SE507189C3

SE507189C3 - Preparation process for new thieno-triazolo-diazepine compounds

Info

Publication number: SE507189C3
Application number: SE9000873A
Authority: SE
Inventors: Pierre Braquet; Andre Esanu; Jean-Pierre Laurent; Alain Rolland
Original assignee: Sod Conseils Rech Applic
Priority date: 1990-03-12
Filing date: 1990-03-12
Publication date: 1998-05-04
Also published as: SE507189C2; SE9000873D0; SE9000873L

Abstract

Prepn. of thieno-triazolo derivs. of formula (I) comprises; (a) reacting a thieno-triazolo-diazepine (II) with a slight stoichiometric excess of (III) under N2 in a pretic solvent, and refluxing for 24 hrs.; (b) reacting the above prod. with a cpd. of formula (IV) under N2 with a slight stoichiometric excess of hydrazine hydrate at 0 deg.C to room temp. for 5 mins. to 1 hr.; and (c) cyclising under N2 in a protic solvent the above prod. with 4 stoichiometric equivs. of triethylorthoacetate at room temp. for 15 mins. to 3 hrs., and then uder reflux for 1/2 hr. to 5 hrs.. R2=2-5C straight chain alkenyl, 1-20C alkyl, 3-6C cycloalkyl, 1-5C straight chain alkyl substd. by (hetero) aryl opt. substd. by Me, phenyl opt. substd. by IZ, a condensed bycyclic gp. contg. a hetero atom or a sulphonyl substd. by phenyl, hetero aryl or by a condensed bicyclic gp.; Z=1-5C alkyl, 1-5C alkoxy, phenoxy, 1-5C alkyl sulphonyl, F, Cl or CF3; Y=O or S; Ar= a gp. of formula (a).

Description

507 189 2 eller betecknar Y syre och R betecknar en bensylgrupp eller en sulfonylgrupp substituerad med en tienyl-, pyridyl- eller morfolingrupp. 507 189 2 or Y represents oxygen and R represents a benzyl group or a sulfonyl group substituted with a thienyl, pyridyl or morpholine group.

Den tidigare tekniken inom området för denna uppfinning kan illustreras med det amerikanska patentet 4 621 083 (eller E.P. 176 927), vari tieno-triazolo-diazepin med PAF-antago- nistisk aktivitet beskrives.The prior art in the field of this invention can illustrated by U.S. Patent 4,621,083 (or E.P. 176,927), wherein thieno-triazolo-diazepine with PAF antagonist economic activity is described.

Dessa nya föreningar har en PAF-antagonistisk aktivitet från tio till tusen gånger större än den hos de beskrivna diaze- pinerna i ovan nämnda patent och är också mer potenta till effektiviteten.These new compounds have a PAF antagonistic activity from ten to a thousand times larger than that of the described diazes. the pins in the above mentioned patents and are also more potent to efficiency.

Enligt uppfinningen kan dessa föreningar framställas genom omsättning under kvävecirkulation av tieno-triazolo- diazepinföreningen med formeln A: Cl Y A. med ett något stökiometriskt överskott av det lämpliga R-N=C=Y derivatet, vari R och Y är definierade som ovan, i ett protiskt lösningsmedel under återlopp under en halv till 24 timmar, varefter man under kvävecirkulation i ett aprot- iskt lösningsmedel omsätter den resulterande föreningen med formeln B: “ cl N R-NH-c-N I I I y s N H 3 507 189 med ett lätt stökiometriskt överskott av hydrazinhydrat vid en temperatur mellan 0°C och rumstemperatur under 5 minuter till ca 1 timme och slutligen under kvävecirkulering i ett protiskt lösningsmedel cykliserar den så erhållna föreningen med formeln C: cl n R-NH-C-N | | f, s N H rm åm _ C. med fyra stökiometriska ekvivalenter av trietylortoacetat vid rumstemperatur under 15 minuter till 3 timmar, och sedan un- der återlopp under en halv timme till 5 timmar.According to the invention, these compounds can be prepared by turnover during nitrogen circulation of thieno-triazolone the diazepine compound of formula A: Cl Y A. with a slightly stoichiometric excess of the appropriate R-N = C = Y derivative, wherein R and Y are defined as above, i a protic solvent under reflux for another half 24 hours, after which, during nitrogen circulation in an The solvent is reacted with the resulting solvent formula B: “ cl N R-NH-c-N I I IN y s N hrs 3 507 189 with a slight stoichiometric excess of hydrazine hydrate at a temperature between 0 ° C and room temperature for 5 minutes to about 1 hour and finally during nitrogen circulation in one protic solvent cyclizes the compound thus obtained of formula C: cl n R-NH-C-N | | f, s N H rm åm _ C. with four stoichiometric equivalents of triethyl orthoacetate at room temperature for 15 minutes to 3 hours, and then there reflux for half an hour to 5 hours.

Utgångsföreningen med formeln (A) kan framställas såsom be- skrives i följande steg: I - (2-kloro)-bensoylmetyl-cyanid Cl c-cx-n-cu O I en lämplig reaktor placerad under kvävecirkulation vid -70°C hälldes 7 l vattenfritt THF och 115,9 g (l,36 mol) av nyligen torkad cyanoättiksyra. Sålunda tillsattes droppvis 1715 ml (2,74 mol) 1,6 M lösning av butyllitium i hexan under det att temperaturen fick stiga från -70°C till OOC. Reak- tionsblandningen omrördes sedan under 1 timme.The starting compound of formula (A) can be prepared as is written in the following steps: 1- (2-chloro) -benzoylmethyl cyanide Cl c-cx-n-cu O In a suitable reactor placed under nitrogen circulation at At -70 ° C, 7 l of anhydrous THF and 115.9 g (1.36 mol) were poured off freshly dried cyanoacetic acid. Thus was added dropwise 1715 ml (2.74 mol) of 1.6 M solution of butyllithium in hexane below that the temperature was allowed to rise from -70 ° C to 0 ° C. Reactive The ion mixture was then stirred for 1 hour.

Därefter kyldes reaktionsblandningen ytterligare en gång vid -70°C, och en lösning av 120 g (0,685 mol) av 2-kloro- -bensoylklorid i l l vattenfri THF tillsattes droppvis. Efter omrörning under 1 timme hela tiden vid -700C, fick tempera- 507 189 turen stiga från -70°C till 0°C under 1 timme. Därefter till- sattes droppvis 3 l IN HCl-lösning, och efter omrörning under nâgra få minuter extraherades den omsatta blandningen med kloroform. Den organiska fasen tvättades med en 10%-ig vat- tenlösning av natriumbikarbonat, sedan med en mättad natrium- kloridlösning, torkades, filtrerades och lösningsmedlet in- dunstades och gav 135 g återstod. Kristallisationen utfördes genom tillsats av diisopropyleter, och produkten filtrerades av och tvättades med hexan och gav 97,2 g av titelföreningen (utbyte 79%).Then the reaction mixture was cooled once more at -70 ° C, and a solution of 120 g (0.685 mol) of 2-chloro- -benzoyl chloride in 11 l of anhydrous THF was added dropwise. After stirring for 1 hour all the time at -70 ° C, the temperature was 507 189 the temperature rise from -70 ° C to 0 ° C for 1 hour. Then add 3 L of 1N HCl solution was added dropwise, and after stirring a few minutes the reacted mixture was extracted with chloroform. The organic phase was washed with a 10% aqueous solution. sodium bicarbonate solution, then with a saturated sodium bicarbonate chloride solution, dried, filtered and the solvent was added evaporated to give 135 g of residue. The crystallization was performed by adding diisopropyl ether, and the product was filtered and washed with hexane to give 97.2 g of the title compound (yield 79%).

