NO173504B

NO173504B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE TIENO-TRIAZOLO-DIAZEPINE DERIVATIVES

Info

Publication number: NO173504B
Application number: NO90901812A
Authority: NO
Inventors: Pierre Braquet; Andre Esanu; Jean-Pierre Laurent; Jaques Pommier
Original assignee: Scras
Priority date: 1990-04-24
Filing date: 1990-04-24
Publication date: 1993-09-13
Also published as: NO901812D0; NO901812L; NO173504C

Description

Oppfinnelsen angår en fremgangsmåte for fremstilling av nye derivater av tieno-triazolo-diazepin som er særlig interessante som anti-ischemiske, antiastmatiske og anti-allergiske midler og som gastrointestinalt beskyttende midler. Forbindelsene fremstillet i henhold til foreliggende oppfinnelse er mer spesielt interessante ved behandling av ischemi. The invention relates to a process for the production of new derivatives of thieno-triazolo-diazepine which are particularly interesting as anti-ischemic, anti-asthmatic and anti-allergic agents and as gastrointestinal protective agents. The compounds produced according to the present invention are more particularly interesting in the treatment of ischemia.

Oppfinnelsen angår mer spesielt en fremgangsmåte for fremstilling av tieno-triazolo-diazepin-derivater med den generelle formel A The invention relates more particularly to a process for the production of thieno-triazolo-diazepine derivatives of the general formula A

hvor Y utgjør et oksygen- eller svovelatom og R utgjør en rettkjedet eller forgrenet alkylgruppe med 1 til 20 karbonatomer; en fenylgruppe som er usubstituert eller substituert med en rettkjedet eller forgrenet alkylgruppe med fra 1 til 5 karbonatomer, en alkoksygruppe med 1 til 5 karbonatomer, et halogenatom, en trifluormetylgruppe eller en fenoksygruppe; eller en furan- eller tiofenring; where Y represents an oxygen or sulfur atom and R represents a straight-chain or branched alkyl group of 1 to 20 carbon atoms; a phenyl group which is unsubstituted or substituted with a straight or branched chain alkyl group of from 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, a halogen atom, a trifluoromethyl group or a phenoxy group; or a furan or thiophene ring;

og terapeutiske salter derav. and therapeutic salts thereof.

I henhold til oppfinnelsen kan disse forbindelsene lett fremstilles ved å behandle tieno-triazolo-diazepin-forbindelsen med formel B According to the invention, these compounds can be easily prepared by treating the thieno-triazolo-diazepine compound of formula B

med en støkiometrisk mengde av RSCH2C00H-derivatet C, hvor R er som ovenfor definert, i et aprotisk oppløsningsmiddel, i nærvær av et svakt støkiometrisk overskudd av dicykloheksylkarbodiimid ved en temperatur på 0-60°C, hvoretter den resulterende forbindelse med formel: omsettes med tre til fem støkiometriske ekvivalenter hydrazinhydrat, i et protisk oppløsningsmiddel ved en temperatur fra romtemperatur til 50°C, hvorpå den oppnådde forbindelse med formel: with a stoichiometric amount of the RSCH2C00H derivative C, where R is as defined above, in an aprotic solvent, in the presence of a slight stoichiometric excess of dicyclohexylcarbodiimide at a temperature of 0-60°C, after which the resulting compound of formula: is reacted with three to five stoichiometric equivalents of hydrazine hydrate, in a protic solvent at a temperature from room temperature to 50°C, whereupon the obtained compound of formula:

tilslutt cykliseres i et protisk oppløsningsmiddel med én til tre støkiometriske ekvivalenter triortoacetat ved en temperatur fra romtemperatur til reaksjonsblandingens kokepunkt, for å oppnå tieno-triazolo-diazepin-derivatet med den generelle formel A, hvor Y er et oksygenatom, og eventuelt fortsette med et sulfureringstrinn [D —> D'] som består i å omsette tieno-diazepin-derivatet med formel D med tre til fem støkiometriske finally cyclized in a protic solvent with one to three stoichiometric equivalents of triorthoacetate at a temperature from room temperature to the boiling point of the reaction mixture, to obtain the thieno-triazolo-diazepine derivative of the general formula A, where Y is an oxygen atom, and optionally continue with a sulfurization step [D —> D'] which consists in reacting the thieno-diazepine derivative of formula D with three to five stoichiometric

ekvivalenter fosforpentasulfid i et aprotisk oppløsningsmiddel ved en temperatur fra 10°C til reaksjonsblandingens kokepunkt, for å oppnå det korresponderende tieno-triazolo-diazepin hvor Y står for et svovelatom. Den tilsvarende reaksjonsfølge er skissert på det vedlagte Reaksjonsskjema 1. equivalents of phosphorus pentasulfide in an aprotic solvent at a temperature from 10°C to the boiling point of the reaction mixture, to obtain the corresponding thieno-triazolo-diazepine where Y stands for a sulfur atom. The corresponding reaction sequence is outlined on the attached Reaction Scheme 1.

Omsetningene ved fremstilling av tieno-triazolo-dizepin foretas i henhold til oppfinnelsen fortrinnsvis i et tørt og vannfritt medium. According to the invention, the reactions in the production of thieno-triazolo-dizepine are preferably carried out in a dry and anhydrous medium.

Hva som er kjent på feltet for denne oppfinnelse, fremgår av US-patent 4.621.083 (eller E.P. 176 927) hvor tieno-triazolo-diazepin med PAF-antagonistisk aktivitet er beskrevet. What is known in the field for this invention appears from US patent 4,621,083 (or E.P. 176,927) where thieno-triazolo-diazepine with PAF-antagonistic activity is described.

Disse nye forbindelsene har en PAF-antagonistisk aktivitet som er fra 10 til 1000 ganger større enn aktiviteten av diazepiner omtalt i ovennevnte patent og har også en mer potent effekt. These new compounds have a PAF-antagonistic activity that is from 10 to 1000 times greater than the activity of diazepines discussed in the above patent and also have a more potent effect.

Fremstilling av utgangsforbindelsen B er beskrevet i det følgende fremstillingseksempel (fra I til VI) som er vist i Reaksjonsskjema 2. Preparation of the starting compound B is described in the following preparation example (from I to VI) which is shown in Reaction Scheme 2.

I - ( 2- klor) benzoylmetyl cyanid I - ( 2- Chloro) benzoylmethyl cyanide

I en passende reaktor ble det under nitrogensirkulasjon ved -70°C anbragt 7 liter vannfri THF og 115,9 g (1,36 mol) på forhånd tørket cyanoeddiksyre. Deretter ble det dråpevis tilsatt 1715 ml (2,74 mol) 1,6M oppløsning butyllitium i heksan, hvorunder temperaturen fikk stige fra -70°C til 0°C. Reaksjonsblandingen ble deretter omrørt i 1 time. Deretter ble reaksjonsblandingen avkjølt igjen til -70°C og dråpevis tilsatt en oppløsning av 120 g (0,685 mol) 2-klor-benzoylklorid i 1 liter vannfri THF. In a suitable reactor, under nitrogen circulation at -70°C, 7 liters of anhydrous THF and 115.9 g (1.36 mol) of previously dried cyanoacetic acid were placed. Then 1715 ml (2.74 mol) of a 1.6M solution of butyllithium in hexane was added dropwise, during which the temperature was allowed to rise from -70°C to 0°C. The reaction mixture was then stirred for 1 hour. The reaction mixture was then cooled again to -70°C and a solution of 120 g (0.685 mol) of 2-chloro-benzoyl chloride in 1 liter of anhydrous THF was added dropwise.

