SE448453B - FTATIMIDODERIVAT - Google Patents
FTATIMIDODERIVATInfo
- Publication number
- SE448453B SE448453B SE8106594A SE8106594A SE448453B SE 448453 B SE448453 B SE 448453B SE 8106594 A SE8106594 A SE 8106594A SE 8106594 A SE8106594 A SE 8106594A SE 448453 B SE448453 B SE 448453B
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- Prior art keywords
- diazepine
- phthalimido
- dibenzo
- propyl
- hydrochloride
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
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- 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
- C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
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- Bioinformatics & Cheminformatics (AREA)
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- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Indole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
448 453 maleinsyra, bärnstenssyra, oxalsyra, cyklohexaminsyra och lik- nande. 448 453 maleic acid, succinic acid, oxalic acid, cyclohexamic acid and the like.
För att demonstrera antidepressiv användbarhet för föreningarna enligt formel I utnyttjas det förfarande som beskrives av E.L.To demonstrate antidepressant utility for the compounds of formula I, the procedure described by E.L.
Englehardt och medarbetare i J. Med. Chem. 11 (2), 325 (1968), vilken tidigare har utnyttjats för att antyda användbarhet hos föreningafiför behandling av mänskliga depressioner. Förfarandet innefattar följande metod: 20 mg/kg av den förening som skulle provas administrerades fem vuxna honmöss (ICR-DUB-stam), intrape- ritonealt, 30 minuter före administration av ptotisk dos (32 mg/ kg intraperitonealt) tetrabenazin (i form av metansulfonatsalt). 30 minuter senare analyserades i närvaro eller frånvaro av full- ständig ögonlockslutning (ptosis) hos varje djur. En EDSO (medi- aneffektív dos) kan uppsättas för varje provad förening för bloc- kering av tetrabenazinframkallade depressioner hos möss enligt det förfarande som användes av Litchfield och medarbetare i J. Pharma- col. Exp. Therap. 96: 99-113 (1949).Englehardt and co-workers in J. Med. Chem. 11 (2), 325 (1968), which has previously been used to suggest usefulness of compounds fi for the treatment of human depression. The method comprises the following method: 20 mg / kg of the compound to be tested, five adult female mice (ICR-DUB strain) were administered intraperitoneally, 30 minutes before administration of ptotic dose (32 mg / kg intraperitoneally) tetrabenazine (in the form of methanesulfonate salt). 30 minutes later, in the presence or absence of complete eyelid closure (ptosis) in each animal was analyzed. An EDSO (Medium Effective Dose) can be set up for each test compound to block tetrabenazine-induced depression in mice according to the procedure used by Litchfield and colleagues at J. Pharmacol. Exp. Therap. 96: 99-113 (1949).
De nya föreningarna i formel I framställes genom cyklodehydrering av de nya N-[§-(1-ftalimido)propyly-o-bensamido-difenylaminerna med formeln IIb och därefter omvandling av ftalimidodelen till amino med hydrazin och syra. Reaktionen följer schemat: /o P0C13 \NH ----+ @Ir@ ($H=)a 448 453 där X har den betydelse som angavs i samband med formel I. För- eningarna med formeln III är också nya.The novel compounds of formula I are prepared by cyclodehydration of the novel N- [§- (1-phthalimido) propyly-o-benzamido-diphenylamines of formula IIb and then conversion of the phthalimido moiety to amino with hydrazine and acid. The reaction follows the scheme: / o POCl 3 \ NH ---- + @ Ir @ ($ H =) a 448 453 where X has the meaning given in connection with formula I. The compounds of formula III are also new.