II - 2-amino-3-(2-klorobensoyl)-6-(etoxikarbonyl)-4,5,6,7- - tetrahvdro-Dvrido[3.4-bltiofen Cl C=:0 cgn-o-c-N | s NW 0 I en 2 l Erlenmeyer-kolv försedd med kylare hälldes 85,5 g (0,50l mol) N-karbetoxi-4-piperidon, 90 g (0,50l mol) av (I), 19,3 g (0,600 mol) svavelblomma och 44,4 g (0,50l mol) morfo- lin i 550 ml metanol. Blandningen återloppskokades under l timme. Efter indunstning av 250 ml lösningsmedel fälldes den önskade föreningen, filtrerades av och tvättades med etanol, sedan med dietyleter och torkades och gav 155,4 g (85%) av titelföreningen.II - 2-amino-3- (2-chlorobenzoyl) -6- (ethoxycarbonyl) -4,5,6,7- - tetrahydro-Dvrido [3,4-b] thiophene Cl C =: 0 cgn-o-c-N | s NW 0 85.5 g were poured into a 2 l Erlenmeyer flask equipped with a condenser (0.50l mol) of N-carbethoxy-4-piperidone, 90 g (0.50l mol) of (I), 19.3 g (0.600 mol) of sulfur flower and 44.4 g (0.50 mol) of morpho- lin in 550 ml of methanol. The mixture was refluxed for 1 hour hour. After evaporation of 250 ml of solvent, it was precipitated the desired compound, filtered off and washed with ethanol, then with diethyl ether and dried to give 155.4 g (85%) of the title association.

III - 2-(bromoacetamido)-3-(2-klorobensoyl)-6-(etoxi- karbonvl)-4.5.6.7-tetrahvdro-pyridof3,4-bltiofen Cl qmo-c-N 507 189 5 I en 5 l reaktor försedd med lämpliga organ och med separer- tratt hälldes 2,5 l kloroform och 146 g (0,400 mol) av (II).III - 2- (bromoacetamido) -3- (2-chlorobenzoyl) -6- (ethoxy- carbonyl) -4,5,6,7-tetrahydro-pyridophyl-3,4-b] thiophene Cl qmo-c-N 507 189 5 In a 5 l reactor equipped with suitable means and with separator funnel was poured 2.5 l of chloroform and 146 g (0.400 mol) of (II).

Därefter tillsattes droppvis 87,7 g (0,43 mol) av bromo- acetylbromid, som förelåg i separertratten. Reaktionsbland- ningen omrördes under 1 timme vid rumstemperatur, tvättades sedan med 300 ml isvatten, och den organiska fasen torkades med vattenfritt magnesiumsulfat och filtrerades. Kloroformen drevs av, och återstoden behandlades med etanol. Den resul- terande fällningen filtrerades av, tvättades med etanol, se- dan med dietyleter och torkades och gav 184,6 g (95%) av ti- telföreningen.Then 87.7 g (0.43 mol) of bromo- acetyl bromide, which was present in the separatory funnel. Reaction mixture The mixture was stirred for 1 hour at room temperature, washed then with 300 ml of ice water, and the organic phase was dried with anhydrous magnesium sulfate and filtered. Chloroform was driven off, and the residue was treated with ethanol. The result- the precipitated precipitate was filtered off, washed with ethanol, with diethyl ether and dried to give 184.6 g (95%) of the telecommunications association.

IV - 2-(aminoacetamido)-3-(2-klorobensoyl)-6-(etoxikarbonyl- -4.5.6.7-tetrahvdro-pvrido[3,4-bïtiofen Cl C::O C,H,0-C- N 3 NH-C-CEQNH, ° | 0 I en 5 l reaktor försedd med en gas-injektor hälldes 174,8 g (0,36 mol) av (III) och 3 1 THF. Suspensionen kyldes till 0°C, och sedan tillsattes gasformig ammoniak, som tidigare torkats över kaliumhydroxid. Tillsatsen fortsattes under 8 timmar (60 g ammoniak absorberades). Blandningen omrördes över natt vid 0°C, sedan drevs 2 l THF av under sänkt tryck, och 750 ml etylacetat tillsattes. Efter dekantering tvättades den organiska fasen en gång med 300 ml av en 10%-ig natrium- kloridlösning, tre gånger med 300 ml vatten och torkades med vattenfritt magnesiumsulfat. Efter filtrering indunstades lösningsmedlet partiellt i rullindunstare. Fällningen fick stå över natt i kyl. Efter filtrering tvättades fällningen med dietyleter och torkades och gav 119 g av titelföreningen.IV - 2- (aminoacetamido) -3- (2-chlorobenzoyl) -6- (ethoxycarbonyl- -4,5,6,7-tetrahydro-pyrido [3,4-bithiophene Cl C :: O C, H, O-C-N NH-C-CEQNH, ° | 0 174.8 g were poured into a 5 l reactor equipped with a gas injector (0.36 mol) of (III) and 3 L of THF. The suspension was cooled 0 ° C, and then gaseous ammonia was added, as before dried over potassium hydroxide. The addition continued below 8 hours (60 g of ammonia were absorbed). The mixture was stirred overnight at 0 ° C, then 2 l of THF was evaporated off under reduced pressure, and 750 ml of ethyl acetate were added. After decanting was washed the organic phase 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, evaporate the solvent partially in roller evaporators. The precipitation was obtained stand overnight in the refrigerator. After filtration, the precipitate was washed with diethyl ether and dried to give 119 g of the title compound.

Den resterande organiska fasen koncentrerades och behandlades med en blandning av 1,5 l dietyleter/THF (3/1 vol/vol) och gav 14,6 g av titelföreningen (totalt utbyte 88%). 5o7 189 6 V - 5-(2-klorofenyl)-8-(etoxikarbonyl)-6,7,8,9-tetrahydro- -3H-Dvrido[4'.3':4.5]tieno[3,2-f]l,4-diazepin-2-on c,H,o -c-N I o I en 2 l reaktor försedd med omrörings-, kyl- och uppvärm- ningsanordningar och placerad under cirkulerande kväve häll- des 126,6 g (0,3 mol) (IV) och 800 ml pyridin. Reaktions- blandningen återloppskokades under 18 timmar. Efter det att man kontrollerat att allt utgångsmaterial hade omsatts in- dunstades pyridinen partiellt i rullindunstare under sänkt tryck.The remaining organic phase was concentrated and treated with a mixture of 1.5 l diethyl ether / THF (3/1 v / v) and gave 14.6 g of the title compound (total yield 88%). 5o7 189 6 V - 5- (2-chlorophenyl) -8- (ethoxycarbonyl) -6,7,8,9-tetrahydro- -3H-Dyrido [4 ', 3': 4.5] thieno [3,2-f] 1,4-diazepin-2-one c, H, o -c-N IN O In a 2 l reactor equipped with stirring, cooling and heating and placed under circulating nitrogen. 126.6 g (0.3 mol) (IV) and 800 ml of pyridine were obtained. Reactional the mixture was refluxed for 18 hours. After it was checked that all starting material had been the pyridine was partially evaporated in a roller evaporator during immersion print.

Den erhållna (mörkbruna) oljan löstes i 1 l etanol. Efter kylning i ett isbad erhölls en fällning, som filtrerades av, tvättades med etanol och diisopropyloxid och gav 101,3 g (83,6%) av titelföreningen.The resulting (dark brown) oil was dissolved in 1 L of ethanol. After cooling in an ice bath a precipitate was obtained which was filtered off, was washed with ethanol and diisopropyl oxide to give 101.3 g (83.6%) of the title compound.

