SE407686B - ANALOGICAL PROCEDURE FOR PREPARING CONDENSED PYRIMIDINE DERIVATIVES - Google Patents

ANALOGICAL PROCEDURE FOR PREPARING CONDENSED PYRIMIDINE DERIVATIVES

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Publication number
SE407686B
SE407686B SE7312873A SE7312873A SE407686B SE 407686 B SE407686 B SE 407686B SE 7312873 A SE7312873 A SE 7312873A SE 7312873 A SE7312873 A SE 7312873A SE 407686 B SE407686 B SE 407686B
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group
sulfur
carbon atoms
pyrimidino
acid
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SE7312873A
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Swedish (sv)
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Der Burg W J Van
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Akzo Nv
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Publication of SE407686B publication Critical patent/SE407686B/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Psychiatry (AREA)
  • Anesthesiology (AREA)
  • Pain & Pain Management (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Description

7z12a7z-a _ atomer eller en trifluormetylgrüpp, R3-betecknar väte, en alkylgrupp med 1-6 kolatomer eller en fenylalkylgrupp med 7-10 kolatomer, X betecknar syre, svavel, gruppen N-R4 eller gruppen -CR5R6-, och R4, RS, R6 betecknar väte eller en lägre alkylgrupp med l-6 kolatomer, jämte de farmaceutiskt godtagbara syraadditionssalterna och de farma- ceutiskt godtagbara kvaternära ammoniumföreningarna, har en fullstän- digt annan farmakologisk profil. Föreningarna enligt denna uppfinning uppvisar, i direkt motsats till de i den brittiska patentskriften beskrivna föreningarna, en positiv effekt i reserpinantagonismtesten, vilket betyder att de har antidepressorverkan, medan antihistamin- och antiserotoninverkan hos de föreliggande föreningarna är avsevärt lägre jämfört med den starka antihistamin- och/eller antiserotonin- verkan hos de~i den brittiska patentskriften beskrivna föreningarna. 7z12a7z-a atoms or a trifluoromethyl group, R 3 represents hydrogen, an alkyl group with 1-6 carbon atoms or a phenylalkyl group having 7-10 carbon atoms, X represents oxygen, sulfur, the group N-R4 or the group -CR5R6-, and R 4, R 5, R 6 represent hydrogen or a lower alkyl group having 1-6 carbon atoms, together with the pharmaceutically acceptable acid addition salts and the culturally acceptable quaternary ammonium compounds, has a complete another pharmacological profile. The compounds of this invention exhibits, in direct contrast to those in the British patent specification described compounds, a positive effect in the reserpine antagonism test, which means that they have antidepressant action, while antihistamines and the antiserotonin effect of the present compounds is considerable lower compared to the strong antihistamine and / or antiserotonin action of the compounds described in the British patent specification.

Föreningarna enligt föreliggande uppfinning kan framställas genom någon känd metod som vanligen används för denna typ av förening- ar. De framställs emellertid lämpligast utgående från ett ämne med följande allmänna formeln ii (R (II) eller ett syraadditionssalt därav, i vilken X, RI,-R2, R3, r och s har den tidigare angivna betydelsen och.Q betecknar väte (H2) eller syre.The compounds of the present invention can be prepared by any known method commonly used for this type of compound are. However, they are most conveniently prepared from a substance with the following general formula ii (R (II) or an acid addition salt thereof, in which X, R 1, -R 2, R 3, r and s have the previously indicated meaning and.Q represents hydrogen (H2) or oxygen.

Utgångsämnet II cykliseras med hjälp av en kondensation med ett reagens med formeln z I Z l (III) i vilken Y betecknar väte (H2), syre eller svavel och Zl och Z2 be- tecknar samma eller olika grupper valda bland halogen, en substituerad eller osubstituerad aminogrupp eller en fri, företrad eller sulfony- 3 7z12a7z-s lerad hydroxigrupp, eller tillsammans kan vara svavel, om Y - svavel, och kan avlägsnas tillsammans med väteatomerna som är bundna till _ båda kväveatomerna hos diaminen II för att på så sätt bilda en för- eníng med formeln (Rl)r ' (R ~ 1 vilken x. Y, Q, RI, BZ, R3, r och s har den tidigare angivna be- tydelsen.The starting material II is cyclized by means of a condensation with one reagents of the formula z I Z l (III) in which Y represents hydrogen (H2), oxygen or sulfur and Z1 and Z2 denotes the same or different groups selected from halogen, a substituted or unsubstituted amino group or a free, etherified or sulfonyl 3 7z12a7z-s hydroxy group, or together may be sulfur, if Y - sulfur, and can be removed together with the hydrogen atoms attached to both nitrogen atoms of diamine II to form a one with the formula (Rl) r '(R Which x. Y, Q, R 1, B 2, R 3, r and s have the previously indicated the interpretation.

Om Y betecknar väte (=H2), betecknar Zl och Z2 företrädesvis halogen eller hydroxigrupper. Reagens III som tillhör denna typ av föreningar är exempelvis metylenklorid, metylenbromid eller metylen- diol (= formaldehydlösning i vatten eller ett vattenhaltigt lösnings- medel).If Y represents hydrogen (= H2), Z1 and Z2 preferably represent halogen or hydroxy groups. Reagent III belonging to this type of compounds are, for example, methylene chloride, methylene bromide or methylene bromide. diol (= formaldehyde solution in water or an aqueous solution average).

Om Y betecknar syre eller svavel, är de lämpligaste betydelserna av Zl och Z2 halogen, substituerade eller osubstituerade amino-_ _ grupper, en företrad eller sulfonylerad hydroxigrupp, eller också är Zl och Z2 tillsammans svavel (i kombination med Y = svavel).If Y represents oxygen or sulfur, the most appropriate meanings are of Z1 and Z2 halogen, substituted or unsubstituted amino groups, a etherified or sulfonylated hydroxy group, or also Z1 and Z2 together are sulfur (in combination with Y = sulfur).

Lämpliga reagens III som tillhör denna typ av föreningar är exempelvis fosgen, tiofosgen, halogenmyrsyraestrar såsom etylklorformiat, estrar av kolsyra såsom dimetyl- eller dietylkarbonat, karbamid och karbamid- derivat såsom tiokarbamid eller N,N'-karbonyl-di-imidazol, och kol- svavla.Suitable reagents III belonging to this type of compounds are, for example phosgene, thiophosgene, haloformic acid esters such as ethyl chloroformate, esters of carbonic acid such as dimethyl or diethyl carbonate, urea and urea derivatives such as thiourea or N, N'-carbonyl-di-imidazole, and carbon sulfur.

Företrädesvis användes metylenhalid eller formaldehyd (i vatten) som reagenset III i den föreliggande kondensationsreaktionen, om ut- gângsmaterialet II inte innehåller en ketogrupp (Q = H2), emedan de ger den önskade slutprodukten enligt uppfinningen direkt.Preferably methylene halide or formaldehyde (in water) is used as reagent III in the present condensation reaction, if the starting material II does not contain a keto group (Q = H2), because they gives the desired end product of the invention directly.

Om ett reagens med formeln III, i vilket Y betecknar syre eller svavel och/eller en utgångsförening II i vilken Q betecknar syre används, måste den bildade föreningen ytterligare reduceras för att man skall erhålla den önskade slutprodukten. För en sådan reduktion kan man använda vilket som helst lämpligt reduktionsmedel, exempelvis metallhydrider såsom natriumhydrid, litiumaluminiumhydrid eller diboran. Denna reduktion kan även utföras katalytiskt genom hydrering 7312873-8 i närvaro av en metall eller en metallförening.If a reagent of formula III, in which Y represents oxygen or sulfur and / or a starting compound II in which Q represents oxygen used, the compound formed must be further reduced to to obtain the desired end product. For such a reduction one can use any suitable reducing agent, for example metal hydrides such as sodium hydride, lithium aluminum hydride or diboran. This reduction can also be carried out catalytically by hydrogenation 7312873-8 in the presence of a metal or a metal compound.