Föreningar med formeln I substituerade i 5-ställning med 3-mono- metylpropylamin framställes genom ytterligare reaktion hos 3-amino- propylföreningen med trietylortoformat följt av en reaktion med natriumborhydrid (förfarande enligt Crocket & Blanton, 1974 (1): 55-6 Synthesis). Reaktionen kan beskrivas på följande sätt: x 1) (ncobcn 2) Nasa, _ ? N I (fH-.Ja Ib (cH2)3 nu i IC . 2 nucna Bensamidoföreningarna, vilka användes som utgångsmateriäl, fram- ställes i ett modifierat förfarande enligt den brittiska patent- skriften 907 646. Ortonitrodifenylamin alkyleras först reduktivt med en lösning av Årklorpropyldimetylamin eller 3-(1-ftalimido)-1- -kloropropan och därefter reduceras nitrogruppen med väte eller palladium-på-kol för att ge motsvarande ortoaminoförening. Amino- gruppen i ortoställning får sedan reagera med bensoylhalogeniden eller en substituerad bensoylhalogenid. Reaktionsförloppet åskåd- liggöres i följande schema: 446 453 4 ' _ OQN ' bll VI n i Cl-(cflaßo Oalü @g@ v (frias Q l Ha/Pd-c 112m _ Iv @1.«@ (?H2)s Q .x f? Pyridin J, C_c1 x cø° _ _ “nu @\b|l I: 4 (912): -Q Q = 1-ftalimido.Compounds of formula I substituted in the 5-position with 3-monomethylpropylamine are prepared by further reaction of the 3-aminopropyl compound with triethyl orthoformate followed by a reaction with sodium borohydride (method according to Crocket & Blanton, 1974 (1): 55-6 Synthesis) . The reaction can be described as follows: x 1) (ncobcn 2) Nasa, _? NI (fH-.Ja Ib (cH2) 3 now in IC. 3- (1-phthalimido) -1- -chloropropane and then the nitro group is reduced with hydrogen or palladium-on-carbon to give the corresponding orthoamino compound.The amino group in the ortho position is then reacted with the benzoyl halide or a substituted benzoyl halide. following scheme: 446 453 4 '_ OQN' bll VI ni Cl- (c fl aßo Oalü @ g @ v (frias Q l Ha / Pd-c 112m _ Iv @ 1. «@ (? H2) s Q .xf? Pyridin J , C_c1 x cø ° _ _ “nu @ \ b | l I: 4 (912): -QQ = 1-phthalimido.
Framställning 1 N-[É-(1-ftalimido)propyL]-o-aminodifenylamin o-nitrodifenylamin fick reagera med natriumhydríd och 3-(1-ftal- i.mido)-1-kloropropan, varvid erhölls N-3-(1-ftalimido)-propyl-o- -nitrodifenylamin, vilken därefter reducerades med väte över palla- dium-på-kol i etanol, varvid titelföreningen erhölls. 448 453 Framställning 2 Om i förfarandet enligt framställning 1 N-3-(1~ftalimido)propyl-o- -aminodifenylamin får reagera med var och en av följande acylklo- rider i överskott, nämligen 2-kloro-bensoylklorid 3-kloro-bensoylklorid 2-fluoro-bensoylklorid 3-fluoro-bensoylklorid 2-bromo-bensoylklorid 3-bromo-bensoylklorid och 4~kloro-bensoylklorid i överskott på det sätt som anges i framställning 1 erhålles N-3-(1-ftalimido)propyl-o-(2-klorobensamido)difenylamin N-3-(1-ftalimido)propyl-o-(3-klorobensamido)difenylamin N-3-(1-ftalimido)propyl-o-(2-fluorobensamido)difenylamin N-3-(1-ftalimido)propyl-o-(3-fluorobensamido)difenylamin N-3-(1-ftalimido)propy1-o-(2-bromobensamido)difenylamin N~3-(1-ftalimido)propyl-o-(3-bromobensamído)difenylamin och N-3-(1-ftalimido)propy1-o-(4-klorobensamido)difenylamin.Preparation 1 N- [E- (1-phthalimido) propyl] -o-aminodiphenylamine o-nitrodiphenylamine was reacted with sodium hydride and 3- (1-phthalimido) -1-chloropropane to give N-3- (1 -phthalimido) -propyl-o- -nitrodiphenylamine, which was then reduced with hydrogen over palladium-on-carbon in ethanol to give the title compound. 448 453 Preparation 2 If in the process according to Preparation 1 N-3- (1-phthalimido) propyl-o- -aminodiphenylamine is allowed to react with each of the following acyl chlorides in excess, namely 2-chloro-benzoyl chloride 3-chloro-benzoyl chloride 2-Fluoro-benzoyl chloride 3-fluoro-benzoyl chloride 2-bromo-benzoyl chloride 3-bromo-benzoyl chloride and 4-chloro-benzoyl chloride in excess In the manner set forth in Preparation 1, N-3- (1-phthalimido) propyl-o- (2-chlorobenzamido) diphenylamine N-3- (1-phthalimido) propyl-o- (3-chlorobenzamido) diphenylamine N-3- (1-phthalimido) propyl-o- (2-fluorobenzamido) diphenylamine N-3- (1 -phthalimido) propyl-o- (3-fluorobenzamido) diphenylamine N-3- (1-phthalimido) propyl-o- (2-bromobenzamido) diphenylamine N-3- (1-phthalimido) propyl-o- (3-bromobenzamido) diphenylamine and N-3- (1-phthalimido) propyl-o- (4-chlorobenzamido) diphenylamine.