Etter omrøring i 1 time, stadig ved -70°C, fikk temperaturen stige fra -70°C til 0°C i løpet av 1 time. Det ble deretter dråpevis tilsatt 3 liter IN HCl, og etter omrøring i noen få minutter, ble reaksjonsblandingen ekstrahert med kloroform. Den organiske fase ble vasket med 10% vandig natriumbikarbonat-oppløsning, deretter med en mettet natriumkloridoppløsning, tørket og filtrert, hvorpå oppløsningsmidlet ble fordampet for å gi 135 g residuum. Krystallisasjon ble foretatt ved tilsetning av diisopropyleter, hvorpå produktet ble frafiltrert og vasket med heksan for å gi 97,2 g av tittelforbindelsen (utbytte 79%). After stirring for 1 hour, constantly at -70°C, the temperature was allowed to rise from -70°C to 0°C within 1 hour. 3 liters of 1N HCl were then added dropwise, and after stirring for a few minutes, the reaction mixture was extracted with chloroform. The organic phase was washed with 10% aqueous sodium bicarbonate solution, then with a saturated sodium chloride solution, dried and filtered, after which the solvent was evaporated to give 135 g of residue. Crystallization was effected by addition of diisopropyl ether, after which the product was filtered off and washed with hexane to give 97.2 g of the title compound (yield 79%).

II - 2- amino- 3-( 2- klorbenzoyl)- 6-( etoksykarbonyl)-4, 5, 6, 7- tetrahydro- pyrido[ 3, 4- b] tiofen II - 2- amino- 3-( 2- chlorobenzoyl)- 6-( ethoxycarbonyl)-4, 5, 6, 7- tetrahydro- pyrido[ 3, 4-b] thiophene

I en to liter Erlenmeyerkolbe forsynt med en kjøler, ble det hellet 85,5 g (0,501 mol) N-karbetoksy-4-piperidon, 90 g (0,501 mol) av (I), 19,3 g (0,600 mol) svovelblomme og 44,4 g (0,501 mol) morfolin i 550 ml metanol. Blandingen ble tilbake-løpsbehandlet i 1 time. Etter fordampning av 250 ml opp-løsningsmiddel utfeltes den ønskede forbindelse, som ble frafiltrert, vasket med etanol og deretter med dietyleter og tørket for å gi 155,4 g (85%) av tittelforbindelsen. Into a two liter Erlenmeyer flask fitted with a condenser was poured 85.5 g (0.501 mol) of N-carbethoxy-4-piperidone, 90 g (0.501 mol) of (I), 19.3 g (0.600 mol) of sulfur and 44.4 g (0.501 mol) morpholine in 550 ml methanol. The mixture was refluxed for 1 hour. After evaporation of 250 ml of solvent, the desired compound was precipitated, which was filtered off, washed with ethanol and then with diethyl ether and dried to give 155.4 g (85%) of the title compound.

III - 2-( bromacetamido)- 3-( 2- klorbenzoyl)- 6-( etoksy-karbonyl)- 4, 5, 6, 7- tetrahydro- pyrido[ 3, 4- b] tiofen III - 2-(bromoacetamido)- 3-( 2- chlorobenzoyl)- 6-( ethoxy-carbonyl)- 4, 5, 6, 7- tetrahydro- pyrido[ 3, 4-b] thiophene

I en fem liter reaktor forsynt med passende anordninger inklusiv skilletrakt, ble det hellet 2,5 liter kloroform og 146 g (0,400 mol) av (II) . 2.5 liters of chloroform and 146 g (0.400 mol) of (II) were poured into a five liter reactor equipped with suitable devices including a separatory funnel.

Deretter ble 87,7 g (0,43 mol) bromacetylbromid som befant seg i skilletrakten dråpevis tilsatt. Then 87.7 g (0.43 mol) bromoacetyl bromide which was in the separatory funnel was added dropwise.

Reaksjonsblandingen ble omrørt i 1 time ved romtemperatur, deretter vasket med 300 ml is-vann, hvorpå den organiske fase ble tørket med vannfri magnesiumsulfat og filtrert. Kloroformen ble fordampet og residuet behandlet med etanol. Det resulterende bunnfall ble frafiltrert, vasket med etanol og deretter med dietyleter og tørket for å gi 184,6 g (95%) av tittelforbindelsen . The reaction mixture was stirred for 1 hour at room temperature, then washed with 300 ml of ice-water, after which the organic phase was dried with anhydrous magnesium sulfate and filtered. The chloroform was evaporated and the residue treated with ethanol. The resulting precipitate was filtered off, washed with ethanol and then with diethyl ether and dried to give 184.6 g (95%) of the title compound.

IV - 2-( aminoacetamido)- 3-( 2- klorbenzoyl)- 6-( etoksykarbonyl)-4, 5, 6, 7- tetrahydro- pyrido[ 3, 4- b] tiofen IV - 2-( aminoacetamido)- 3-( 2- chlorobenzoyl)- 6-( ethoxycarbonyl)-4, 5, 6, 7- tetrahydro- pyrido[ 3, 4-b] thiophene

I en fem liter reaktor med gassinnløp ble det hellet 174,8 g (0,36 mol) av (III) og 3 liter THF. Suspensjonen ble avkjølt til 0°C, hvoretter ammoniakkgass på forhånd tørket over kaliumhydroksyd, ble tilført. Tilsetningen ble utført i løpet av 8 timer. (60 g ammoniakk ble absorbert). Blandingen ble omrørt over natten ved 0°C, hvorpå 2 liter THF ble fordampet under redusert trykk og 750 ml etylacetat tilsatt. Etter dekantering ble den organiske fase vasket én gang med 300 ml av en 10% natriumkloridoppløsning, tre ganger med 300 ml vann og tørket med vannfri magnesiumsulfat. Etter filtrering ble oppløsningsmidlet delvis fordampet på rotasjonsfordamper. Bunnfallet fikk stå over natten i kjøleskap. 174.8 g (0.36 mol) of (III) and 3 liters of THF were poured into a five liter reactor with gas inlet. The suspension was cooled to 0°C, after which ammonia gas, previously dried over potassium hydroxide, was added. The addition was carried out over 8 hours. (60 g of ammonia was absorbed). The mixture was stirred overnight at 0°C, whereupon 2 liters of THF were evaporated under reduced pressure and 750 ml of ethyl acetate added. After decantation, the organic phase was washed once with 300 ml of a 10% sodium chloride solution, three times with 300 ml of water and dried with anhydrous magnesium sulfate. After filtration, the solvent was partially evaporated on a rotary evaporator. The precipitate was allowed to stand overnight in a refrigerator.

Etter filtrering ble bunnfallet vasket med dietyleter og tørket for å gi 119 g av tittelforbindelsen. After filtration, the precipitate was washed with diethyl ether and dried to give 119 g of the title compound.

Den gjenværende organiske fase ble konsentrert og behandlet med en blanding av 1,5 liter dietyleter/THF (3/1 volumdeler) for å gi 14,6 g av tittelforbindelsen (totalutbytte 88%). The remaining organic phase was concentrated and treated with a mixture of 1.5 liters of diethyl ether/THF (3/1 v/v) to give 14.6 g of the title compound (overall yield 88%).

V - 5-( 2- klorfenyl)- 8-( etoksykarbonyl)- 6, 7, 8, 9- tetrahydro-3H- pyrido[ 4', 3' :4, 5] tieno[ 3, 2- f] 1, 4- diazepin- 2- on V - 5-( 2- chlorophenyl)- 8-( ethoxycarbonyl)- 6, 7, 8, 9- tetrahydro-3H- pyrido[ 4', 3' :4, 5] thieno[ 3, 2-f] 1, 4-diazepin-2-one

I en to liter reaktor forsynt med omrørings-, kjøle- og oppvarmingsinnretninger og anbragt under nitrogensirkulasjon, ble det hellet 126,6 g (0,3 mol) av (IV) og 800 ml pyridin. Reaksjonsblandingen ble tilbakeløpsbehandlet i 18 timer. 126.6 g (0.3 mol) of (IV) and 800 ml of pyridine were poured into a two liter reactor equipped with stirring, cooling and heating devices and placed under nitrogen circulation. The reaction mixture was refluxed for 18 hours.

Etter å ha kontrollert at alt utgangsmateriale var omsatt, ble pyridinet delvis fordampet på en rotasjonsfordamper under redusert trykk. Den oppnådde (mørkebrune) olje ble oppløst i 1 liter etanol. After checking that all starting material had been reacted, the pyridine was partially evaporated on a rotary evaporator under reduced pressure. The obtained (dark brown) oil was dissolved in 1 liter of ethanol.

