IL31669A - Thiopyranothienopyrimidines and process for their manufacture - Google Patents

Description

31669/2 Thiopyranothienopyrimidinea and prooees for their manufacture 31669/2 .

The present invention provides 5 , 6-dihydro-8H-thio-pyrano.4' ,3' :4,5 ] thieno [2 , 3-d Jpyrimidines of the formula^ wherein n represents 2, 1 or preferably 0, alk denotes a straight-chain or branched lower alkylene residue which separates Rq from the nitrogen atom in the 4-position by 2 to 5, especially 2 to 3, above all 2 carbon atoms, Rq represents a di-lower alkylamino or a saturated heterocyclic residue, especially as represented by a lower alkyleneamino , oxaalkyleneamino , thiaalkyleneamino or optionally ' -lower alkylated azaalkyleneamino group, such as a piperidino or pyrrolidino group which is optionally C- lower alkylated, or an optionally C- lower alkylated tftorpholino, thiomorpholino , piperazino, ' -lower alkylpiperazino or piperazino group such as ' -methyl- or ' -ethyl-piperazino group, R^ denotes a lower alkyl residue or especially a hydrogen atom, each of the residue R2 and R^ represents a phenyl residue which is optionally substituted, -£«r--O amp-je as specified, and denotes a lower alkyl residue or above all a hydrogen atom. 31669/2 As lower alkyl residues there should especially be mentioned methyl, ethyl, propyl, isopropyl, straight-chain or branched butyl, pentyl, hexyl or heptyl residues bonded in any desired position.

As lower alkylene, oxaalkylene, thiaalkylene and optionally N' - lower-alkylated azaalkylene radicals forming together with the amino nitrogen the preferred saturated heterocyclic residues, there should be especially mentioned butylene- (1, 4) , pentylene- (1 , 5) , hexylene- (1, 5) , hexylene- (1, 6) , hexylene- (2 , 5) heptylene- (1, 7) .heptylene- (2 , 7) , heptylene- (2 , 6) , 3-oxapen-tylene- (1, 5) , 3-thiapentylene- (1 , 5) , 2 , 4-dimethyl-3-thiapen-tylene- (1, 5) , 3-azapentylene- (1, 5) , 3-lower-alkyl-3-aza-pentylene- (1 , 5) , such as 3-methyl-3-aza-pentylene- (1, 5) , 3-oxahexylene- (1 , 6) or 3-azahexylene- (1 , 6) radicals.

The lower alkylene residue alk is especially an ethylene- (1, 2) , propylene- (1 , 3) , butylene- (1 , ) , pentylene-(1, 5) , pentylene- (2 , 5) , butylene- (2 , 4) , propylene- (1, 2) , propylene- (2 , 3) or butylene- (3 , 4) residue. 31669/2 The following substituents of the phenyl residues should be particularl < mentioned: lower alkyl residues, above all those having 1 to 6 carbon atoms such as methyl, ethyl, ropyl, isopropyl, straight-chain or branohed butyl, pentyl or hexy residues bonded in any desired position, lower alkoxy residues such as methoxy, ethoxy, propoxy or butoxy residues, methylenedioxy groups, halogen atoms as fluorine, chlorine or bromine atoms, and trifluoromethyl groups.

The'hew'oompounds possess valuable pharmacological properties,' above all an anti-bacterial and anti-parasit'ar , action. Thus ihey especially exhibit an action against plas- 51 modia, for^ example' Plasmodium berghei, as is found in animal experiments, for' example on mice. The new compounds are also active againisit strains or Plasmodia which are resistant to other anti-malaria agents, as for example primaquine. The , new compounds are therefore1 useful as chemotherapeutics * against malaria and also, in particular, as prophylactics against that desease. Furthermore, as has been shown in animal experiments, for example on hamsters, they have an amoebicidal effect and are therefore useful as amoebicides.

' In addition they possess an anti-inflammatory action, The new compounds are however also valuable inter- mediates for the manufacture of other useful substanoes, espeoially of pharmacologically active compounds., Compounds to be particularly emphasised are those t of the formula I , wherein n, R and R have the significance methyl groups and/or especially lower alkoxy groups and/or ¾uerine wnift atoms or especially chlorine atoms (with preferably at least one substituent being in the p-position) .

Compounds to be particularly emphasised because of their good anti-malaria action are those of the formula wherein Ph and Ph1 represent phenyl residues which are substituted by one, two or more lower alkoxy groups halogen atoms, above all chlorine atoms (preferably in the p-position), alk©represents a straight-chain or branched lower alkylene residue which separates the two nitrogen atoms by 2 to.5, especially 2 to >, above all 2, carbon atoms, and Rg and ^ denote lower alkyl residues, and especially the com wherein alk' represents a lower alkylene residue having 2 to > carbon atoms, especially the 1, ^-propylene or preferably the 1,2-ethylene residue, Rg and represent lower 31669/1 £ of the formula Y in 'which n, I^. R^> and have the same meanings as above, and Y represents a bromine or especially a chlorine atom, is reacted with an amine of the formula R, -NH-alk-R , in which 1 o alk, Rq and R^ have the meanings given above The reaction is effected in the usual manner, appropriately at elevated temperature; if desired, an excess of the amine may be used. The reaction can be effected in the presence or absence of a diluent, optionally i a closed vessel under pressure and/or in an inert gas atmosphere.

In resulting compounds which possess alkoxy residues on an aromatic ring, such residues can be converted into free hydroxyl groups in the usual manner. This conversion is for example effected by hydrolysis, above all by means of strong acids, such as for example hydriodic acid or hydrobromic acid and optionally in the presence of light metal halides such as aluminium bromide or boron bromide, or also with pyridine hydrochloride or aluminium chloride in pyridine.

In resulting compounds which contain aryl residues capable of nitration, the latter may be nitrated. The nitration is effected in a manner which is in itself known, for example by treatment with a mixture of concentrated sulphuric acid and concentrated nitric acid or with the mixed anhydride of nitric acid and a carboxylic acid, for example a lower alkanecarboxylic acid such as acetic acid.

In resulting compounds which contain nitroaryl residues, the latter can be reduced to aminoaryl residues, for example by means of catalytlcally activated hydrogen such as hydrogen in the presence of a hydrogenation catalyst, for example a platinum, nickel or palladium catalyst, such as platinum oxide, Raney nickel or palladium charcoal.

In resulting acylamino compounds the acyl residues may be split off in the usual manner, for example by hydrolysis preferably in the presence of acid or basic catalysts.

Resulting S-unsubstituted compounds can be oxidised to the S-oxides ( sulphoxides ) or S-dioxides (sulphones).

The oxidation to' the sulphoxides or sulphones may be effected in a known manner, for example by reaction with an In this reaction the sulphoxides are obtained at lower temperatures, that is to say with good cooling or when using only 1 mol equivalent of the oxidising agent, whilst on warming and/or using at least 2 mol equivalents of the oxidising agent the sulphones are obtained.

Resulting S-oxides can be oxidised to the S-dioxides. This oxidation takes place in a known manner, for example as in the oxidation described above which leads to the dioxides.

These subsequent reactions may be carried out individually or in combination and in any desired sequence.

Depending on the process conditions and starting substances the final substances are obtained in the free form or in the form of their acid addition salts, which is also comprised by the invention. Thus for example basic ,. neutral or mixed salts, and optionally also hemihydrates, mono-hydrates, sesquihydrates or polyhydrates thereof, may be obtained. The acid addition salts of the new compounds may be converted to the free compound in a manner which is in itself known, for example by means of basic reagents such as alkalis or ion exchangers . On the other hand the resulting free bases can form salts with organic or inorganic acids. In order to manufacture acid addition salts, acids which are suitable for the ," formation of therapeutically useably salts are especially used. As such acids there may for example be mentioned: hydrohalic acids, sulphuric acids, phosphoric acids, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulphonic acids such as formic, acetic, propionic, succinic, glycollic, acid, embonic acid, me hanesulphonic, ethanesulphonic, hydroxyethanesulphonic and ethylenesulphonic acid; halo-genobenzenesulphonic, toluenesulphonic , naphthalenesulphonic or sulphanilic acid; methionine, tryptophane, lysine or arginine .

These or other salts of the new compounds, such as for example the picrates, may also serve for the purification of the resulting free bases by converting the free bases into salts, separating these off and again liberating the bases from the salts. In view of the close relation between a free base and a base in the form of salt thereof, whenever a free base is referred to in this context, a corresponding salt is also intended provided such is possible or applicable under the circumstances.

Depending on the choice of the starting substances and procedures the new compounds may be present as optical antipodes, racemates or isomer mixtures (racemate mixtures).

Resulting isomer mixtures (racemate mixtures) may be separated into the two.. stereoisomeric (diastereomeric ) pure isomers (raeemates) in a known manner on the basis of the physico-chemical differences of the constituents, for example by chromatography and/or fractional crystallisation.