Följande icke begränsande exempel belyser föreningarna enligtupp- finningen.The following non-limiting examples illustrate the compounds according to the invention.
Exempel 1 5-¿§-(1-ftalimido)propyl7-11-fenyl-5H-dibenso_§,§'¿1,47-diazepin- fumarat En omrörd blandning av (0,05 mol) N-3-(1-ftalimido)propyl-o-bens- amidodifenylamin och (0,2 mol) fosforoxiklorid fick reagera i 1,1,2,2-tetrakloretan vid 150OC i kväveatmosfär under ca 1,5 tim- mar. Reaktionsblandningen kyldes med ca 1000 ml krossad is och ut- späddes till en slutlig volym på 1000 ml. Vattenfasen extraherades med metylenklorid och metylenkloridfasen kastades. Vattenfasen gjordes basisk med 3N natriumhydroxid och extraherades med tre gånger 250 ml metylenklorid. Den torkade metylenkloridfasen in- dunstades under förminskat tryck och fick upplöst i varm isopro- pylalkohol reagera med (0,05 mol) fumarsyra. Fumaratsaltet uppsam- lades genom filtrering och utgjordes av titelföreningen. 4-48 453 Om vid förfarandet enligt exempel 1 före tillsatsen av fumarsyra N-3-(1-ftalimido)propyl-o-bensamidodifenylamin utbytes mot N-3-(1-ftalimido)propyl-o-(2-klorobensamido)difenylamin N~3-(1-ftalimido)propyl-o-(3-klorobensamido)difenylamin N-3-(1-ftalimido)propyl-o-(2-fluorobensamido)difenylamin N~3-(1-ftalimido)propyl-o-(3~fluorobensamido)difenylamin N-3-(1-ftalimido)propyl-o-(2-bromobensamido)difenylamin N-3-(1-ftalamido)propyl-o-(3-bromobensamido)difenylamin och N-3-(1-ftalimido)propyl-o-(4-klorobensamido)difenylamin erhölls 5-¿§-(1-ftaljmido)propyl?-11-(2-klorofenyl)-SH-dibenso[ß,e7[fi,§]- diazepin 5-[§-(1-ftalimido)propyl7-11-(3-klorofenyl)-5H-dibenso[§,e]¿ï,§7- diazepin 5-[§-(1-ftalimido)propyl]-11-(2-fluorofenyl)-SH-dibenso[B,e7¿fi,¶]- diazepin 5-[3- (wftaimimacnpropyljq 1-(3-f1uor0feny1) -su-aibenso/jø, e_7[1 , 4]- diazepin 5-[É-(1-ftalimido)propyl]-11-(2-bromofenyl)-5H-dibensoLß,e][fi,Q]- diazepin 5-[3-(wftaiimidoypropygfl1-(3-bromofeny1)-sa-aibensoß» ,e]/_°1 , 4_7- diazepin och 5-[3-(1-ftalimido)propylf-11-(4-klorofenyl)-SH-dibenso¿E,e][fl,§]- diazepin ëxempel 2 5-(3~aminopropyl)-11-fenyl-5H-dibensoáf,_7Ll,@f-diazepin-hydro- klorid En blandning av 0,035 mol 5-¿§-(1-ftalimido)propy{]-11-fenyl-5H- dibenso[§,e][3,Q7-diazepin, 0,039 mol hydrazinhydrat och 175 ml 190%-ig etylalkohol återflödeskokades under 2,5 timmar och tilläts stå under flera timmar. En lösning av 10 ml konc. saltsyra i 50 ml vatten tillsattes blandningen och blandningen omrördes flera tim- mar. Blandningen filtrerades och filtratet indunstades under för- minskat tryck. Hydrokloridsaltet isolerades genom omkristallisation ur ett lämpligt lösningsmedel och torkades under förminskat tryck. 