Etter avkjøling i et is-bad ble det oppnådd et bunnfall som ble frafiltrert, vasket med etanol og diisopropyleter for å gi 101,3 g (83,6%) av tittelforbindeisen. After cooling in an ice bath, a precipitate was obtained which was filtered off, washed with ethanol and diisopropyl ether to give 101.3 g (83.6%) of the title compound ice.

VI - 5-( 2- klorfenyl)- 6, 7, 8, 9- tetrahydro- 3H- pyrido-[ 4', 3' :4, 5] tieno[ 3, 2- f] 1, 4- diazepin- 2- on VI - 5-( 2- chlorophenyl)- 6, 7, 8, 9- tetrahydro- 3H- pyrido-[ 4', 3' :4, 5] thieno[ 3, 2-f] 1, 4- diazepine- 2 - wed

I en reaktor forsynt med oppvarmingsinnretninger og anbragt under nitrogensirkulasjon, ble det hellet 94,5 g (0,234 mol) av V, 152,1 g (2,34 mol) pelletert (90%) kaliumhydroksyd og 900 ml etylenglykol-monoetyleter. Blandingen ble i løpet av 1 time oppvarmet til tilbakeløpstemperatur og tilbakeløpet opprettholdt i 1 time. Oppløsningen ble deretter tilsatt til 1,2 kg knust is og surgjort med (d = 1,18) saltsyre til pH 5,3. Deretter ble kaliumkarbonat tilsatt for å justere pH til 8,3. Oppløsningen ble deretter ekstrahert tre ganger med 500 ml metylenklorid. Den organiske fase ble vasket med 450 ml av en 10% vandig natriumkloridoppløsning, tørket over vannfri magnesiumsulfat, filtrert og inndampet. Det resulterende residuum ble behandlet med diisopropyleter. Etter vasking med diisopropyleter og tørking, ble det oppnådd 55,9 g av tittelforbindelsen (utbytte 72%) . Into a reactor provided with heating devices and placed under nitrogen circulation, 94.5 g (0.234 mol) of V, 152.1 g (2.34 mol) of pelleted (90%) potassium hydroxide and 900 ml of ethylene glycol monoethyl ether were poured. The mixture was heated to reflux temperature within 1 hour and reflux maintained for 1 hour. The solution was then added to 1.2 kg of crushed ice and acidified with (d = 1.18) hydrochloric acid to pH 5.3. Then potassium carbonate was added to adjust the pH to 8.3. The solution was then extracted three times with 500 ml of methylene chloride. The organic phase was washed with 450 ml of a 10% aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting residue was treated with diisopropyl ether. After washing with diisopropyl ether and drying, 55.9 g of the title compound were obtained (yield 72%).

Syntese av andre mellomprodukter (fra I' til II'): Fremstilling av isopropyltio-eddiksyre (R-S-CH2C02H-derivat når R = isopropyl). Synthesis of other intermediates (from I' to II'): Preparation of isopropylthioacetic acid (R-S-CH2CO2H derivative when R = isopropyl).

1<1> - Etyl- isopropyltioacetat 1<1> - Ethyl isopropyl thioacetate

I en én liter reaktor forsynt med passende anordninger, ble det hellet 300 ml metanol og 25,4 g (0,333 mol) isopropyl-tiol. Into a one liter reactor fitted with suitable devices, 300 ml of methanol and 25.4 g (0.333 mol) of isopropyl thiol were poured.

Deretter ble 57,3 g (0,333 mol) etyl-bromacetat dråpevis tilsatt ved romtemperatur og blandingen omrørt i 4 timer ved romtemperatur. Deretter ble 135 ml 2,5N natriumhydroksyd-oppløsning dråpevis tilsatt uten at pH-verdien overskred 7-7,5. Deretter ble blandingen omrørt over natten, hvorpå metanolen fordampet. Residuet ble behandlet med 100 ml vann og den oppnådde blanding ekstrahert med 350 ml dietyleter. Den organiske fase ble vasket én gang med en 5% natriumhydroksyd-oppløsning og deretter tre ganger med vann og tørket med vannfri magnesiumsulfat. Etter filtrering og fordampning på en rotasjonsfordamper, ble det oppnådd 46 g av tittelforbindelsen (utbytte 85%). Then 57.3 g (0.333 mol) of ethyl bromoacetate was added dropwise at room temperature and the mixture was stirred for 4 hours at room temperature. Then 135 ml of 2.5N sodium hydroxide solution was added dropwise without the pH value exceeding 7-7.5. The mixture was then stirred overnight, after which the methanol evaporated. The residue was treated with 100 ml of water and the resulting mixture extracted with 350 ml of diethyl ether. The organic phase was washed once with a 5% sodium hydroxide solution and then three times with water and dried with anhydrous magnesium sulfate. After filtration and evaporation on a rotary evaporator, 46 g of the title compound were obtained (yield 85%).

II' - Isopropyltio- eddiksyre II' - Isopropylthio-acetic acid

C. C.

I en to liter reaktor forsynt med passende anordninger, ble det hellet 40 g (0,246 mol) etyl-isopropyltioacetat og 380 ml metanol. Deretter ble en oppløsning av 20,7 g (0,369 mol) kaliumhydroksyd i 380 ml vann dråpevis tilsatt. Temperaturen steg og ble holdt ved 35-38°C i 2 timer. Deretter ble metanolen fordampet og det resulterende residuum behandlet med ca. 500 ml is-vann. Oppløsningen ble deretter surgjort til pH 3 ved tilsetning av 10% saltsyre. Bunnfallet ble frafiltrert, vasket med vann til nøytral reaksjon og tørket. Den således oppnådde forbindelse ble krystallisert med 200 ml av en blanding av diisopropylacetat/diisopropyleter (4/6 volumdeler). Oppløsningen ble filtrert i varm tilstand og satt til krystallisasjon. Etter filtrering og vasking med diisopropyleter ble det oppnådd 26,7 g av tittelforbindelsen (utbytte 80,5%). Into a two liter reactor fitted with suitable devices, 40 g (0.246 mol) of ethyl isopropylthioacetate and 380 ml of methanol were poured. Then a solution of 20.7 g (0.369 mol) of potassium hydroxide in 380 ml of water was added dropwise. The temperature rose and was maintained at 35-38°C for 2 hours. The methanol was then evaporated and the resulting residue treated with approx. 500 ml ice water. The solution was then acidified to pH 3 by adding 10% hydrochloric acid. The precipitate was filtered off, washed with water to a neutral reaction and dried. The compound thus obtained was crystallized with 200 ml of a mixture of diisopropyl acetate/diisopropyl ether (4/6 parts by volume). The solution was filtered while hot and allowed to crystallize. After filtration and washing with diisopropyl ether, 26.7 g of the title compound were obtained (yield 80.5%).

Eksempel 1: 6-(2-klorfenyl)-9-(isopropyl-tiometyl-karbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepin Example 1: 6-(2-chlorophenyl)-9-(isopropyl-thiomethyl-carbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3':4,5]thieno [3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepine

Y = 0 R = isopropyl Y = 0 R = isopropyl

1. trinn B + C -> D: 1st step B + C -> D:

Fremstilling av 5-(2-klorfenyl)-8-(isopropyl-tiometyl-karbonyl)-6,7,8,9-tetrahydro-3H-pyrido[4 *,3':4,5]tieno[3,2-f]1,4-diazepin-2-on Preparation of 5-(2-chlorophenyl)-8-(isopropyl-thiomethyl-carbonyl)-6,7,8,9-tetrahydro-3H-pyrido[4*,3':4,5]thieno[3,2- f]1,4-diazepin-2-one