Om Zl och/eller Zz betecknar halogen sättes vanligen till reak- tionsblandningen ett ämne som förmår eliminera den under kondensa- tionsreaktionen bildade vätehaliden, såsom pyridin, trietylamin etc.If Z1 and / or Z2 represent halogen, it is usually added to the reaction. mixture a substance capable of eliminating it during condensation the hydrogen reaction formed the hydrogen halide, such as pyridine, triethylamine, etc.

Kondensationsreaktionen kan genomföras i något lämpligt lösnings- medel. När metylenhalid användes som reagenset III, är ett aprotiskt polärt lösningsmedel särskilt föredraget, såsom dimetylsulfoxid, sul- folan eller'acetonitril. Man kan emellertid även genomföra kondensa- tionen uteslutande i reagenset III, sålunda i frånvaro av något (yt- terligare) lösningsmedel. I vissa fall, exempelvis när karbamid an- vänds som reagenset III, kan kondensationen genomföras i en smälta; De-utgångsämnen med formeln II, som erfordras enligt uppfinningen, kan framställas genom något förfarande som är beskrivet för liknande föreningar. Sålunda kan exempelvis föreningen 6-klor-metyl-llH-dibenso- ¿fb,e_7azepin omsättas med ett cyanat, exempelvis natriumcyanat. Den bildade nitrilen kan därefter antingen reduceras till den motsvarande aminoföreningen eventuellt åtföljt av införande av den önskade R3- gruppen, för att man på så sätt skall erhålla en förening II med Q = H2, eller hydrolyseras eventuellt åtföljt av införande av R3- gruppen, för att man på så sätt skall erhålla en förening II i vilken Q = syre. 7 Syraadditionssalterna av föreningarna enligt uppfinningen fram- ställs på konventionellt sätt genom omsättning av den fria basen med en farmaceutisktgodtagbar syra, såsom klorvätesyra, bromvätesyra eller jodvätesyra, fosforsyra, ättiksyra, propionsyra, glykolsyra, maleinsyra, malonsyra, bärnstenssyra, vinsyra, citronsyra, askorbin- syra, salicylsyra eller bensoesyra.The condensation reaction can be carried out in any suitable solution. average. When methylene halide is used as reagent III, it is an aprotic polar solvent particularly preferred, such as dimethyl sulfoxide, folan or acetonitrile. However, it is also possible to carry out condensate exclusively in reagent III, thus in the absence of any (surface further) solvents. In some cases, for example when urea is used turned as reagent III, the condensation can be carried out in a melt; The starting materials of formula II required by the invention can be prepared by any process described for the like associations. Thus, for example, the compound 6-chloro-methyl-11H-dibenzo- ¿Fb, e_7azepine is reacted with a cyanate, for example sodium cyanate. The formed nitrile can then either be reduced to the corresponding one the amino compound optionally accompanied by the introduction of the desired group, in order to obtain a compound II with Q = H2, or optionally hydrolyzed followed by the introduction of R3 group, in order to obtain a compound II in which Q = acid. 7 The acid addition salts of the compounds of the invention are prepared in a conventional manner by reacting the free base with a pharmaceutically acceptable acid, such as hydrochloric acid, hydrobromic acid or hydroiodic acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, succinic acid, tartaric acid, citric acid, ascorbic acid acid, salicylic acid or benzoic acid.

De farmaceutiskt godtagbara kvaternära ammoniumföreningarna, i synnerhet de kvaternära lägre (1-4 C) alkylammoniumföreningarna, erhålls genom.omsättning av föreningarna med den allmänna formeln I med en alkylhalid, exempelvis metyljodid eller metylbromid.The pharmaceutically acceptable quaternary ammonium compounds, in particular the quaternary lower (1-4 C) alkylammonium compounds, is obtained by reacting the compounds of general formula I with an alkyl halide, for example methyl iodide or methyl bromide.

Från den ovanstående allmänna formeln I Üframgår att föreningarna enligt uppfinningen har en asymmetrisk kolatom. Följaktligen är op- tiska antipoder möjliga, vilka även faller under uppfinningen. Dessa optiska antipoder kan isoleras från den racemiska blandningen på konventionellt sätt. Man kan även separera den racemiska utgångspro- dukten II i dess optiska antipoder och utföra kondensationsreaktionen efter detta, eller separera en mellanprodukt erhållen under den ovan- nämnda syntesen av föreningarna I.From the above general formula I it appears that the compounds according to the invention has an asymmetric carbon atom. Consequently, op- possible antipodes, which also fall within the scope of the invention. These optical antipodes can be isolated from the racemic mixture on conventional way. One can also separate the racemic starting product duct II in its optical antipodes and perform the condensation reaction after this, or separate an intermediate obtained under the above said synthesis of the compounds I.

Man kan naturligtvis införa eller modifiera substituenterna vid 5 " p 7312873-s den ena eller båda fenylkärnorna efter kondensationsreaktionen. Sålun- da kan exempelvis en närvarande hydroxigrupp acyleras eller omvandlas till en alkoxigrupp, en aminogrupp till en halogengrupp, en metoxi- grupp till en hydroxigrupp etc.One can, of course, introduce or modify the substituents at 5 "p 7312873-s one or both phenyl nuclei after the condensation reaction. Sålun- then, for example, a hydroxy group present can be acylated or converted to an alkoxy group, an amino group to a halogen group, a methoxy- group to a hydroxy group etc.

Substituenten (R3) vid N3~kväveatomen kan även erhållas efter kondensationsreaktionen genom alkylering eller aralkylering av den osubstituerade kväveatomen (R3 = H) eller genom acylering av den osubstituerade kväveatomen åtföljt av en reduktion av karbonyldelen hos den så erhållna N-acylföreningen.The substituent (R3) at the N3 nitrogen atom can also be obtained after the condensation reaction by alkylation or aralkylation thereof unsubstituted nitrogen atom (R3 = H) or by acylation thereof unsubstituted nitrogen atom accompanied by a reduction of the carbonyl moiety of the N-acyl compound thus obtained.

Det är även tydligt och känt att man kan omvandla den alkyl- eller aralkylsubstituerade N3~kväveatomen (avformeln I) till det osubstituerade kvävet, exempelvis genom värmning med klormyrsyraester, âtföljt av hydrolys av den så erhållna föreningen.It is also clear and well known that the alkyl or the aralkyl-substituted N3 nitrogen atom (Formula I) thereof unsubstituted nitrogen, for example by heating with chloroformic acid ester, followed by hydrolysis of the compound thus obtained.

Föreningarna enligt föreliggande uppfinning har såsom redan anförts en helt annan farmakologisk profil än de besläktade kända piperazinderivaten, som är beskrivna i den brittiska patentskriften 'l 229 252.The compounds of the present invention have, as already stated a completely different pharmacological profile than the related known ones piperazine derivatives, which are described in the British patent specification 'l 229 252.

De föreliggande uppfinningarna uppvisar en positiv effekt i reserpin-antagonismtesten och i reserpin-reverseringstesten, vilket“ betyder att de kan användas som antídepressormedel. De föreliggande föreningarna har mera allmänt starka CNS-stimulerande egenskaper, vilka tillsammans med deras verkningar mot aggression betyder att föreningarna enligt föreliggande uppfinning även har starka anxio- lytiska egenskaper.The present inventions have a positive effect in the reserpine antagonism test and in the reserpine reversal test, which “ means that they can be used as antidepressants. The present the compounds have more generally strong CNS stimulating properties, which together with their effects against aggression means that the compounds of the present invention also have strong anxiolytic lytic properties.

De kan administreras både oralt och parenteralt, företrädesvis i en dos mellan 0,01 och l0 mg/kg kroppsvikt. I blandning med lämp- liga hjälpmedel kan föreningarna pressas till fasta dosenheter, såsom piller, tabletter och överdragna tabletter. De kan även bearbetas till kapslar, eventuellt i blandning med hjälpmedel. Med hjälp av lämpliga vätskor kan föreningarna I användas som injektionspreparat i form av lösningar, emulsioner eller suspensioner.They can be administered both orally and parenterally, preferably in a dose between 0.01 and 10 mg / kg body weight. In mixture with suitable For example, the compounds may be compressed into solid dosage units, such as pills, tablets and coated tablets. They can also be processed to capsules, possibly in admixture with adjuvants. Using suitable liquids, the compounds I can be used as injection preparations in the form of solutions, emulsions or suspensions.