7 448 453 šrflëfiäffflLå Förfarandet enligt exempel 2 följdes men med utbyte av 5-¿§~(1- «ftal1mido)propyl?-11-fenyl-SH-dibenso¿ß,e][fi,§]-diazepin mot ek- vimolära mängder av följande 11-(z-klorfenyl)-s-Q-(1-fta1imido)propyÜ-sn-dibensoßhe] _'1 ,4]- diazepín 11-(3-klorofenyl)-5-[š-(1-ftalimido)propyl7~5H-dibenso[E,;7¿',§]~ diazepin . 11- diazepin _ 11-(3-fluorofenyl)-5-[É-(1-ftalimido)propylj-5H-dibenso[ß,e7¿_,{]- diazepine 11-(2~bromofenyl)-5-[§-(1-ftalimido)propyl7-5H~dibensoLš,e]Lï,¶7- díazepin 11-(3-bromofenyl)-5-lä-(1-ftalimido)propylf-SH-dibenso[§,e7[fi,g]f diazepin och 1 1- (4-k1orofeny1) -s-[z- (1-fta11mi_d0) propy1_7-5n-aibenso/_E,e] j ,4]- diazepin varvid erhölls 5-(3~amin0propyl)~11-(2-klorofenyl)-SH-dibenso[B,_][1,@f-diazepin- hydroklorid ~ 5~(3-aminopropyl)~11-(3-klorofenyl)-SH-dibensoLÉ,e7[ï,§]-diazepin- hydroklorid 5-(3-aminopropyl)-11-(2-fluorofenyl)-5H-dibenso¿E,e7¿fi,4]-diazepin- hydroklorid 5-(3-aminopropyl)-11-(3-fluorøfenyl)-SH-dibenso¿E,e][ï,¶]-diazepin~ hydroklorid b-(3-aminopropyl)-11-(2-bromofenyl)-SH-dibenso¿§,e7¿¶,4]-diazepin- hydroklorid 5-(3-aminopropyl)-11-(3-bromofenyl)-5H-dibensoLÉ,e][fi,4]-diazepin- hydroklorid 5-(3-aminopropyl)-11-(4-klorofenyl)-5H-dibenso_ß,e]¿ï,¶7-diazepin- hydroklorid.Example 1 5-β- (1-Phthalimido) propyl7-11-phenyl-5H-dibenzo-, 1,47-diazepine fumarate A stirred mixture of (0.05 mol) N-3- (1- phthalimido) propyl-o-benzamidodiphenylamine and (0.2 mol) phosphorus oxychloride were reacted in 1,1,2,2-tetrachloroethane at 150 ° C under a nitrogen atmosphere for about 1.5 hours. The reaction mixture was cooled with about 1000 ml of crushed ice and diluted to a final volume of 1000 ml. The aqueous phase was extracted with methylene chloride and the methylene chloride phase was discarded. The aqueous phase was basified with 3N sodium hydroxide and extracted three times with 250 ml of methylene chloride. The dried methylene chloride phase was evaporated under reduced pressure and dissolved in hot isopropyl alcohol was reacted with (0.05 mol) of fumaric acid. The fumarate salt was collected by filtration and consisted of the title compound. 4-48 453 If in the procedure of Example 1 before the addition of fumaric acid N-3- (1-phthalimido) propyl-o-benzamidodiphenylamine is replaced by N-3- (1-phthalimido) propyl-o- (2-chlorobenzamido) diphenylamine N 3- (1-Phthalimido) propyl-o- (3-chlorobenzamido) diphenylamine N-3- (1-phthalimido) propyl-o- (2-fluorobenzamido) diphenylamine N-3- (1-phthalimido) propyl-o- (3-fluorobenzamido) diphenylamine N-3- (1-phthalimido) propyl-o- (2-bromobenzamido) diphenylamine N-3- (1-phthalamido) propyl-o- (3-bromobenzamido) diphenylamine and N-3- ( 1-Phthalimido) propyl-o- (4-chlorobenzamido) diphenylamine was