I en to liter reaktor forsynt med passende anordninger ble det hellet 49,8 g (0,150 mol) 5-(2-klorfenyl)-6,7,8,9-tetrahydro-3H-pyrido[4',3<1>:4,5]tieno[3,2-f]1,4-diazepin-2-on og 250 ml dikloretan. Suspensjonen ble avkjølt til 5°C. Deretter ble det samtidig tilsatt 34 g (1,65 mol) karbodicykloheksylimid, 400 ml dikloretan, 20,1 g (0,150 mol) isopropyltio-eddiksyre og 400 ml dikloretan mens temperaturen ble holdt ved 10°C. Blandingen fikk stå i 30 minutter i et is-bad og ble deretter bragt til romtemperatur og oppvarmet til 50°C for homogenisering. Deretter ble blandingen omrørt over natten ved romtemperatur, hvorpå dikloretanet ble fordampet. 49.8 g (0.150 mol) of 5-(2-chlorophenyl)-6,7,8,9-tetrahydro-3H-pyrido[4',3<1> were poured into a two liter reactor equipped with suitable devices: 4,5]thieno[3,2-f]1,4-diazepin-2-one and 250 ml of dichloroethane. The suspension was cooled to 5°C. Then 34 g (1.65 mol) of carbodicyclohexylimide, 400 ml of dichloroethane, 20.1 g (0.150 mol) of isopropylthioacetic acid and 400 ml of dichloroethane were added at the same time while the temperature was maintained at 10°C. The mixture was allowed to stand for 30 minutes in an ice bath and was then brought to room temperature and heated to 50°C for homogenization. The mixture was then stirred overnight at room temperature, after which the dichloroethane was evaporated.

Det oppnådde residuum ble behandlet med 600 ml N,N-dimetylformamid. Deretter ble 150 ml vann tilsatt og blandingen omrørt i 2 timer. Oppstått dicykloheksylurea ble frafiltrert og oppløsningen vasket med N,N-dimetylformamid. En del av N,N-dimetylformamidet ble deretter fordampet. Det oppnådde residuum ble behandlet med is-vann, hvorved det inntrådte utfelling. Deretter ble 0,150 mol eddiksyre tilsatt og blandingen omrørt. The residue obtained was treated with 600 ml of N,N-dimethylformamide. Then 150 ml of water was added and the mixture stirred for 2 hours. The resulting dicyclohexylurea was filtered off and the solution washed with N,N-dimethylformamide. A portion of the N,N-dimethylformamide was then evaporated. The obtained residue was treated with ice-water, whereby precipitation occurred. Then 0.150 mol of acetic acid was added and the mixture stirred.

Bunnfallet ble frafiltrert, vasket med en 10% vandig eddiksyreoppløsning, med vann og deretter med en 10% natrium-bikarbonatoppløsning, tørket under redusert trykk og deretter behandlet med 600 ml kokende etylacetat. Oppløsningen ble avkjølt og fikk stå i 3 timer i kjøleskap. Etter filtrering, vask med etylacetat og deretter med dietyleter og tørking, ble det oppnådd 45,7 g av tittelforbindelsen (utbytte 68%). The precipitate was filtered off, washed with a 10% aqueous acetic acid solution, with water and then with a 10% sodium bicarbonate solution, dried under reduced pressure and then treated with 600 ml of boiling ethyl acetate. The solution was cooled and allowed to stand for 3 hours in a refrigerator. After filtration, washing with ethyl acetate and then with diethyl ether and drying, 45.7 g of the title compound were obtained (yield 68%).

2. trinn D -> E: 2nd step D -> E:

Fremstilling av 5-(2-klorfenyl)-8-(isopropyl-tiometylkarbonyl)-2-hydrazino-6,7,8,9-tetrahydro-3H-pyrido[4',3':4,5]tieno[3,2-f]1,4-diazepin Preparation of 5-(2-chlorophenyl)-8-(isopropyl-thiomethylcarbonyl)-2-hydrazino-6,7,8,9-tetrahydro-3H-pyrido[4',3':4,5]thieno[3, 2-f]1,4-diazepine

I en to liter reaktor forsynt med passende anordninger og anbragt under nitrogensirkulasjon, ble det hellet 42,5 g (0,095 mol) 5-(2-klorfenyl)-8-(isopropyl-tiometylkarbonyl)-6.7.8.9- tetrahydro-3H-pyrido[4',3':4,5]tieno[3,2-f]1,4-diazepin-2-on, 1 liter metanol og 19,06 g (0,376 mol) hydrazinhydrat. Suspensjonen fikk stå i 90 minutter ved romtemperatur (25°C). Nærvær av utgangsmateriale ble påvist ved TLC-analyse. Blandingen ble deretter oppvarmet til 40°C i 30 minutter og holdt ved romtemperatur i 1 time for å fullføre reaksjonen. Into a two liter reactor equipped with suitable devices and placed under nitrogen circulation, 42.5 g (0.095 mol) of 5-(2-chlorophenyl)-8-(isopropyl-thiomethylcarbonyl)-6,7,8,9-tetrahydro-3H-pyrido were poured [4',3':4,5]thieno[3,2-f]1,4-diazepin-2-one, 1 liter of methanol and 19.06 g (0.376 mol) of hydrazine hydrate. The suspension was allowed to stand for 90 minutes at room temperature (25°C). The presence of starting material was detected by TLC analysis. The mixture was then heated to 40°C for 30 minutes and kept at room temperature for 1 hour to complete the reaction.

Blandingen ble filtrert og etter vask med metanol og dietyleter, ble det oppnådd 36,4 g av tittelforbindelsen (utbytte 83%). The mixture was filtered and after washing with methanol and diethyl ether, 36.4 g of the title compound were obtained (yield 83%).

3. trinn E —> A: Tittelforbindelse. 3rd step E —> A: Title connection.

Fremstilling av 6-(2-klorfenyl)-9-(isopropyl-tiometylkarbonyl)-7.8.9.10- tetrahydro-l-metyl-4H-pyrido[4',31:4,5]tieno[3,2-f]-1,2,4-triazolo[4,3-a]1,4-diazepin Preparation of 6-(2-chlorophenyl)-9-(isopropyl-thiomethylcarbonyl)-7.8.9.10-tetrahydro-1-methyl-4H-pyrido[4',31:4,5]thieno[3,2-f]- 1,2,4-triazolo[4,3-a]1,4-diazepine

I en 1 liter reaktor forsynt med kjøleanordninger og anbragt under nitrogensirkulasjon, ble det hellet 32,4 g Into a 1 liter reactor equipped with cooling devices and placed under nitrogen circulation, 32.4 g were poured

(0,070 mol) 5-(2-klorfenyl)-8-(isopropyl-tiometyl-tiokarbonyl)-2-hydrazino-6,7,8,9-tetrahydro-3H-pyrido[4<1>,3<1>:4,5]tieno[3,2-f]l,4-diazepin, 600 ml metanol og 45 g (0,28 mol) trietylortoacetat. Suspensjonen ble kokt under tilbakeløpskjøling i 90 minutter. Etter tilbakeløpsbehandling i 15 minutter ble det oppnådd en oppløsning og utfelling inntrådte etter 45 minutters tilbakeløpsbehandling. Alt utgangsmaterialet var omsatt. Blandingen ble deretter avkjølt og bunnfallet frafiltrert, vasket med metanol og deretter med dietyleter. Etter tørking ved romtemperatur og deretter ved 110°C over natten under redusert trykk, ble det oppnådd 30,3 g av tittelforbindelsen (utbytte 89%). (0.070 mol) 5-(2-chlorophenyl)-8-(isopropyl-thiomethyl-thiocarbonyl)-2-hydrazino-6,7,8,9-tetrahydro-3H-pyrido[4<1>,3<1>: 4,5]thieno[3,2-f]1,4-diazepine, 600 ml of methanol and 45 g (0.28 mol) of triethyl orthoacetate. The suspension was boiled under reflux for 90 minutes. After refluxing for 15 minutes, a solution was obtained and precipitation occurred after 45 minutes of refluxing. All the starting material had been sold. The mixture was then cooled and the precipitate filtered off, washed with methanol and then with diethyl ether. After drying at room temperature and then at 110°C overnight under reduced pressure, 30.3 g of the title compound was obtained (yield 89%).