Resulting racemates can be resolved according to known methods, for example by recrystallisation from an optically active solvent, by means of micro-organisms, or by reaction with an optionally active acid which forms salts with the racemic compound and separation of the salts obtained in this manner, for example on the basis of their differing solubilities into the diastereomers from which the anti odes D- and L-forms of tartaric acid, di-o-toluyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid or quinic acid. The more active of the two antipodes is advantageously isolated.

If isomerisation occurs during a reaction then, if desired, the separation can again be carried out, for example as described above, after the reaction has taken place.

The invention also relates to those embodiments of the process according to which one starts from a compound obtainable as an intermediate at any stage of the process and carries out the remaining process stages or in which a starting substance is formed under the reaction conditions or in which a reaction component is optionally present in the form of its salts.

It is appropriate to use such starting substances....... for carrying out the reactions according to the invention as lead to the groups of final substances especially mentioned above, and especially to the final substances which have been particularly described' or emphasised.

The starting substances ' are known or may, where they are new, be obtained according to methods which are in them¬ selves known. .

■ Thus for example the jkch^^ dihydro-8H-thiopyrano[ ' , 31 : , 5 ] thieno[ 2, d] pyrimidines phenyl each , having ai/ 7&i»yi- residue in ag loaot-one -of the positions o and 8, which are used as preferred starting materials, or their S-oxides can be obtained by converting the hydroxyl group in a 4-hydroxy-5,6-dihydro-8H-thiopyrano[4 ' ,3* :4,5] chlorine or bromine atom.

The conversion of the hydroxyl group into a chlorine or bromine atom is effected for example by treatment with corre ponding halides of sulphur or especially of phosphorus, for example phosphorus pentachloride , phosphorus oxychloride, phosphorus trichloride or corresponding bromides.

The 4-hydroxy-5,6-dihydro-8H-thiopyrano[ 4 ' ,3' :4,53 thieno[2,;5-d]pyrimidines which in at least one of positions 6 and 8 possess an aryl residue, and their S-oxides can be obtained if a 2-amino-;5-Z,'-4,5-dihydro-7H-thieno[2,3-c]thio-pyrane which in at least one of positions 5 and 7 has an aryl residue and in which Z" denotes a free carboxyl group or an esterified carboxyl group such as a carbalkoxy group, or a carbamyl group, or a S-oxide thereof, is reacted with a reactive acid derivative of a carboxylic acid which is capable of pyrimidine ring closure, such as an ester, amide, halide (e.g. chloride), iminoether, anhydride or nitrile with the proviso that at least the residue Z" or the functionally converted carboxyl group of the carboxylic acid mentioned possesses a nitrogen atom.

The 2-amino- Y"-4,5-dihydro-7H-thieno[2, c]thio-pyranes which in at least one of positions 5 and 7 possess an aryl residue and wherein Y" denotes a free or functionally converted carboxyl group, for example a group Z" or a nitrile group, and their S-oxides can be obtained if a 2,3,5>6-tetrahydrothiopyran- (4 )-one which is substituted by an aryl residue in at least one of positions 2 and 6, or an S-oxide thereof is reacted with a compound of the formula Y^CH^-C^N in which Y" has the significance mentioned, and simultaneously or subsequently with sulphur.

The reaction is effected in the usual manner.

Compounds having a free carboxyl group may be obtained in the free form or in the form of their salts with bases, for example salts with organic amines, or metal salts. Possible metal salts are above all alkali metal salts or alkaline earth metal salts such as sodium, potassium, magnesium or calcium salts.

The resolution of the resulting raeemate mixtures and/or racemates may be carried out analogously to the procedure described above.

Compounds having basic groups may be obtained in the free form or in the form of their acid addition salts.

The new compounds may for example be used in the form of pharmaceutical preparations in which they are present in the free form or in the form of their salts, especially of the therapeutically acceptable salts, in admixture or conjunction with an organic or inorganic, solid or liquid ex-cipient which is for example suitable for enteral or parenteral administration. Suitable substances for forming the latter are those which do not react with the new compounds, such as for example water, gelatine, lactose, starch, stearyl alcohol, magnesium stearate, talc, vegetable oils, benzyl alcohols, gum, propylene glycols, white petroleum jelly or other known medicinal excipients. The pharmaceutical preparations may for example be in the form of tablets, dragees, They are optionally sterilised and/or. contain auxiliary substances such as preservatives, stabilisers, wetting agents or emulsifiers, solubilising agents or salts for regulating the osmotic pressure or buffers. They may also contain other therapeutically valuable substances. The pharmaceutical preparations are formulated according to usual methods.

The active compounds may also be utilised in veterinary medicine, for example in one of the abovementioned forms or in the form of feedstuffs or of additives for animal fodder. Herein the usual extenders and diluents or feedstuffs are for example used.

The invention is described in more detail in the following examples.

Example 1 g of the stereoisomer, of melting point 199 - 200°C, of 4-chloro-6,8-diphenyl-5,6-dihydro-8H-thiopyrano[4t :4,5] thieno[2,3-d]pyrimidine are warmed for ^ hours with 50 ml of β-diethylamino-ethylamine in an oil bath at 120°C. The mixture is thereafter evaporated to dryness in vacuo and the residue dissolved in j500 ml of 0.5 N hydrochloric acid with slight warming. The filtered solution is adjusted to a pH-value of 8 - 9 with 2 N sodium hydroxide solution, whereupon a precipitate separates out which is filtered off, washed with water and thereafter recrystallised from ethanol. A mixture of the cis- and trans-forms of 4- (β-diethylamino-ethylamino)-6, 8-diphenyl-5,6-dihydro-8H-thiopyrano[ ' ,3' :4, ] thieno[2,3-d]pyrimidine of formula is thus obtained in the form of white crystals of melting point 155 - 160°C.

Fractional crystallisation of this product from ethanol yields the two stereoisomers in the pure form. They melt at 171 - 172°C and l6l - l62°C.

On dissolving the base of melting point 171 - 172°C in the calculated quantity of 1 N alcoholic hydrochloric acid and adding isopropyl ether until crystallisation results, the dihydrochloride . of melting point 167 - 170°C is obtained. Starting from the base of melting point Ιβΐ - l62°C, a dihydrochloride of melting point 228 - 2^1°C (with decomposition) is obtained analogously.

In an analogous manner, the stereoisomer of melting point 200 - 201°C of 4-chlor.o-6,8-diphenyl-5,6-dihydro-8H- i i t1 thiopyrano[ ' ,5' : ,5]thieno[2, 3-d]pyrimidine yields a mixture of the stereoisomers of -(β-diethylamino-ethyl-amino)-6J8-diphenyl-5,6-dihydro-8H-thiopyrano[4' ,3' : ,5]thieno[2, d] . . pyrimidine in the form of white crystals of melting point . 155 - 160°C. i · The 4-chloro-6,8-diphenyl-5,6-dihydro-8H-thiopyrano 13Λ g of 2,6-diphenyl-2,3, , 6-tetrahydro-thiopyran-one, 5·β5 g of ethyl cyanoacetate, 1.6 g of powdered sulphur and 5 ml of morpholine are suspended In 50 ml of absolute ethanol and stirred for 2 hours in a bath at 45°C. After allowing the mixture to stand for about 16 hours, the precipitated reaction product is filtered off and washed with ethanol. A mixture of the cis- and trans-forms of 2-amino-5-carbethoxy-5,7-diphenyl- J5-dihydro-7H-thieno[2,3-c]thio-pyrane is thus obtained and this, after recrystallisation from a large quantity of absolute ethanol, forms yellowish crystals of melting point 212 - 2l4°C. g of a mixture of cis- and trans-2-amino-3-carb-ethoxy-5,7-diphenyl-4,5-dihydro-7H-thieno[2,3-c]thiopyrane are heated with 50 ml of formamide for 4 hours under nitrogen whilst stirring, in an oil bath at l80 - 190°C. After cooling the resulting precipitate is filtered off and washed with ethanol. In order to purify it, the resulting product is dissolved hot in 3 parts by volume of dimethylformamide, clarified with active charcoal and caused to crystallise by adding 9 parts by volume of ethanol . A mixture of the cis- and trans-forms of 4-hydroxy-6,8-diphenyl-5,6-dihydro- ' 8H-thiopyrano[4',5' :4,5]thieno[2,3-d]pyrimidine of melting point 220 - 225°C is thus obtained. g of a mixture of cis- and trans-4-hydroxy-6, 8-diphenyl- ,6-dihydro-8H-thiopyrano[ ' ,3' : , ] thienot 2, d] pyrimidine are warmed with 50 ml of phosphorus oxychloride for 2 hours in an oil bath at 120°C. Thereafter the excess phosphorus oxychloride is evaporated off in vacuo and the with water and then triturated with ethanol and filtered off. On fractional recrystallisation from benzene, the two stereoisomers of 4-chloro-6, 8-diphenyl-5, 6-dihydro-8H-thio-pyrano[ 4 ' , 3 ' : 4 5]thieno[ 2 , 3-d]pyrimidine may be separated from one another. One form melts at melting point 199 - 200°C and the other at 200 - 201°C.