Föreningar som företrädesvis används enligt uppfinningen är följande: 3-metyl4l,2,3,4,10,l4b-hexahydro-pyrimidino¿“3,4-a_7dibenso¿_c,f_7- azepin, > a-metyi-i , 3 , 4 , Mza-tetrahyaro-zn-pyrimidinofs , 4-a_7aibenso[b , f_7- (l,4)oxazepin, ' ' _ 3,11-dimetyl-l,3,4,l4b~tetrahydro-2H~pyrimidino¿_3,4-d_7dibenso- [_b,f_7(l,4)oxanzepin.HCl, 3-metyl-7-trifluormetyl-1,3,4,14b-tetrahydro-2H-pyrimidino¿_3,4~d_75 dibenso¿"b,f_7(l,4)tiazepin, vanan-s p 6 3-metyl-13-klor-1 , 3 , 4 , lßlb-tetrahydro-2H-pyrimidino-_¿_3 , 4-d_7dibenso- ['b , f__7 (1 ,í4 ) oxaeepin , 3 , l0-dimetyl-l3-metoxi-l, 2 , 3 , 4 , 10 , 14b-hexahydrofpyrimidino['3 , 4-d__7- dibenso['b,f_7(l,4)diazepin. * Följande exempel tjänar till att ytterligare belysa uppfinningen.Compounds which are preferably used according to the invention are following: 3-methyl4l, 2,3,4,10,14b-hexahydro-pyrimidino [3,4-a_7dibenzo3c, f_7- azepine,> α-methyl-i, 3,4,4-Mza-tetrahyaro-zn-pyrimidinofs, 4-a_7aibenzo [b, f_7- (1,4) oxazepine, 3,11-dimethyl-1,3,4,14b-tetrahydro-2H-pyrimidino [3,4-d] benzibenzo- [_b, f_7 (1,4) oxanzepine.HCl, 3-Methyl-7-trifluoromethyl-1,3,4,14b-tetrahydro-2H-pyrimidino [3,4-d] 75 dibenzo "b, f_7 (1,4) thiazepine, vanan-s p 6 3-methyl-13-chloro-1,3,4,4,11b-tetrahydro-2H-pyrimidino-3,4-dibenzo- ['b, f__7 (1, í4) oxaeepin, 3,0-dimethyl-13-methoxy-1,2, 3, 4, 10, 14b-hexahydro-pyrimidino [3,4-d] -7- dibenzo ['b, f_7 (1,4) diazepine. * The following examples serve to further illustrate the invention.

I exemplen har följande nomenklatur och numrering används: l , 3 , 4 , 1415-tetrahydrö-2H-pyrimidino- _/__3 , 4-d_7dibenso¿_b , f__7(l , 4 ) oxazepin. _ 9 10 IJ ' ' s °Kï7°\íT// fz 1,3,4,14b-tetranyaro-2n-pyrimiaino- /"3 4-d 7aibens°/"b,f 7(1,4)tiazepin. 77 13 _ f __ _ _ ßtqub G - 11-» , 1 a N 10 2 n _ a N \ u -; p \\ _ _ .In the examples, the following nomenclature and numbering have been used: 1,3,4,4,1415-tetrahydro-2H-pyrimidino- _ / __ 3,4-d_7dibenzo¿_b, f__7 (1,4) oxazepine. _ 9 10 IJ '' s ° Kï7 ° \ íT // fz 1,3,4,14b-tetranyaro-2n-pyrimiaino- / "4 4-d 7aibens ° /" b, f 7 (1,4) thiazepine. 77 13 _ f __ _ _ ßtqub G - 11- », 1 and N 10 2 n _ a N \ u -; p \\ _ _.

I I 1 , 2 , 3 , 4 , 10 , l4b-hexahydro-pyr1m1d1no- - V 1 \N__ - ¿¿,1a ¿'3,4-a_/a1bens0¿fb,f_7(1,4)d1azepin. l , 2 , 3 , 4 , 10 , lllb-hexahydro-pyrimidino- á-B , 4-a__',7dibenso[_c , f_7azepin .I I 1, 2, 3, 4, 10, 14b-hexahydro-pyridinyldino- - V 1 \ N__ - ¿¿, 1a ¿'3,4-a_ / a1bens0¿fb, f_7 (1,4) d1azepine. 1,2, 3, 4, 10,11b-hexahydro-pyrimidino- á-B, 4-a __ ', 7dibenso [_c, f_7azepin.

X = O: ll-aminoetyl-lüJl-dihydro- dibensoá-b ; f_7(l , 4 ) oxazepin . x = s= 11-aminoetyl-10,11ldihyaro- dibenso_/__b , f_7 ( l , 4 ) tiazepin.X = O: 11-aminoethyl-11H-dihydro- dibenzoá-b; f_7 (1,4) oxazepine. x = s = 11-aminoethyl-10,11ldihyaro- dibenso _ / __ b, f_7 (l, 4) thiazepine.

X = N: 1l-aminoetyl-lO-ll-dihydro- SH-dibensoif-b , e_7 ( 1 , 4 ) diazepin . 7 7312873-8 6-aminoetyl-5,6-dihydro-llH- dibenso¿~b,e_7azepin eller 6-aminoetyl-5,6-dihydro-morfan- tridin.X = N: 11-aminoethyl-10-11-dihydro- SH-dibenzoif-b, e_7 (1, 4) diazepine. 7 7312873-8 6-aminoethyl-5,6-dihydro-11H- dibenso¿ ~ b, e_7azepine or 6-aminoethyl-5,6-dihydro-morphan- tridine.

EXEMPEL 1 å o É 3-metyi-1,2,3,4,1o;14b-hexanyara-pyrimiaino/'3,Ã-a 7a1benso- ¿*c,f 7azepin.fumarat 2 gavdiaminen 6-metylaminoetyl-5,6-dihydro-llH-dibenso¿_b,e_7¥ azepin (smp 124-l27°C) löstes i 25 ml 96 % etanol. Därefter tillsattes 10 ml av en 35 % formaldehydlösning i vatten, varefter blandningen lämnades att stå i 30 min. Därefter hälldes denna blandning i 250 ml vatten, varefter blandningen extraherades_med metylenklorid.EXAMPLE 1 å o É 3-methyl-1,2,3,4,1o; 14b-hexanyara-pyrimino-β, α-α ¿* C, f 7azepin.fumarat 2 gave diamine 6-methylaminoethyl-5,6-dihydro-11H-dibenzo [b], e_7 ¥ azepine (mp 124-127 ° C) was dissolved in 25 ml of 96% ethanol. Then added 10 ml of a 35% formaldehyde solution in water, then the mixture was left to stand for 30 min. Then this mixture was poured into 250 ml water, after which the mixture was extracted with methylene chloride.

Extraktet tvättades med vatten och torkades på natriumsulfat, varefter CH2Cl2~fasen förângades (olja) och återstoden löstes i 10 ml etanol.The extract was washed with water and dried over sodium sulfate. after which the CH 2 Cl 2 phase was evaporated (oil) and the residue was dissolved in 10 ml ethanol.

Denna lösning sattes till en lösning av 1,5 g fumarsyra i etanol.This solution was added to a solution of 1.5 g of fumaric acid in ethanol.

Den erhållna fällningen filtrerades, tvättades och torkades (1,7 g) och omkristalliserades därefter från etanol. smp 189-192°c.The resulting precipitate was filtered, washed and dried (1.7 g). and then recrystallized from ethanol. mp 189-192 ° C.

Rf i bensenzmetanol (9:l) = 0,48 på Si02.Rf in benzene methanol (9: 1) = 0.48 on SiO2.