Eksempel 2: 6-(2-klorfenyl)-9-(isopropyltiometyl-tiokarbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4<1>,3<1>:4,5]tieno[3,2-f]1,2,4-triazolo[4,3-a]l,4-diazepin Example 2: 6-(2-chlorophenyl)-9-(isopropylthiomethyl-thiocarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4<1>,3<1>:4,5 ]thieno[3,2-f]1,2,4-triazolo[4,3-a]l,4-diazepine

Y = S R = isopropyl Y = S R = isopropyl

1. trinn A —> B: 1st step A —> B:

Fremstilling av 5-(2-klorfenyl)-8-(isopropyl-tiometyl-karbonyl)-6,7,8,9-tetrahydro-3H-pyrido[4<1>,3':4,5]tieno[3,2-f]1,4-diazepin-2-on Preparation of 5-(2-chlorophenyl)-8-(isopropyl-thiomethyl-carbonyl)-6,7,8,9-tetrahydro-3H-pyrido[4<1>,3':4,5]thieno[3, 2-f]1,4-diazepin-2-one

Denne omsetningen er utførlig beskrevet i Eksempel 1 (første trinn). This transaction is described in detail in Example 1 (first step).

2. trinn D -> D': 2nd step D -> D':

Fremstilling av 5-(2-klorfenyl)-8-(isopropyl-tiometyl-tio-karbonyl)-6,7,8,9-tetrahydro-3H-pyrido[4<*>,3':4,5]tieno[3,2-f]-1,4-diazepin-2-tion Preparation of 5-(2-chlorophenyl)-8-(isopropyl-thiomethyl-thio-carbonyl)-6,7,8,9-tetrahydro-3H-pyrido[4<*>,3':4,5]thieno[ 3,2-f]-1,4-diazepin-2-thione

I en fem liter reaktor forsynt med passende anordninger og anbragt under nitrogensirkulasjon, ble det hellet 40,3 g Into a five liter reactor equipped with suitable devices and placed under nitrogen circulation, 40.3 g were poured

(0,090 mol) 5-(2-klorfenyl)-8-(isopropyltiometyl-karbonyl)-6,7,8,9-tetrahydro-3H-pyrido[4',3':4,5]tieno[3,2-f]1,4-diazepin-2-on og 1,25 liter 1,2-dimetoksyetan. Suspensjonen ble oppvarmet til 60°C og ble deretter tilsatt 87,1 g (0,392 mol) fosforpentasulfid og 65,4 g (0,785 mol) natriumbikarbonat. Tilsetningen (0.090 mol) 5-(2-chlorophenyl)-8-(isopropylthiomethylcarbonyl)-6,7,8,9-tetrahydro-3H-pyrido[4',3':4,5]thieno[3,2- f]1,4-diazepin-2-one and 1.25 liters of 1,2-dimethoxyethane. The suspension was heated to 60°C and then 87.1 g (0.392 mol) of phosphorus pentasulfide and 65.4 g (0.785 mol) of sodium bicarbonate were added. The addition

ble foretatt i løpet av 15 minutter. Temperaturen ble deretter holdt ved 70°C i 90 minutter. Siden TLC-analyse viste spor av mellomprodukter, ble blandingen tilbakeløpsbehandlet i 30 minutter for å fullføre reaksjonen. Deretter ble blandingen avkjølt til 15°C og tilsatt 2,5 liter is-vann. Blandingen ble deretter hellet over i et 5 liter begerglass og tilsatt en 0,4M natriumbikarbonatoppløsning for å bringe pH til 8. Blandingen ble omrørt i 30 minutter og bunnfallet frafiltrert, vasket med vann, med etanol og deretter med dietyleter og behandlet med 1 liter diklormetan. Uoppløselig materiale ble frafiltrert. Deretter ble blandingen vasket med 300 ml diklormetan, hvorpå diklormetanet ble fordampet. Det resulterende residuum ble behandlet med acetonitril og fikk deretter stå over natten i en "icebox". was carried out within 15 minutes. The temperature was then maintained at 70°C for 90 minutes. Since TLC analysis showed traces of intermediates, the mixture was refluxed for 30 min to complete the reaction. The mixture was then cooled to 15°C and 2.5 liters of ice water were added. The mixture was then poured into a 5 liter beaker and a 0.4 M sodium bicarbonate solution was added to bring the pH to 8. The mixture was stirred for 30 minutes and the precipitate filtered off, washed with water, with ethanol and then with diethyl ether and treated with 1 liter of dichloromethane . Insoluble material was filtered off. The mixture was then washed with 300 ml of dichloromethane, after which the dichloromethane was evaporated. The resulting residue was treated with acetonitrile and then allowed to stand overnight in an icebox.

Etter filtrering, vask med acetonitril og deretter med dietyleter og tørking, ble det oppnådd 28,1 g av tittelforbindelsen (utbytte 65%). After filtration, washing with acetonitrile and then with diethyl ether and drying, 28.1 g of the title compound were obtained (yield 65%).

3. trinn D' -> E: 3rd step D' -> E:

Fremstilling av 5-(2-klorfenyl)-8-(isopropyl-tiometyl-tio-karbonyl)-2-hydrazino-6,7,8,9-tetrahydro-3H-pyrido[4',3':4,5]-tieno[3,2-f]1,4-diazepin Preparation of 5-(2-chlorophenyl)-8-(isopropyl-thiomethyl-thio-carbonyl)-2-hydrazino-6,7,8,9-tetrahydro-3H-pyrido[4',3':4,5] -thieno[3,2-f]1,4-diazepine

I en to liter reaktor forsynt med passende anordninger og anbragt under nitrogensirkulasjon, ble det hellet 19,7 g (0,041 mol) 5-(2-klorfenyl)-8-(isopropyl-tiometyl-tiokarbonyl)-6,7,8,9-tetrahydro-3H-pyrido[4',3<1>:4,5]tieno[3,2-f]1,4-diazepin-2-tion, 500 ml metanol og 8,22 g (0,162 mol) hydrazinhydrat. Suspensjonen fikk stå i 90 minutter ved romtemperatur (25°C). Nærvær av utgangsmateriale ble påvist ved TLC-analyse. Blandingen ble deretter oppvarmet til 40°C i 30 minutter og holdt ved romtemperatur i 1 time for å fullføre reaksjonen. Blandingen ble filtrert og det ble oppnådd 16,4 g av tittelforbindelsen etter vask med metanol og med dietyleter (utbytte 84%). Into a two liter reactor equipped with suitable devices and placed under nitrogen circulation, 19.7 g (0.041 mol) of 5-(2-chlorophenyl)-8-(isopropyl-thiomethyl-thiocarbonyl)-6,7,8,9 -tetrahydro-3H-pyrido[4',3<1>:4,5]thieno[3,2-f]1,4-diazepin-2-thione, 500 ml methanol and 8.22 g (0.162 mol) hydrazine hydrate . The suspension was allowed to stand for 90 minutes at room temperature (25°C). The presence of starting material was detected by TLC analysis. The mixture was then heated to 40°C for 30 minutes and kept at room temperature for 1 hour to complete the reaction. The mixture was filtered and 16.4 g of the title compound were obtained after washing with methanol and with diethyl ether (yield 84%).

4. trinn E -> A: 4th step E -> A:

Fremstilling av 6-(2-klorfenyl)-9-(isopropyl-tiometyl-tio-karbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[41,31:4,5] - tieno[3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepin Preparation of 6-(2-chlorophenyl)-9-(isopropyl-thiomethyl-thio-carbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[41,31:4,5]-thieno [3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepine

I en 1 liter reaktor forsynt med kjøleanordninger og anbragt under nitrogensirkulasjon, ble det hellet 12 g (0,025 mol) 5-(2-klorfenyl)-8-(isopropyl-tiometyl-tiokarbonyl)-2-hydrazino-6,7,8,9-tetrahydro-3H-pyrido[4',3':4,5]tieno[3,2-f]l,4-diazepin, 250 ml metanol og 16,1 g (0,100 mol) trietylortoacetat. Into a 1 liter reactor equipped with cooling devices and placed under nitrogen circulation, 12 g (0.025 mol) of 5-(2-chlorophenyl)-8-(isopropyl-thiomethyl-thiocarbonyl)-2-hydrazino-6,7,8, 9-tetrahydro-3H-pyrido[4',3':4,5]thieno[3,2-f]1,4-diazepine, 250 ml of methanol and 16.1 g (0.100 mol) of triethyl orthoacetate.