VI - Framställning av 5-(2-klorofenyl)-8-(etoxikarbonyl)- -6,7,8,9-tetrahydro-3H-pyrido[4',3':4,5]tieno[3,2-f]- 1,4-diazepin-2-tion cgno-c-N ° I I en 3 1 reaktor försedd med lämpliga anordningar hälldes 93 g (0,230 mol) av V och 1,75 l pyridin. Efter solubiliser- ing tillsattes 56,3 g (0,25 mol) fosforpentasvavel, och reak- tionsblandningen omrördes under 3 timmar vid 80-85°C. Där- efter avdrevs pyridinen, och den erhållna återstoden behand- 507 189 7 lades med isvatten. Blandningen extraherades sedan med mety- lenklorid, torkades med vattenfritt magnesiumsulfat, filtrer- ades, indunstades och behandlades med dietyleter. Därefter filtrerades den resulterande produkten av och behandlades med 700 ml acetonitril. Suspensionen värmdes vid 60°C under 30 minuter och fick sedan svalna.VI - Preparation of 5- (2-chlorophenyl) -8- (ethoxycarbonyl) - -6,7,8,9-tetrahydro-3H-pyrido [4 ', 3': 4,5] thieno [3,2-f] - 1,4-diazepine-2-thione cgno-c-N ° I In a 3 l reactor equipped with suitable devices was poured 93 g (0.230 mol) of V and 1.75 l of pyridine. After solubilizing 56.3 g (0.25 mol) of phosphorus pentase sulfur were added, and the reaction The ion mixture was stirred for 3 hours at 80-85 ° C. Where- after, the pyridine was evaporated off, and the resulting residue was treated. 507 189 7 loaded with ice water. The mixture was then extracted with methyl chlorine chloride, dried over anhydrous magnesium sulfate, filtered was evaporated, evaporated and treated with diethyl ether. Then the resulting product was filtered off and treated with 700 ml of acetonitrile. The suspension was heated at 60 ° C for 30 minutes minutes and then allowed to cool.

Efter filtrering och tvätt med acetonitril sedan med dietyl- eter torkades återstoden och gav 80,2 g (83%) av titelfören- ingen.After filtration and washing with acetonitrile then with diethyl ether, the residue was dried to give 80.2 g (83%) of the title compound. No.

VII - Framställning av 5-(2-klorofenyl)-6,7,8,9-tetrahydro-3H- rido 4' 3':4 5 tieno 3 2-f 1 4-diaze in-2-tion H-'N N I H S I en 2 1 reaktor försedd med lämpliga organ hälldes 71,4 g (0,l7 mol) av (VI), 116 g (l,30 mol) av (85%) kaliumhydroxid i tablettform och 1 1 av en blandning av etanol/vatten (19/1 vol/vol). Reaktionsblandningen återloppskokades 18 timmar.VII - Preparation of 5- (2-chlorophenyl) -6,7,8,9-tetrahydro-3H- rido 4 '3': 4 5 tieno 3 2-f 1 4-diaze in-2-tion H-'N N IN H S 71.4 g were poured into a 2 L reactor equipped with suitable means (0.7 mol) of (VI), 116 g (1.30 mol) of (85%) potassium hydroxide in tablet form and 1 l of a mixture of ethanol / water (19/1 vol / vol). The reaction mixture was refluxed for 18 hours.

Efter det att man kontrollerat att allt utgångsmaterial hade omsattas avdrevs etanolen, och återstoden behandlades med is- vatten. Blandningen extraherades sedan tvâ gånger med kloro- form. Vattenfasen surgjordes till pH = 6,5 med ättiksyra, och pH-värdet justeraded sedan till pH = 7,5 genom tillsats av natriumbikarbonat. Fällningen filtrerades av, torkades två gånger med vatten, två gånger med etanol och en gång med eter och tvättades sedan under återlopp med 500 ml blandning av diklorometan/etanol (3/1 vol/vol) under 30 minuter. Efter filtrering, tvätt med dietyleter och torkning under sänkt tryck erhölls 47,3 g av titelföreningen (utbyte 80%). 507 189 8 Utgångsföreningen, vari Y = s, erhålles genom omsättning av föreningen (V) med ett medel för borttagning av VIII - Framställning av 5-(2-klorofenyl)-6,7,8,9-tetra- h dro ido 4' 3':4 5 tieno 3 2-f 1 4-diaze in-2-on I en reaktor försedd med uppvärmningsorgan och placerad under cirkulerande kväve hälldes 94,5 g (0,234 mol) (V), 152,1 g (2,34 mol) av 90%-ig kaliumhydroxid i tablettform och 900 ml etylenglykolmonoetyleter. Blandningen värmdes under över 1 timme till återloppskokningstemperatur, och återlopp upprätt- hölls under 1 time. Lösningen sattes sedan till 1,2 kg kros- sad is och surgjordes med (d = 1,18) saltsyra vid pH 5,3.After checking that all starting material had the ethanol was evaporated off, and the residue was treated with ice- water. The mixture was then extracted twice with chloro- form. The aqueous phase was acidified to pH = 6.5 with acetic acid, and The pH was then adjusted to pH = 7.5 by adding sodium bicarbonate. The precipitate was filtered off, dried two times times with water, twice with ethanol and once with ether and then washed under reflux with 500 ml of a mixture of dichloromethane / ethanol (3/1 v / v) for 30 minutes. After filtration, washing with diethyl ether and drying under reduced pressure pressure, 47.3 g of the title compound were obtained (yield 80%). 507 189 8 The starting compound, wherein Y = s, is obtained by reacting compound (V) with a means for removing VIII - Preparation of 5- (2-chlorophenyl) -6,7,8,9-tetra- h dro ido 4 '3': 4 5 tieno 3 2-f 1 4-diaze in-2-on In a reactor equipped with heating means and located below circulating nitrogen was poured 94.5 g (0.234 mol) (V), 152.1 g (2.34 mol) of 90% potassium hydroxide in tablet form and 900 ml ethylene glycol monoethyl ether. The mixture was heated for over 1 hour hour to reflux temperature, and reflux held for 1 hour. The solution was then added to 1.2 kg of crushed saturated ice and acidified with (d = 1.18) hydrochloric acid at pH 5.3.

Därefter tillsattes kaliumkarbonat för att justera pH till 8,3. Lösningen extraherades sedan tre gånger med S00 ml me- tylenklorid. Den organiska fasen tvättades med 450 ml 10%-ig natriumkloridlösning, torkades med vattenfritt magnesium- sulfat, filtrerades och indunstades. Den resulterande åter- stoden behandlades med diisopropyleter. Efter tvätt med di- isopropyleter och tork erhölls 55,9 g av titelföreningen (utbyte 72%).Then potassium carbonate was added to adjust the pH to 8.3. The solution was then extracted three times with 500 ml of medium. tylene chloride. The organic phase was washed with 450 ml of 10% strength sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting return the stand was treated with diisopropyl ether. After washing with di- isopropyl ether and dryer 55.9 g of the title compound were obtained (yield 72%).

Uppfinningen ska nu beskrivas närmare närmare med hjälp av följande exempel: EXEMPEL l : 6-(2-klorofenyl)-9-[4-(metoxi)-fenyltiokarbamoyl]-7,8,9,10- -tetrahydro-1-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]1,2,4- -triazolo[4,3-a]l,4-diazepin Y = S R = 4-(metoxi)-fenyl- 9 so7 189 Första steg A -) B: Framställning av: 5-(2-klorofenyl)-8-[4-(metoxi)-fenyl- tiokarbamoyl]-6,7,8,9-tetrahydro-3H-pyrido[4',3':4,5]- tieno[3,2-f]1,4-diazepin-2-tion I en 1 l reaktor försedd med omrörnings- och kylorgan och placerad under kvävecirkulation hälldes 40 g (0,115 mol) av 5-(2-klorofenyl)-6,7,8,9-tetrahydro-3H-pyrido[4',3':4,5]- tieno[3,2-f]1,4-diazepin-2-tion (93%) och 500 ml metanol.The invention will now be described in more detail by means of the following examples: EXAMPLE 1: 6- (2-chlorophenyl) -9- [4- (methoxy) -phenylthiocarbamoyl] -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- (methoxy) -phenyl- 9 so7 189 First step A -) B: Preparation of: 5- (2-chlorophenyl) -8- [4- (methoxy) -phenyl- thiocarbamoyl] -6,7,8,9-tetrahydro-3H-pyrido [4 ', 3': 4,5] - thieno [3,2-f] 1,4-diazepine-2-thione In a 1 l reactor equipped with stirring and cooling means and placed under nitrogen circulation, 40 g (0.115 mol) were poured off 5- (2-chlorophenyl) -6,7,8,9-tetrahydro-3H-pyrido [4 ', 3': 4,5] - thieno [3,2-f] 1,4-diazepine-2-thione (93%) and 500 ml of methanol.