Example 2 3 g of the stereoisomer of melting point 199 - 200°C of 4-chloro-6, 8-diphenyl-5, 6-dihydro-8H-thiopyrano[ 4 ' ,3 ' : 4, 5J thieno[ 2, 3-d]pyrimidine are warmed with 20 ml of 4-amino-l-(diethylamino)-pentane for 3 hours in an oil bath at 120°C, The reaction solution is poured into 300 ml of water and the resulting precipitate is filtered off. The resulting product is dissolved in 100 ml of 0 . 5 N hydrochloric acid and the filtered solution is adjusted to a pH-value of 8 - 9 with" 2N sodium hydroxide solution, whereupon a solid precipitate separates out and is filtered off and washed with water. On recrystallisation from isopropyl ether, a mixture of the stereoisomeric forms of 4- (4-diethylamino-l-methyl-butyl- ■ amino )-6 , 8-diphenyl-5, 6-dihydro-8H-thiopyrano[ 4 ' , 3 ' : , 5 ] thieno[ 2, 3-d]pyrimidine of formula melts at 210 - 220°C (with decomposition).

Example 3 g of the stereoisomer of melting point 186 - l88°C of 4-chloro-6, 8-bis- (p-chlorophenyl )-5* 6-dihydro-8H-thiopyrano-[ ' ,3' : ,5]thieno[2, -d]pyrimidine are warmed with 50 ml of β-diethylamino-ethylamine for 3 hours in an oil bath at 120°C. The mixture is thereafter evaporated ID dryness in vacuo and the residue triturated with water. Recrystallisation of the resulting product from benzene yields a mixture of the cis-and trans-forms of 4- (β-diethylamino-ethylamino )-6, 8-bis- (p-chlorophenyl)-5,6-dihydro-8H-thiopyrano[4' , j5' :4,5-thieno [2,j5- of melting point 200 - 205°C.

Fractional recrystallisation from ethanol yields the stereoisomers of -( -diethylamino-ethylamino)-6,8-bis-(p-chlorophenylJ-S^-dihydro-SH-thiopyrano ' , :4,5]thieno ■ [2,j5-d]pyrimidine of formula in the pure form, of melting point 220 - 222°C and 204 - 205°C.

In an analogous manner, the stereoisomer of melting point 201 - 202°C of 4-chloro-6,8-bis-(p-chlorophenyl)-5,6-dihydro-8H-thiopyrano[4' ,3' :4,51thieno[2, 3-d]pyrimidine yields a mixture of the stereoisomers of 4- (β-diethyl-amino-ethyl-amino)-6J8-bis- (p-chlorophenyl )-5i -dihydro-8H-thiopyrano [ 1 :4,5]-thieno[2, d]pyrimidine of melting point 200 -205°C On dissolving this mixture of the stereoisomeric bases in the calculated quantity of 1 N alcoholic hydrochloric acid and adding isopropyl ether until crystallisation results, a · mixture of the corresponding dihydrochlorides of melting point 2?0°C (with decomposition) may be obtained.

In an analogous manner, the base of melting point 220 - 222°C yields a dihydrochloride of melting point 2j55 -239°C (with decomposition) and the base of melting point 204 - 205°C . yields a dihydrochloride of melting point 244 -, 248°C I The 4-chloro-6,8-bis-(p-chlorophenyl )-5, 6-dihydro-8H-thiopyrano[4' ,3' :4,5]thieno[2, -d]pyrim'dine used as the 16.85 g of 2,6-bis-(p-chlorophenyl)-2,3,5,6-tetrahydro thiopyran-4-one, 5 « g of ethyl cyanoacetate, 1.6 g of powdered sulphur and ml of morpholine are suspended in 50 ml of absolute ethanol and stirred for 2 hours in a bath at 45°C and thereafter for a further 4 hours at room temperature. The precipitated reaction product is filtered off, triturated with ethanol and again filtered off. A mixture of the cis- and trans-form of 2-amino-^-carbethoxy-5,7-bis-(p-chlorophenyl)-4, -dihydro-7H-thieno[ 2,5-c]thiopyrane is thus obtained and this, when recrystallised from absolute ethanol, has a melting point of 90 - 100°C and forms yellowish crystals. g of the mixture of cis- and fcrans-2-amino-3-carb-ethoxy-5,7-bis- (p-chlorophenyl)-4,5-dihydro-7H-thieno-[2, 3-c ]~ thiopyrane are heated for 4 hours under nitrogen with 50 ml of formamide whilst stirring, in an oil bath at l80 - 190°C. After cooling, the resulting precipitate is filtered off and thoroughly washed with ethanol. In order to purify it, the resulting product is dissolved hot in 2 parts by volume of. dimethylformamide, clarified with active charcoal, and caused to crystallise by adding 6 parts by volume of ethanol. A mixture of the cis- and trans-forms of 4-hydroxy-6,8-bis- (p-chloro-phenyl)-5,6-dihydro-8H-thiopyrano[4' ,2' :4,5l thieno[2, d] j pyrimidine melting point 26o°C is thus obtained. g of cis- and trans-4-hydroxy-6,8-bis- (p-chloro-phenyl)-4,6-dihydro-8H-thiopyrano[4' ,3' :4,5]thieno[2, d] ' pyrimidine are warmed for 2 hours with 50 ml of phosphorus \ oxychloride in an oil bath at 120°C. Thereafter the excess precipitate thus obtained is filtered off, triturated with ethanol and again filtered off. Fractional crystallisation of the resulting product from benzene allows the two stereoisomers of -chloro-6J8-bis- (p-chlorophenyl )-5i6-dihydro-8H-thiopyrano[4' ,3' :4,5]thieno[2,3-d]pyrimidine to be separated. One form melts at 186 - l88°C and the other at melting point 201 - 202°C.

Example 4 3 g of the stereoisomer of' melting point l86-l88°C of 4-chloro-6,8-bis- (p-chlorophenyl)-5 6-dihydro-8H-thiopyrano [4' ,3' :4,5]thieno[2i3-d]pyrimidine are warmed for 3 hours with 20 ml of 4-amino-l- (diethylamino )-pentane in an oil bath at 120°C. The reaction solution is poured into 300 ml of water, whereupon a semi-solid precipitate forms which is separated off and dissolved in 100 ml of 0.5 N hydrochloric acid. The filtered hydrochloric acid solution is adjusted to a pH-value of 8 - 9 with 2 N sodium hydroxide solution and thereafter extracted with ether. After drying the ether solution and evaporating the ether, a solid residue is obtained which is recrystallised from isopropyl ether.

A mixture of the stereoisomeric forms of 4- (4-diethylamino- · 1-methyl-butylamino )-6, 8-bis- (p-chlorophenyl )-5, 6-dihydro- 8H-thiopyrano[4t ,3' :4,5]thieno[2,3-d]pyrimidine of formula melting point 100 - 140°C, is thus obtained.

The hydrochloride manufactured therefrom melts at 200 - 215°C (with decomposition).

In an analogous manner, the stereoisomer of melting point 201 - 202°C of 4-chloro-6, 8-bis- (p-chlorophenyl )-5,6-dihydro-8H-thiopyrano[4 ' ,3* :4,5]thieno[2,3-d]pyrimidine yields a mixture of the stereoisomers of 4- (4-diethylamino-l-methyl-butylamino)-6, 8-bis- (p-chlorophenyl )-5,6-dihydro-8H-thiopyrano[4' ,3' :4J5]thieno[2J3-d]pyrimidine of melting point 100 - l40°C.

Example .5 4.6 g of the stereoisomer of melting point 186 - 188 of 4-chloro-6, 8-bis- (p-chlorophenyl)-5,6-dihydro-8H-thio-pyrano{ ' Λ 1 :4J5]thieno[2J3-d]pyrimidine are dissolved warm in 150 ml of absolute toluene and heated to boiling for 3 hours with 2.8 g of 7-diethylamino-propylamine, whilst stirring. The mixture is thereafter evaporated to dryness in vacuo and the residue is triturated with water. Recry-stallisation of the resulting product from ethanol yields · the pure stereoisomer of melting point 173-174°C of 4-(<Y-di-ethylamino-propylamino ) -6, 8-bis- (p-chlorophenyl )-5 , 6-di-hydro-8H-thiopyrano[4' ,3' :4,5]-thieno[2,3-d]pyrimidine j of formula /°2H5 in the form of white crystals.

On dissolving the base in the calculated quantity of 1 N ethanolic hydrochloric acid and adding isopropyl ether until crystallisation results, the dihydrochloride of melting point 180°C (with decomposition) is obtained.

Example 6 4.6 g of the stereoisomer of melting point 186 - 188°C of 4r-chloro-6,8-bis-(p-chlorophenyl)-5, 6-dihydro-8H-thio- pyrano[41 , 3 ' ί , 5]thieno[2, 3-d]pyrimidine are dissolved warm in 150 ml of absolute toluene and heated for 3 hours to boiling, with the addition of 2.2 g of β-dimethylamino- ethylamine, whilst stirring. The mixture is thereafter evaporated to dryness in vacuo and the residue" triturated with water. The recrystallisation of the resulting product from ethanol yields the pure stereoisomer of melting point 208 - 209°C of 4-(P-dimethylamino-ethylamin'o)-6,8-bis-(p- ' chlorophenyl)-5,6-dihydro-8H-thiopyrano[4' ,3' :4,5]thieno [2,3-d]pyrimidine of formula in the form of white crystals.

