ved filtrering og omkrystallisert fra isopropanol/vann.
Man fikk 7-klor-l-methyi-2-fenyluréidomethyl-5-fenyl-2,3-dihydro-lH-1,4-benzodiazepin-hydroklorid med smp. 198 - 207°C.
Eksempel 9
En oppløsning av 21 g 7-klor-l-methyl-2-aminomethyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin ble efter hverandre tilsatt med 7,1 g triethylamin og 7,6 g ethylklorformiat. Efter 24 timer blé reaksjonsblandingen vasket med vann, methylenkloridfasen ble fraskilt, tørret over natriumsulfat og inndampet i vakuum. Råproduktet ble filtrert med toluen over A^O^ (aktivitetstrinn II-III) , eluatet ble oppsamlet og inndampet i vakuum. For felning av hydrokloridet ble deri erholdte olje oppløst i isopropanol og tilsatt etherisk hydrogenklorid. Man fikk 7-klor-l-' methyl-2-ethoxycarbonylaminomethy1-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin-hydroklorid med smp. 196-197°C.
Eksempel 10
88 g 7-klor-l-methyl-2-klormethyl-5-fenyl-2,3-dihydro-lH-1,4-berizodiazepin ble oppløst i 1000 ml methanol og.oppvarmet med 19,8 g kaliumcyanid og 2 g kaliumjodid i 24 timer under til-bakeløp. Derefter ble oppløsningsmidlet avdestillert i vakuum, residuet ble tilsatt vann og ekstrahert med kloroform. De for-enede kloroformekstrakter 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-cyanomethyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin-hydroklorid med smp. 210-214°C i et utbytte på 87,5%.
Fra 7-klor-l-methyl-2-klormethyl-5-(2'-klorfenyl)-2,3-dihydro-lH-1,4-benzodiazepin-hydroklorid fikk man i lignende ut-, bytte 7-klor-l-methyl-2-cyanomethyl-5-(2'-klorfenyl)-2,3-dihydro-lH-1,4-benzodiazepin-hydroklorid med smp. 171-174°C.
Fra 7-klor-l-methyl-2-klormethyl-5-(2'-fluorfenyl)-2,3-dihydro-lH-1,4-benzbdiazepin fikk man i lignende utbytte 7-klor-l-methyl-2-cyanomethyl-5-(2'-fluorfenyl)-2,3-dihydro-lH-l, 4-benzodiazepin-hydroklorid med smp. 221-225°C.
Videre fikk man fra 7-brom-l-methyl-2-klormethyl-5-(2'-klorfenyl)-2,3-dihydro-lH-l,4-benzodiazepin 7-brom-l-methyl-2-cyanomethyl-5-(2'-klorfenyl)-2,3-dihydro-lH-l,4-benzodiazepin-hydroklorid med smp. 147-149°C.
7-brom-l-methyl-2-klormethyl-5-(2'-fluorfenyl)-2,3-dihydro-1H-1,4-benzodiazepin ga 7-brom-l-methyl-2-cyanomethyl-5-(2'-fluorfenyl)-2,3-dihydro-lH-l,4-benzodiazepin-hydroklorid med smp. 218-220°C.
7-klor-l-methyl-2-klormethyl-5-(2'-trifluormethylfenyl)-2,3-dihydro-lH-1,4-benzodiazepin ga 7-klor-l-methyl-2-cyanomethyl-5-(2 ' -trif luormethylfenyl)-2 ,3-dihydro-lH-l, 4-benzodiazepin som en olje.
7-brom-l-methyl-2-klormethyl-5-(2'-trifluormethylfenyl)-2,3-dihydro-lH-1,4-benzodiazepin ga 7-brom-l-methyl-2-cyanomethyl-5-(2'-trifluormethylfenyl)-2,3-dihydro-lH-l,4-benzodiazepin som en olje.
Eksempel 11
72,3 g 7-klor-l-methyl-2-cyanomethyl-5-fenyl-2,3-dihydro-lH-1,4-benzodiazepin-hydrokldrid ble oppløst i 360 ml 18%-ig ethanol-oppløsning av hydrogenklorid og hensatt ved 40°C inntil intet av utgangsmaterialet kunne påvises ved tynnskiktskromatografi. Massen ble så behandlet med ether og omkrystallisert• Man fikk således 7-klor-l-methyl-2-ethoxycarbonyImethyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin-hydroklorid med smp. 204-206°C.
Eksempel 12
71,1 g 7-klor-:l-methyl-2-ethoxycarbonylmethyl-5-f enyl-2, 3-dihydro-lH-1,4-benzodiazepin-hydroklorid ble oppvarmet i 450 ml methanol med 900 ml ml 10%-ig natriumhydroxyd i 1" time' uridéf til-, bakeløp. Efter avdestillering av oppløsniirgsmidlet ble det erholdte bunnfall tatt opp i kloroform og behandlet med gass-formig hydrogenklorid. Efter frafiltrering av det utfelte natrium-klorid ble kloroformoppløsningen inndampet i vakuum. Residuet ble omkrystallisert fra methanol/ether. Man fikk således 7-klor-l-methyl-2-carboxymethyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin-hydroklorid som ble spaltet ved 229°C.