EXEMPEL II _ . 1,2,3,4,1o,14b-hexanyaro-Dyrimiaino/'3,4-a 7-aibenso/"a,f 7- azegin och HCl-salt ' På samma sätt som beskrivits i exempel I löstes 2 g av diaminen 6-aminoetyl-s,6-ainydro-11n-aibensa¿'b,e_7-azepin (smp 152-1s3°o) i 10 ml av en 35 % formaldehydlösning vatten. Lösningen sattes åt sidan vid 20°C i 30 min, varefter den hälldes ut i 250 ml vatten och extraherades 3 ggr med metylenklorid, tvättades med vatten och indunstades med hjälp av en filmindunstare. Den återstående oljan renades med hjälp av en kromatograferingskolonn (lösningsmedelsb1and- ningen var bensen:metanol_i förhållandet 9:1) Rf i bensen:metanol (8:2) = 0,50 på SiO2.EXAMPLE II _. 1,2,3,4,1o, 14b-hexanyaro-Dyrimiaino / 3,4-a 7-aibenzo / "a, f 7- azegin and HCl salt ' In the same manner as described in Example I, 2 g of the diamine were dissolved 6-aminoethyl-s, 6-amino-11n-aibenzaba, e7-azepine (m.p. 152-13 ° C) in 10 ml of a 35% formaldehyde solution of water. The solution was added side at 20 ° C for 30 minutes, after which it was poured into 250 ml of water and extracted 3 times with methylene chloride, washed with water and was evaporated using a film evaporator. The remaining oil was purified by means of a chromatography column (solvent mixture). The reaction was benzene: methanol in a ratio of 9: 1) Rf in benzene: methanol (8: 2) = 0.50 on SiO2.

Därefter löstes den erhållna oljan i så litet Hcl-haltig alkohol som möjligt, varefter lösningen kyldes. De bildade kristallerna av- filtrerades. smp 212~217°c. vznzievzi-s 8 i j, Separering av 3*metyl-l,2,3,4,lO,l4b-hexahydro-pyrimidinof /_3,4-a 7-dibenso/_c,f 7-azepin _ Racemisk3-meeyl-1,z,3,4,1o,1ab-nexahyafo-pyrimiaino¿f3,4-a_7- fdibenso¿fc,f_7Fazepin (olja från exempel I, l,7 g) löstes i 20 ml etanol. Till denna lösning sattes en lösning av 1,3 g (+)~dibensoyl- vinsyra, även i 20 ml etanol. Efter 4 dagar filtrerades den bildade fällníngen och tvättades med etanol. Däreïter Behandlades fällningen med en lN natriumhydroxidlösning och eterl Eterskiktet utskildes, tvättades med vatten, torkades över natriumsulfat och indunstades.Thereafter, the resulting oil was dissolved in so little HCl-containing alcohol as possible, after which the solution was cooled. The crystals formed was filtered. mp 212 ~ 217 ° C. vznzievzi-s 8 i j, Separation of 3 * methyl-1,2,3,4,10,14b-hexahydro-pyrimidinoph / _3,4-a 7-dibenzo / _c, f 7-azepine _ Racemic-3-methyl-1, z, 3,4,1o, 1ab-nexahyafo-pyriminoino [3,4-a] -7- fdibenzofc, f_7Fazepine (oil from Example I, 1.7 g) was dissolved in 20 ml ethanol. To this solution was added a solution of 1.3 g of (+) - dibenzoyl- tartaric acid, also in 20 ml of ethanol. After 4 days, the formed was filtered the precipitate and washed with ethanol. Then the precipitate was treated with a 1N sodium hydroxide solution and ether The ether layer was separated, washed with water, dried over sodium sulfate and evaporated.

Hos den återstående oljan bestämdes vridningen. ¿'uD_725 = -437° (c = 0,1 1 etanol). l Den ovan beskrivna behandlingen av oljan upprepades 2 ggr för erhållande av en förening med ¿_aD_725 = -496° (c = 0,1 i etanol). smp 101-1o3°c.In the case of the remaining oil, the rotation was determined. ¿'UD_725 = -437 ° (c = 0.1 l ethanol). l The treatment of the oil described above was repeated twice to give a compound with ¿_aD_725 = -496 ° (c = 0.1 in ethanol). mp 101-1o3 ° c.

På samma sätt erhölls den-(+) vridande isomeren genom omsättning av racematet med K-)-dibensoylvinsyra. ¿~aD_725 = +492° (c = 0,1 i metanol).In the same way, the - (+) rotating isomer was obtained by reaction of the racemate with K -) - dibenzoyltartaric acid. Δ ~ aD_725 = + 492 ° (c = 0.1 in methanol).

EXEMPEL 'IV Genom det i exempel I beskrivna förfarandet framställdes föl- jande ämnen: 1. 3-metyl-1,3,4,14b-tetranyaro-za-pyrimid1no¿"3,4-a_7aibens°- ¿fb,f_7(1,4)oxazepin.Hc1, smp 215-21e°c; ' 2. 13-klor-3-metyi-1,3,4,14b-tetrahyaro-zn-pyrimiaino¿"3,4-aj7- dibenso¿_b,f_7(l,4)oxazepin.HCl, smp 220-22200; 3. 3,ll-dimetyl-l,3,4,l4b-tetrahydro-2H-pyrimidino¿~3,4-d_7F dibenso¿_b,f_7(l,4)oxazepin.HCl, smp 219-222°C; 4. 3-metyl-7-triflüorometyl-l,3,4,l4b-tetrahydror2H-pryimidino~ ¿f3,4-d_7aibenzo¿fb,f_7(1,4)tiazepin.HBr, smp 190-193°c; 5. 3,7-aimetyi-1,3,4,14b-tetranyarø-za-pyr1m1aino¿"3,4-a¿7- dibenso¿~b,f_7(l,4)oxazepin.maleat, smp l64-l66°C; 6. 3,13-dimetyl-1,3,4,14b-tetranydro-zu-pyrimidin0¿"3,4-a_7- dibenso¿_b,f_7(l,4)oxazepin.EXAMPLE IV By the procedure described in Example I, the following topics: 3. 3-Methyl-1,3,4,14b-tetranyaro-za-pyrimidino-3,4-α-7-benzyl ¿Fb, f_7 (1,4) oxazepine.Hc1, mp 215-21e ° c; ' 2. 13-Chloro-3-methyl-1,3,4,14b-tetrahyaro-zn-pyriminoino] 3,4-aj7- dibenzoβ, f_7 (1,4) oxazepine.HCl, m.p. 220-22200; 3,1,11-dimethyl-1,3,4,4,4-tetrahydro-2H-pyrimidino [3,4-d] -7F dibenzoβ, f_7 (1,4) oxazepine.HCl, mp 219-222 ° C; 4. 3-Methyl-7-trifluoromethyl-1,3,4,14b-tetrahydror2H-pyrimidino- ¿F4,4-d_7aibenzo¿fb, f_7 (1,4) thiazepine.HBr, mp 190-193 ° c; 5. 3,7-Amethyl-1,3,4,14b-tetranyaro-za-pyrrolimino-3,4-a77- dibenzoβ, f_7 (1,4) oxazepine maleate, mp 164-166 ° C; 6. 3,13-dimethyl-1,3,4,14b-tetranydro-zu-pyrimidino [3,4-a] -7- dibenzo¿_b, f_7 (1,4) oxazepine.