On dissolving the base in the calculated quantity of 1 N ethanolic hydrochloric acid and adding isopropyl ether until crystallisation results, the dihydrochloride of melting point 260-262°C is obtained. The bis-methanesulfonate melts at 155°C .

The dihydrochloride of the other isomer (trans-form) which can be prepared in an analogous manner starting from the trans-isomer melts at 258-260°C.

Example 4.6 g of the stereoisomer of melting point l86-l88°C of 4-chloro-6, 8-bis- (p-chlorophenyl)-5, 6-dihydro-8H-thiopyrano-[ 4 ' , 3 ' : 4 , 5]thieno[2, -cl]pyrimidine are dissolved warm in 150 ml of absolute toluene and heated to boiling with 4.0 g of 7-dibutylamino-propylamine for 3 hours, whilst stirring. The mixture is thereafter evaporated to dryness in vacuo and the residue triturated with water. Recrystallisation of the resulting product from ethanol yields the pure stereoisomer of melting point l8j5-l84°C of 4- (7-dibutyl-amino-propylamino ) -6t 8-bis- (p-chlorophenyl )-5> 6-dihydro-8H-thiopyrano[ ' , 3 ' : 4 , 5]thieno[ 2 -d]pyrimidine of formula in the form of white crystals. pyrano[ ' ,3' :4,5]pyrimidine are dissolved warm in 150 ml ' of absolute toluene and heated for 3 hours to boiling with 3.5 g of -(P-diethylaminoethyl)-ethylamine , whilst stirring. Thereafter the mixture is evaporated to dryness in vacuo.

The residue is triturated with water and allowed to stand until it solidifies. On recrystallisation from isopropyl ether-petroleum ether, it yields one stereoisomer of 4-[N-( P-diethylamino-ethyl)-ethylamino]-6,8-bis-(p-chlorophenyl)- , 6-dihydro-3H-thiopyrano[ 4 ' , 31 4, ]thieno[ 2 , 3-d]pyrimi-dine of formula in the form of white crystals of melting point 115-117 C..

Example 9 2.5 g of 4-chloro-6,8-bis-(p-tolyl)-5,6-dihydro-8H- I thiopyrano[4' ,3 ' : 4 , ]thieno[2,3-d]pyrimidine are dissolved j warm in 50 ml of absolute toluene and heated to boiling j for 3 hours with 1.7 g of p-diethylamino-ethylamine whilst stirring. The mixture is thereafter' evaporated to j dryness in vacuo and the residue is triturated with water, j i Recrystallisation of the resulting product from ethanol ! yields the 4-( P-diethylamino-ethylamino)-6 , 8-bis-(p- tolyl)-5,6-dihydro-8H-thiopyrano[4' ,3' :4,5]thieno[2,3~d] pyrimidine of formula in the form of v/hite crystals of melting point 178-181 C.

The dihydrochloride of melting point 215-220°C is obtained by dissolving the base in the calculated quantity of 1 N ethanolic hydrochloric acid and adding isopropyl ether until crystallisation occurs.

The 4-chloro-6,8-bis-(p-tolyl)-5 , 6-dihydro-8H-thiopyrano [4» ,3 ' :4,5]thieno[2,3-d]pyrimidine used as the starting product may for example be manufactured as follows: 130 gof l,5-bis-(p-tolyl')-penta-l,4-dien-3-one and 115 g of anhydrous sodium acetate are. heated to boiling in 3.5 1 of 90 °/ strength ethanol, whilst stirring. Thereafter- a vigorous stream of hydrogen sulphide gas is introduced for 7 hours. After cooling, a stream of air is passed through for a short time and 2 1 of water are then added. The mixture is stirred for a further 3 hours and the resulting precipitate then filtered off. Recrystallisation from - - -t l l -2 6-tetrah dro- thiopyran-4-one in the form of white crystals of melting point 127 - 130°C. 29.6 g of 2,6-bis-(p-tolyl)-2,3,5,6-tetrahydro-thiopyran-4-one, 11.3 g of ethylc ano'ace ate, 3.2 g of powdered sulphur and 10 ml of morpholine are suspended in 100 ml of absolute ethanol and stirred for 4 hours in a bath at 50°C and thereafter for a further 8 hours at room temperature. The precipitated reaction product is filtered off. Recrystall-isation from ethanol yields the 2-amino-3-carbethoxy-5 ,7-bis-(p-tolyl)-4,5-dihydro-7H-thieno[2,3-c]-thiopyrane of melting point 158-160°C. g of 2-amino-3-carbethoxy-5>7-bis-(p-tolyl)-4,5-dihydro~7H-thieno[2,3-c]thiopyrane are heated for 6 hours under nitrogen with 100 ml of formamide, whilst stirring, · in an oil bath at 180-190°0. After cooling, the resulting precipitate is filtered off and thoroughly washed with ethanol. Recrystallisation of the resulting product from ethanol yields the 4-hydroxy-6,8-bis-(p-tolyl)-5 , 6-dihydro-8H-thiopyrano[4* ,3' :4,5]thieno[2,3-d]pyrimidine of melting point 212-215°C. g of 4-hydroxy-6,8-bis-(p-tolyl)-5,6-dihydro-8H-thiopyrano[4' ,3' :4,5]thieno[2,3~d]pyrimidine are warmed for ■ 2 hours with 50 ml of phosphorus oxychloride in an oil bath at 120°C. Thereafter the e cess phosphorus oxychloride is evaporated off in. vacuo and the residue is mixed with ice water, while cooling. Fractional recrystallisation of the residue thus obtained from ethyl acetate permits the two stereoisomers of 4-chloro-6 , 8-bis-( p-tolyl)-5 , 6-dihydro-8H-thiopyrano[4' ,3' :4, 5]thieno[2,3-d]pyrimidine to be separated.

One form melts at 248-249°C and the other at 145-147°C.

Example 10 4.5 g of 4-chloro-6,8-bis-(p-methoxyphenyl)-5,6-dihydro- 8H-thiopyrano[4 ' ,3' :4,5]thieno[2,3-d]pyrimidine are dissolved warm in 150 ml of absolute toluene and heated to boiling v/ith 2.9 g of β-diethylamino-ethylamine for 3 hours, whilst stirring. The mixture is thereafter evaporated to dryness and' the residue triturated with water. Boiling the resulting product with ethanol yields the 4-( β-diethyl-amino-ethylamino )-6 , 8-bis-(p-methoxyphenyl)- , 6-dihydro-8H-thiopyrano[ ' , 3 ' :4, ]thieno[2, 3-d]pyrimidine of formula in t The dihydrochloride of melting point 218-220°C is obtained by dissolving the base in the calculated quantity of 1 N ethanolic hydrochloric acid and adding ethyl acetate and isopropyl ether until crystallisation results.

The 4-chlo o-6, 8-bis-(p-methoxyphenyl)- , 6-dihydro-8H-thiopyrano[4 ' , 3 ' ί , ]thieno[2, 3-d]pyrimidine used as the starting product may for example be manufactured as follows: 32.8. of 2, 6-bis-(p-methoxyphenyl) -2,3,5, 6-tetrahydro-thiopyran-4-one , 11.3 g of ethyl cyanoacetate , 3.2 g of . ethanol are stirred for 8 hours in a bath at 50°C and thereafter for a further 4- hours at room temperature. On trituration, a solid product crystallises out from the reaction solution and this is filtered off and boiled with ethanol. The 2-amino-3-carbethoxy-5 , 7-bis-(p-methoxyphenyl) , 5-dihydro-7H-thieno[2 , 3-c] thiopyrane of melting point 170-180°C is thus obtained. g of 2-amino-3-carbe'thoxy- ,7-bis-(p-methoxyphenyl)- 4. -dihydro-7H-thieno[ 2, 3-c]thiopyrane are heated for 6 hours with 250 ml of formaraide under nitrogen and whilst stirring, in an oil bath at 180-190°C. The reaction mixture obtained after cooling is filtered off and boiled with ethanol. 4-Hydroxy-6,8-bis-(p-methoxyphenyl)- , 6-dihydro-8H-thiopyrano[4 ' ,3' :4,5]thieno[2,3-d]pyrimidine of melting point 240 - 250°C with decomposition is thus obtained. 9 g of 4-hydroxy-6,8-bis-(p-methoxyphenyl)-5,6-dihydro-8H-thiopyrano[ ,3' :4,5]thieno[2,3-d]pyrimidine are warmed for 2 hours with 90 ml of phosphorus oxychloride in an oil . bath at 120°C. The mixture is thereafter evaporated to dryness in vacuo and the residue mixed with ice water. After filtering off the reaction product and boiling with ethanol, 4-chloro-6,8-bis-(p-methoxyphenyl)- , 6-dihydro-8H-thiopyrano[4' ,3' :4,5]thieno[2,3-dJpyrimidine of melting point 175-185°C (with decomposition) is obtained.