11,5 g av det således erholdte syrederivat ble omsatt i
200 ml methylenklorid ved 0°C efter hverandre med 8,5 ml triethylamin og 3,7 g av ethylklorformiat. 25 ml av en 70%-ig vandig isopropylaminoppløsning ble så tilsatt efter 30 minutter. Massen ble til slutt vasket med vann efter 24 timer, og methylenkloridfasen ble fraskilt, tørret over natriumsulfat og inndampet i vakuum. Residuet ble oppløst i ether og omsatt med en isopropanol-oppløsning av hydrogenklorid. Man fikk således 7-klor-l-methyl-2-isopropylcarbamoylmethyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin-hydroklorid med smp. 220-223°C.
Eksempel 13
11,5 g 7-klor-l-methyl-2-carboxymethyl-5-fenyl-2,3-dihydro-1H-1,4-benzodiazepin-hydroklorid ble omsatt i 200 ml methylenklorid ved 0°C efter hverandre med 8,5 ml triethylamin og 3,7 g ethylklorformiat. 25 ml av en konsentrert vandig ammoniakkoppløs-ning ble så tilsatt efter 30 minutter. Massen ble så vasket med vann efter 24 timer, og methylenkloridfasen ble fraskilt, tørret over natriumsulfat og inndampet i vakuum. Residuet ble oppløst
i ether og omsatt med en methanoloppløsning av hydrogenklorid. Man fikk således 7-klor-l-methyl-2-carbamoylmethyl-5-fenyl-2,3-dihydro-lH-1,4-benzodiazepin-hydroklorid med smp. 229-23.1°C. Molekylvekten av hydrokloridet, bestemt ved massespektroskopi, var 364.
Eksempel 14
En oppløsning av 16,5 g 7-klor-l-methyl-2-hydroxymethyl-5-fenyl-2, 3-dihydro-lH-l, 4-benzodiazepin i 5,0 ml methylenklorid ble fremstilt. Oppløsningen ble så omsatt med 6 ml ethyliso-cyanat. Massen ble så efter 24 timer omsatt med en liten mengde methanol, og oppløsningsmidlet ble avdestillert under vakuum. Residuet ble omkrystallisert fra aceton. Man fikk således 7-klor-l-methyl-2-(ethylcarbamoyloxy)-methyl-5-fenyl-2,3-dihydro-1H-1,4-benzodiazepin med smp. 175-177°C.
Claims (1)
- Analogifremgangsmåte ved fremstilling av terapeutisk aktive benzodiazepinderivater med den generelle formel:hvor R1 er hydrogen, lavere alkyl eller benzyl,R2 er hydroxy, rettkjedet eller forgrenet alkoxy med 1-5 carbonatomer, ethoxycarbonyl, cyano, carboxy, amino, carbamoyl, methylcarbonylamino, ethoxycarbonylamino, isopropylcarbamoyl, methyl-carbamoyloxy, ethylcarbamoyloxy, fenoxy, klorfenoxy, benzoyloxy, fenylthio, benzylamino, trimethoxybenzoylamino, fenylcarbamoyloxy, ureido, methylureido, isopropylureido, fenylureido, fthalimido, methylpiperazino, morfolino eller piperidino, og A og B er benzenringer som kan være substituert med halogen, alkyl med 1-4 carbonatomer, alkoxy med 1-4 carbonatomer, trifluormethyl, eller nitro, eller A kan være substituert med methylthio eller ethylendioxy;såvel som syreaddisjonssalter derav,karakterisert ved at a) en forbindelse med den generelle formel I, hvor R2 er klor eller brom, og R^, A og B er som ovenfor angitt, under-kastes alkalisk hydrolyse, hvorved man får en forbindelse med formel I hvor R2 er hydroxy, og R^, A og B er som ovenfor angitt, eller b) en forbindelse med den generelle formel I, hvor R2 er hydroxy, og 'R^, A og Ber som ovenfor angitt,.omsettes med methyl-, ethyl- eller fenyl-isocyanat, hvorved man får en for-, bindelse med formel I hvor R2 er hhv. methyl-, ethyl- eller fenyl-carbamoyloxy, eller c) en forbindelse med den generelle formel I, hvor R2 er klor eller brom, og R^, Å og.B er som ovenfor angitt, omsettes med et nucleofilt reagens bestående av ammoniakk, benzylamin, morfolin, methylpiperazin, piperidin, alkalisalter av fthalimid, tri-methoxybenzamid, acetamid, benzoat, cyanid, alkoholat med 1-5 carbonatomer, fenolat, klorfenolat eller thiofenolat ved forhøyet temperatur i et inert oppløsningsmiddel, hvorved man får en forbindelse hvor R2 er amino, benzylamino, morfolino, methylpiperazino, piperidino, fthalimido, trimethoxybenzoylamino, methylcarbonylamino, benzoyloxy, cyano, alkoxy med 1-5 carbonatomer, fenoxy, klorfenoxy eller fenylthio, eller d) en forbindelse med den generelle formel I hvor R2 er amino, og R^, A og B er som ovenfor angitt, omsettes