EXEMPEL V _ g _ 3,10-aimetyl-1,2,3,4,10,14b-nexahyaro-pyrimiaino/"3,4-d 7= dibenso/*b,f 7(1,4)diazepinaerivat f 1 gnav diaminen 5-metyl-ll-metylaminoetyl-lÖ,ll-dihydro-5H- -dibenso¿_b,e_7(l,4)diazepin löstes i 20 ml 90 % etanol. Till denna lösning sattes 5 ml av en 35 % formaldehydlösning i vatten. Bland- ningen lämnades att stå i llh vid rumstemperatur och därefter hälldes ..._... _ ..-.-n«v« u-.wflo-a-.ø-A-a m. - - ~ ............ ...wa-nu ._.~..\_..~.....°_. ...m . M...- 7z12a?3-s den i 150 ml vatten. Extrahering med metylenklorid och indunstning av denna CH2C12*fas gav den fria basen som en olja.EXAMPLE V _ g _ 3,10-Amethyl-1,2,3,4,10,14b-nexahyaro-pyrimino [3,4-d 7 = dibenzo / * b, f 7 (1,4) diazepine derivative f 1 g of diamine 5-methyl-11-methylaminoethyl-10,11-dihydro-5H- -dibenzoβ, e7 (1,4) diazepine was dissolved in 20 ml of 90% ethanol. To this solution was added 5 ml of a 35% formaldehyde solution in water. Among- The mixture was allowed to stand for 11 h at room temperature and then poured ..._... _ ..-.- n «v« u-.w fl o-a-.ø-Aa m. - - ~ ............ ... wa-nu ._. ~ .. \ _ .. ~ ..... ° _. ... m. M ...- 7z12a? 3-s it in 150 ml of water. Extraction with methylene chloride and evaporation of this CH 2 Cl 2 * phase gave the free base as an oil.

Rf i metanol = 0,35 på S102. Jodmetylat: smp 212-2l5°C.Rf in methanol = 0.35 on S102. Iodomethylate: mp 212-215 ° C.

Utgående från diaminen: 2-metoxi-5-metyl-ll-metylaminoetyl- -10,ll-dihydro-SH-dibensolfb,e_7(l,4)diazepin (smp för HB:-saltet 207-208°C) framställdes den fria basen 3,l0-dimetyl-13-metoxi-l,2,3,~ 4 ,1ßlb-hexahyaro-pyrlmialnofs; 4-a_7-dlbenso[b , f_7 (l , 4 nllagopln som en olja på samma sätt. Pikratets smp var 103-l08QC.Starting from the diamine: 2-methoxy-5-methyl-11-methylaminoethyl- -10,11-dihydro-5H-dibenzolbb, e_7 (1,4) diazepine (m.p. for the HB: salt 207-208 ° C) the free base 3,10-dimethyl-13-methoxy-1,2,3 4,11β-hexahyaro-pyriminalnofs; 4-a_7-dlbenzo [b, f_7 (1,4 nllagopln som an oil in the same way. The melting point of the picrate was 103-108 ° C.

Rf i metanol = 0,45.pâ SiO2. ¿ En del av detta ämne omvandlades därefter dill fumaratet (se exempel I), smp 216-2l5°C, en annan del till jodmetylatet (smp zo4-2o1°c) med hjälp av cn3a.Rf in methanol = 0.45 on SiO2. ¿ Some of this substance was then converted to the dill fumarate (see Example I), mp 216-215 ° C, another portion of the iodomethylate (m.p. zo4-2o1 ° c) using cn3a.

EXEMPEL VI Genom samma förfarande som beskrivits i exempel II framställdes följande föreningar: l. 1,3,4,14b-tetrahydro-2H-pyrimidino¿_3,4-d_7dibenso¿fb,f_7- (l,4)oxazepin.HCl; smp 199-204°C.EXAMPLE VI By the same procedure as described in Example II was prepared the following compounds: 1,3,4,4,14b-tetrahydro-2H-pyrimidino3,4-d-7-dibenzo [b], f_7- (1,4) oxazepine.HCl; mp 199-204 ° C.

Rf i metanol = 0,90 på S102. _ 2. 7-trifluorometyl-1,3,4,l4b-tetrahydro-2H-pyrimidino¿"3,4-d_7- dibenso¿_b,f_7(l,4)tiazepin; smp 123-l26°C.Rf in methanol = 0.90 on S102. _ 2. 7-Trifluoromethyl-1,3,4,14b-tetrahydro-2H-pyrimidino [3,4-d] -7- dibenzoβ, f_7 (1,4) thiazepine; mp 123-126 ° C.

Rf i bensen: etylacetat (7:3) = 0,25 på SiO2. 3. 10-metyl-13-metoxi-1,2,3,4,10,l4b-hexahydro-pyrimidino- [3,bajalbonsofb,f_7(l,4)aiazopln (olja) Rf i metanol = 0,51 på S102. j ' Rf i etylacetat = 0,40 på S102. 4. ll-metyl-1,3,4,l4b-tetrahydro-2H-pyrimidinoí 3,4-d_/-dibenso- ¿fb,f_7(l,4)oxazepin.maleat; smp l77~l79°C. 5. 8-metoxi-l,3,4,14b-tetrahydro-2H-pyrimidinoífä,4~d_7dibenso- ¿_b,f_7(l,4)oxazepin (olja) ' Rf i metanol = 0,45 på Si02. 6 . s-hydroxi-l , 3 , 4 , l41o-totrahyaro-zH-pyrimiainqï , :l-djalbonso- ¿~b,f_7(l,4)oxazepin.Rf in benzene: ethyl acetate (7: 3) = 0.25 on SiO2. 3. 10-methyl-13-methoxy-1,2,3,4,10,14b-hexahydro-pyrimidino- [3, bajalbonsofb, f_7 (1,4) aiazopln (oil) Rf in methanol = 0.51 on S102. j ' Rf in ethyl acetate = 0.40 on S102. 4. 11-methyl-1,3,4,14b-tetrahydro-2H-pyrimidino-3,4-dβ-dibenzo- ¿Fb, f_7 (1,4) oxazepine.maleate; mp 177 ~ 179 ° C. 5. 8-Methoxy-1,3,4,14b-tetrahydro-2H-pyrimidinophosphate, 4-dibenzo- ¿_B, f_7 (1,4) oxazepine (oil) ' Rf in methanol = 0.45 on SiO2. 6. s-hydroxy-1,3,4,4,14o-totrahyaro-2H-pyrimining, 1-jalbonso- ¿~ B, f_7 (l, 4) oxazepine.

Rf i metanol = 0,25 på Si02. 7. 7-metyl-l,3,4,l4b-tetrahydro-ZH-pyrimidino¿“3,4-d_7dibenso- “ [b,f_7(1,ßnoxazepirmmaloat; smp ls4-l6a°cf. 8. 3,7-dimetyl-13-klor-1,3,4,l4b-tetrahydro-2H-pyrimidino- ['3,4-a_7aibonso[b, fjumoxazopln (olja) . , 1s12a7s-se 10.Rf in methanol = 0.25 on SiO2. 7. 7-Methyl-1,3,4,1,4b-tetrahydro-2H-pyrimidino [3,4-d] dibenzo- [b, f_7 (1, ßnoxazepirmmaloate; mp ls4-16a ° cf). 8. 3,7-dimethyl-13-chloro-1,3,4,14b-tetrahydro-2H-pyrimidino- ['3,4-a_7aibonso [b, fjumoxazoplin (oil). , 1s12a7s-se 10.

EXEMPEL VII 3-etyl-1,2,3,4,l0,l4b-hexahydro-pyrimidino/-3,4-a 7dibenso- /*c,f 7azepin.HCl (direkt väg) _ Pâ samma sätt som beskrivits i exempel I löstes diaminen 6-etylaminoetyl-5,6-dihydro-lH¥dibenso¿_b,e_7azepin i etanol. Lös- ningen behandlades med en formaldehydlösning och blandningen extra- herades med metylenklorid. Metylenkloridextrakten tvättades och tor- kades, varefter den erhållna återstoden löstes i HCl-haltig etanol.EXAMPLE VII 3-ethyl-1,2,3,4,10,14b-hexahydro-pyrimidino [3,4-a] dibenzo- / * c, f 7azepin.HCl (direct route) In the same manner as described in Example I, the diamine was dissolved 6-ethylaminoethyl-5,6-dihydro-1H-dibenzo [b, e] 7 -zepine in ethanol. Loose- The mixture was treated with a formaldehyde solution and the mixture cured with methylene chloride. The methylene chloride extracts were washed and dried. after which the residue obtained was dissolved in HCl-containing ethanol.