Suspensjonen ble tilbakeløpsbehåndlet i 90 minutter. Etter 15 minutters tilbakeløpsbehandling ble det herunder oppnådd en oppløsning og etter 45 minutters tilbakeløpsbehandling inntrådte utfelling. Alt utgangsmateriale var omsatt. Blandingen ble deretter avkjølt og bunnfallet frafiltrert, vasket med metanol og deretter med dietyleter. Etter tørking ved romtemperatur og deretter ved 110°C over natten under redusert trykk, ble det oppnådd 11,1 g av tittelforbindelsen (utbytte 88%). The suspension was refluxed for 90 minutes. After 15 minutes of reflux treatment, a solution was obtained below and after 45 minutes of reflux treatment precipitation occurred. All starting material had been sold. The mixture was then cooled and the precipitate filtered off, washed with methanol and then with diethyl ether. After drying at room temperature and then at 110°C overnight under reduced pressure, 11.1 g of the title compound were obtained (yield 88%).

De følgende forbindelser ble fremstillet som beskrevet i Eksempel 1, når Y = 0, og som beskrevet i Eksempel 2 når Y = S, men ved å gå ut fra det passende R-S-CH2C02H-derivat. The following compounds were prepared as described in Example 1, when Y = 0, and as described in Example 2 when Y = S, but starting from the appropriate R-S-CH 2 CO 2 H derivative.

Eksempel 3: 6-(2-klorfenyl)-9-(t.butyltiometyl-karbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]1,2,4-triazolo[4,3-a]-1,4-diazepin Example 3: 6-(2-chlorophenyl)-9-(t-butylthiomethylcarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3':4,5]thieno [3,2-f]1,2,4-triazolo[4,3-a]-1,4-diazepine

Y = 0 R = t.butyl Y = 0 R = t.butyl

Eksempel 4: 6-(2-klorfenyl)-9-(t.butyltiometyl-tiokarbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3<1>:4,5]tieno[3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepin Example 4: 6-(2-chlorophenyl)-9-(t-butylthiomethyl-thiocarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3<1>:4,5 ]thieno[3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepine

Y = S R = t.butyl Y = S R = t.butyl

Eksempel 5: 6-(2-klorfenyl)-9-(heksadecyltiometyl-karbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepin Example 5: 6-(2-chlorophenyl)-9-(hexadecylthiomethylcarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3':4,5]thieno[3 ,2-f]1,2,4-triazolo[4,3-a]1,4-diazepine

Y = 0 R = heksadecyl Y = 0 R = hexadecyl

Eksempel 6: 6-(2-klorfenyl)-9-(heksadecyltiometyl-tiokarbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepin Example 6: 6-(2-chlorophenyl)-9-(hexadecylthiomethyl-thiocarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3':4,5]thieno[3 ,2-f]1,2,4-triazolo[4,3-a]1,4-diazepine

Y = S R = heksadecyl Y = S R = hexadecyl

Eksempel 7: 6-(2-klorfenyl)-9-(fenyl-tiometyl-karbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]1,2,4-triazolo[4,3-a]-1,4-diazepin Example 7: 6-(2-chlorophenyl)-9-(phenyl-thiomethyl-carbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3':4,5]thieno [3,2-f]1,2,4-triazolo[4,3-a]-1,4-diazepine

Y = 0 R = fenyl Y = 0 R = phenyl

Eksempel 8: 6-(2-klorfenyl)-9-(fenyltiometyl-tiokarbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4<1>,3':4,5]tieno[3,2-f]1,2,4-triazolo-[4,3-a]1,4-diazepin Example 8: 6-(2-chlorophenyl)-9-(phenylthiomethyl-thiocarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4<1>,3':4,5]thieno [3,2-f]1,2,4-triazolo-[4,3-a]1,4-diazepine

Y = S R = fenyl Y = S R = phenyl

Eksempel 9: 6-(2-klorfenyl)-9-(4-metoksyfenyltiometyl-karbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepin Example 9: 6-(2-chlorophenyl)-9-(4-methoxyphenylthiomethylcarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3':4,5]thieno [3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepine

Y = 0 R = 4-metoksyfenyl Y = 0 R = 4-methoxyphenyl

Eksempel 10: 6-(2-klorfenyl)-9-(4-metoksyfenyltiometyl-tiokarbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]1,2,4-triazolo[4,3-a]l,4-diazepin Example 10: 6-(2-chlorophenyl)-9-(4-methoxyphenylthiomethyl-thiocarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3':4,5]thieno [3,2-f]1,2,4-triazolo[4,3-a]l,4-diazepine

Y = S R = 4-metoksyfenyl Y = S R = 4-methoxyphenyl

Eksempel 11: 6-(2-klorfenyl)-9-(3,4-dimetoksyfenyltiometyl-karbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4<*>,3':4,5]tieno[3,2-f]-1,2,4-triazolo[4,3-a]1,4-diazepin Example 11: 6-(2-chlorophenyl)-9-(3,4-dimethoxyphenylthiomethylcarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4<*>,3':4 ,5]thieno[3,2-f]-1,2,4-triazolo[4,3-a]1,4-diazepine

Y = 0 R = 3,4-dimetoksyfenyl Y = 0 R = 3,4-dimethoxyphenyl

Eksempel 12: 6-(2-klorfenyl)-9-(3,4-dimetoksyfenyltiometyl-tiokarbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3<1>:4,5]tieno[3,2-f]-1,2,4-triazolo[4,3-a]1,4-diazepin Example 12: 6-(2-chlorophenyl)-9-(3,4-dimethoxyphenylthiomethyl-thiocarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3<1>:4 ,5]thieno[3,2-f]-1,2,4-triazolo[4,3-a]1,4-diazepine

Y = S R = 3,4-dimetoksyfenyl Y = S R = 3,4-dimethoxyphenyl

Eksempel 13: 6-(2-klorfenyl)-9-(3,4,5-trimet6ksyfenyltiometyl-karbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]-1,2,4-triazolo[4,3-a]l,4-diazepin Example 13: 6-(2-chlorophenyl)-9-(3,4,5-trimethoxyphenylthiomethylcarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3':4 ,5]thieno[3,2-f]-1,2,4-triazolo[4,3-a]l,4-diazepine

Y = 0 R = 3,4,5-trimetoksyfenyl Y = 0 R = 3,4,5-trimethoxyphenyl

Eksempel 14: 6-(2-klorfenyl)-9-(3,4,5-trimetoksyfenyltiometyl-tiokarbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]-1,2,4-triazolo[4,3-a]1,4-diazepin Example 14: 6-(2-chlorophenyl)-9-(3,4,5-trimethoxyphenylthiomethyl-thiocarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3':4 ,5]thieno[3,2-f]-1,2,4-triazolo[4,3-a]1,4-diazepine

Y = S R = 3,4,5-trimetoksyfenyl Y = S R = 3,4,5-trimethoxyphenyl

Eksempel 15: 6-(2-klorfenyl)-9-(2,3,4-trimetoksyfenyltiometyl-karbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]-1,2,4-triazolo[4,3-a]1,4-diazepin Example 15: 6-(2-chlorophenyl)-9-(2,3,4-trimethoxyphenylthiomethylcarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3':4 ,5]thieno[3,2-f]-1,2,4-triazolo[4,3-a]1,4-diazepine

Y = 0 R = 2,3,4-trimetoksyfenyl Y = 0 R = 2,3,4-trimethoxyphenyl

Eksempel 16: 6-(2-klorfenyl)-9-(2,3,4-trimetoksyfenyltiometyl-tiokarbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3<1>:4,5]tieno[3,2-f]-1,2,4-triazolo[4,3-a]1,4-diazepin Example 16: 6-(2-chlorophenyl)-9-(2,3,4-trimethoxyphenylthiomethyl-thiocarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3<1> :4,5]thieno[3,2-f]-1,2,4-triazolo[4,3-a]1,4-diazepine