Därefter tillsattes 18,5 ml (0,l23 mol) para-metoxi-fenyl- isotiocyanat till den oranga suspensionen, som sedan åter- loppskokades under 2 timmar. Efter att ha kontrollerat att allt utgångsmaterial hade omsatts kyldes blandningen. Efter filtrering tvättades återstoden med etanol sedan med di- isopropyloxid och torkades över natt vid 65°C och gav 49 g (83%) av titelföreningen. 2:a steg B -) C: Framställning av 5-(2-klorofenyl)-8-[4-(metoxi)-fenyl- tiokarbamoyl]-2-hydrazino-6,7,8,9-tetrahydro-3H-pyrido- [4',3':4,5]-tieno[3,2-f]1,4-diazepin I en 1 l reaktor försedd med omrörnings- och kylorgan och placerad under kvävecirkulation hälldes 40 g (0,078 mol) av 5-(2-klorofenyl)-8-[4-(metoxi)-fenyltiokarbamoyl]-6,7,8,9- tetrahydro-3H-pyrido-[4',3':4,5]-tieno[3,2-f]1,4-diazepin-2- -tion och 350 ml tetrahydrofuran. Därefter kyldes blandningen till l0°C, och 4,1 ml (0,081 mol) hydrazinhydrat tillsattes.Then 18.5 ml (0.123 mol) of para-methoxy-phenyl- isothiocyanate to the orange suspension, which is then was boiled for 2 hours. After checking that all starting material had been reacted, the mixture was cooled. After filtration, the residue was washed with ethanol then with di- isopropyl oxide and dried overnight at 65 ° C to give 49 g (83%) of the title compound. 2nd step B -) C: Preparation of 5- (2-chlorophenyl) -8- [4- (methoxy) -phenyl- thiocarbamoyl] -2-hydrazino-6,7,8,9-tetrahydro-3H-pyrido- [4 ', 3': 4,5] -thieno [3,2-f] 1,4-diazepine In a 1 l reactor equipped with stirring and cooling means and placed under nitrogen circulation, 40 g (0.078 mol) were poured off 5- (2-chlorophenyl) -8- [4- (methoxy) -phenylthiocarbamoyl] -6,7,8,9- tetrahydro-3H-pyrido- [4 ', 3': 4,5] -thieno [3,2-f] 1,4-diazepine-2- -tion and 350 ml of tetrahydrofuran. The mixture was then cooled to 10 ° C, and 4.1 ml (0.081 mol) of hydrazine hydrate was added.

Tillsatsen fortsattes under 15 minuter. Sålunda erhölls en rödbrun lösning med en något mörk fällning, som sedan fil- trerades av. Därefter avdrevs 9/10 av tetrahydrofuranen, och 400 ml absolut etanol tillsattes till återstoden. Utfällning skedde efter priming. Blandningen omrördes på ett isbad under 1 timme. Fällningen filtrerades sedan av, tvättades med eta- nol, sedan med diisopropyloxid och torkades över natt under sänkt tryck vid 65°C vilket gav 29,7 g av titelföreningen.The addition was continued for 15 minutes. Thus, one was obtained reddish-brown solution with a slightly dark precipitate, which is then was removed by. Thereafter, 9/10 of the tetrahydrofuran was evaporated, and 400 ml of absolute ethanol was added to the residue. Precipitate happened after priming. The mixture was stirred on an ice bath below 1 hour. The precipitate was then filtered off, washed with ethyl acetate. zero, then with diisopropyl oxide and dried overnight reduced pressure at 65 ° C to give 29.7 g of the title compound.

Tvättvätskorna koncentrerades och den resulterande återstoden 507 189 10 behandlades med etanol, filtrerades, tvättades med etanol se- dan med dietyleter och gav 4,5 g av titelföreningen (totalt utbyte 86%). 3:e steg C -) Titelförening: Framställning av 6-(2-klorofenyl)-9-[4-(metoxi)-fenyl- tiokarbamoyl]-7,8,9,l0-tetrahydro-l-metyl-4H-pyrido- [4',3':4,5]-tieno[3,2-f]l,2,4-triazolo[4,3-a]1,4-diazepin I en l l reaktor försedd med omrörnings- och kylorgan och placerad under kvävecirkulation hälldes 25,5 g (0,005 mol) 5-(2-klorofenyl)-8-[4-(metoxi)-fenyltiokarbamoyl]-2-hydra- zino-6,7,8,9-tetrahydro-3H-pyrido[4',3':4,5]-tieno[3,2-f]- 1,4-diazepin och 500 ml absolut etanol. Därefter tillsattes 37 ml (0,20 mol) trietylortoacetat. Efter 30 minuter blev lösningen röd och återloppskokades sedan under 2 timmar (utfällningen började vid 7o°c) .The washings were concentrated and the resulting residue 507 189 10 treated with ethanol, filtered, washed with ethanol. with diethyl ether to give 4.5 g of the title compound (total) yield 86%). 3rd step C -) Title compound: Preparation of 6- (2-chlorophenyl) -9- [4- (methoxy) -phenyl- thiocarbamoyl] -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 In a reactor equipped with stirring and cooling means and placed under nitrogen circulation was poured 25.5 g (0.005 mol) 5- (2-chlorophenyl) -8- [4- (methoxy) -phenylthiocarbamoyl] -2-hydra- Zino-6,7,8,9-tetrahydro-3H-pyrido [4 ', 3': 4,5] -thieno [3,2-f] - 1,4-diazepine and 500 ml of absolute ethanol. Then added 37 ml (0.20 mol) of triethyl orthoacetate. After 30 minutes became the solution was red and then refluxed for 2 hours (precipitation started at 70 ° C).

Därefter kyldes blandningen till l0°C, och fällningen fil- trerades av, tvättades med etanol, sedan med dietyleter och torkades under sänkt tryck vid 90°C för att ge 24,6 g (92%) av titelföreningen.The mixture was then cooled to 10 ° C, and the precipitate was filtered. was triturated, washed with ethanol, then with diethyl ether and dried under reduced pressure at 90 ° C to give 24.6 g (92%) of the title association.

Följande exempel har framställts såsom beskrivits i Exemp- el l, vari Y = S, när Y = O utföres omsättningen också i tre steg under samma betingelser som beskrivits i Exempel 1 men utgående ifrån 5-(2-klorofenyl)-6,7,8,9-tetrahydro-3H-pyrido- [4',3':4,5]-tieno[3,2-f]1,4-diazepin-2-on (i stället för 5- -(2-klorofenyl)-6,7,8,9-tetrahydro-3H-pyrido[4',3':4,5]tieno- [3,2-f]1,4-diazepin-2-tion) och omsättning med lämpliga iso- cyanatderivatet i stället för isotiocyanatderivatet.The following examples have been prepared as described in Examples el l, where Y = S, when Y = 0 the turnover is also performed in three steps under the same conditions as described in Example 1 but starting from 5- (2-chlorophenyl) -6,7,8,9-tetrahydro-3H-pyrido- [4 ', 3': 4,5] -thieno [3,2-f] 1,4-diazepin-2-one (instead of 5- - (2-chlorophenyl) -6,7,8,9-tetrahydro-3H-pyrido [4 ', 3': 4,5] thieno- [3,2-f] 1,4-diazepine-2-thione) and reaction with appropriate iso- the cyanate derivative instead of the isothiocyanate derivative.