De erhållna kristallerna omkristalliserades från etanol. utbyte 72 t; smp,19a-2od°c. * Rf i ety1acetat = o,1s på sioz.. I På samma sätt framställdes de motsvarande 3-bensyl- och 3-fenyl- derivaten.The obtained crystals were recrystallized from ethanol. yield 72 h; mp, 19a-2od ° c. * Rf in ethyl acetate = 0.1s on sioz .. I In the same manner, the corresponding 3-benzyl and 3-phenyl- derivatives.

EXEMPEL VIII 3-etyl-l,2,3,4,10,l4b-hexahydro-pyrimidino/_3,4-a 7dibenso- ]_c,f 7azepin.HCl (indirekt väg) 1,3 g l,2,3;4,lO,l4b-hexahydro-pyrimidino¿_3,4-a_7dibenso- ¿_c,f_7azepin (exempel II) acylerades i bensen med hjälp av 2 ml' ättiksyraanhydrid.EXAMPLE VIII 3-ethyl-1,2,3,4,10,14b-hexahydro-pyrimidino [3,4-a] dibenzo- ] _c, f 7azepin.HCl (indirect route) 1.3 g 1,2,3,4,14,14b-hexahydro-pyrimidino [3,4-a] dibenzo- Az _c, f_7azepine (Example II) was acylated in benzene using 2 ml acetic anhydride.

Efter 30 min omröring vid 20°C indunstades lösningen och åter- stoden renades med hjälp av kolonnkromatografi (lösningsmedel etyl- acetat; kolonn silikagel).After stirring for 30 minutes at 20 ° C, the solution was evaporated and The column was purified by column chromatography (solvent ethyl acetate; silica gel column).

Den återstående oljan, N-acetylderivatet av utgångsämnet, hade ett Rf-värde av 6,48 i etylacetat.The residual oil, the N-acetyl derivative of the starting material, had an Rf value of 6.48 in ethyl acetate.

Av denna olja löstes 0,8 g i 10 ml tetrahydrofuran och sattes försiktigt till en suspension av 0,5 g LiAlH4 i 25 ml tetrahydrofuran.0.8 g of this oil was dissolved in 10 ml of tetrahydrofuran and added gently to a suspension of 0.5 g of LiAlH4 in 25 ml of tetrahydrofuran.

Därefter värmdes blandningen under återflöde i l h, varefter den kyldes. Därefter tillsattes 2 ml vatten.The mixture was then heated under reflux for 1 hour, after which it cooled. Then 2 ml of water were added.

Den bildade fällningen avfiltrerades och filtratet indunstades.The precipitate formed was filtered off and the filtrate was evaporated.

Den erhållna återstoden löstes i HCl-haltig alkohol, varefter pro- dukten fick utkristallisera. utbyte 0,5 g. smp 19e-2oo°c.' Rf i etylacetat = 0,16 på SiO2.The residue obtained was dissolved in HCl-containing alcohol, after which the the duct had to crystallize out. yield 0.5 g. mp 19e-20 ° C. ' Rf in ethyl acetate = 0.16 on SiO2.

En blandning av ämnena (3-etylderivat) som framställts i exempel vn och vn: smäite vid 19s-2oo°c. i äggen. Ix 3-metyl-l,2,3,4,10,14b-hexahydro-pyrimidino/_3,4-a 7dibenso- ¿_c,f 7azeEin En blandning av 2,4 g 6~metylaminoetyl-5,6-díhydro-llH-dibenso- [b,e_7az@p1n, 1o m1 metynznkioria, 2 m1 triety1amin (TEA) och 1o m1 11 73121373-8 dimetylsulfoxid (DMSO) värmdes under återflöde i 5 h. Överskottet av metylenklorid, TEA och en stor mängd av DMSO avdestillerades i vakuum.A mixture of the substances (3-ethyl derivatives) prepared in examples vn and vn: forge at 19s-2oo ° c. in the eggs. Ix 3-methyl-1,2,3,4,10,14b-hexahydro-pyrimidino [3,4-a] dibenzo- ¿_C, f 7azeEin A mixture of 2.4 g of 6-methylaminoethyl-5,6-dihydro-11H-dibenzo- [b, e_7az @ p1n, 1o m1 methynzynchioria, 2 m1 triethylamine (TEA) and 1o m1 11 73121373-8 dimethyl sulfoxide (DMSO) was heated under reflux for 5 hours. methylene chloride, TEA and a large amount of DMSO were distilled off in vacuo.

Den återstående vätskan späddes med vatten och extraherades därefter med eter. Eterlösningen tvättades därefter med vatten, torkades och indunstades till torrhet. ' g Återstoden behandlades med fumarsyra i etanol. Fumaratets smp: 188-191°c.The remaining liquid was diluted with water and then extracted with ether. The ether solution was then washed with water, dried and evaporated to dryness. 'g The residue was treated with fumaric acid in ethanol. Fumaratets smp: 188-191 ° C.

EXEMPEL x . f, På samma sätt som beskrivits i exempel IX framställdes följande föreningar: l,2,3,4,10,l4b-hexahydro-pyrimidino¿_3,4~a_7dibenso¿_c,f_7azepin.HCl smp 215-zi6°c). 3,7-dimetyl-l,2,3,4,10,l4b-hexahydro-pyrimidino¿_3,4-a_7dibenso- .¿fc,f_7àzepin. (olja) 3-metyl-s-metoxi-1,2,3,4,10,14b-nexahyaro-pyrim1aino¿“3,4-a_7- dibenso¿_c,f_7azepin, (olja) 3-metyl-1,3,4,14b-tetrahyaro-2n~pyrimia1no¿'3,4-d_7aibens0¿'b,f_jL (1,4>°xazepin,nc1 (smp 215-21s°c) 13-klor-3-metyl-l,3,4,l4b-tetrahydro~2H-pyrimidino¿_3,4-d_7F a1bens0¿"b,f_7(1,4)oxazepin.ac1 (smp 220-z22°c) 3,11-aimetyl-1,3,4,14B-tetranydr@-za-pyr1miaino¿"3,4-a_7aibens°- ¿fb,f_7(1,4)oxazepin.Hc1 (smp 219-222°c) 3-metyl-7-trifluorometyl-1,3,4,l4b-tetrahydro-2H~pyrimidino- ¿"3,4-q¿ZaibensQ¿"b,¿¿7(1,4>tiazep1n.aßr 3,7-dimetyl-l,3,4,l4b-tetrahydro-2H-pyrimidino¿_3,4-d_7dibenso- ¿_b,f_7(l,4)oxazepin.maleat (smp l64-l66°C) 3,13-aimetyl-1,3,4,14b-tetranyaro-2n-pyrimiaino¿“3,4-a_7aibenso- ¿_b,f_7(l,4)oxazepin.EXAMPLE x. f, In the same manner as described in Example IX, the following were prepared compounds: 1,2,3,4,10,14b-hexahydro-pyrimidino3,4,4-a_7dibenzo_c, f_7azepin.HCl mp 215-16 ° C). 3,7-dimethyl-1,2,3,4,10,14b-hexahydro-pyrimidino [3,4-a] dibenzo- .¿Fc, f_7àzepin. (oil) 3-Methyl-s-methoxy-1,2,3,4,10,14b-nexahyaropyrimino-3,4-α-7- dibenzo_c, f_7azepine, (oil) 3-Methyl-1,3,4,14b-tetrahyaro-2n-pyriminyl-3,4-d] -7benzo [b], (1.4> xazepine, nc1 (m.p. 215-21 ° C) 13-chloro-3-methyl-1,3,4,4,4-tetrahydro-2H-pyrimidino [3,4-d] 7F a1benzo [b], f_7 (1,4) oxazepine.ac1 (m.p. 220 DEG-22 DEG C.) 3,11-methyl-1,3,4,14B-tetranydr @ -za-pyrimino [3,4-a] -benzyl ¿Fb, f_7 (1,4) oxazepine.Hc1 (mp 219-222 ° c) 3-methyl-7-trifluoromethyl-1,3,4,14b-tetrahydro-2H-pyrimidino- ¿"3,4-q¿ZaibensQ¿" b, ¿¿7 (1,4> tiazep1n.aßr 3,7-dimethyl-1,3,4,4,4-tetrahydro-2H-pyrimidino [3,4-d] dibenzo- ¿_B, f_7 (1,4) oxazepine.maleate (m.p. 164-166 ° C) 3,13-methyl-1,3,4,14b-tetranyaro-2n-pyrimino [3,4-a] benzoic acid ¿_B, f_7 (l, 4) oxazepine.