med kaliumiso-cyanat, methyl-, isopropyl- eller fenylisocyanat for dannelse av den tilsvarende forbindelse hvor R2 er ureido, methyl-, isopropyl- eller fenylureido, eller e) en forbindelse med formel I hvor R2 er amino, og R^, A og B er som ovenfor angitt, behandles efter hverandre med triethylamin og ethylklorformiat, hvorved man får en forbindelse hvor R2 er ethoxycarbonylamino, ellerf) en forbindelse med den generelle formel I, hvor R2 er cyano, og Rj, A og B er som ovenfor angitt, behandles med ethanolisk hydrogenklorid, hvorved man får en forbindelse hvor R2 er ethoxycarbonyl, eller g) eri forbindelse med den generelle formel I, hvor R0 er ethoxycarbonyl, og R^, A og B er som ovenfor angitt, behandles med alkali og derpå med hydrogenklorid-gass, hvorved mån får en forbindelse hvor R2 er carboxy, eller h) en forbindelse med den generelle formel I, hvor R2 er carboxy, og R^, A og B er som ovenfor angitt, behandles efter hverandre med triethylamin, ethylklorformiat og ammoniakk eller isopropylamin, hvorved man får en forbindelse hvor R2 er carbamoyl eller isopropylcarbamoyl,og 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 |
|---|---|
| NO793013L NO793013L (no) | 1973-11-06 |
| NO144885B true NO144885B (no) | 1981-08-24 |
| NO144885C NO144885C (no) | 1981-12-02 |
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 (4)
| 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 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO793012A NO144386C (no) | 1972-05-03 | 1979-09-19 | Fremgangsmaate ved fremstilling av benzodiazepinderivater |
Country Status (18)
| Country | Link |
|---|---|
| US (6) | US3998809A (no) |
| JP (3) | JPS5541231B2 (no) |
| AT (3) | AT327920B (no) |
| BE (1) | BE799001A (no) |
| CA (3) | CA984388A (no) |
| CH (5) | CH611607A5 (no) |
| DD (1) | DD105222A5 (no) |
| DE (3) | DE2265371C3 (no) |
| DK (3) | DK147050C (no) |
| ES (1) | ES414279A1 (no) |
| FR (3) | FR2183735B1 (no) |
| GB (3) | GB1429666A (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) |
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| 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 |
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-
1972
- 1972-05-03 DE DE2265371A patent/DE2265371C3/de not_active Expired
- 1972-05-03 DE DE2265370A patent/DE2265370C2/de not_active Expired
- 1972-05-03 DE DE2221558A patent/DE2221558C2/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 GB2491075A patent/GB1429666A/en not_active Expired
- 1973-04-25 GB GB3581775A patent/GB1429667A/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 CH598873A patent/CH605834A5/xx not_active IP Right Cessation
- 1973-04-26 CH CH1605677A patent/CH611608A5/xx not_active IP Right Cessation
- 1973-04-26 CH CH1605777A patent/CH611609A5/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 JP JP4900373A patent/JPS5541231B2/ja 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
- 1973-05-02 BE BE130663A patent/BE799001A/xx not_active IP Right Cessation
- 1973-05-02 DK DK238573A patent/DK147050C/da not_active IP Right Cessation
- 1973-05-02 FR FR7315752A patent/FR2183735B1/fr not_active Expired
- 1973-05-02 NO NO1797/73A patent/NO142866C/no unknown
- 1973-05-02 SE SE7306128A patent/SE409709B/sv unknown
- 1973-05-02 ES ES414279A patent/ES414279A1/es not_active Expired
- 1973-05-03 SU SU731918571A patent/SU625607A3/ru active
- 1973-05-03 ZA ZA733013A patent/ZA733013B/xx unknown
- 1973-05-03 AT AT389973A patent/AT327920B/de not_active IP Right Cessation
- 1973-05-03 AT AT143875*1A patent/AT327927B/de not_active IP Right Cessation
- 1973-05-03 SU SU1920527A patent/SU526290A3/ru active
- 1973-05-03 AT AT389873A patent/AT327919B/de not_active IP Right Cessation
-
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 JP52148666A patent/JPS589101B2/ja not_active Expired
- 1977-12-09 JP JP52148667A patent/JPS5813535B2/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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