Example 11 2.9 g of 4~chloro-6,8-bis-(3,4,5-trimethoxy-phenyl)- .6-dihydro-8H-thiopyrano [41 , 31 : , 5 ] thieno[ 2 , 3-d]pyrimidine are suspended in 250 ml of absolute toluene and heated to - - whilst stirring. The hot reaction solution is clarified with active "charcoal and evaporated to dryness in vacuo. The residue is triturated with isopropyl ether until it solidifies and thereafter recrystallised from ethanol. The 4-(β-diethylamino-ethylamino)-6,8-bis-( 3 ,4, 5-trime hoxy-phenyl)-5 , 6-dihydro-8H-thiopyrano[41 ,3' : 4, 5]thieno[2 , 3-d]pyrimidine of formula of melting point 182-185 C is thus obtained.

The 4-chloro-6 , 8-bis-(3,4, 5-trimethoxy-phenyl)-5 , 6-dihydro 8H-thiopyrano[4' , 3' :4, 5]thieno[2, 3-d]pyrimidine used as the starting product may for example be manufactured as follows: 28.5 g of l,5-bis-(3,4,5-trimethoxyphenyl)-penta-l,4-dien- 3-one and 17 g of anhydrous sodium acetate are heated to boiling in 2 1 of 90 $ strength methanol, whilst stirring.

By introducing a stream of hydrogen sulphide gas for 7 hours and subsequent mixing with 2 1 of water whilst cooling, 2,6-bis-( 3 , , -trimethoxy-phenyl)-2, 3,5, 6-tetrahydro-thiopyran- 4-one is obtained after recrystallisation from 50 °/o strength methanol in the form of white crystals of melting point 174~ 175°C. 22.4 g of 2,6-bis-(3,4,5-trimethoxyphenyl)-2, 3 , 5,6-tetrahydro-t iopyran-4-one , 5.65 g of ethyl cyanoacetate_ 1.6 g of powdered sulphur and 5 ml of morpholine are suspended in 100 ml of absolute ethanol and stirred for 4 hours in a bath at 50°C and thereafter for a further 10 hours at room temperature. The precipitated reaction product is filtered off and boiled with ethanol. 2-Amino-3-carb-ethoxy- , 7-bis-( 3 , , 5-trimethoxyphenyl)-4 , 5-dihydro-7H-thieno[2,3-'c]thiopyrane of melting point 202-203°C is thus obtained. g of 2-amino-3-carbethoxy- ,7-bis-( , 4, 5-trimethoxyphenyl)-4, 5-dihydro-7H-thieno[ 2, 3-c]thiopyrane in 60 ml of forma ide are heated for 6 hours under nitrogen whilst stirring, in an oil bath at 180-190°C. After cooling the .. reaction product is filtered off and recrystallised from dimethylformamide-ethanol. The 4-hydroxy-6,8-bis-( 3,4,5-trimethoxyphenyl)-5,6-dihydro-8H-thiopyrano[4' »3'.:4, 5 ]-thieno[2, 3-d]pyrimidine of melting point 255-260°C is thus obtained. 7 g. of 4-hydroxy-6,8-bis-(3,4,5-trimethoxyphenyl)-5,6-dihydro-8H-thiopyrano[4' , 3 ' :4, 5]thieno[2, 3-d]pyrimidine are heated for 2 hours v/ith 70 ml of phosphorus oxychloride in an oil bath at 120°0. The excess phosphorus oxychloride is evaporated off in vacuo and the residue mixed with ice water The 4-chloro-6,8-bis-(3,4, -trimethoxyphenyl) - ,6-dihydro-8K-thiopyrano[4' ,3' :4,5].thieno[2,3-d]pyrimidine of melting point 255-260°C (with decomposition) is thus obtained.

Example 12 8 g of 4-chloro-6,8-bis-(p-fluorophenyl) -5,6-dihydro- 3H-thiopyrano[4! ,3' :4,5]thieno[2,3-d]pyrimidine are dissolved warm in 100 ml of absolute toluene and heated to boiling for 3 hours with 7.0 g of β-diethylamino-ethylamine whilst stirring. The mixture is thereafter evaporated to dryness in vacuo and the residue triturated with 50 a/o strength aqueous ethanol. Recrystallisation of the resulting product from ethanol yields the 4-( P-diethylamino-ethyl-aminoJ-S ,8-bis-(p-fluorophenyl)-5 , 6-dihydro-8H-thiopyrano-[4' ,3' :4,5]thieno[2,3-d]pyrimidine of formula in the form of white crystals of melting point 16.4-168°C.

The dihydrochloride of melting point 208-210°0 is obtained by dissolving the base in the calculated quantity of 1 U ethanolic hydrochloric acid and adding isopropyl ether until crystallisation results.

The 4-chloro~6,8-bis-(p-fluorophenyl)-5 , 6-dihydro-8H-thiopyrano[4' ,3' :4,5]thieno[2,3-d]pyrimidine used as the starting product can for example be manufactured as follows: and 80 g of anhydrous sodium acetate in 2 1 of 90 J strength etha ol are heated to boiling whilst stirring. By introducing a stream of hydrogen sulphide gas for 6 hours and subsequently gradually adding 2 1 of water whilst cooling, the 2, 6-bis-(p-fluorophenyl) -2 , 3, 5 , 6-tetrahydro-thiopyran-4-one of melting point 125-126°C is obtained after recrystall-isation from ethanol. .4 g of 2,6-bis-(p-fluorophenyl)-2,3,5,6-tetrahydro-thiopyran-4-one , 11.3 g of ethyl cyahoacetate , 3.2 g of powdered sulphur and 10 ml of morpholine are suspended in 100 ml of absolute ethanol and stirred for 4 hours in a bath at 50°C and thereafter for a further 8 hours at room 'temper- . ature. After filtering off the reaction product and re-crystallising from absolute ethanol, 2-amino-3-carbethoxy-5, 7-bis-(p-fluoro phenyl )-4,5-dihydro-7H-thieno[ 2, 3-c]thio-pyrane of melting pointT6l-1-62°_C is obtained. 26 g of 2-amino-3-carbethoxy-5 ,7-bis-(p-fl orophenyl)-4,5-dihydro-7H-thieno[2,3-c]thiopyrane are heated with 130 ml of formamide under nitrogen for 4 hours whilst stirring, in an oil bath at 180-190°0¾ The reaction product is filtered off and recrystallised from ethanol. The 4-hydroxy~6,8-bis- ( p-fluoro phenyl )-5 , 6-dihydro-8H-thiopyrano[4 * , 31 : , 5 ]-thieno[2, 3-d]pyrimidine of melting point 255-260°C is thus obtained. g of 4-hydroxy-o, 8-bis-(p-fluoro phenyl) -5, 6-dihydro-8H-thiopyrano[4' ,3 ' :4,5]thieno[2, -d]pyrimidine are warmed with 100 ml of phosphorus oxychloride for 2 hours in an oil bath at-120°C. The excess phosphorus oxychloride is thereafter evaporated off in vacuo and the residue mixed with ice water. The resulting precipitate is filtered off, triturated wit ethanol and recrystallised from ethanol. 4-Chloro-6 , 8-bis-(p-fluorophenyl )-5 , 6-dihydro-8H-thiopyrano~ [4' ,3' :4,5]thieno[2,3-d]pyrimidine of melting point 160-161°0 is thus obtained.

Example 13 2.3 g of 4-chloro-6,8-bis-(o-chlorophenyl)-5f 6-dihydro-8H-thiopyrano[4' ,3' ί ,5]thieno[2,3-d]pyrimidine are dissolved warm in 150 ml of absolute toluene and heated to boiling for 3 hours with 1.5 g of β-diethylamino-ethylamine whilst stirring The mixture is thereafter evaporated to dryness in vacuo and the residue triturated with water. The product thus obtained is recrystallised from ethanol. 4-( β-diethylamino-ethyl-amino)-6 ,8-bis-(o-chlorophenyl)- , 6-dihydro-8H-thiopyrano-[41 ,3' : 4, ]thieno[2, 3-d]pyrimidine of formula is thus obtained in the form of v/hite crystals of melting point 240-245°C · • The 4-chloro-6,8-bis-(o-chlorophenyl)-5,6-dihydro-8H-thio-pyrano[4' ,3' :4,5]thieno[2, 3-d]pyrimidine used as the starting product may for example be manufactured as follows: ' 80 g of l,5-bis-(o-chlorophenyl)-penta-l,4-dien-3-one and 65 g of anhydrous sodium acetate are heated to boiling in 3 1 of 90 i<> strength ethanol, whilst stirring. By introducing a stream of hydrogen sulphide gas for 6 hours and subsequently adding 2 1 of water whilst cooling, 2,6-bis-(o-chlorophenyl)-2,3,5,6-tetrahydro-thiopyran-4-one of melting point -120-122°C is obtained after recrystallisation from ether. 16.8 g .of 2,6-bis-(o-chlorophenyl)-2,.3,5,6~tetrahydro-thiopyran-4-one , 5.65 g of ethyl cyanoacetate , 1.6 g of powdered sulphur and 5 ml of morpholine in 50 ml of absolute' ethanol are stirred for 5 hours in a bath at 50°C and thereafter for a further 8 hours at room temperature. After filtering off the reaction product and recrystallising from ethanol, 2-amino-3-carbethoxy-5 ,7-bis-(o-chlorophenyl)-4,5-dihydro-7H-thieno[2, 3-c] thiopyrane of melting point 166 ~- 167°C is obtained. g of 2-amino-3-carbethoxy-5,7-bis-(o-chlorophenyl)-4,5-dihydro-7H-thieno[ 2 , 3-c]thiopyrane are heated with 50 ml' of formamide under nitrogen for 4 hours in an oil bath at 180-190°C, whilst stirring. After filtering off the reaction product and recrystallising from dimethylformamide-ethanol, 4-hydroxy-6,8-bis-(o-chlorophenyl)- , 6-dihydro-8H-thiopyrano-[4* ,3' :4,5]thieno[2,3-d]pyrimidine of melting point 290-300°C (with decomposition) is obtained. 6 g of 4-hydroxy-6,8-bis-(o-chlorophenyl)-5 , 6-dihydro-8H-thiopyrano[4 ' ,3' :4,5]thieno[2, 3-d]pyrimidine are warmed for 2 hours with 60 ml of phosphorus oxychloride in a bath at 120°C. The excess phosphorus oxychloride is evaporated off in vacuo and the residue mixed with ice water. After recrystallisation from benzene of the reaction product thus obtained, 4-chloro-6,8-bis-(o-chlorophenyl)-5 , 6-dihydro-SK-thiopyrano[ ' ,3' :4,5]thieno[2,3-d]pyrimidine of melting point 250-252°C is obtained.