EXEMPEL 2: 6-(2-klorofenyl)-9-(4-metoxi)-fenyltiokarbamoyl-7,8,9,10- -tetrahydro-1-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]l,2,4- -triazolo[4,3-a]1,4-diazepin Y = 0 R = (4-metoxo)-fenyl- 507 189 ll EXEMPEL 3: 6-(2-klorofenyl)-9-tf-butylkarbamoyl-7,8,9,10-tetrahydro- -1-metyl-4H-pyrido[4',3':4,5]tíeno[3,2-f]l,2,4-triazolo- [4,3-a]l,4-diazepin Y = O R = t.-butyl- EXEMTEL 4: 6-(2-klorofenyl)-9-t.-butyltiokarbamoyl-7,8,9,l0-tetra- hydro-1-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]l,2,4- -triazolo[4,3-a]1,4-diazepin Y = S R t.-butyl- EXEMPEL 5: 5-(2-klorofenyl)-9-hexadecyltiokarbamoyl-7,8,9,10-tetra- hydro-1-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]1,2,4-tria- zolo[4,3-a]1,4-diazepin Y = S R = hexadecyl- EXEMPEL 6: 6-(2-klorofenyl)-9-isopropylkarbamoyl-7,8,9,10-tetrahydro -1-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]l,2,4-triazolo- [4,3-a]1,4-diazepin Y = 0 R = isopropyl- EXEMPEL 7: 6-(2-klorofenyl)-9-isopropyltiokarbamoyl-7,8,9,l0-tetra- hydro-1-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]1,2,4-tria- zolo[4,3-a]l,4-diazepin Y = S R = isopropyl- 507 189 12 EXEMPEL 8: 6-(2-klorofenyl)-9-(3,4,5-trimetoxi)-fenylkarbamoyl-7,8,9,10- -tetrahydro-1-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]1,2,4- -triazolo[4,3-a]1,4-diazepin Y = O R = (3,4,5-trimetoxi)-fenyl- EXEMPEL 9: 6-(2-klorofenyl)-9-(3,4,5-trimetoxi)-fenyltiokarbamoy1- -7,8,9,10-tetrahydro-1-metyl-4H-pyrido[4',3':4,5]tieno- [3,2-f]l,2,4-triazolo[4,3-a]1,4-diazepin Y = S R = (3,4,5-trimetoxi)-fenyl- EXEMPEL 10: 6-(2-klorofenyl)-9-(4-t.-butyl)-fenylkarbamoyl-7,8,9,10- -tetrahydro-1-metyl-4H-pyrído[4', ':4,5]tieno[3,2-f]l,2,4- -triazolo[4,3-a]1,4-diazepin Y = 0 R = (4-t.-butyl)-feny1- EXEMPEL ll: 6-(2-klorofenyl)-9-(4-t.-butyl)-fenyltiokarbamoyl-7,8,9,l0- -tetrahydrc-1-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]l,2,4- -triazolo[4,3-a]1,4-diazepin Y = S R = (4-t.-butyl)-fenyl- EXEMPEL 12: 6-(2-klorofenyl)-9-(2-trifluorometyl)-fenyltiokarbamoyl- -7,8,9,10-tetrahydro-1-metyl-4H-pyrido[4',3':4,5]tieno- [3,2-f]l,2,4-triazolo[4,3-a]1,4-diazepin Y = S R = (2-trifluorometyl)-fenyl- 507 189 13 EXEMPEL 13: 6-(2-klorofenyl)-9-(3-trifluorometyl)-fenyltiokarbamoyl- -7,8,9,10-tetrahydro-1-metyl-4H-pyrido[4',3':4,5]tieno- [3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepin Y = S R = (3-trifluorometyl)-fenyl- EXEMPEL 14: 6-(2-klorofenyl)-9-(4-trifluorometyl)-fenylkarbamoyl- -7,8,9,10-tetrahydrc-1-metyl-4H-pyrido[4',3':4,5]tieno- [3,2-f]l,2,4-triazolo[4,3-a]1,4-diazepin Y = O R = (4-trifluorometyl)-feny1- EXEMWEL 15: 6-(2-klorofenyl)-9-(4-trifluorometyl)-fenyltiokarbamoyl- -7,8,9,10-tetrahydro-1-metyl-4H-pyrido[4',3':4,5]tieno- [3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepin Y = S R = (4-trifluorometyl)-feny1- EXEMPEL 16: 6-(2-klorofenyl)-9-(4-fluoro)-fenyltiokarbamoyl-7,8,9,10- -tetrahydro-1-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]1,2,4- -triazolo[4,3-a]l,4-diazepin Y = S R = (4-fluoro)-feny1- EXEMPEL 17: 6-(2-klorofenyl)-9-(2,3-dikloro)-fenylkarbamoyl-7,8,9,10- -tetrahydro-1-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]l,2,4- -triazolo[4,3-a]1,4-diazepin Y = O R = (2,3-dik1oro)-fenyl- 507 189 14 EXEMPEL 18: 6-(2-klorofenyl)-9-(4-fenoxi)-fenylkarbamoyl-7,8,9,10-tetra- hydro-1-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]l,2,4-triazolo- [4,3-a]1,4-diazepin Y = O R (4-fenoxi)-fenyl- EXEMPEL 19: 6-(2-klorofenyl)-9-(a-metyl)-fenetyltiokarbamoyl-7,8,9,10- -tetrahydro-1-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]1,2,4- -triazolo[4,3-a]1,4-diazepin Y = S R = (a-mety1)-fenetyl- EXEMPEL 20: 6-(2-klcrofenyl)-9-(ß-metyl)-fenetyltiokarbamoyl-7,8,9,l0- -tetrahydro-1-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]1,2,4- -triazolo[4,3-a]1,4-diazepin Y = S R = (ß-metyl)-fenetyl- EXEMPEL 21: 6-(2-klorofenyl)-9-(4-metylsulfonyl)-fenyltiokarbamoyl- -7,8,9,l0-tetrahydro-1-metyl-4H-pyrido[4',3':4,5]tieno- [3,2-f]1,2,4-tríazolo[4,3-a]l,4-diazepin Y = S R = (4-metylsulfonyl)-fenyl- EXEMPEL 22: 6-(2-klorcfenyl)-9-(2,4-dit.-butyl)-fenyltíokarbamoyl- -7,8,9,10-tetrahydro-1-metyl-4H-pyrido[4',3':4,5]tieno- [3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepin Y = S R = (2,4-dit.-butyl)-fenyl- 507 189 15 EXEMPEL 23: 6-(2-klorofenyl)-9-bensylkarbamoyl-7,8,9,l0-tetrahydro- -1-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]1,2,4-triazolo- [4,3-a]l,4-diazepin Y = O R = bensyl- EXEMPEL 24: 6-(2-klorofenyl)-9-(2-furfuryl)-tiokarbamoyl-7,8,9,l0-tetra- hydro-1-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]1,2,4-triazolo- [4,3-a]l,4-diazepin Y = S R = (2-furfuryl)- EXEMPEL 25: 6-(2-klorofenyl)-9-(3-kinolyl)-tiokarbamoyl-7,8,9,10-tetra- hydro-1-metyl-4H-pyrido[4', ':4,5]tieno[3,2-f]1,2,4-triazolo- [4,3-a]1,4-diazepin Y = S R = (3-kinolyl)- EXEMPEL 26: 6-(2-klorofenyl)-9-cykløhexyltiokarbamoyl-7,8,9,10-tetra- hydro-1-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]1,2,4-tríazolo- [4,3-a]1,4-diazepin Y = S R = cyklohexyl- EXEMPEL 27: 6-(2-klorofenyl)-9-cyklohexylkarbamoyl-7,8,9,10-tetrahydro-1- -metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]1,2,4-triazo1o[4,3a]- 1,4-diazepin Y = O R = cyklohexyl- 507 189 EXEMPEL 28: 16 6-(2-klorofenyl)-9-allyltiokarbamoyl-7,8,9,10-tetrahydro-l- -metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]l,2,4-triazolo[4,3a]- 1,4-diazepin Y = S R = allyl- EXEMPEL 29: 6-(2-klorofenyl)-9-(2,4-difluoro)-fenylkarbamoyl-7,8,9,10- -tetrahydro-1-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]1,2,4- -triazo1o[4,3a]1,4-diazepin Y = 0 R = (2,4-difluoro)-fenyl- EXEMPEL 30: 6-(2-klorofenyl)-9-(fenylsulfonyl)-tíokarbamoyl-7,8,9,10- -tetrahydro-1-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]l,2,4- -triazolo[4,3a]1,4-diazepin Y = S R = fenylsulfonyl- EXEMPEL ål: 6-(2-klorofenyl)-9-(2-furylsulfonyl)-tiokarbamoyl-7,8,9,10- -tetrahydro-1-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]l,2,4- -triazolo[4,3a]1,4-diazepin Y = S R = (2-(furyl)-sulfonyl- EXEMPEL 32: 6-(2-klorofenyl)-9-(2-tienylsulfonyl)-karbamoyl-7,8,9,10- -tetrahydro-1-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]l,2,4- -triazolo[4,3a]1,4-diazepin Y = 0 R = (2-(tienyl)-sulfony1- 507 189 17 EXEMPEL QS: 6-(2-klorofenyl)-9-(2-pyrrolylsulfonyl)-tiokarbamoyl- -7,8,9,l0-tetrahydro-1-metyl-4H-pyrido[4',3':4,5]tieno- [3,2-f]l,2,4-triazolo[4,3a]1,4-diazepin Y = S R = (2-(pyrrolyl)-sulfonyl- EXEMPEL 34: 6-(2-klorofenyl)-9-(3-pyridylsulfonyl)-karbamoyl-7,8,9,10- -tetrahydro-1-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]1,2,4- -triazolo[4,3a]1,4-diazepin Y = 0 R = 3-(pyridyl)-sulfonyl- EXEMPEL 35: 6-(2-klorofenyl)-9-(4-kinolylsulfonyl)-tiokarbamoyl-7,8,9,10- -tetrahydro-1-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]l,2,4- -triazolo[4,3a]l,4-diazepin Y = S R = 4-(kinolyl)-sulfonyl- EXEMPEL 36: 6-(2-klorofenyl)-9-(4-morfolinylsulfonyl)-karbamoyl-7,8,9,l0- -tetrahydro-1-metyl-4H-pyrido[4',3':4,5]tieno[3,2-f]l,2,4- -triazolo[4,3a]1,4-diazepin Y = Q* R = 4-(morfolinyl)-sulfonyl- TOXICITET Föreningarna enligt uppfinningen är inte toxiska på möss per os vid dosen l g/kg. Vid IP-administrering på möss presenter- ade endast föreningarna enligt Exemplen 10, 17, 18 och 33 ett LD50-värde mellan 0,4 och 1 g/kg, och alla de andra förening- arna var inte toxiska vid 1 g/kg. 19 507 189 3) Inverkan på bronkospasm, inducerad av PAF Den intravenös injektionen av PAF på sövda marsvin inducerar en bronkokonstriktion med leukepeni och trombocytopeni med metoden beskriven i S. Desquand, C. Touvay, J. Randon, V.EXAMPLE 2: 6- (2-chlorophenyl) -9- (4-methoxy) -phenylthiocarbamoyl-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-methoxo) -phenyl- 507 189 ll EXAMPLE 3: 6- (2-chlorophenyl) -9-t-butylcarbamoyl-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 = O R = t.