EXEMPEL XI 1,2,3,4,io,14b-hexahyarø-pyrimiaino/"3,4-a 7aibenso/“c,f 7- aze2in.HCl _ A. En lösning av 1,2 g tiofosgen i 10 ml toluen sattes försiktigt vid OOC till en lösning av 2,4 g 6~aminoetyl-5,6-dihydro-llH-dibenso- ¿_b,e_7azepin i 20 ml toluen, vartill hade satts 5 ml pyridin. Reak- tionsblandningen fick stå i l h och efter detta tillsattes 20 ml vat- ten. Blandningen omrördes kraftigt, varefter vattenskiktet avskiljdes från toluenskiktet. Toluenfasen tvättades med vatten, därefter med 0,2 M svavelsyra och slutligen med vatten. \ Toluenlösningen torkades därefter och indunstades till torrhet. Återstoden omkristalliserades från etanol (2,2 g). 7312873-8 12 Smältpunkten för 1,2,3,4,l0,l4b-hexahydro-4-tion-pyrimidino- _ ¿f3,4-a_7dibenso¿fc,f_7azepin var 196-l98°C.EXAMPLE XI 1,2,3,4,io,14b-hexahyaro-pyriminoino / "3,4-a 7aibenzo /" c, f 7- aze2in.HCl _ A. A solution of 1.2 g of thiophosgene in 10 ml of toluene was carefully added at 0 ° C to a solution of 2.4 g of 6-aminoethyl-5,6-dihydro-11H-dibenzo- ¿_B, e_7azepine in 20 ml of toluene, to which had been added 5 ml of pyridine. Reactive The reaction mixture was allowed to stand for 1 hour and then 20 ml of water were added. ten. The mixture was stirred vigorously, after which the aqueous layer was separated from the toluene layer. The toluene phase was washed with water, then with 0.2 M sulfuric acid and finally with water. \ The toluene solution was then dried and evaporated to dryness. The residue was recrystallized from ethanol (2.2 g). 7312873-8 12 Melting point of 1,2,3,4,10,14b-hexahydro-4-thione-pyrimidino- ¿F3,4-a_7dibenzo¿fc, f_7azepine was 196-198 ° C.

B. 2 g av det i A.erhållna ämnet sattes till en suspension av 4 g LiAlH4 i 50 ml dioxan. Blandningen värmdes under återflöde i l,5 h.B. 2 g of the substance obtained in A. was added to a suspension of 4 g LiAlH4 in 50 ml of dioxane. The mixture was heated under reflux for 1.5 hours.

"Efter kylning sattes blandningen droppvis till 15 ml vatten. Bland- ningen filtrerades och filtratet indunstades till torrhet i vakuum. Återstoden löstes i klorvätesyrahaltig alkohol, varefter lösningen kyldes för erhållande av en fällning. k smp 213-217°c. utbyte 0,9 q. After cooling, the mixture was added dropwise to 15 ml of water. The filtrate was filtered and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in hydrochloric acid-containing alcohol, followed by the solution cooled to obtain a precipitate. k mp 213-217 ° C. yield 0.9 q.

C. Samma förening erhölls i 2 steg, om kolsvavla användes i stället för tiofosgen i toluen både som reagens och som lösningsmedel.C. The same compound was obtained in 2 steps, if carbon sulfur was used instead for thiophosgene in toluene both as a reagent and as a solvent.

EXEMPEL XII _ 3-metyl-l,2,3,4,l0,14b-hexahydro-pyrimidino/-3,4-a Ydibenso- /_c,f 7aseEin Genom den i exempel XI A'beskrivna processen omvandlades l g fosgen och 2,5 g 6-metylaminoetyl-5,6-dihydro-llH-dibensoífb,e_7F azepin till 3-metyl-1,2,3,4,10,l4b-hexahydro-4-keto-pyrimidino- 1-3,4-a_7dibenso¿_o,f_7azepin. Z Detta ämne reducerades med LiAlH4 i tetrahydrofuran genom det i exempel XI B beskrivna förfarandet.EXAMPLE XII 3-methyl-1,2,3,4,10,14b-hexahydro-pyrimidino [3,4-a] / _c, f 7aseEin By the process described in Example XI A ', 1 g was converted phosgene and 2.5 g of 6-methylaminoethyl-5,6-dihydro-11H-dibenzoifb, e_7F azepine to 3-methyl-1,2,3,4,10,14b-hexahydro-4-keto-pyrimidino- 1-3,4-a_7dibenso¿_o, f_7azepin. Z This substance was reduced with LiAlH 4 in tetrahydrofuran through it the procedure described in Example XI B.

Fumaratets smp 192-l93°C.Melting point of the fumarate is 192-193 ° C.

EXEMPEL XIII s-metyl-l , 2 , 3 , 4 , :Lo,14b-hexahyaro-pyfimiaino/"s , 4-a 7aibenso- /_c,f 7azeEin Till 2,4 g 6-metylaminoetyl-5,6-dihydro-1lH-dibenso¿fb,e_]ï azepin (smp 124-l26°C), löst i 50 ml tetrahydrofuran sattes en lös- ning av 2 g N,N'-karbonyldiimidazol i 30 ml tetrahydrofuran under omröring. Efter 1,5 h omröring vid rumstemperatur avdestillerades omkring 65 ml tetrahydrofuran, varefter återstoden späddes med vatten." Extrahering av denna blandning med bensen, tvättning av extrakten med vatten, torkning på natriumsulfat och indunstning av bensenlös- ningen gav 2,4 g 3-metyl-1,2,3,4,l0,l4b-hexahydro-4-keto-pyrimidino- ¿_3,4-a_7dibenso¿_c,f_7azepin. 7 Detta ämne löstes i 80 ml tetrahydrofuran, varefter en lösning av 0,8 g diboran i 50 ml tetrahydrofuran tillsattes. Biandningen värmdes i en sluten ampull i 5 h vid_45°C. Därefter sattes alkohol till blandningen, varefter den omrördes under någon tid. Därefter indunstades blandningen partiellt, surgjordes med utspädd syra (0,1 N HCl) och extraherades med bensen.EXAMPLE XIII s-methyl-1,2, 3, 4,: Lo, 14b-hexahyaro-pyfimiaino / "s, 4-a 7aibenzo- / _c, f 7azeEin To 2.4 g of 6-methylaminoethyl-5,6-dihydro-11H-dibenzo [b] e azepine (mp 124-126 ° C), dissolved in 50 ml of tetrahydrofuran, a solution was added. 2 g of N, N'-carbonyldiimidazole in 30 ml of tetrahydrofuran stirring. After stirring for 1.5 hours at room temperature, it was distilled off about 65 ml of tetrahydrofuran, after which the residue was diluted with water. " Extraction of this mixture with benzene, washing of the extracts with water, drying over sodium sulphate and evaporation of benzene solution The mixture gave 2.4 g of 3-methyl-1,2,3,4,10,14b-hexahydro-4-keto-pyrimidino- ¿_3,4-a_7dibenso¿_c, f_7azepin. 7 This substance was dissolved in 80 ml of tetrahydrofuran, followed by a solution of 0.8 g of diborane in 50 ml of tetrahydrofuran was added. The mix was heated in a closed ampoule for 5 hours at -45 ° C. Then alcohol was added to the mixture, after which it was stirred for some time. Then the mixture was partially evaporated, acidified with dilute acid (0.1 N HCl) and extracted with benzene.

Bensenextrakten bearbetades på konventionellt sätt.The benzene extracts were processed in a conventional manner.