obtained 5-β- (1-phthalimido) propyl-11- (2-chlorophenyl) -SH-dibenzo [ß, e7 [fi, §] - diazepine 5- [§- (1-phthalimido) propyl7-11- (3-chlorophenyl) -5H-dibenzo [§, e] ¿ï, §7- diazepine 5- [§- (1-phthalimido) propyl] -11- (2-fluorophenyl) -SH-dibenzo [B, e7], ¶] - diazepine 5- [3- (trifluoromethylpropyl] 1- (3-fluorophenyl) -suabenzo [io] e [7 [1,4] diazepine - [E- (1-phthalimido) propyl] -11- (2-bromophenyl) -5H-dibenzolS, e] [fi, Q] - diazepine 5- [3- (phthalimidoypropyg fl1- (3-bromophenyl) -sa-aibenzoess », E] / _ ° 1, 4_7- diazepine and 5- [3- (1-phthalimido) propyl] -11- (4-chlorophenyl) -SH-dibenzo [e] [fl, §] -diazepine Example 2 5- (3-aminopropyl) -11-phenyl- 5H-dibenzoaf, 7L1, [f] -diazepine hydrochloride A mixture of 0.035 mol of 5-β- (1-phthalimido) propyl {] - 11-phenyl-5H-dibenzo [§, e] [3, Q7- diazepine, 0.039 mol of hydrazine hydrate and 175 ml of 190% ethyl alcohol were refluxed for 2.5 hours and allowed to stand for several hours. A solution of 10 ml conc. hydrochloric acid in 50 ml of water was added to the mixture and the mixture was stirred for several hours. The mixture was filtered and the filtrate was evaporated under reduced pressure. The hydrochloride salt was isolated by recrystallization from a suitable solvent and dried under reduced pressure. 7 448 453 šr fl ë fi äffflLå The procedure of Example 2 was followed but substituting 5-¿§ ~ (1- «phthalimido) propyl? -11-phenyl-SH-dibenzoß, e] [fi, §] - diazepine against equimolar amounts of the following 11- (z-chlorophenyl) -sQ- (1-phthalimido) propyl-sn-dibenzo] [1,4] diazepine 11- (3-chlorophenyl) -5- [β- (1-phthalimido) propyl7 ~ 5H-dibenzo [E,; 7¿ ', §] ~ diazepine. 11- diazepine _ 11- (3-fluorophenyl) -5- [ε- (1-phthalimido) propyl] -5H-dibenzo [β, β], {] - diazepine 11- (2-bromophenyl) -5- [§ - (1-phthalimido) propyl7-5H-dibenzoLš, e] L1, ¶7-diazepine 11- (3-bromophenyl) -5-lä- (1-phthalimido) propylph-SH-dibenzo [§, e7 [fi, g d-diazepine and 1- (4-chlorophenyl) -s- [z- (1-phthalimino) -propyl] -7-5n-aibenzo] -E, e] j, 4] -diazepine to give 5- (3-aminopropyl) -11 - (2-chlorophenyl) -SH-dibenzo [B, _] [1,1'-f-diazepine hydrochloride-5 (3-aminopropyl) -11- (3-chlorophenyl) -SH-dibenzoLÉ, e7 [ï, § ] -diazepine hydrochloride 5- (3-aminopropyl) -11- (2-fluorophenyl) -5H-dibenzo [e, 7], 4] - diazepine hydrochloride 5- (3-aminopropyl) -11- (3- fluorophenyl) -SH-dibenzo [e, [], [d]] -diazepine hydrochloride b- (3-aminopropyl) -11- (2-bromophenyl) -SH-dibenzo [α] [4] -diazepine hydrochloride 5- (3-aminopropyl) -11- (3-bromophenyl) -5H-dibenzolE, e] [fi, 4] - diazepine hydrochloride 5- (3-aminopropyl) -11- (4-chlorophenyl) -5H -dibenzo_ß, e] ¿ï, ¶7-diazepine hydrochloride.