Y = S R = 2,3,4-trimetoksyfenyl Y = S R = 2,3,4-trimethoxyphenyl

Eksempel 17: 6-(2-klorfenyl)-9-(4-t.butylfenyltiometyl-karbonyl5-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]-1,2,4-triazolo[4,3-a]1,4-diazepin Example 17: 6-(2-chlorophenyl)-9-(4-t.butylphenylthiomethyl-carbonyl-5-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3':4,5] thieno[3,2-f]-1,2,4-triazolo[4,3-a]1,4-diazepine

Y = 0 R = 4-t.butylfenyl Y = 0 R = 4-t.butylphenyl

Eksempel 18: 6-(2-klorfenyl)-9-(4-t.butylfenyltiometyl-tiokarbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4<1>,3':4,5]tieno[3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepin Example 18: 6-(2-chlorophenyl)-9-(4-t.butylphenylthiomethyl-thiocarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4<1>,3':4 ,5]thieno[3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepine

Y = S R = 4-t.butylfenyl Y = S R = 4-t.butylphenyl

Eksempel 19: 6-(2-klorfenyl)-9-(2-trifluormetylfenyltiometyl-karbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]-1,2,4-triazolo[4,3-a]1,4-diazepin Example 19: 6-(2-chlorophenyl)-9-(2-trifluoromethylphenylthiomethylcarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3':4,5]thieno [3,2-f]-1,2,4-triazolo[4,3-a]1,4-diazepine

Y = 0 R = 2-trifluormetylfenyl Y = 0 R = 2-trifluoromethylphenyl

Eksempel 20: 6-(2-klorfenyl)-9-(2-trifluormetylfenyltiometyl-tiokarbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3<1>:4,5]tieno[3,2-f]-1,2,4-triazolo[4,3-a]1,4-diazepin Example 20: 6-(2-chlorophenyl)-9-(2-trifluoromethylphenylthiomethyl-thiocarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3<1>:4,5 ]thieno[3,2-f]-1,2,4-triazolo[4,3-a]1,4-diazepine

Y = S R = 2-trifluormetylfenyl Y = S R = 2-trifluoromethylphenyl

Eksempel 21: 6-(2-klorfenyl)-9-(3-trifluormetylfenyltiometyl-karbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]-1,2,4-triazolo[4,3-a]1,4-diazepin Example 21: 6-(2-chlorophenyl)-9-(3-trifluoromethylphenylthiomethylcarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3':4,5]thieno [3,2-f]-1,2,4-triazolo[4,3-a]1,4-diazepine

Y = 0 R = 3-trifluormetylfenyl Y = 0 R = 3-trifluoromethylphenyl

Eksempel 22: 6-(2-klorfenyl)-9-(3-trifluormetylfenyltiometyl-tiokarbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]-1,2,4-triazolo[4,3-a]1,4-diazepin Example 22: 6-(2-chlorophenyl)-9-(3-trifluoromethylphenylthiomethyl-thiocarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3':4,5]thieno [3,2-f]-1,2,4-triazolo[4,3-a]1,4-diazepine

Y = S R = 3-trifluormetylfenyl Y = S R = 3-trifluoromethylphenyl

Eksempel 23: 6-(2-klorfenyl)-9-(4-trifluormetylfenyltiometyl-karbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]-1,2,4-triazolo[4,3-a] ,4-diazepin Example 23: 6-(2-chlorophenyl)-9-(4-trifluoromethylphenylthiomethylcarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3':4,5]thieno [3,2-f]-1,2,4-triazolo[4,3-a],4-diazepine

Y = 0 R = 4-trifluormetylfenyl Y = 0 R = 4-trifluoromethylphenyl

Eksempel 24: 6-(2-klorfenyl)-9-(4-trifluormetylfenyltiometyl-tiokarbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]-1,2,4-triazolo[4,3-a]1,4-diazepin Example 24: 6-(2-chlorophenyl)-9-(4-trifluoromethylphenylthiomethyl-thiocarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3':4,5]thieno [3,2-f]-1,2,4-triazolo[4,3-a]1,4-diazepine

Y = S R = 4-trifluormetylfenyl Y = S R = 4-trifluoromethylphenyl

Eksempel 25: 6-(2-klorfenyl)-9-(4-fluorfenyltiometyl-karbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3 *:4,5]tieno[3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepin Example 25: 6-(2-chlorophenyl)-9-(4-fluorophenylthiomethylcarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3*:4,5]thieno [3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepine

Y = 0 R = 4-fluorfenyl Y = 0 R = 4-fluorophenyl

Eksempel 26: 6-(2-klorfenyl)-9-(4-fluorfenyltiometyl-tiokarbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepin Example 26: 6-(2-chlorophenyl)-9-(4-fluorophenylthiomethyl-thiocarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3':4,5]thieno [3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepine

Y = S R = 4-fluorfenyl Y = S R = 4-fluorophenyl

Eksempel 27: 6-(2-klorfenyl)-9-(2,3-diklorfenyltiometyl-karbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3': 4,5]tieno[3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepin Example 27: 6-(2-chlorophenyl)-9-(2,3-dichlorophenylthiomethylcarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3': 4.5 ]thieno[3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepine

Y = 0 R = 2,3-diklorfenyl Y = 0 R = 2,3-dichlorophenyl

Eksempel 28: 6-(2-klorfenyl)-9-(2,3-diklorfenyltiometyl-tiokarbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepin Example 28: 6-(2-chlorophenyl)-9-(2,3-dichlorophenylthiomethyl-thiocarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3':4,5 ]thieno[3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepine

Y = S R = 2,3-diklorfenyl Y = S R = 2,3-dichlorophenyl

Eksempel 29: 6-(2-klorfenyl)-9-(4-fenoksyfenyltiometyl-karbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepin Example 29: 6-(2-chlorophenyl)-9-(4-phenoxyphenylthiomethylcarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3':4,5]thieno [3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepine

Y = 0 R = 4-fenoksyfenyl Y = 0 R = 4-phenoxyphenyl

Eksempel 30: 6-(2-klorfenyl)-9-(4-fenoksyfenyltiometyl-tiokarbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4<1>,3<1>:4,5]tieno[3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepin Example 30: 6-(2-chlorophenyl)-9-(4-phenoxyphenylthiomethyl-thiocarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4<1>,3<1>:4 ,5]thieno[3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepine

Y = S R = 4-fenoksyfenyl Y = S R = 4-phenoxyphenyl

Eksempel 31: 6-(2-klorfenyl)-9-(2-furyl-tiometyl-karbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]1,2,4-triazolo-[4,3-a]1,4-diazepin Example 31: 6-(2-chlorophenyl)-9-(2-furyl-thiomethyl-carbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3':4,5 ]thieno[3,2-f]1,2,4-triazolo-[4,3-a]1,4-diazepine

Y = 0 R = 2-furyl Y = 0 R = 2-furyl

Eksempel 32: 6-(2-klorfenyl)-9-(2-furyltiometyl-tiokarbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepin Example 32: 6-(2-chlorophenyl)-9-(2-furylthiomethyl-thiocarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3':4,5]thieno [3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepine

Y = S R = 2-furyl Y = S R = 2-furyl

Eksempel 33: 6-(2-klorfenyl)-9-(2-tienyltiometyl-karbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]l,2,4-triazolo-[4,3-a]1,4-diazepin Example 33: 6-(2-chlorophenyl)-9-(2-thienylthiomethylcarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4',3':4,5]thieno [3,2-f]l,2,4-triazolo-[4,3-a]1,4-diazepine

Y = 0 R = 2-tienyl Y = 0 R = 2-thienyl

Eksempel 34: 6-(2-klorfenyl)-9-(2-tienyltiometyl-tiokarbonyl)-7,8,9,10-tetrahydro-l-metyl-4H-pyrido[4",3':4,5]tieno[3,2-f]l,2,4-triazolo-[4,3-a]1,4-diazepin Example 34: 6-(2-chlorophenyl)-9-(2-thienylthiomethyl-thiocarbonyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4,3':4,5]thieno [3,2-f]l,2,4-triazolo-[4,3-a]1,4-diazepine

Y = S R = 2-tienyl Y = S R = 2-thienyl

Toksisitet Toxicity

Forbindelsene fremstillet i henhold til oppfinnelsen er ikke giftige for mus ved i.p. eller oral dosering av 1 g/kg. The compounds produced according to the invention are not toxic to mice by i.p. or oral dosage of 1 g/kg.