Fumaratets smp 190-19253, 7312873-8 13 EXEMPEL XIV 2-keto-l,2,3,4,l0,l4b-hexahydro-pyrimidino/-3,4-a 7dibenso- ¿_c,f 7azeEin a. 10 g 6-karboxamidometyl-5,6-dihydromorfantridin löstes i 300 ml I etanol (70 %), varefter 100 ml av en 37 % formaldehydlösning i vat- ten tillsattes. Blandningen värmdes under återflöde i 6 h, varefter lösningsmedlet i huvudsak förângades. Den erhållna återstoden fil- trerades och det fasta materialet torkades. u Smp 181-l85°C; utöyte 85 %.Fumaratets m.p. 190-19253, 7312873-8 13 EXAMPLE XIV 2-keto-1,2,3,4,10,14b-hexahydro-pyrimidino [3,4-a] dibenzo- ¿_C, f 7azeEin a. 10 g of 6-carboxamidomethyl-5,6-dihydromorphantridine were dissolved in 300 ml In ethanol (70%), then 100 ml of a 37% formaldehyde solution in aqueous was added. The mixture was heated under reflux for 6 hours, after which time the solvent was substantially evaporated. The residue obtained is and the solid was dried. u Mp 181-185 ° C; yield 85%.

Rf i etylacetat = 0,3 på S102. __ 1,2,3,4,1o,14b-hexahydro-pyrimiaino/"3,4-a 7dibenso/'c,f 7- azeEin.HCl ' b. § g av den i a. erhållna föreningen löstes i 75 ml tetrahydro- _furan (THF). Lösningen sattes försiktigt till en suspension av 4 g LiAlH4 i 100 ml THF. Blandningen värmdes under återflöde i 3 h och kyldes därefter till OOC. Den till kylda blandningen sattes försik- tigt l6 ml vatten, varefter blandningen filtrerades. Det erhållna filtratet indunstades och den återstående oljanlöstes i Höl/EtOH.Rf in ethyl acetate = 0.3 on S102. __ 1,2,3,4,1o, 14b-hexahydro-pyriminoino / "3,4-a 7dibenzo / 'c, f 7- azeEin.HCl ' b. § g of the compound obtained in a. was dissolved in 75 ml of tetrahydro- _furan (THF). The solution was carefully added to a suspension of 4 g LiAlH4 in 100 mL of THF. The mixture was heated under reflux for 3 hours and was then cooled to 0 ° C. The cooled mixture was added carefully. 16 ml of water, after which the mixture was filtered. The obtained the filtrate was evaporated and the remaining oil was dissolved in H6 / EtOH.

Lösningen filtrerades och det erhållna fasta ämnet torkades.The solution was filtered and the resulting solid was dried.

Hcl-saltets smp 214-21s°c; utbyte sa %.Mp HCl salt mp 214-21 ° C; yield in%.

Claims (3)

a vanan-s Q '14 Biologiska data >Nr . Förening Reserpin- Toxicitet hos _ antagonism- möss i.p. X test i.p. LDSO mg/kg 40 mg/kg R1 R2 % inhiberíng g-É _ av temp.- fall ' w l å _ 3 a X -Rl i R2; Ra l. CH2 H É H CH3 62 100 <20O 2. o H H cH3o 4 77 zoo <3oo 3. CH2 H H H _ - 35 200 <300 4. o 7-CH3 H cn3 lsa zoo <3oo 5. CHZ H H CH3 ' 60 200 <3OO (vänsterroterande enantiomer) 6. cH2 H H _cH3 o 30 l - zoo <3oo- (högerroterande enantiomer) 7. O. H l3-CH3 CH3 80 200 <3OO PATENTKRAVa vanan-s Q '14 Biological data> Nr. Compound Reserpin- Toxicity in antagonism mice i.p. X test i.p. LDSO mg / kg 40 mg / kg R1 R2% inhibition g-É _ of temp.- fall 'w l å _ 3 a X -R1 in R2; Ra l. CH2 H É H CH3 62 100 <20O 2. o HH cH3o 4 77 zoo <3oo 3. CH2 HHH _ - 35 200 <300 4. o 7-CH3 H cn3 lsa zoo <3oo 5. CHZ HH CH3 ' 60 200 <300 (left-rotating enantiomer) 6. cH2 HH _cH3 o 30 l - zoo <300- (right-rotating enantiomer) 7. O. H l3-CH3 CH3 80 200 <300 CLAIMS l. Förfarande för framställning av biologiskt verksamma pyrimidin~ derivat med den allmänna formeln 15 7312873-8 i vilken X betecknar syre, svavel, gruppen NR4 eller gruppen -CRSRG-, r och s betecknar ett heltal från O till 4, Rl och R2 betecknar halogen, hydroxi, en alkyl- eller alkoxigrupp med l-6 kolatomer eller en trifluormetylgrupp, R3 betecknar väte, en alkylgrupp med 1-6 kolatomer elleren fenyl- alkylgrupp med 7-10 kolatomer, och R4, RS och R6 betecknar väte eller en alkylgrupp med l-6 kolatomer, jämte deras farmaceutiskt godtagbara syraadditionssalter eller kva- 'ternära ammoniumföreningar, k ä n n e t e c k_n a t därav, att en diamin med formeln § d eller ett syraadditionssalt av denna, i vilken Q betecknar väte (H2) eller syre och Rl, R2, R3, X, r och s har ovan angiven be- tydelse, kondenseras med ett reagens med formeln Z \\\Z Y 2 i vilken Y betecknar väte (H2), svavel eller syre och Zl och Z2 betecknar samma eller olika grupper valda bland halogen, en sub- stituerad eller osubstituerad aminogrupp eller en fri, företrad eller sulfonylerad hydroxigrupp, eller tillsammans kan vara svavel om Y = svavel, den erhållna föreningen reduceras och eventuellt omvandlas till en kvaternär ammoniumförening eller ett syraadditions- salt, varefter slutprodukten eventuellt upplöses.A process for the preparation of biologically active pyrimidine derivatives of the general formula 7312873-8 in which X represents oxygen, sulfur, the group NR4 or the group -CRSRG-, r and s represent an integer from 0 to 4, R1 and R2 represent halogen, hydroxy, an alkyl or alkoxy group having 1-6 carbon atoms or a trifluoromethyl group, R 3 represents hydrogen, an alkyl group having 1-6 carbon atoms or a phenylalkyl group having 7-10 carbon atoms, and R 4, R 5 and R 6 represent hydrogen or an alkyl group having 1 to 6 carbon atoms, together with their pharmaceutically acceptable acid addition salts or quaternary ammonium compounds, may be characterized in that a diamine of the formula § d or an acid addition salt thereof, in which Q represents hydrogen (H2) or oxygen and R1 , R 2, R 3, X, r and s have the meaning given above, are condensed with a reagent of the formula Z 1, Z 2 in which Y represents hydrogen (H 2), sulfur or oxygen and Z 1 and Z 2 represent the same or different groups selected from halogen, a substituted or unsubstituted amino group or a free, etherified or sulfonylated hydroxy group, or together may be sulfur if Y = sulfur, the resulting compound is reduced and optionally converted to a quaternary ammonium compound or an acid addition salt, after which the final product may be dissolved. 2. Förfarande enligt krav 1, k ä n n e t e c k n a t därav, att reagenset är metylenhalogenid eller en vattenlösning av form- faldehyd.2. A process according to claim 1, characterized in that the reagent is methylene halide or an aqueous solution of formaldehyde. 3. Förfarande enligt krav 1, k ä n n e t e c k n a t därav, att reagenset är fosgen, halogenmyrsyraester eller CS2. ANFÖRDA PUBLIKATIONER: Sverige patentansökningar 865/73, 3 099/73, 397 354 (C070 487/04)3. A process according to claim 1, characterized in that the reagent is phosgene, haloformic acid ester or CS2. PROMISED PUBLICATIONS: Sweden patent applications 865/73, 3,099/73, 397,354 (C070 487/04)
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