-butyl- EXAMPLE 4: 6- (2-chlorophenyl) -9-t-butylthiocarbamoyl-7,8,9,10-tetra- hydro-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 t.-butyl- EXAMPLE 5: 5- (2-chlorophenyl) -9-hexadecylthiocarbamoyl-7,8,9,10-tetra- hydro-1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4-tria- zolo [4,3-a] 1,4-diazepine Y = S R = hexadecyl- EXAMPLE 6: 6- (2-chlorophenyl) -9-isopropylcarbamoyl-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- EXAMPLE 7: 6- (2-chlorophenyl) -9-isopropylthiocarbamoyl-7,8,9,10-tetra- hydro-1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4-tria- zolo [4,3-a] 1,4-diazepine Y = S R = isopropyl- 507 189 12 EXAMPLE 8: 6- (2-chlorophenyl) -9- (3,4,5-trimethoxy) -phenylcarbamoyl-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 = O R = (3,4,5-trimethoxy) -phenyl- EXAMPLE 9: 6- (2-chlorophenyl) -9- (3,4,5-trimethoxy) -phenylthiocarbamoyl- -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-trimethoxy) -phenyl- EXAMPLE 10: 6- (2-chlorophenyl) -9- (4-t-butyl) -phenylcarbamoyl-7,8,9,10- -tetrahydro-1-methyl-4H-pyrido [4 ',': 4,5] thieno [3,2-f] 1,2,4- -triazolo [4,3-a] 1,4-diazepine Y = 0 R = (4-t.-butyl) -phenyl- EXAMPLE 11: 6- (2-chlorophenyl) -9- (4-t-butyl) -phenylthiocarbamoyl-7,8,9,10- -tetrahydride-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-t.-butyl) -phenyl- EXAMPLE 12: 6- (2-chlorophenyl) -9- (2-trifluoromethyl) -phenylthiocarbamoyl- -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-trifluoromethyl) -phenyl- 507 189 13 EXAMPLE 13: 6- (2-chlorophenyl) -9- (3-trifluoromethyl) -phenylthiocarbamoyl- -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-trifluoromethyl) -phenyl- EXAMPLE 14: 6- (2-chlorophenyl) -9- (4-trifluoromethyl) -phenylcarbamoyl- -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 = O R = (4-trifluoromethyl) -phenyl- EXAMPLE 15: 6- (2-chlorophenyl) -9- (4-trifluoromethyl) -phenylthiocarbamoyl- -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-trifluoromethyl) -phenyl- EXAMPLE 16: 6- (2-chlorophenyl) -9- (4-fluoro) -phenylthiocarbamoyl-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-fluoro) -phenyl- EXAMPLE 17: 6- (2-chlorophenyl) -9- (2,3-dichloro) -phenylcarbamoyl-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 = O R = (2,3-dichloro) -phenyl- 507 189 14 EXAMPLE 18: 6- (2-chlorophenyl) -9- (4-phenoxy) -phenylcarbamoyl-7,8,9,10-tetra- hydro-1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4-triazolo- [4,3-a] 1,4-diazepine Y = O R (4-phenoxy) -phenyl- EXAMPLE 19: 6- (2-chlorophenyl) -9- (α-methyl) -phenethylthiocarbamoyl-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 = (α-methyl) -phenethyl- EXAMPLE 20: 6- (2-chlorophenyl) -9- (β-methyl) -phenethylthiocarbamoyl-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 = (β-methyl) -phenethyl- EXAMPLE 21: 6- (2-chlorophenyl) -9- (4-methylsulfonyl) -phenylthiocarbamoyl- -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-methylsulfonyl) -phenyl- EXAMPLE 22: 6- (2-Chloro-phenyl) -9- (2,4-dith-butyl) -phenylthiocarbamoyl- -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 = (2,4-dit.-butyl) -phenyl- 507 189 15 EXAMPLE 23: 6- (2-chlorophenyl) -9-benzylcarbamoyl-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 = O R = benzyl- EXAMPLE 24: 6- (2-chlorophenyl) -9- (2-furfuryl) -thiocarbamoyl-7,8,9,10-tetra- hydro-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-furfuryl) - EXAMPLE 25: 6- (2-chlorophenyl) -9- (3-quinolyl) -thiocarbamoyl-7,8,9,10-tetra- hydro-1-methyl-4H-pyrido [4 ',': 4,5] thieno [3,2-f] 1,2,4-triazolo- [4,3-a] 1,4-diazepine Y = S R = (3-quinolyl) - EXAMPLE 26: 6- (2-chlorophenyl) -9-cyclohexylthiocarbamoyl-7,8,9,10-tetra- hydro-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 = cyclohexyl- EXAMPLE 27: 6- (2-chlorophenyl) -9-cyclohexylcarbamoyl-7,8,9,10-tetrahydro-1- -methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4-triazolo [4,3a] - 1,4-diazepine Y = O R = cyclohexyl- 507 189 EXAMPLE 28: 16 6- (2-chlorophenyl) -9-allylthiocarbamoyl-7,8,9,10-tetrahydro-1- -methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4-triazolo [4,3a] - 1,4-diazepine Y = S R = allyl- EXAMPLE 29: 6- (2-chlorophenyl) -9- (2,4-difluoro) -phenylcarbamoyl-7,8,9,10- -tetrahydro-1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4- -triazolo [4,3a] 1,4-diazepine Y = 0 R = (2,4-difluoro) -phenyl- EXAMPLE 30: 6- (2-chlorophenyl) -9- (phenylsulfonyl) -thiocarbamoyl-7,8,9,10- -tetrahydro-1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4- -triazolo [4,3a] 1,4-diazepine Y = S R = phenylsulfonyl- EXAMPLE eel: 6- (2-chlorophenyl) -9- (2-furylsulfonyl) -thiocarbamoyl-7,8,9,10- -tetrahydro-1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4- -triazolo [4,3a] 1,4-diazepine Y = S R = (2- (furyl) -sulfonyl- EXAMPLE 32: 6- (2-chlorophenyl) -9- (2-thienylsulfonyl) -carbamoyl-7,8,9,10- -tetrahydro-1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4- -triazolo [4,3a] 1,4-diazepine Y = 0 R = (2- (thienyl) -sulfonyl- 507 189 17 EXAMPLE QS: 6- (2-chlorophenyl) -9- (2-pyrrolylsulfonyl) -thiocarbamoyl- -7,8,9,10-tetrahydro-1-methyl-4H-pyrido [4 ', 3': 4,5] thieno- [3,2-f] 1,2,4-triazolo [4,3a] 1,4-diazepine Y = S R = (2- (pyrrolyl) -sulfonyl- EXAMPLE 34: 6- (2-chlorophenyl) -9- (3-pyridylsulfonyl) -carbamoyl-7,8,9,10- -tetrahydro-1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4- -triazolo [4,3a] 1,4-diazepine Y = 0 R = 3- (pyridyl) -sulfonyl- EXAMPLE 35: 6- (2-chlorophenyl) -9- (4-quinolylsulfonyl) -thiocarbamoyl-7,8,9,10- -tetrahydro-1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4- -triazolo [4,3a] 1,4-diazepine Y = S R = 4- (quinolyl) -sulfonyl- EXAMPLE 36: 6- (2-chlorophenyl) -9- (4-morpholinylsulfonyl) -carbamoyl-7,8,9,10- -tetrahydro-1-methyl-4H-pyrido [4 ', 3': 4,5] thieno [3,2-f] 1,2,4- -triazolo [4,3a] 1,4-diazepine Y = Q * R = 4- (morpholinyl) -sulfonyl- TOXICITY The compounds of the invention are not toxic to mice os at the dose of l g / kg. For IP administration in mice presented only the compounds of Examples 10, 17, 18 and 33 a LD50 value between 0.4 and 1 g / kg, and all the other compounds were not toxic at 1 g / kg. 19 507 189 3) Effect on bronchospasm, induced by PAF The intravenous injection of PAF on anesthetized guinea pigs induces a bronchoconstriction with leukepeni and thrombocytopenia with the method described in S. Desquand, C. Touvay, J. Randon, V.