Exemgel 4 N-metyl-11-fenyl-SH-dibensoÅÉ,e][ï,Q]-diazepin-5-propanamin-hyd- roklorid Hydrokloridsaltet av 5~(3-aminopropyl)-11-fenyl-SH-dibenso¿§]e]~ 448 13f53_ /1,4/-diazepin omvandlades till den fria basen genom fördelning mellan utspädd natriumhydroxid och metylenklorid, torkning och koncentrering av metylenkloridfasen till torrhet, tillsats av torr bensen och åter koncentration för avdrivning av bensenen. Den re- sulterande fria basen upplöstes i ett stort överskott nydestille- rad trietylortoformiat och återflödeskokades under åtskilliga tim- mar. Blandningen koncentrerades i vakuum, etanol tillsattes och blandningen koncentrerades åter. Det resulterande imidatet upplös- tes i etanol och natriumborhydrid tillsattes under omröring vid 15-ZOOC till dess tunnskiktskromatografi visade frånvaro av väsent- liga mängder utgångsmaterial. Blandningen kyldes och tvättades för- siktigt med rikligt med vatten följt av extraktion med etylacetat.Example 4 N-methyl-11-phenyl-5H-dibenzo [e, [], [Q] -diazepine-5-propanamine hydrochloride The hydrochloride salt of 5- (3-aminopropyl) -11-phenyl-5H-dibenzo] 444 13f53_ / 1,4 / -diazepine was converted to the free base by partitioning between dilute sodium hydroxide and methylene chloride, drying and concentrating the methylene chloride phase to dryness, adding dry benzene and again concentrating to evaporate the benzene. The resulting free base was dissolved in a large excess of freshly distilled triethyl orthoformate and refluxed for several hours. The mixture was concentrated in vacuo, ethanol was added and the mixture was concentrated again. The resulting imidate was dissolved in ethanol and sodium borohydride was added with stirring at 15-ZOOC until its thin layer chromatography showed the absence of significant amounts of starting material. The mixture was cooled and carefully washed with plenty of water followed by extraction with ethyl acetate.
Etylacetatet tvättades till neutral reaktion och filtrerades och indunstades. Oren fri bas isolerades med kolonnkromatografi och fick reagera med en eterlösning av väteklorid och omkristalliserades, varvid titelföreningen erhölls.The ethyl acetate was washed until neutral and filtered and evaporated. The crude free base was isolated by column chromatography and reacted with an ethereal solution of hydrogen chloride and recrystallized to give the title compound.
Exemgel 5 Förfarandet enligt exempel 4 följdes genom utbyte av 5-(3-amino- propyl)-11-fenyl-5H-dibenso¿§,e][],g7-diazepin mot ekvimolära mäng- der av följande 5-(3-aminopropyl)-11-(2-klorofenyl)-5H-dibenso[ß,§7[ï,@7-diazepin- hydroklorid s- (s-aminapropyl) -1 1-<3-1<1<>rofeny1) -sa-aibenso[ ,e_7 [ , 4_7-diazepin- hydroklorid _ 5-(3-aminopropyl)-11-(2-fluorofenyl)-5H-dibenso;§,;7_í,Q7-diazepin- hydroklorid 5-(3-aminopropyl)-11-(3-fluorofenyl)-SH-dibenso[É,e]¿ï,47-diazepin- hydroklorid 5-(3-aminopropyl)-11-(2-bromofenyl)-5H-dibenso[§,e7[',_]-diazepin- hydroklorid s-(a-aminopropyl)-11-(3-brom0feny1)-sH-aibenscß ,e]/_'1 , fzj-aiazepin- hydroklorid och 5-(3-aminopropyl)~11-(4-klorofenyl)-SH-dibenso[§,e]¿ï,Q]-diazepin- hydroklorid varvid