Example 14 14 g of .4-chloro-6,8-bis-(m-chlorophenyl)-5»6-dihydro-8H-thiopyrano[4 ' ,31 :4,5]thieno[2, 3-d]pyrimidine are dissolved warm in 400 ml of absolute toluene and heated to boiling for 3 hours with 8.0 g of β-diethylamino-ethylamine, whilst stirring. The mixture is thereafter evaporated, to dryness in vacuo and the residue triturated with water.

Recrystallisation of the resulting product from ethanol yields 4-( P-diethylamino-ethylamino)-6 ,8-bis-(m-chlorophenyl). -5,6-dihydro-8H-thiopyrano[4' ,3 · :4,5]thieno[2,3-d] pyrimidine of formula in the form of white crystals of melting point 178-18.0°C.

On dissolving the base in the calculated quantity of 1 N ethanolic hydrochloric acid and adding isopropyl ether until crystallisation takes place, the dihydrochloride of melting point 238-240°C (with decomposition) is obtained.

The 4-chloro-6, 8-bis-(m-chlorophenyl)-5 , 6-dihydro-8H-thiopyrano[4 ' ,3 ' :4, 5]thieno[2, 3-d]pyrimidine used as the starting product may for example be manufactured as follows: 90 g of 1 , 5-bis-(m-chlorophenyl)-penta-l , 4-dien-3-one and 80 g of anhydrous sodium acetate in 3 1 of 90 strength ethanol are heated to boiling whilst stirring. By introducing a stream of hydrogen sulphide gas for 6 hours and subsequently adding 2 1 of water whilst cooling, 2,6-bis-(m-chlorophenyl)-2 ,3,5, 6-tetrahydro-thiopyran-4-one is obtained in the form of white crystals of melting point 166-167°C after recrystallisation from ethyl acetate. 16.8 g of 2,6-bis-(m-chlorophenyl)-2,3,5,6-tetrahydro- '· thiopyran-4-one , 5.65 g of ethyl cyano.acetate ,.1.6 g of powdered sulphur and 5 ml of morpholine are suspended in 100 ml of- absolute ethanol and stirred for 5 hours in a bath at 50°G and thereafter for a further 8 hours at room temperature. After filtering off the reaction product and recrystallising from ether, 2-amino-3-carbethoxy- ,7-bis-(m-chlorophenyl)-4, 5-dihydro-7H-thieno['2, 3-c]thiopyrane of melting point 145-149°C is obtained. g of 2-amino-3-carbethoxy-5 ,7-bis-(m-chlorophenyl)-4, 5-dihydro-7H-thieno[ 2, 3-d] thiopyrane are heated for 4 hours under nitrogen with 50 ml of formamide, whilst stirring, in an oil bath at 180-190°C. After filtering off. the reaction product and recrystallising from dimethylformamide-ethanol, 4-hydroxy-6 ,8-bis-(m-chlorophenyl )- , 6-dihydro-8H-thio- pyrano[4' >3' :4,5]thieno[2,3-d]pyrimidine of melting point 224-226°C is obtained. ' . 4 g of 4-hydroxy~6,8-bis-(m-chlorophenyl)-5,6-dihydro-8H-thiopyrano[41 , 31 ·*4, 5] thieno[2, 3-d]pyri idine are warmed for 2 hours with 40 ml of phosphorus oxychloride in an oil bath at 120°C. The excess phosphorus oxychloride is thereafter evaporated off in vacuo and the residue mixed with ice ■ water. The resulting precipitate is filtered off and washed with water. Recrystallisation from benzene-petroleum ether yields 4-chloro-6,8-bis-(m-chlorophenyl)-5 , 6-dihydro-8H-thiopyrano[ 1 , 3 ' : 4 , 5 ] hieno[ 2, 3-0" ]pyrimidine of melting point 214-215°C. . ' Example 15 .3.6 g of 4-chloro-6,8-bis-(2,4-dichlorophenyl)-5, 6-dihydro-8H-thiopyrano[ ' ,3' :4,5]thieno[2,3-d]pyrimidine are dissolved warm in 60 ml of absolute toluene and heated to boiling for 3 hours with 2.0 g of β-diethylamino-ethylamine , whilst stirring. The mixture is thereafter evaporated to dryness in vacuo and the residue triturated with water. Re-crystallisation of the resulting product from benzene yields.4-( P-diethylamino-ethylamino)-6 ,8-bis-( , 4-dichloro-phenyl)-5 , 6-dihydro-8H-thiopyrano[4 ' , 3 ' : 4 , 5 ]thieno[ 2.,'3-d] pyrimidine of formula in the form of white crystals of melting point 234-242°C.

The 4-chloro-6,8-bis-(2,4-dichlorophenyl)-5,6-dihydro-8H-thiopyrano[ ' ,3 ' :4,5] thieno[2, 3-dJpyrimidine used as the starting product may for example be manufactured as follows: 29 g of l,5-bis-(2,4-dichlorophenyl)-penta-l,4-dien-3-one and 25 g of anhydrous sodium acetate in 1 1 of 90 # strength ethanol are heated to boiling whilst stirring. By introducing a stream of hydrogen sulphide gas for 5 hours and adding 500 ml of water whilst cooling, 2,6-bis-(2, 4-dichloro-phenyl)-2,3,5,6-tetrahydro-thiopyran-4-one is obtained in the form of v/hite crystals of melting point 167-170°C after re-crystallisation from ethyl acetate. .3 g of 2,6-bis-(2,4-dichlorophenyl)-2,3,5,6-tetrahydro-thiopyran-4-one , 5.65 g of ethyl cyanoacetate , 1.6 g of powdered sulphur and 5 ml of morpholine are suspended in 100 ml of absolute ethanol and stirred for 6 hours in a bath at 50°C and thereafter for a further 8 hours at room temperature. The reaction product is filtered off and recrystall-ised from ethanol. 2-Amino-3-carbethoxy-5 , 7-bis-( 2 ,4-dichlorophenyl)-4,5-dihydro-7H-thieno[2,3-c]thiopyrane of melting point 140-160°C is thus obtained. g of 2-amino-3-carbethoxy-5,7-bis-(2,4-dichlorophenyl)-.' 4,5-dihydro-7H-thieno[2, 3-c] thiopyrane are heated for 6 hours j under nitrogen with 100 ml "of forma ide, whilst stirring, in. j an oil bath at 180-190°0. After filtering off the reaction j mixture and boiling with ethanol, 4-hydroxy-6, S-bis-( , 4-dichlorophenyl)-5,6-dihydro-8H-thiopyrano[4' ,3 ' :4,5]thieno- j [2, 3-d]pyrimidine of melting point 285°C (with decomposition): is obtained. . ' 4 g of 4-hydroxy-6,8-bis-(2, 4-dichlorophenyl)-5,6- dihydro-8H-thiopyrano[41 ,3' :4,5]thieno[2,3-d]pyrimidine are warmed for 2 hours with 40 ml of phosphorus oxychloride in an oil bath at 120°C. The mixture is thereafter evaporated to dryness in vacuo and the residue mixed with ice water, ftecrystallisation from ethyl o.cetate of the product thus obtained yields 4-chloro-6,8-bis-(2,4-dichlor,ophenyl)-5 , 6-dihydro-8H-thiopyrano[4' >3' :4,5]thieno[2,3-d]pyrimidine of melting point 245-247°C Example 16 1 g of 4-chloro-6 , 8-bis-(p-chlorophenyl)-5 , 6-dihydro-8H-thiopyrano[4' ,3' :4, 5]thieno[2,3-d]pyrimidine-7-oxide is dissolved in 25 ml of β-diethylamino-ethylamine at room temperature. The solution is. immediately poured into ½ 1 of water and the resulting precipitate is filtered off.