Lagente, B. Vilain, I. Maridonneau-Parini, A. Etienne, J.Lagente, B. Vilain, I. Maridonneau-Parini, A. Etienne, J.

Lefort, P. Braquet och B. Vargaftig. Interference of BN 52021 (Ginkolide B) with the bronchopulmonary effects of PAF-aceth- er in the guinea-pig. Eur. J. Pharmacol. 127: 83-95, 1986.Lefort, P. Braquet and B. Vargaftig. Interference of BN 52021 (Ginkolide B) with the bronchopulmonary effects of PAF-aceth- er in the guinea-pig. Eur. J. Pharmacol. 127: 83-95, 1986.

Hartley-marsvin av hankön (400-450 g) (Charles River) sövda med uretan (2 g/kg IP) trakeotomiseras och utsattes för en forcerad andning med en andningspump: 70-80 slag/mm, 1 ml luft/100 g per slag. En kateter införes i jugularvenen för injektionerna, en annan införes i karotisartären för blod- prover. Ursprungligt motstånd hålles konstant under andningen på 10 cm vatten enligt Konzett och Rössler-metoden, och luft i överskott mätes med en givare för bronkospasm UGO BASILE tillsamans med en registrerande anordning GEMINI. Marsvinen fick en IV injektion av pankuronium (Pavulon) för att inhi- bera deras spontana andning.Male Hartley guinea pigs (400-450 g) (Charles River) anesthetized with urethane (2 g / kg IP) is tracheotomized and exposed to a forced breathing with a breathing pump: 70-80 beats / mm, 1 ml air / 100 g per stroke. A catheter is inserted into the jugular vein injections, another is inserted into the carotid artery for prover. Initial resistance is kept constant during respiration of 10 cm of water according to the Konzett and Rössler method, and air in excess is measured with a UGO BASILE bronchospasm sensor together with a recording device GEMINI. Guinea pigs received an IV injection of pancuronium (Pavulon) to inhale carry their spontaneous breathing.

Föreningen enligt uppfinningen och referensföreningen WEB 2086 (se ovan citerade Boehringer patent) har framställts som en suspension i gummihaltigt vatten och administrerades oralt 1 timme före stimuleringen med PAF.The compound of the invention and the reference compound WEB 2086 (see Boehringer patent cited above) has been produced as a suspension in gummy water and administered orally 1 hour before stimulation with PAF.

Bronkokonstriktionen beredes genom beräkning av procenten bronkokonstriktion A x 100, där A står för inducerad bronko- B konstriktion i mm och B står för maximal bronkokonstriktion i 111m.The bronchoconstriction is prepared by calculating the percentage bronchoconstriction A x 100, where A stands for induced bronchoconstriction B constriction in mm and B stands for maximum bronchoconstriction in 111m.

Resultaten rapporteras i Tabell II. 507 189 20 PRESENTATION - DOSERING Inom humanterapi administreras föreningarna enligt uppfin- ningen företrädesvis oralt. Föredragna former av administrer- ing inkluderar tabletter, gelatinkapslar och liknande. Den vanliga dosen är från 50 mg till 500 mg per dag beroende på fallet.The results are reported in Table II. 507 189 20 PRESENTATION - DOSAGE In human therapy, the compounds are administered according to the invention. preferably orally. Preferred forms of administration includes tablets, gelatin capsules and the like. The the usual dose is from 50 mg to 500 mg per day depending on the case.