Farmakologi Pharmacology

Diverse farmakologiske undersøkelser av forbindelsene er foretatt: Various pharmacological investigations of the compounds have been carried out:

1) Hemming av blodplateaggregasjon indusert av PAF. 1) Inhibition of platelet aggregation induced by PAF.

Dette forsøk ble foretatt etter fremgangsmåten til R. Kinlough. Rathbone, J.P. Cazenave, M. Packham og F. Mustard, Lab. Invest. 48, 98, 1980. I denne undersøkelse ble det benyttet New Zealand-kaniner (New Zealand-hannkaniner med en gjennomsnittsvekt på 5 kg). This experiment was carried out according to the method of R. Kinlough. Rathbone, J.P. Cazenave, M. Packham and F. Mustard, Lab. Invest. 48, 98, 1980. In this investigation, New Zealand rabbits (male New Zealand rabbits with an average weight of 5 kg) were used.

Bestemmelsene ble foretatt ved 57°C på et chrono-log Coultronics aggregometer forbundet med en skriver. Resultatene av disse undersøkelsene (i molare konsentrasjoner) er angitt i Tabell I i den midtre kolonne. The determinations were made at 57°C on a chrono-log Coultronics aggregometer connected to a printer. The results of these investigations (in molar concentrations) are given in Table I in the middle column.

2) Hemming av bindingen til benzodiazepinreseptorer 2) Inhibition of binding to benzodiazepine receptors

Interessen for det foregående forsøk bygger på resultater oppnådd gjennom følgende: når en forbindelse fremstillet i henhold til oppfinnelsen har en benzodiazepin-lignende struktur, er det viktig å undersøke hvorvidt den spesifikke benzodiazepin-aktivitet ikke fremkommer ved doser som hindrer blodplate-aggregas jon . The interest in the previous experiment is based on results obtained through the following: when a compound produced according to the invention has a benzodiazepine-like structure, it is important to investigate whether the specific benzodiazepine activity does not appear at doses that prevent platelet aggregation.

Forsøket er foretatt etter fremgangsmåten til Mohler H. & Richard J.G. "Agonist and antagonist benzodiazepine receptor interaction in vitro", Nature, vol. 294, 763-765, 1981. The experiment was carried out according to the method of Mohler H. & Richard J.G. "Agonist and antagonist benzodiazepine receptor interaction in vitro", Nature, vol. 294, 763-765, 1981.

Forsøket er utført på rottehjerner inkubert i 1,5 timer ved 4°C under bruk av sh-ro-15-1788 og <3>H-R0-5-4864 (NEN) som tracere og RO-15-4788 og RO-5-4864 som referanse-antagonister. The experiment was carried out on rat brains incubated for 1.5 hours at 4°C using sh-ro-15-1788 and <3>H-R0-5-4864 (NEN) as tracers and RO-15-4788 and RO- 5-4864 as reference antagonists.

Resultatene i molkonsentrasjoner er angitt i høyre kolonne i Tabell I. The results in molar concentrations are given in the right column of Table I.

3) Global ischemi på gerbiller 3) Global ischemia in gerbils

Ved denne undersøkelse ble hann-gerbiller anestetisert med brietal i doser på 35 mg/kg i.p., hvorpå begge carotider ble overbundet i 10 minutter og overbindingen deretter fjernet. Behandlede dyr fikk hver 10 mg/kg av forbindelsene fremstillet In this examination, male gerbils were anesthetized with brietal in doses of 35 mg/kg i.p., after which both carotids were ligated for 10 minutes and the ligating was then removed. Treated animals each received 10 mg/kg of the compounds produced

i henhold til et av eksemplene. according to one of the examples.

En uke senere ble dyrene avlivet og hippocampus på hver side tatt ut, veiet og nedfrosset ved -80°C. One week later, the animals were euthanized and the hippocampus on each side was removed, weighed and frozen at -80°C.

Etter utgnidning med 1 ml Tris-HCl-buffer (pH 7,4) i 30 sekunder, ble alikvoter på 50 pl av dette preparat inkubert i 1 ml porsjoner Tris-HCl-buffer inneholdende <3>H-PK 11195 ved 2nM (90Ci/mmol, NENE, Vest-Tyskland) i 1 time ved 25°C. After trituration with 1 ml Tris-HCl buffer (pH 7.4) for 30 seconds, 50 µl aliquots of this preparation were incubated in 1 ml portions of Tris-HCl buffer containing <3>H-PK 11195 at 2nM (90Ci /mmol, NENE, West Germany) for 1 hour at 25°C.

For hvert preparat ble det foretatt 3 bestemmelser. Tettheten av omega-3-seter (merket med den spesifikke <3>H-PK 11195-markør) er uttrykt i f-mol av PK 11195/mg friskt vev og konvertert til prosent beskyttelse sammenlignet med kontrollene. For each preparation, 3 determinations were made. The density of omega-3 sites (labeled with the specific <3>H-PK 11195 marker) is expressed in f-mol of PK 11195/mg fresh tissue and converted to percent protection compared to controls.

Resultatene av dette forsøk er angitt i Tabell II. The results of this experiment are shown in Table II.

Presentasjon - Posolog,i Presentation - Posolog,i

Ved humanterapeut.... ■ anvendelse administreres de nye forbindelser fortrinnsvis per os. Foretrukne administrasjons-former innbefatter tabletter, gelatinkapsler og lignende. Vanlig dosering er fra 50 mg til 500 mg per dag, avhengig av tilfellet. Den foretrukne enhetsdose er 50 mg i en tilberedning med passende bæremidler og hjelpestoffer. De kan administreres ved injeksjon. Vanlig dosering er fra 5 mg til 100 mg per dag alt etter tilstanden. Enhetsdoser utgjør fra 1 til 20 mg. In the case of human therapist... ■ application, the new compounds are preferably administered per os. Preferred forms of administration include tablets, gelatin capsules and the like. Usual dosage is from 50 mg to 500 mg per day, depending on the case. The preferred unit dose is 50 mg in a preparation with suitable carriers and excipients. They can be administered by injection. Usual dosage is from 5 mg to 100 mg per day depending on the condition. Unit doses range from 1 to 20 mg.

Claims

Analogy method for the preparation of therapeutic

active thieno-triazolo-diazepine derivatives of formula A

where Y represents an oxygen or sulfur atom and R represents a straight-chain or branched alkyl group of 1 to 20 carbon atoms; a phenyl group which is unsubstituted or substituted with a straight or branched chain alkyl group of from 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, a halogen atom, a trifluoromethyl group or a phenoxy group; or a furan or thiophene ring, characterized by

reaction of the thieno-triazolo-diazepine compound of formula B with a stoichiometric amount of the RSCH2COOH derivative C, where R is as defined above, in an aprotic solvent, in the presence of a slight stoichiometric excess of dicyclohexylcarbodiimide at a temperature of 0-60 °C, after which the resulting compound of formula:

where R is as defined above, is reacted with three to five stoichiometric equivalents of hydrazine hydrate, in a protic solvent at a temperature from room temperature to 50°C, whereupon the obtained compound of formula:

finally cyclized in a protic solvent with one to three stoichiometric equivalents of triorthoacetate at a

temperature from room temperature to the boiling point of the reaction mixture, in order to obtain the thieno-triazolo-diazepine derivative of the general formula A, where Y is an oxygen atom, and optionally continue with a sulfurization tririn [D - > D'] which consists in reacting the thieno-diazepine -the derivative of formula D with three to five stoichiometric equivalents of phosphorus pentasulfide, in an aprotic solvent at a temperature from 10°C to the boiling point of the reaction mixture, to obtain the corresponding thieno-triazolo-diazepine where Y stands for a sulfur atom.