erhölls J* 448 453 7-diazepin~5-propan- 11- (z-klorofenyl) -N-mety1-5H-dibenso/_BAfiß , amin-hydroklorid 11-(3-klorofenyl)~N-metyl-5H-dibenso[_,éY_fi,Q]-diazepin-5-propan~ amJIn-hydroklorid 11-(2-fluorofenyl)-N-metyl-5H-dibensolß,Q];ï,4]-diazepin-5-propan- amin-hydroklorid 11-(3-fluorofenyl)-N-metyl-5H-dibenso[E,e'Lï,{]-diazepin~5-pr0pan- amin-hydroklorid 11-(2-bromøfenyl)-N-metyl-5H-dibenso[š,q7;ï,{7~diazepin-5-propan- amin-hyarokloria ¶ 11-(3-bromofenyl)-N-metyl-SH-dibensoLE,e][Ü,4]-diazepin-5-propan~ amin-hydroklorid och 11-(4-klorofenyl)-N-metyl-5H-dibenso[E,e_[f,Q]-diazepin-5-propan- amin-hydroklorid.Example 5 The procedure of Example 4 was followed by exchanging 5- (3-aminopropyl) -11-phenyl-5H-dibenzo [e] [], 77-diazepine for equimolar amounts of the following 5- (3- aminopropyl) -11- (2-chlorophenyl) -5H-dibenzo [β, §7 [α, β-diazepine hydrochloride s- (s-aminapropyl) -1 1- <3-1 <1 <> rophenyl) - sa-aibenzo [, e_7 [, 4_7-diazepine hydrochloride _ 5- (3-aminopropyl) -11- (2-fluorophenyl) -5H-dibenzo; §,; 7_í, Q7-diazepine hydrochloride 5- (3-aminopropyl ) -11- (3-fluorophenyl) -SH-dibenzo [ε, e] β, 47-diazepine hydrochloride 5- (3-aminopropyl) -11- (2-bromophenyl) -5H-dibenzo [§, e7 [ 1- [3] -Diazepine hydrochloride s- (α-aminopropyl) -11- (3-bromophenyl) -sH-aylbenzyl, e] -1H-1,6-aiazepine hydrochloride and 5- (3-aminopropyl) -11 - (4-chlorophenyl) -SH-dibenzo [§, e] β, Q] -diazepine hydrochloride to give J * 448 453 7-diazepine-5-propane-11- (z-chlorophenyl) -N-methyl- 5H-Dibenzo [BABA] β, amine hydrochloride 11- (3-chlorophenyl) -N-methyl-5H-dibenzo [_, eY_ fi, Q] -diazepine-5-propan-amino] hydrochloride 11- (2-fluorophenyl) -N -methyl-5H-dibenzol, Q], [4] -diazepine-5-propanamide n-hydrochloride 11- (3-fluorophenyl) -N-methyl-5H-dibenzo [E, e'L1, {] - diazepine-5-propanamine hydrochloride 11- (2-bromophenyl) -N-methyl-5H -dibenzo [š, q7; ï, {7-diazepine-5-propanamine-hyarochloria ¶ 11- (3-bromophenyl) -N-methyl-SH-dibenzoLE, e] [Ü, 4] -diazepine-5- propan-amine hydrochloride and 11- (4-chlorophenyl) -N-methyl-5H-dibenzo [E, e- [f, Q] -diazepine-5-propan-amine hydrochloride.
Claims (1)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US30507681A | 1981-09-24 | 1981-09-24 |
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| SE448453B true SE448453B (en) | 1987-02-23 |
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| BE (1) | BE891535A (en) |
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| DE (1) | DE3149923A1 (en) |
| DK (1) | DK531281A (en) |
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| GR (1) | GR75123B (en) |
| HK (1) | HK85785A (en) |
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| AT228215B (en) * | 1959-01-23 | 1963-07-10 | Wander Ag Dr A | Process for the production of new diazepine derivatives |
| GB907646A (en) * | 1959-01-23 | 1962-10-10 | Wander S A A | Method of production of new derivatives of diazepin |
| NL256053A (en) * | 1959-09-22 | |||
| AT226721B (en) * | 1959-09-22 | 1963-04-10 | Wander Ag Dr A | Process for the preparation of new, 5-substituted diazepines |
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