Recrystallisation from ethanol yields 4-( β-diethylamino-ethylamino)-6 , 8-bis-(p-chlorophenyl)-5 , 6-dihydro-8H-thio- " ' pyrano[4' ,3' :4,5]thieno[2,3-d]pyrimidine-7-oxide of formula in the form of white crystals of melting point 205-207°C. The 4--chloro-6,8-bis-(p-chlorophenyl)-5, 6~dihydro-8H- thiopyrano[4' ,3' :4,5]thieno[2,3-d]pyriraidine-7-oxide used as the starting- product can for example be manufactured as fallows: 4.6 g of a mixture of cis- and trans-4-chloro-6,8-bis- (p-chlorophenyl)-5 , 6-dihydro-8H-thiopyrano[4 ' , 3 '·'4, 5]- thieno[2,3-d]pyrimidine are dissolved in 100 ml of methylene chloride and mixed over the course of 45 minutes, whilst stirring, with a solution of 1.9 g of 85 5' strength m- chloroperbenzoic acid in 100 ml of methylene chloride. The reaction solution is stirred for a further 2 hours at room temperature and is then extracted by shaking with 100 ml of saturated sodium bicarbonate solution. The methylene chloride solution is separated off, dried and evaporated to dryness in vacuo. The residue is triturated with ethanol and boiled with benzene. 4-Chloro-6,8-bis-(p- chlorophenyl )- , 6-dihydro-8H-thiopyrano[ 4 ' , ' : , J thieno- [2,3-d]pyrimidine-7-oxide of melting point 210-215°C (with decomposition) is thus obtained.

Sxanvole 17 3.5 g of 4-chloro-6,8-bis-(p-chlorophenyl)-5,6-dihydro-. · 8H-thiopyrano[4 ' , 31 : 4 , ] hieno[ 2 , 3-d]pyrimidine-7 ,7- dioxide are dissolved hot in 200 ml of absolute toluene ,and heated for 3 hours to boiling with 2.0 g of β-diethyl- amino-ethylamine , whilst stirring. The mixture is thereafter evaporated to drynsss -in vacuo and the residue tri- j I turated with water until it solidifies. Recrystallisation j from ethanol yields 4-( P-diethylamino-ethylamino)-6,8-bis- (p-chlorophenyl)-5,o-dihydro-8K-thiopyrano[4' ,3' : , 5] i thieno[2,3-d]pyrimidine-7,7-dioxide of formula " 1 in the form of white crystals of melting point 234-236°Q The 4-chloro-6,8-bis-(p-chlorophenyl)-5,6-dihydro-8H-thiopyrano[4 V, 31 :4, 5]thieno[2, 3-d] pyrimidine-7,7-dioxide used as the starting product can for example be manufactured as follows : 4.6 g of a mixture of cis- and trans-4-chloro-6,8-bis-(p-chlorophenyl)-5,6-dihydro-8H-thiopyrano 41 ,31 :4, 5]thieno[2,3-d] pyrimidine are dissolved in 100 ml of methylene chloride and mixed with 4.4 g of 85 strength ui-chloroperbenzoic acid whilst stirring. The methylene chloride solution is stirred for a further 3 hours at room temperature and is then thoroughly shaken with 100 ml of 0.5 N sodium hydroxide solution. The methylene chloride solution is "separated off, dried and. eva- i porated to dryness in vacuo. The residue crystallises on trituration with 50 ml of ethanol. The product thus obtainedis briefly boiled up with benzene. 4-Chloro-6,8-bis-(p-chloro-phenyl)-5,6-dihydro-8H-thiopyrano[4' ,3! :4,5]thieno[2,3-d] , pyrimidine-7,7-dioxide is thus obtained in the form of white i crystals of melting point 280-285°C (with decomposition).

Example 18 13 · 9 g of cis-4-chloro-6, 8-bis-(para-chlorophenyl)-5 , 6-dlhydro-8H-thiopyrano[ ' , 3 ' : , 5] thieno[ 2 , 3-d] pyrimldine are dissolved in 300 ml of absolute toluene while heating, and the solution mixed with 8.6 g of β-morpholino-ethylamine, then boiled while stirring for hours. The batch is then evaporated to dryness under vacuum, and the residue triturated with water. Boiling of the resulting product with.ethanol yields cis-4- ( 3-morpholino-ethylamlno)-6, 8-bis- (para-chloro-phenyl )-5 , 6-dihydro-8H-thiopyrano[ 1 , 31 : , 51 thieno[ 2, -d]-pyrimldine of the formula in the form of white crystals of melting point 228 - 230°C.

Example 19 .15 g of cis-4-chloro-6, 8-bis-(para-fluorophenyl)-5 , 6-dihydro-8H-thiopyrano[ 4 ' , 3 ' : , 5] thieno[ 2 , 3- ] pyrimldine are dissolved in 100 ml of absolute toluene with the application of heat, and the solution boiled with 2 .4 g of β-di-methylamino-ethylamine while stirring for 3 hours. The batch resulting product from absolute ethanol gives cis-4- (β-dimethyl amino-ethylamino)-6, 8-bis- (para-fluorophenyl )-5,6-dihydro-8H-thiopyrano-[41 ,3* :4,5lthieno [2,2-d]-pyrimidine of the formula in the form of white crystals melting at 196 - 197°C.

The dihydrochloride of this compound melts at 240°C (with decomposition) and its bismethanesulfonate melts at I88 - 190°C.

Example 20 .4.7 g of trans-4-chloro-6, 8-bis- (para-fluorophenyl )-5,6-dihydro-8H-thiopyrano[4' ,5' :4J5]thieno[2, d]pyrimidine are dissolved in 150 ml of absolute toluene with the application of heat, and the solution boiled with 2.j5 g of β-di-methylamino-ethylamine while stirring for 3 hours. The batch is then evaporated to dryness under reduced pressure and the residue is triturated with water. The resulting product is recrystallised from absolute ethanol, and trans-4-(3-dlmethyl-amino-ethylamino )-6, 8-bis- (para-fluorophenyl 6-dihydro-8H-thiopyrano[4* ,3' :4,5]thieno[2, d]pyrimidine of the formula obtained in the form of white crystals which melt at l83-l84°C.

The dihydrochloride of this compound melts at 2 5°C (with decomposition) and its bismethanesulfonate at l40°C.

The pure trans- and cis-forms of 4-chloro-6, 8-bis-(para-fluorophenyl )-5,6-dihydro-8H-thiopyrano[4 ' ,3' :4,5lthieno [2,3-d]pyrimidine used as starting material can be obtained as follows: 27·5 g of a mixture of the two stereoisomers of 4-chloro-6, 8-bis- (para-fluorophenyl )-5>6-dihydro-8H-thiopyrano[41 ,3 ' : , 5] thieno[2,3-d]pyrimidine are dissolved in 80 ml of chloroform and chromatographed over a column of 1.3 kg of silica gel "Merck',' 0.05 - 0.2 mm, Elution is performed with a mixture of 4 parts of isopropyl ether and 1 part of chloroform, the fractions being currently checked by thin-layer chromatography. From the first usable fractions there is obtained by crystallisation from benzene trans-4-chloro-6, 8-bis- (para-fluorophenyl )-5, 6-dihydro-8H-thio-pyrano[4' ,3' :4,5]thieno[2,3-d]pyrimidine which melts at 191 - 192°L From the fractions which follow there is obtained by crystallisation from much isopropylether cis-4-chloro-6, 8-bis- (para-fluorophenyl )-5, 6-dihydro-8H-thiopyranot 4 ' ,5' : 4, 5]thienot2, 3-d] yrimi-dine which melts at 193 - 194°C.

Example 21 4.8 g of 2-Methyl-4-chloro-6,8-bis- (para-chloro-phenyl)-5,6-dihydro-8H-thiopyrano[4' ,3' :4,5lthieno[2,3-d] pyrimldlne are dissolved in 300 ml of absolute toluene while heating, and the solution stirred with 2.0 g of β-dimethylamino-ethylamine in an oil bath for 3 hours at 120°C. The batch is then evaporated to dryness under reduced pressure, and the residue triturated with water.

Recrystallisation of the resulting product from ethanol gives 2-methyl- - ( -dimethylamino-ethylamino)-6, 8-bis-(para-chlorophenyl )-5,6-dihydro-8H-thiopyrano[ 4 ' , 3' ·'4,5] thieno[2,3-d]pyrimidine of the formula in the form of crystals which melt at 176-177 0.

The 2-methyl-4-chloro-6, 8-bis- (para-chlorophenyl )-5,6-dihydro-8H-thiopyrano[4' , T :4,5]-thieno[2,3-d]pyrimidine used as starting material can be prepared for example as follows: 22 g of 2-Amino-3-carbamoyl-5,7-bis- (para-chloro- The reaction solution is then poured into 1 liter of water and stirred until a solid precipitate forms. The latter is filtered off and dried. The product so obtained is dissolved in 5 parts by volume of chloroform and the solution poured over a chromatographic column of 50 times the quantity of silica gel "Merck" 0.05 - 0.2 mm. Elution is performed with a mixture of 19 parts of chloroform and 1 part of ethyl acetate, and the resulting fractions currently checked by thin-layer chromatography. From the middle fractions there can be isolated by crystallisation 2-methyl-4-hydroxy-6, 8-bis- (para-chlorophenyl )-5i 6-dihydro-8H-thiopyrano[ ' , 3 * 5l thieno[ 2, d]pyrimidine melting at 249-251°C. g of 2-Methyl-4-hydroxy-6, 8-bis-(para-chlorophenyl)-5 , 6-dihydro-8H-thiopyrano[ ' , 3 ' : 4 , 5] thieno[ 2, 3-d]pyrimidine and 1 .5 ml of N, N-dimethyl-aniline are heated for 1 hours with 50 ml of phosphorus oxychloride in an oil bath of 120°C. The excess phosphorus oxychloride is then evaporated in vacuo, and the residue is mixed with ice water while cooling. The resulting solid precipitate is filtered off with suction and dried. The resulting product is then dissolved in a small quantity of chloroform and the solution poured over a chromatographic column with the 40-fold quantity of silica gel "Merck" 0.05 - 0.2 mm. Elution is performed with chloroform and the resulting fractions currently checked by thin-layer chromatography. It is thus possible to isolate from the first usable fractions 2-methyl-4-chloro-6 , 8-bis- (para-chlorophenyl )-5, 6-dihydro-8H-thiopyrano[ , 3 ' : 4 , 5]thieno[ 2, d]pyrimidine which, after being recrystallised from isopropyl ether, ° Example 22 I Tablets, each containing 100 mg of the active substance, can be prepared, for example, from the following in gredients: Composition per tablet 4- ( β-dimethylaminoethyl-amino )-6, 8-bis- (para-chlorophenyl )-5, 6-di-hydro-8H-thiopyrano -[ ,3' : ,5]-thieno[2, d] pyrimidine dihydrochlorlde 100 mg lactose 50 mg wheat starch 7^ m colloidal silicic acid ± > mg talc 12 mg magnesium stearate 1 mg 250 mg Preparation 4- (3-dimethylaminoethylamino)-6, 8-bis- (para-chloro- phenyl)-5,6-dihydro-8H-thiopyrano[4' ,3' :4,5]thieno[2, d]-pyrimidine dihydrochlorlde is mixed with the lactose, part of the wheat starch and with colloidal silicic acid, and the mixture forced through a sieve. Another portion of the wheat starch is pasted on a water .bath with five times its quantity of water, and the powder mixture kneaded with the resulting paste until a slightly plastic mass is obtained. This mass is pressed through an approx. 5 m mesh sieve, dried and the resulting dry granulate passed through a sieve. The remainder of the wheat starch, the talc and the magnesium stearate are then admixed and the resulting mixture compressed into Example 2¾3¾ Tablets, each containing 10 mg of active principle can be prepared, for example, from the following ingredient Composition per tablet 4- ( β-dimethylaminoethylamino )-6, 8-bis- (para-chlorophenyl )-5, 6-dihydro-8H-thiopyrano-[ , > X : 4,5] thieno.2, 3-d] pyrlmidine dihydrochloride .10.0 mg wheat starch 29·5 m lactose 50.0 mg colloidal silicic acid . 5.0 mg talc 5.0 mg magnesium stearate 0.5 mg Preparation 4- (3-dimethylaminoethylamino)-6,8-bis- (para-chloro phenyl )-5,6-dihydro-8H-thiopyrano[4' ,3' :4,5]thieno[2,3-d]~ pyrlmidine dihydrochloride is mixed with part of the wheat starch, with lactose, and with colloidal silicic acid, and the mixture forced through a sieve. Another portion of the wheat starch is pasted on a water bath with five times its quantity of water, and the powder mixture kneaded with the resulting paste until a slightly plastic mass is obtained. This mass is pressed through an approx. mm mesh sieve, dried, and the resulting dry granulate passed through a sieve. The remainder of the wheat starch, the talc and the magnesium stearate are then admixed and the resulting mixture compressed into tablets each weighing 100 mg.

Tablets of this kind are suitable especially for 31669/2

Claims (1)

1. CLAIMS compound of the in which n stands for 1 or for a lower alkylene radical which separates from the nitrogen atom in by 2 to 5 carbon represents a lower alkylamino group or a saturated heterocyclic a lower radical or a hydrogen each of the radicals R and a phenyl radical optionally substituted by lower alkyl trifluoromethy1 lower alkoxy meth groups halogen and represents a lower alkyl radical or a hydrogen A compound of the formula in which n represents 1 or alk stands for a lower alkylene radical which separates from the nitrogen atom in by 2 to 5 carbon for a alkylamino group or a lower thiaalkyleneamino or an optionally lower azaalkyleneamino each of the radicals and fo a phenyl radical optionally substituted by lower alkyl trifluororaethyl lower alkoxy groups and halogen and for a lower alkyl or a hydrogen A compound of the formula which n represents 1 or stands for a lower alkjlene radical which separates from the nitrogen atom in by 2 to 5 carbon for a alkylamino optionally alkylated or piperazino and and stand for phenyl radicals which may be substituted by lower alkyl lower alkoxy groups halogen and for a lower alkylradical or hydrogen A compound of the formula in which n represents 1 or alk stands for a lower alkylene radical which separates the nitrogen atom in by 2 to 3 carbon for a alkylamino a or piperazino and for phenyl radicals which may be substituted by chlorine fluorine atoms lower alkoxy and for a hydrogen atom or a lower alkyl compound of the formula in which n represents 1 or stands for a lower alkyl radical or a hydrogen m for and R for an or radical or an or each of the radicals and is phenyl optionally substituted by lower alkyl trifluoromethyl lower alkoxy groups halogen and represents a lower alkyl radical or a hydrogen A compound of the in which n stands for 1 or and each represents a phenyl radical substituted by two or more lower alkoxy groups or halogen stands for a linear or branched alkylene radical which separates the two nitrogen atoms by 2 to 3 carbon and and for lower alkyl A compound according to Claim in which n represents A compound as claimed in any one of Claims 6 and 7 in the A compound as claimed in any one of claims and in the A compound as claimed in any one of claims and to in the laevorotatory A compound as claimed in any one of claims and 9 to in the dextrorotatory An acid addition salt of a compound as claimed in any one of claims to A physiologically tolerable acid addition salt of 4 a compound as claimed in any one of claims to compound of the formula in which represents a lower alkylene radical containing 2 to 5 carbon and R each stands for a lower alkyl and Hal and each for a chlorine bromine A compound of the formula 6 which represents the or and each stands for a methyl or ethyl and Hal each for a chlorine or bromine A compound as claimed in either of claims y and in the A compound as claimed in either of and in the A compound as claimed in any one of claims to in the laevorotatory to A compound as claimed in any one of claims yf to in the dextrorotatory imed in salt of V d3 chlorophenyl chlorophenyl 20 A compounders any of claims to in the compound as claimed in any one of claims in the compound as claimed in any one of claims 5 to in the laevorotatory A compound as claimed in any one of claims to in the dextrorotatory An acid addition salt of a compound as claimed in any one of claims to A physiologically tolerable acid addition salt of a compound as claimed any one of claims to pyrimidine phenyl v pheny1 4 pyrimidine pyrimidine chlorophenyl hieno thieno 4 pyrimidine 44 phenyl pyrimidine phenyl pheny1 4 A compound as claimed in any one of claims to in the A compound as claimed in any one of claims to in the A compound as claimed in any one of claims to in the laevorotatory A compound as claimed in any one of claims to the acid addition salt of a compound as claimed in SZ j any one of claims to physiologically tolerable acid addition salt 34 a compound as claimed in any one of claims to pyrimidine pyrimidine pyrimidine 5 as claimed in an one of claims to and in admixture A pharmaceutical composition containing a compound as claimed in any one of claims 34 to and 54 in admixture or conjunction with a pharmaceutical A pharmaceutical composition containing a compound as claimed in any one of claims 55 to 63 and 65 in admixture or conjunction with a pharmaceutical A process for the manufacture of a compound as claimed in any one of claims 12 and wherein a 5 thieno ί 2 or an of the formula in which have the meanings given in claim and in which Y represents a bromine or chlorine is reacted with an appropriate amine of the formula 1 o in which and have the meanings given in claim A process as claimed in claim wherein an substituted compound is used as starting A process as In 76 wherein a resulting or compound Is A process as claimed In any one of Claims 76 and 77 wherein a resulting mixture of Is split into the pure and a resulting is resolved into the optical antipodes a resulting free base is converted into a salt or a resulting salt the free A process as claimed in Claim 75 wherein a resulting mixture of isomers is split into the pure and a resulting raoemate is resolved into the optical antipodes a resulting ee base is converted into a salt a resulting salt into the free insufficientOCRQuality