Föredragen enhetsdos är 50 mg tillsammans med lämpliga bärare och medel.The preferred unit dose is 50 mg together with suitable carriers and means.

TABELL I A 21 507 189 EXEMPEL IKSO BDZ receptore_r 1 3.01 1o'7 2 1o'° z 1.21 m” 1.1 1o'5 3 1.11 10* 4.3 1o'7 4 6.112 1o'° 1.3: 10"' s 2.91 m” 6.3 1o'5 6 z.ss m* 6.6 10* 1 3.211 16"' 1o'° 11 1.1: 1o" 1.5 1o'° 9 3.61 1o'° 4.5 1o'° 111 11.: 1o'° s.zs 1o'° 11 9.44 1o'9 1.2 1o'° 12 1.11 10"' s.s 1o'° 507 189 22 TABELL I B EXEMPEL 12x50 BDz receptorer' 13 1.11 1o'7 6.25 1o'° 14 1.5 1o"7 1.05 1o"5 15 2.2 1o"7 1.25 1o"° 16 6.4 10"* 1. 1o"7 11 5.5 16"* 9.2 10"? 1s 3.: m* 11.6 1o"7 19 4.25 10"” 3.6 10"' 2o 6.11 1o"9 1.2 1o"7 21 2.4 10"* 1.1 1o"° 22 3.66 1o"7 6.3 1o"7 23 6.6: 10"* 1.6 1o"° 24 4.11 10"* 6.5 1o"7 23 TABELI. 1 c EXEMPEL IKSO BDZ receptorerf ._._..._._..:...__. __. 25 1.112 10°7 3.5 10” 26 5.33 10* 4.1 10'° 27 4.52 10'8 2. 10'6 211 9.05 10'9 1.4 10” 29 5.06 104 2.2 10” 30 1.1 10"* 6.3 10” 31 11.15 10'9 6.15 10” 32 6.66 10* 4.33 10'6 33 2.05 10” 9.1 1o'° 34 1.0 1o'7 4. 10'5 35 3.4 10'8 2.2 10'6 36 6.10 10'9 7.25 10'° 507 189 5Û7 189 _14 TABELL II Exempel. Procent bronkokonstriktion Procent verkan 'kontroller _19_ 4. 5_55 - WEB 2086 25.3 + 11.56 '“ - 68.0 1 '13 + 4.39 “' - 83.5 3 211.7 + 9.30 °°° - 63.7 5 30.3 o 8.80 "' - 61.6 7 23.4 + 10.50 °" - 70.4 8 16.2 + 8.38 “' - 79-5 10 26.7 -1- 11.0 °" . - 66-2 14 48.6 o 14.32 ” - 38.5 13 14.1 + 11.25 '°' _ - 81-8 22 25.5 + 13.2 "° - 67-7 24 33.3 + 12.8 °'° - 57-9 30 31.2 + 14.95 °°° - 52-9 33 22.4 + 9.: "° - 'HJTABLE I A 21 507 189 EXAMPLE IKSO BDZ receptor_r 1 3.01 1o'7 2 1o '° of 1.21 m ”1.1 1o'5 3 1.11 10 * 4.3 1o'7 4 6.112 1o '° 1.3: 10 "' s 2.91 m ”6.3 1o'5 6 z.ss m * 6.6 10 * 1 3.211 16 "'1o' ° 11 1.1: 1o "1.5 1o '° 9 3.61 1o '° 4.5 1o' ° 111 11 .: 1o '° s.zs 1o' ° 11 9.44 1o'9 1.2 1o '° 12 1.11 10 "'s.s 1o' ° 507 189 22 TABLE I B EXAMPLE 12x50 BDz Receptors' 13 1.11 1o'7 6.25 1o '° 14 1.5 1o "7 1.05 1o" 5 15 2.2 1o "7 1.25 1o" ° 16 6.4 10 "* 1. 1o" 7 11 5.5 16 "* 9.2 10"? 1s 3 .: m * 11.6 1o "7 19 4.25 10 "” 3.6 10 "' 2o 6.11 1o "9 1.2 1o" 7 21 2.4 10 "* 1.1 1o" ° 22 3.66 1o "7 6.3 1o" 7 23 6.6: 10 "* 1.6 1o" ° 24 4.11 10 "* 6.5 1o" 7 23 TABLE. 1 c EXAMPLE IKSO BDZ receptor ref ._._..._._ ..: ...__. __. 25 1.112 10 ° 7 3.5 10 ” 26 5.33 10 * 4.1 10 '° 27 4.52 10'8 2. 10'6 211 9.05 10'9 1.4 10 ” 29 5.06 104 2.2 10 ” 30 1.1 10 "* 6.3 10" 31 11.15 10'9 6.15 10 ” 32 6.66 10 * 4.33 10'6 33 2.05 10 ”9.1 1o '° 34 1.0 1o'7 4. 10'5 35 3.4 10'8 2.2 10'6 36 6.10 10'9 7.25 10 '° 507 189 5Û7 189 _14 TABLE II Example. Percent bronchoconstriction Percent effect 'controls _19_ 4. 5_55 - WEB 2086 25.3 + 11.56 '“- 68.0 1 '13 + 4.39 “'- 83.5 3 211.7 + 9.30 °°° - 63.7 5 30.3 or 8.80 "'- 61.6 7 23.4 + 10.50 ° "- 70.4 8 16.2 + 8.38 “'- 79-5 10 26.7 -1- 11.0 ° ". - 66-2 14 48.6 or 14.32 ”- 38.5 13 14.1 + 11.25 '°' _ - 81-8 22 25.5 + 13.2 "° - 67-7 24 33.3 + 12.8 ° '° - 57-9 30 31.2 + 14.95 °°° - 52-9 33 22.4 + 9 .: "° - 'HJ

Claims

BNS DOCID: 507 189 25 A PATENT CLAIM Process for the preparation of thieno-triazolo-diazepine derivatives of the formula: Cl R-mæ-cN ls NY ca: -¿ <\\ \\ š \ u / wherein Y represents oxygen or sulfur and R represents - a straight lower alkenyl group having up to C5 - a straight or branched alkyl group having up to C20 - a phenyl group substituted by one or more alkyl groups or lower alkoxy groups having up to C5, a phenoxy group, a lower alkylsulfonyl group having up to C5 to C5, or fluorine or chlorine atoms or trifluoromethyl groups or a sulfonyl group substituted with phenyl or Y represents sulfur and R represents a furfuryl or a kinclyl group or a sulfonyl group substituted with a furyl, pyrrolyl or quinolyl group or Y represents oxygen and R a benzyl group or a sulfonyl group substituted by a thienyl, pyridyl or morpholinyl group, characterized in that thieno-tr is reacted during nitrogen circulation. the azolo-diazepine compound of formula A: with a slightly stoichiometric excess of the appropriate R- N = C = Y derivative, wherein R and Y are defined as above, in a Mprotic solvent under reflux for one-half to 24 hours, after which under nitrogen circulation in an aprotic solvent, the resulting compound of formula B: R-NH-CN is reacted with a slight stoichiometric excess of hydrazine hydrate at a temperature between 0 ° C and room temperature for 5 minutes to about 1 hour and finally under nitrogen circulation in a protic solvent cyclizes the compound of formula C: 507189433 I> 507 189 27 5 cl N R-NH-cN | | § s N H rm '| with four stoichiometric equivalents of triethyl orthoacetate at room temperature for 15 minutes to 3 hours, and then under reflux for half an hour to 5 hours. BNSDOCID: