CH502376A - 4 5-dihydro-7h-thieno 2 3-c-thiopyran derivs sedatives anti-inflammato - ries hypotensives etc - Google Patents

Abstract

Thiophene derivs. (4,5-dihydro-7H-thieno (2,3-c) thiopyrane derivs.) of general formula I and their S-oxides R = H or acyl R' = COOH or a functional deriv. e.g. CN, CONH2 or COOX where X = alkyl, aryl, aralkyl or pyridyl R2 = opt. substd. aryl with R2' = H R3 = opt. substd. aryl with R3' = H or R2R2' and/or R3R3' may be -(CH2)- R4 = H, OH or Hal. Sedatives, anti-inflammatory agents, hypotensive agents; Intermediates for drugs.

Description

  

  
 



  Process for the preparation of new 5,6-dihydro-8-H -thiopyrano [4 ', 3': 4,5] thieno [2,3-dlpyrimidines
The invention relates to a process for the preparation of 5,6bDihydro-8H-thiopyranot4 ', 3': 4,5] thieno (2,3-d] pyrimidines of the formula
EMI1.1
 which have an aryl radical in at least one of positions 6 and 8, can be further substituted in positions 2, 5, 6 and 8 and in which n is 0, 1 or 2 and Rz is an amino lower alkylamino group, and their salts.



   The terminal amino group of the aminoalkylamino group in the 4-position can be unsubstituted or substituted. A substituted amino group is preferably an aliphatic amino group, i. an amino group mono- or disubstituted by residues of aliphatic character. Aliphatic hydrocarbon radicals are primarily referred to as radicals of aliphatic character. Examples of substituents of a terminal secondary or tertiary amino group are: lower hydrocarbon radicals of aliphatic character, which are also interrupted in the carbon chain by heteroatoms such as oxygen, sulfur or nitrogen atoms and / or e.g. can be substituted by hydroxyl groups.

  Lower hydrocarbon radicals of aliphatic character as substituents of the terminal amino group are above all alkyl, alkenyl or alkylene radicals containing at most 8 carbon atoms. Residues of this type interrupted by heteroatoms are mainly oxaalkylene, azaalkylene or thiaalkylene radicals.

  Particularly to be mentioned as substituents of the terminal amino group are: methyl, ethyl, allyl, propyl, isopropyl, methallyl, straight or branched butyl, pentyl, hexyl or heptyl radicals, butylene radicals connected at any point. (1.4), pentylene (1.5), hexylene (1.5), hexylene (1.6), hexylene (2.5), heptylene (1.7) -, heptylene- (2.7) -, heptylene- (2.6) -, 3-oxapentylene- (1,5) -, 3-thiapentylene- (1.5) -, 2,4-dimethyl -3-thiapentylene- (1,5) -, 3-aza-pentylene- (1,5) -, 3-lower alkyl-3-aza-pentylene- (1,5) - such as 3-methyl-3-aza-pentylene - (1 , 5) -, 3- (Hydroxy-lower alkyl) -3 -azapentylene- (1,5) - like 3-q3-hydroxyethyl) -3-aza-pentylene- (1,5) -, 3-oxahexylene - (1 , 6) or 3-azahexylene (1,6) radicals.



   In the amino lower alkylamino group in the 4-position, the lower alkylene radical connecting the two nitrogen atoms is in particular a straight or branched alkylene radical with preferably at most 6 carbon atoms, which separates the two nitrogen atoms by 2 to 5, in particular 2 to 3, especially 2, carbon atoms, such as a Ethylene (1,2), propylene (1,3), butylene (1,4), pentylene (1,5), pentylene (2,5), butylene (2, 4), propylene (1,2), propylene (2,3) or butylene (3,4) radical.



   In the aminoalkylamino group mentioned, a substituent of the amino group can also be bonded to the alkylene radical connecting the two nitrogen atoms.



   The nitrogen atom of the aminoalkylamino group located on the pyrimidine ring is preferably unsubstituted, but it can also, e.g. be substituted by a lower alkyl radical such as one of those mentioned.



   The aminoalkylamino group in the 4-position is in particular a mono-lower alkylamino-lower alkylamino group or, above all, a di-lower alkylamino-lower alkylamino group, a pyrrolidino or piperidinone-lower alkylamino group which is optionally C-lower alkylated in the ring and / or a p-monounsaturated pyrrolidino or piperidinone-lower alkylamino group, an optionally C-lower alkylamino group, N ' -Lower alkyl or N '- (hydroxy-lower alkyl) -piperazino, thiomorpholino or morpholino lower alkylamino group, or an N-lower alkylpyrrolidinyl-2- or -3-lower alkylamino or N-lower alkylpiperidyl-2-, -3 or -4-lower alkylamino group, where the nitrogen atom located on the pyrimidine nucleus can also be further substituted by a lower alkyl radical and thus be tertiary.



   The aryl radical in the 6- or 8-position is in particular a phenyl radical which, e.g. as indicated below for the aryl radicals, may be substituted.



   As mentioned, the new compounds can contain further substituents in the 2, 5, 6 and 8 positions.



   In particular, they can carry further substituents in addition to the aryl radical already mentioned in the 6- and / or 8-position. Such substituents are, for example, mono- or divalent, optionally substituted hydrocarbon radicals or heterocyclic radicals. In particular, the following should be mentioned: alkyl radicals, such as lower alkyl radicals, especially those with 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, straight or branched butyl, pentyl or hexyl radicals connected in any position, alkenyl radicals , such as lower alkenyl radicals, e.g. Allyl or methallyl radicals, alkylene radicals such as straight or branched lower alkylene radicals e.g.

  Butylene (1,4), pentylene (1,5) or hexylene (1,6) radicals, or aryl or aralkyl radicals, such as in particular phenyl or phenyl lower alkyl radicals, such as benzyl, phenylethyl or phenylpropyl radicals, where the aromatic parts can also be substituted, or optionally substituted heterocyclic radicals which have a hetero atom, such as Pyridyl residues.

  The following are to be mentioned in particular as substituents of aryl radicals or of the aryl part of aralkyl radicals: lower alkyl radicals, e.g. the lower alkoxy radicals mentioned, such as methoxy, ethoxy, propoxy or butoxy radicals, methylenedioxy groups, halogen atoms such as fluorine, chlorine or bromine atoms, trifluoromethyl groups, hydroxyl groups, nitro groups, amino groups, such as free, mono-lower alkylated or di-lower alkylated amino groups, where the lower alkyl radicals are preferably those mentioned, or acyloxy groups or acylamino groups, in which the acyl radicals are in particular those of saturated carboxylic acids with preferably at most 8 carbon atoms, in particular lower alkanoic acids such as acetic acid, propionic acid or butyric acid, or phenyl lower alkanoic acids such as benzoic acids or phenylacetic acids, which are also e.g.

   as indicated above for the aryl radicals, can be substituted. Substituents on the heterocyclic radicals are primarily lower alkyl radicals, e.g. the mentioned, into consideration.



   The new compounds preferably each contain an aryl radical in positions 6 and 8.



   In the 5-position, the new compounds can in particular be substituted or unsubstituted hydrocarbon radicals, such as phenyl or phenyl lower alkyl radicals, e.g. the mentioned, or especially lower alkyl radicals, e.g. those mentioned.



   Furthermore, the new compounds can also be substituted in the 2 position, in particular by optionally substituted hydrocarbon radicals, such as e.g. lower alkyl, alkenyl or aralkyl radicals, e.g. the mentioned, or by cycloalkyl or cycloalkyl-alkyl radicals, e.g.



  optionally lower alkylated, such as methylated, cyclopropyl, cyclopentyl or cyclohexyl radicals or cyclopropyl, cyclopentyl or cyclohexylmethyl or ethyl radicals.



   The new compounds have valuable pharmacological properties, especially an antibacterial and anti-parasitic effect. In particular, they have an effect against plasmodia, e.g. Plasmodium berghei, as shown in animal experiments, e.g. with oral administration of 4 × 100 to 300 mg / kg (administered on 4 consecutive days) to albino mice, shows. The new compounds are also effective against those strains of plasmodia which are resistant to other agents against malaria, e.g. Primaquine, have shown to be resistant.



  The new compounds can therefore be used as chemotherapeutic agents against malaria, in particular also for prophylaxis. Furthermore, they have, e.g.



  in animal experiments, e.g. can be shown to have an amoebicidal effect on hamsters and can be used accordingly. They also have an anti-inflammatory effect.



   However, the new compounds are also valuable intermediates for the preparation of other useful substances, in particular pharmacologically active compounds.



   The compounds of the general formula deserve special mention
EMI2.1
 where n is 2, 1 or preferably 0, alk is a straight or branched lower alkylene radical which separates Ro from the nitrogen atom in the 4-position by 2 to 5, in particular 2 to 3, especially 2, carbon atoms, Ro is an amino group , preferably a mono-lower alkylamino or in particular a di-lower alkylamino or a lower alkylenamino, oxaalkylenamino, azaalkylenamino or thiaalkyleneamino group, such as an optionally monounsaturated and / or C-lower alkylated piperidino or pyrrolidino group or an optionally C-lower alkylated morpholino group , Thiomorpholino, piperazino, N'-lower alkylpiperazino or N '- (hydroxy-lower alkyl) -piperazino group,

   such as N'-methyl or N '- (i-hydroxyethyl) -piperazino group, R1 denotes a lower alkyl radical or, above all, a hydrogen atom, one of the radicals R and R3 optionally, e.g. as indicated, substituted phenyl radical and the other a lower alkyl radical, an optionally, e.g. Phenyl-lower alkyl or phenyl radical substituted as indicated, an optionally, e.g.

   as indicated, denotes substituted pyridyl radical or a hydrogen atom, R, 'and R3' denote hydrogen atoms, or either R2 and R2, or R3 and R3 'each together is an optionally lower alkylated pentylene (1,5) or butylene (1,4) - represent radical and one of the other two radicals for a hydrogen atom and the other for an optionally for example as indicated, is substituted phenyl radical, R4 is a lower alkyl radical or especially a hydrogen atom and R5 is a lower alkyl radical or, in particular, a hydrogen atom.

 

   Of this group of compounds, the compounds of the general formula Ia in which n, R 1, R4 and R5 have the meanings given, R1, R2 'and R3' are hydrogen atoms and R and R3, which are identical or different, are of very particular importance can be, for optionally by one, two or more lower alkyl radicals, trifluoromethyl groups and / or in particular lower alkoxy groups and / or especially halogen atoms, such as Bromine atoms or especially chlorine atoms, substituted phenyl radicals (at least one substituent preferably being in the p-position).



   The compounds of the general formula deserve special mention because of their good anti-malarial action
EMI3.1
 wherein Ph and Ph 'by one, two or more lower alkoxy groups and / or. Halogen atoms, especially chlorine atoms, represent substituted phenyl radicals (preferably in the p-position), alk represents a straight or branched lower alkylene radical which separates the two nitrogen atoms by 2 to 5, in particular 2 to 3, especially 2, carbon atoms, and RG and R7 are lower alkyl radicals and in particular the compounds of the formula
EMI3.2
 wherein alk 'is a lower alkylene radical having 2 to 3 carbon atoms, in particular the 1,3-propylene or preferably the 1,2-ethylene radical, R6 and R7 are lower alkyl radicals, especially methyl or ethyl radicals, and Hal and Hal' are Fluorine-,

   Bromine or especially chlorine atoms are, and especially the 4-P -diethylaminoäthylamino) -6, 8 -bis- (p-fluorophenyl) -5,6-dihydro-8H-thiopyrnno [4 ', 3': 4,5] thieno [2,3-d] - pyrimidine and above all the cis-4- (p-diethylaminoethylamino) -6,8-bis- (p-chlorophenyl) -5,6-dihydro-8H-thiopyrano! [4 ' , 3 ': 4,5] thieno- [2,3-djpyrimidine, the trans-4- (p-diethylaminoethylamino) -6,8-bis- (p-chlorophenyl) -5,6-dihydro-8H- thiopyranoI4 ', 3': 4,5] thieno- [2,3-d] pyrimidine, and the 4-P-dimethylaminoethylamino) -6, 8-bis- (p-chlorophenyl) -5,6-dihydro-8H -thiopyrano [4 ', 3':

   4,5] thienol2,3-d] - pyrimidine, which, for example, in the form of their dihydrochloride in albino mice, when administered orally on four consecutive days in a dose of 100 mg / kg each, have a marked antimalarial effect.



   The compounds of the general formula are also of importance
EMI3.3
 wherein n, Rl, R2, R2 ', R3, R3', R4 and R5 have the meanings given generally and preferably above, m is 1 or 2 and R is an N-lower alkyl-pyrrolidinyl-2- or -3-radical or a N-lower alkyl-piperidinyl -2-, -3- or -4-radical.



   The process according to the invention for the preparation of the new compounds is characterized in that a 4-Y-5,6-dihydro-8H-thiopyranol4 ', 3': 4,5] thieno [2,3-djpyrimidine of the formula
EMI3.4
 which has an aryl radical in at least one of positions 6 and 8 and can be further substituted in positions 2, 5, 6 and 8, n is an integer from 0 to 2 and Y is a radical that can be exchanged for an amino lower alkylamino group with an amino lower alkylamine of the formula R2, in which Rz has the meaning given.



   A group Y which can be exchanged for an amino lower alkylamino group is above all a reactive esterified or etherified hydroxyl group, an ammonium group, a mercapto group or a sulfonyl group.



   A reactive esterified hydroxyl group is above all a hydroxyl group esterified with a strong inorganic acid, e.g. a halogen atom such as a chlorine or bromine atom, or one with a strong organic acid such as an organic sulfonic acid, e.g. of the p-toluenesulfonic acid esterified hydroxyl group. The etherified hydroxyl groups are primarily lower alkoxy groups, e.g. Methoxy or ethoxy, or aralkoxy groups such as benzyloxy groups into consideration. Particularly suitable ammonium groups are trialkylammonium, such as lower trialkylammonium groups, e.g. the trimethylammonium group. Mercapto groups are in particular free or etherified mercapto groups, such as lower alkyl mercapto, e.g. Methyl mercapto or ethyl mercapto groups, or aralkyl mercapto such as benzyl mercapto groups.

  A sulfonyl group is primarily a lower alkylsulfonyl group such as the methylsulfonyl group.



   The reaction with the amino lower alkylamine can be carried out in a customary manner, expediently at elevated temperature; if desired, an excess of amino lower alkylamine can be used. The reaction can be carried out in the presence or absence of a diluent, if appropriate in a closed vessel under pressure and / or in an inert gas atmosphere. It is advantageous to work among those for analogous reactions in the literature, e.g. in quinazoline chemistry, known conditions.



   In the compounds obtained, in the context of the definition of the end products, substituents can be introduced, modified or split off.



   For example, in 4- (amino lower alkylamino) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4,5] -thiend [2,3-d] pyrimidines which are in at least one of the positions 6 and 8 have an aryl radical and have at least one hydrogen atom on the nitrogen atom in the 4-position or on the nitrogen atom of the terminal amino group of the amino lower alkylamino group, substitute these amino groups, for example by the substituents mentioned for the 4 amino lower alkylamino groups.



   This substitution takes place by reaction with a reactive ester of a corresponding alcohol or with an epoxide or by reductive alkylation. Reactive esters are in particular those with strong inorganic or organic acids, preferably with hydrohalic acids such as chloric, bromine or hydroiodic acid, sulfuric acid or with arylsulfonic acids such as benzene, p-bromobenzene or p-toluenesulfonic acid. The reaction with the reactive ester takes place in the customary manner, advantageously in the presence of a basic condensing agent.



   The reductive alkylation takes place, e.g. by reaction with a corresponding oxo compound, such as a corresponding aldehyde or ketone, and subsequent or simultaneous reduction of the condensation product thus obtained. The oxo compound mentioned can also be used in the form of its reactive functional oxo derivatives, such as acetals, acylals, enol ethers or enol esters. The reduction takes place in the usual way, e.g. with hydrogen in the presence of a catalyst, such as a platinum, palladium or nickel catalyst, or with formic acid. A Schiff base obtained as a condensation product can also be obtained by means of a dichlorometal hydride, e.g. an alkali metal-earth metal hydride, such as sodium borohydride or.



   Lithium aluminum hydride.



   The reactions mentioned are carried out in the customary manner, advantageously under the conditions known for analogous reactions.



   S-unsubstituted compounds obtained can be oxidized to the S-oxides (sulfoxides) or S-dioxides (sulfonates).



   The oxidation to the sulfoxides or sulfones can be carried out in a known manner, e.g. by reaction with an S-oxidizing agent, such as hydrogen peroxide, peracids, such as especially peracetic acid, perbenzoic acids or phthalic monoperacids, which can also be substituted, e.g. by halogen atoms, chromic acid, potassium permanganate, hypohalites, or nitric acid, nitrous gases and the like. Like. Or electrolytically.



  In this reaction, at lower temperatures, i. E. with good cooling, or when using only one molar equivalent of the oxidizing agent, the sulfoxides, while when heating and / or using at least 2 molar equivalents of the oxidizing agent, the sulfones are obtained.



   S-oxides obtained can be oxidized to the S-dioxides. This oxidation takes place in a known manner, e.g. as in the above-described oxidation leading to the dioxides.



   Sulfoxides obtained can be reduced to the corresponding S-unsubstituted compounds, e.g.



  with a reducing agent such as nascent hydrogen, e.g. Zinc and mineral acids such as hydrochloric acid or e.g. with sulfites or hydriodic acid.



   Sulfones obtained can be reduced to the corresponding S-unsubstituted compounds, e.g. by reduction with lithium aluminum hydride. The solvent used is advantageously an ether such as ethyl butyl ether or tetrahydrofuran.



   These subsequent conversions can be carried out individually or in combination and in any order.



   Depending on the process conditions and starting materials, the end products are obtained in free form or in the form of their acid addition salts, which is also included in the invention. For example, basic, neutral or mixed salts, optionally also hemi-, mono-, sesqui- or polyhydrates thereof, can be obtained.



  The acid addition salts of the new compounds can be converted into the free compound in a manner known per se, e.g. with basic agents such as alkalis or ion exchangers. On the other hand, the free bases obtained can form salts with organic or inorganic acids. For the preparation of acid addition salts, those acids are used in particular which are suitable for the formation of therapeutically useful salts.

  Examples of such acids are: hydrohalic acids, sulfuric acids, phosphoric acids, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, succinic, glycolic, lactic, apple and wine -, citric, ascorbic, maleic, hydroxyl maleic or pyruvic acid; Phenylacetic, benzoic, p-aminobenzoic, anthranil, p -hydroxybenzoic, salicylic or p-aminosalicylic acid, emboxylic acid, methanesulphonic, ethanesulphonic, hydroxyethanesulphonic, ethylene sulphonic acid; Halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic acid or sulfanilic acid; Methionine, tryptophan, lysine or arginine.

 

   These or other salts of the new compounds, e.g. the picrates can also be used to purify the free bases obtained by converting the free bases into salts, separating them and in turn freing the bases from the salts. As a result of the close relationships between the new compounds in the free form and in the form of their salts, the free compounds in the preceding and in the following are meaningful and expedient, if appropriate also to mean the corresponding salts.



   The new compounds can, depending on the choice of starting materials and working methods, exist as optical antipodes, racemates or as mixtures of isomers (mixtures of racemates).



   Mixtures of isomers (mixtures of racemates) obtained can be separated into the two stereoisomeric (diastereomeric) pure isomers (racemates) in a known manner, for example by chromatography and / or fractional crystallization, due to the physico-chemical differences between the constituents.



   Racemates obtained can be purified by known methods, for example by recrystallization from an optically active solvent, with the aid of microorganisms, or by reaction with an optically active acid which forms salts with the racemic compound and separation of the salts obtained in this way, e.g.



  due to their different solubilities, decompose into the diastereomers, from which the antipodes can be released by the action of suitable agents. Optically active acids which are particularly common are e.g. the D and L forms of tartaric acid, di-o-toluyl tartaric acid, malic acid, mandelic acid, camphorsulphonic acid or quinic acid. It is advantageous to isolate the more effective of the two antipodes.



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



   The invention also relates to those embodiments of the process in which one starts from a compound obtainable as an intermediate at any stage of the process and carries out the missing process steps, or in which a starting material is formed under the reaction conditions, or in which a reaction component, optionally in the form of it Salts present;
For carrying out the reactions according to the invention, it is expedient to use those starting materials which lead to the groups of end products particularly mentioned at the beginning and especially to the end products specifically described or emphasized.



   The starting materials are known or, if they are new, can be obtained by methods known per se.



   Thus, for example, the 4-halo- or 4-mercapto-5,6-dihydro-8H-thiopyrano [4 ', 3': 4,5] thieno [2,3-d] pyrimidines used as preferred starting materials can be used , which have an aryl radical in at least one of the positions 6 and 8, obtained if one in a corresponding 4-hydroxy-5,6-dihydro-8H-thiopyranotype ', 3': 4,5] thieno [2,3 -d] pyrimidine, which has an aryl radical in at least one of positions 6 and 8, which converts the hydroxyl group into a halogen atom or a mercapto group.



   The conversion of the hydroxyl group into a halogen atom takes place e.g. by treatment with halides of sulfur or especially of phosphorus, e.g. Phosphorus pentachloride, phosphorus oxychloride, phosphorus trichloride or corresponding bromides.



   The conversion of a hydroxyl group into a free mercapto group takes place e.g. by reacting with phosphorus pentasulfide.



   In the compounds obtained which have a halogen atom such as chlorine or bromine in the 4-position, this can be exchanged for etherified hydroxyl groups or, if appropriate, etherified mercapto groups, e.g.



  by reaction with a compound of the formula HZ ', where Z' denotes an etherified hydroxy group or a free or etherified mercapto group. The compound of the formula HZ 'is preferably used in the form of its alkali metal salts or one works in the presence of such salts-forming condensation agents.



   Compounds obtained which have free mercapto groups in the 4-position can be etherified. The etherification takes place e.g. by reaction with hydrohalic acid esters of corresponding alcohols, which is advantageously carried out in the presence of bases or the 4-mercapto compound is used in the form of its alkali metal salts.



   The corresponding 4-ammonium compounds can be obtained by reacting a 4-halogen compound with a tertiary amine such as trimethylamine.



   The 4-hydroxy-5,6-dihydro-8H-thiopyrano t4 ', 3': 4,5] thieno [2,3-d] pyrimidines which have an aryl radical in at least one of the 6 and 8 positions can be obtained if you have a corresponding 2-amino -3-Z "-4,5-dihydro-7H-thieno [2,3-c] thiopyran, which carries an aryl radical in at least one of the positions 5 and 7 and in the Z" a free or a functionally modified carboxyl group having an oxo group, e.g.



  an esterified carboxyl group, such as a carbalkoxy group, or a carbamyl group, with a reactive acid derivative of a carboxylic acid capable of pyrimidine ring closure, such as an ester, amide, a halide (e.g. chloride), imino ether, anhydride, or a nitrile, with the stipulation that at least the radical Z ″ or the functionally modified carboxyl group of the carboxylic acid mentioned has a nitrogen atom.



   The mentioned 2-amino-3-Y "-4,5-dihydro-7H-thieno12,3-c] thiopyrans which have an aryl radical in at least one of the 5 and 7 positions and in which Y" is a free or functionally modified carboxyl group, e.g.



  a group Z ″ or a nitrile group, can be obtained, for example, if a corresponding 2,3,5,6-tetrahydrothiopyran- (4) -one which is substituted in at least one of the positions 2 and 6 by an aryl radical, with a compound of the general formula Y "-CH, -CrN wherein Y" has the meaning given, and simultaneously or subsequently reacts with sulfur.



   The reaction is carried out in the usual way.

 

   Compounds with free carboxyl groups can be used in free form or in the form of their salts with bases, e.g.



  obtained in the form of their salts with organic amines, or their metal salts. Particularly suitable metal salts are alkali metal salts or alkaline earth metal salts, such as sodium, potassium, magnesium or calcium salts.



   The resolution of any mixtures of racemates and / or racemates can be carried out analogously to that described above.



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



   The new compounds can e.g. in the form of pharmaceutical preparations which can be used in free form or in the form of their salts, especially the therapeutically useful salts, in admixture with a e.g. for enteral or parenteral administration suitable pharmaceutical organic or inorganic rule, solid or liquid carrier material. For the formation of the same, substances come into question that do not react with the new compounds, e.g.



  Water, gelatin, lactose, starch, stearyl alcohol, magnesium stearate, talc, vegetable oils, benzyl alcohol, gum, propylene glycol, petroleum jelly, or other known excipients. The pharmaceutical preparations can e.g. as tablets, dragees, capsules, suppositories or in liquid form as solutions (e.g. as elixirs or syrups), suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliary substances, such as preservatives, stabilizers, wetting agents or emulsifiers, solubilizers or salts for changing the osmotic pressure or buffers. They can also contain other therapeutically valuable substances. The pharmaceutical preparations are obtained using conventional methods.



   The new compounds can also be used in veterinary medicine, e.g. in one of the forms mentioned above or in the form of feed or additives for animal feed. E.g. the usual extenders and thinners or feed used.



   The invention is described in more detail in the following examples. The temperatures are given in degrees Celsius.



   example 1
5 g of the stereoisomer with a melting point of 199-2000 of 4-chloro -6,8-diphenyl-5,6-dihydro-8H-thiopyrano [4 ', 3': 4.5] thieno [2,3-d ] pyrimidine are heated with 50 ml of N-diethylaminoethylamine in a 1200 oil bath for 3 hours. It is then evaporated to dryness in vacuo and the residue is dissolved in 300 ml of 0.5N hydrochloric acid with gentle warming. The filtered solution is adjusted to a pH of 8-9 using 2N sodium hydroxide solution, a precipitate separating out, which is suction filtered, washed with water and then recrystallized from ethanol.

  This gives a mixture of the cis and trans forms of 4 - (, 3-diethylamino-ethylamino) -6,8-diphenyl-5,6-dihydro-8H-thiopyrano [4 ', 3': 4.5 ] thienoL2,3-dJpyrimidines of the formula
EMI6.1
 in the form of white crystals from F. 155 - 1600.



   Fractional recrystallization of this product from ethanol gives the two stereoisomers in pure form. They melt at 171-1720 and 161-1620.



   By dissolving the base with a temperature of 171-1720 in the calculated amount of 1N alcoholic hydrochloric acid and adding isopropyl ether until crystallization, the dihydrochloride with a temperature of 167-1700 is obtained. Starting with the base with a temperature of 161-1620, one obtains analogously a dihyirochloride from F. 228-2310 (and decomp.).



   In an analogous manner, from the stereoisomer om F. 200-2010 of 4-chloro-6,8-diphenyl-5,6-dihydro 8H-thiopyran0 [4 ', 3': 4,5] thieno [2,3- dApyrimidine a genic of the stereoisomers of 4 - (- diethylamino-ethyl-mino) -6,8-diphenyl-5,6-dihydro-8H-thiopyrano [4 ', 3': 4.5] - hieno [2,3- d] pyrimidines in the form of white crystals zom F. 155 - 1600.



   The 4-chloro-6,8-dihenyl-5,6-dihydro-811-thiopyrano [4 ', 3': 4,5] thieno [2,3d] pyrimidine used as starting material can e.g. can be obtained as follows:
13.4 g of 2,6-diphenyl - 2,3,5,6 - tetrahydro-thiopyrano-4one, 5.65 g of cyanoacetate, 1.6 g of powdered sulfur and 5 ml of morpholine are suspended in 50 ml of absolute ethanol and during 2 Stirred in a bath of 150 hours. After about 16 hours of standing, the precipitated reaction product is filtered off with suction and washed with ethanol.

  This gives a mixture of the: is and trans forms of 2-amino-3-carbethoxy-5,7-dihenyl-4,5-dihydro-7H-thieno [2,3-c] thiopyran, which is a lot recrystallized from absolute ethanol, forms yellowish crystals of F. 212-2140.



   10 g of a mixture of cis- and trans-2-amino-3-carbethoxy-5,7-diphenyl-4,5-dihydro-7H-thieno [2,3-cj-biopyran are stirred with 50 ml of formamide under nitrogen for 1 hour heated in an oil bath from 180 to 1900.



     After cooling, the precipitate which has separated out is suction filtered and washed with ethanol. For purification, the product obtained is dissolved in 3 parts by volume of hot dimethyl: formamide, clarified with activated charcoal and crystallized 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-thio-3yrano [4 ', 3': 4.5] thieno [2,3- d] pyrimidines from F. 220 to 1250.



   5 g of a mixture of cis- and trans-4-hydroxy-6,8diphenyl-5,6-dihydro-8H-thiopyrano [4 ', 3': 4,5] thieno 2,3-d] pyrimidine are mixed with 50 ml of phosphorus oxychloride Heated for z hours in an oil bath of 1200. The excess phosphorus oxychloride is then evaporated off in a vacuum and ice water is added to the residue, while cooling, so that it solidifies. The product obtained is suction filtered, washed with water and then triturated with Ethasol and filtered off.

  By fractional recrystallization from benzene, the two stereosomers of 4-chloro-6,8-diphenyl-5,6-dihydro-8H-thio? Yrano [4 ', 3': 4.5] thieno [2.3 - d3 pyrimidins run from each other. One form melts at F. 199-2000, the other at 200-2010.



   Example 2
3 g of the stereoisomer of m.p. 199-200 of 4-chloro -6,8-diphenyl-5,6-dihydro-8H-thiopyrano [4 ', 3': 4,5] thieno [2,3-d] pyrimidine are heated with 20 ml of 4-amino-1- (diethyl rmino) pentane in an oil bath of 1200 for 3 hours.

 

  The reaction solution is poured into 300 ml of water and the deposited precipitate is suction filtered. The product obtained is dissolved in 100 ml of 0.5N hydrochloric acid and the filtered solution is adjusted to a pH of 8-9 with 2N sodium hydroxide solution, a solid precipitate separating out, which is filtered off with suction and washed with water. A mixture of the stereoisomeric forms of [- (4-diethylamino-1-methyl-butylamino) -6,8-diphenyl-5,6- .dihydro-8H-thiopyrano [4 ", 3": 4) is obtained by recrystallization from isopropyl ether , 5] thieno'C2,3 -d] pyrimidines of the formula
EMI7.1
 in white crystals of m. 128-1340. The dihydrochloride produced from it melts at 210-2200 (with decomposition).



   Example 3
5 g of the stereoisomer of F. 186-1880 of 4-chloro-6,8-bis (p-chlorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4.5] thieno [2 , 3-d] pyrimidine are heated with 50 ml of 8-diethylamino-ethylamine in an oil bath of 1200 for 3 hours. It is then evaporated to dryness in vacuo and the residue is triturated with water. Recrystallization of the product obtained from benzene gives a mixture of the cis and trans forms of 4- (k-diethylamino-ethylamino) -6,8-bis (p-chlorophenyl) -5,6-dihydro -8H-thiopyranot4 ', 3: 4.5] thieno [2,3 -d] pyrimidine of the formula
EMI7.2
 from F. 220 - 2220 and 204 - 2050.



   In an analogous manner, the stereoisomer of F. 201-2020 of 4-chloro-6,8-bis (p-chlorophenyl) -5,6-dihydro-8H-thiopyranof4 ', 3': 4.5 is obtained ] thieno [2,3-d] - pyrimidine a mixture of the stereoisomers of 4- (fi-diethylamino-ethylamino) -6,8-bis (p-chlorophenyl) -5,6-dihydro-8H-thiopyranol4 '.3': 4,5] thieno [2,3-d] pyrimidines dated February 200-2050.



   By dissolving this mixture of the stereoisomeric bases in the calculated amount of 1-n alcoholic hydrochloric acid and adding isopropyl ether until crystallization, a mixture of the corresponding dihydrochlorides with a melting point of 2300 (u. Decomp.) Can be obtained.



   In an analogous manner, the base of F.



  220-2220 a dihydrochloride with a temperature of 235-2390 (decomp.) And a dihydrochloride with a temperature of 244-2480 from the base with a temperature of 204-2050.



   The 4-chloro-6,8-bis (p-chlorophenyl) -5,6-dihydro-8H-thiopyranol4 ', 3': 4,5] thieno [2,3-d] pyrimidine used as the starting material can e.g. can be produced as follows:
EMI7.3
 from F. 200-2050.



   Fractional recrystallization from ethanol gives the stereoisomers of -diethylamino-ethylamino) -6,8-bis (p-chlorophenyl) -5,6-dihydro-8H-thiopyrano in 4 ', 3': 4.5] in pure form] thieno [2,3-d] pyrimidine of the formula
16.85 g of 2,6-bis (p-chlorophenyl) -2,3,5,6-tetrahydro-thiophyran-4-one, 5.65 g of cyanoacetic ester, 1.6 g of powdered sulfur and 5 ml of morpholine suspended in 50 ml of absolute ethanol and stirred for 2 hours in a bath of 450 and then for 4 more hours at room temperature. The precipitated reaction product is suction filtered, triturated with ethanol and suction filtered again.



  A mixture of the cis and trans forms of 2-amino-3-carbethoxy -5,7- bis (p-chlorophenyl) -4,5-dihydro-7H-thieno [2,3-c ] thiopyrans, which recrystallized from absolute ethanol, has a F. of 90-1000 and forms yellowish crystals.



   10g of the mixture of cis- and trans-2-amino-3-carbethoxy-5,7-bis (p-chlorophenyl) -4,5-dihydro-7H-thie- no [2,3-c] thiopyran are with 50 ml of formamide heated from 180 to 1900 under nitrogen for 4 hours while stirring in an oil bath. After cooling, the precipitate is filtered off with suction and washed out with ethanol.



  For purification, the product obtained is dissolved in 2 parts by volume of hot dimethylformamide, clarified with activated charcoal and crystallized by adding 6 parts by volume of ethanol. A mixture of the cis and trans forms of 4-hydroxy-6,8-bis (p-chlorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4.5] thienol2 is obtained in this way , 3 -d] pyrimidines, F. 2600.



   5 g of cis- and trans-4-hydroxy-6,8-bis (p-chlorophenyl) -4,6-dihydro-8H-thiopyrano [4 ', 3': 4,5] thieno '[2,3- d] pyrimidine are heated with 50 ml of phosphorus oxychloride for 2 hours in a 1200 oil bath. The excess phosphorus oxychloride is then evaporated in vacuo, and ice water is added to the residue while cooling.



  The solid precipitate obtained in this way is suction filtered, triturated with ethanol and suction filtered again.



  By fractional recrystallization of the product obtained from benzene, the two stereoisomers of 4-chloro-6,8-bis (p-chlorophenyl) -5,6-dihydro-8H-thiopyranot4 ', 3': 4.5] Separate thieno [2,3-dEpyrimidines. One shape melts at 186-1880, the other at 201 by 2020.



   Example 4 3 g of the stereoisomer of F. 186-1880 of 4-chloro-6,8-bis (p-chlorophenyl) -5,6-dihydro-8H-thiopyra n6 [4 ', 3': 4.5] thieno [2,3-d] pyrimidine are heated with 20 ml of 4-amino-l - (diethylamino) pentane in a 1200 oil bath for 3 hours. The reaction solution is poured into 300 ml of water, a semi-solid precipitate separating out, which is separated off and dissolved in 100 ml of 0.5N hydrochloric acid. The filtered hydrochloric acid solution is adjusted to a pH value of 8-9 with 2N sodium hydroxide solution and then extracted with ether. After drying the ethereal solution and evaporation of the ether, a solid residue is obtained, which is recrystallized 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 [4 ', 3 ': 4,5] thieno [2,3-d] pyrimidine of the formula
EMI8.1
 F. 100140o.



   The hydrochloride produced from it melts at 200-2150 (u. Decomp.).



   In an analogous manner, from the stereoisomer of F. 201-2020 of 4-chloro-6,8-bis (p-chlorophenyl) - -5,6 - dihydro - 8H - thiopyranof4 ', 3': 4.5] thieno [2,3-dJpyr- imidine a mixture of the stereoisomers of 4- (4-diethylamino- 1-methyl-butylamino) -6,8 -bis- (p-chlorophenyl) -5,6 dihydro-8H-thiopyranol4 ' , 3 ': 4,5] thieno [2,3-dApyrimidins of m. 100-1400.



   Example 5 4.6 g of the stereoisomer of mp 186-1880 of 4-chloro-6,8-bis (p-chlorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4 , 5] thieno [2,3-d] pyrimidines are dissolved in 150 ml of absolute toluene and heated to boiling with 2.8 g of γ-diethylamino-propylamine for 3 hours with stirring. It is then evaporated to dryness in vacuo and the residue is triturated with water.

  Recrystallization of the product obtained from ethanol gives the pure stereoisomer of mp 173-1740 of 4- (Y-diethylamino-propylamino) -6,8-bis (p-chlorophenyl) -5,6-dihydro-8H - thiopyrano [4 ', 3': 4.5] thieno [2,3-d] pyrimidine of formula
EMI8.2
 in the form of white crystals.



   By dissolving the base in the calculated amount of l-n ethanolic hydrochloric acid and adding isopropyl ether until crystallization occurs, the dihydrochloride from F.

 

  1800 (under decomposition) preserved.



   Example 6 4.6 g of the stereoisomer of F. 186-1880 des 4 -chloro-6,8-bis (p-chlorophenyl) -5,6-dihydro-8H-thiopyra no [4 ', 3': 4, 5] thieno [2,3-d] pyrimidines are dissolved warm in 150 ml of absolute toluene and heated to the boil for 3 hours with the addition of 2.2 g -dimethylamino-ethylamine. It is then evaporated to dryness in vacuo and the residue is triturated with water.



  Recrystallization of the product obtained from ethanol gives the pure stereoisomer with a melting point of 208 to 2090 of 4- (k-dimethylamino-ethylamino) -6,8-bis (p-chlorophenyl) -5,6-dihydro-8H - thiopyrano [4 ', 3': 4.5] thieno [2,3-d] pyrimidine of the formula
EMI8.3
 in the form of white crystals.



   By dissolving the base in the calculated amount of 1-N ethanolic hydrochloric acid and adding isopropyl ether until crystallization occurs, the dihydrochloride from F.



  260-2620 received. The bis-methanesulfonate melts at 1550.



   The dihydrochloride of the other isomer (trans form), which can be prepared in an analogous manner starting from the trans isomer, melts at a melting point of 258-2600.



   Example 7 4.6 g of the stereoisomer of F. 186-1880 of 4 -chloro-6,8-bis (p-chlorophenyl) -5,6-dihydro-8H-thiopyra no [4 ', 3': 4, 5] thieno [2,3-dpyrimidines are dissolved warm in 150 ml of absolute toluene and heated to boiling with 4.0 g of γ-dibutylamino-propylamine for 3 hours while stirring. It is then evaporated to dryness in vacuo and the residue is triturated with water. Recrystallization of the product obtained from ethanol gives the pure stereoisomer of mp 183-1840 of 4- (γ-dibutylamino-propylamino) -6,8-bis (p-chlorophenyl) -5,6-dihydro-8H - thiopyrano [4 ', 3': 4.5] thieno [2,3-d] pyrimidine of formula
EMI9.1
 in the form of white crystals.



   Example 8 4.6 g of the stereoisomer of m. 201-2020 des 4 -chloro-6,8-bis- (p-chlorophenyl) .5,6-dihydro-8H-thiopyra not4 ', 3': 4.5] pyrimidines are dissolved warm in 150 ml of absolute toluene and mixed with 3.5 g of N - (- diethylaminoethyl).



  ethylamine heated to boiling for 3 hours with stirring.



  It is then evaporated to dryness in a vacuum. The residue is triturated with water and left to stand until it solidifies. Recrystallization from isopropyl ether-petroleum ether gives one stereoisomer of 4- [N---diethylaminoethyl) -ethylamino] -6,8-bis (P-chlorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4,5] thie.



     no [2,3.d] pyrimidines of the formula
EMI9.2
 in the form of white crystals from F. 115 - 1170.



   Example 9
2.5 g of 4-chloro-6,8-bis- (p-tolyl) -5,6-dihydro-8H-thio pyrang [4 ', 3': 4.5] thieno [2,3-d] pyrimidine are dissolved warm in 50 ml of absolute toluene and heated to boiling with 1.7 g -diethyl-amino-ethylamine for 3 hours with stirring. It is then evaporated to dryness in vacuo and the residue is triturated with water. Recrystallization of the product obtained from ethanol gives 4- (p-diethylamino-ethylamino) -6,8-bis (p -tolyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4, 5] thieno [2,3-d] pyrimidine of the formula
EMI9.3
 in the form of white crystals from F. 178 - 1810.



   By dissolving the base in the calculated amount of 1-n ethanolic hydrochloric acid and adding isopropyl ether until crystallization, the dihydrochloride with a melting point of 215-2200 is obtained.



   The 4-chloro-6,8-bis (p-tolyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4,5] thieno- [2,3.djpyrimidine used as starting product can e.g. can be produced as follows:
130 g of 1,5-bis- (p-tolyl) -penta-1,4-dien-3-one and 115 g of anhydrous sodium acetate are heated to the boil in 3.5 liters of 90% ethanol with stirring. A vigorous stream of hydrogen sulfide gas is then passed in for 7 hours. After cooling, a stream of air is passed through for a short time and then 2 liters of water are added. The mixture is stirred for a further 3 hours and then the precipitate formed is filtered off with suction. Recrystallization from ethanol gives 2,6-bis (p -tolyl) -2,3,5,6-tetrahydro-thiopyran-4-one in the form of white crystals with a melting point of 127-1300.



   29.6 g of 2,6-bis (p-tolyl) -2,3,5,6-tetrahydro-thiopyran-4-one, 11.3 g of cyanoacetate, 3.2 g of powdered sulfur and 10 ml of morpholine are in Suspended 100 ml of absolute ethanol and stirred for 4 hours in a bath of 50 and then for 8 more hours at room temperature.



  The precipitated reaction product is filtered off with suction.



  Recrystallization from ethanol gives 2-amino-3-carbethoxy-5,7 - bis - (p-tolyl) -4,5-dihydro-7H-thienol2,3-c] thiopyran with a melting point of 158-1600.



   10 g of 2-amino-3-carbethoxy-5,7-bis (-p-tolyl) -4,5-dihydro-7H-thienot2,3-c] thiopyran are stirred with 100 ml of formamide under nitrogen for 6 hours heated in an oil bath from 180-1900. After cooling, the precipitate is filtered off with suction and washed out with ethanol. Recrystallization of the product obtained from ethanol gives 4-hydroxy-6,8-bis - (p-tolyl) -5,6-dihydro-8H-thiopyran6 [4 ', 3': 4,5] thienot2, 3-d] pYrimidin from F. 212-2150.



   5 g of 4-hydroxy-6,8-bis- (p-tolyl) -5,6-dihydro-8H-thio pyrano [4 ', 3': 4,5] thieno, 3-d] pyn.midin are mixed with 50 ml of phosphorus oxychloride heated in an oil bath of 1200 for 2 hours. The excess phosphorus oxychloride is then evaporated in vacuo, and ice water is added to the residue while cooling. By fractional recrystallization of the residue obtained in this way from ethyl acetate, the two stereoisomers of 4-chloro -6.8-bis (p-tolyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4.5] - Separate thieno [2,3-d] pyrimidino. One shape melts at 248 - 2490, the other at 145 - 1470.



   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 150ml of absolute toluene and heated to boiling with 2.9 g of 3-diethylaminoethylamine for 3 hours with stirring. It is then evaporated to dryness and the residue is rubbed with water.

  By boiling the product obtained with ethanol, the 4- (p-diethylamino-ethylamino) -6,8-bis - (p-methoxyphenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4, 5] thieno [2,3-d] pyrimidine of the formula
EMI10.1
 in the form of white crystals from F. 175 - 1800
By dissolving the base in the calculated amount of 1N ethanolic hydrochloric acid and adding ethyl acetate and isopropyl ether until crystallization occurs, the dihydrochloride is obtained with a temperature of 218-2200.



   The starting product used is 4-chloro-6,8-bis (p-methoxyphenyl-5,6-dihydro-8H-thiopyrano "[4 ', 3': 4,5] -thieno [2,3-d] pyrimidine can e.g. be produced as follows:
32.8 g of 2,6-bis- (p-methoxyphenyl) -2,3, 5,6-tetrahydro-thiopyran-4-one, 11.3 g of cyanoacetic ester, 3.2 g of powdered sulfur and 10 ml of morpholine Stirred in 150ml of absolute ethanol for 8 hours in a bath of 500 and then for 4 more hours at room temperature. A solid product crystallizes out of the reaction solution when rubbed, which is suction filtered and boiled with ethanol. The 2-amino-3-carbethoxy-5,7-bis (p-methoxyphenyl) -4,5-dihydro-7H-thieno [2,3-c] thiopyran with a melting point of 170-1800 is obtained in this way.



   25 g of 2-amino-3-carbethoxy -5,7- bis (p-methoxyphenyl) -4,5-dihydro-7H-thieno [2,3-c] thiopyran are stirred with 250 ml of formamide under nitrogen for 6 hours heated in an oil bath from 180-1900. The reaction mixture obtained after cooling is suction filtered and boiled with ethanol. This gives 4-hydroxy-6,8-bis (p-methoxyphenyl) -5,6-dihydro-8H-thiopyra- no [4 ', 3': 4.5] thieno [2,3-d] pyrimidine with a temperature of 240-2500 with decomposition.



   9 g of 4-hydroxy-6,8-bis- (p-methoxyphenyl) -5,6-dihydro- - 8H-thiopyrano [4 ', 3': 4,5] thieno [2,3-d] pyrimidine are mixed with 90 ml of phosphorus oxychloride heated in an oil bath of 1200 for 2 hours. It is then evaporated to dryness in vacuo, and ice water is added to the residue.



  After filtering off the reaction product with suction and boiling it with ethanol, 4-chloro-6,8-bis (p-methoxyphenyl) -5,6-dihydro-8H-thiopyrano ', 3': 4,5] thieno- [2, 3-d] pyrimidine from F. 175 - 1850 (and decomp.).

 

   Example 11
2.9 g of 4-chloro-6,8-bis (3,4,5-trimethoxyphenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4.5] thieno [ 2,3-d] pyrimidine are suspended in 250 ml of absolute toluene and heated to boiling with 3.0 g of B-diethylaminoethylamine for 3 hours while stirring. The hot reaction solution is clarified with activated charcoal and evaporated to dryness in vacuo. The residue is rubbed with isopropyl ether until it solidifies and then recrystallized from ethanol. This gives 4- (M-diethylamino-ethylamino) -6,8-bis (3,4,5-trimethoxyphenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4,5] thiend [2,3-d] pyrimidine of the formula
EMI10.2
 from F. 182 - 1850.



   The 4-chloro-6,8-bis (3,4,5-trimethoxyphenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4.5] thieno '[2 , 3-d] pyrimidine can, for example can be produced as follows:
28.5 g of 1,5-bis- (3,4,5-trimethoxyphenyl) -penta-1P- -dien-3-one 17 g of anhydrous sodium acetate are heated to the boil in 2 liters of 90% methanol with stirring. By introducing a stream of hydrogen sulfide gas for 7 hours and then adding 2 liters of water while cooling, after recrystallization from 50% methanol, the 2,6-bis (3,4,5-trimethoxyphenyl) -2,3, 5,6-tetrahydro-thiopyran -4-one in the form of white crystals from F. 174 - 1750.



   22.4 g of 2,6-bis- (3,4,5-trimethoxyphenyl) -2,3,5,6-tetrahydro-thiopyran-4-one, 5.65 g of cyanoacetic ester, 1.6 g of powdered sulfur and 5 ml of morpholine are suspended in 100 ml of absolute ethanol and stirred for 4 hours in a bath of 500 and then for 10 more hours at room temperature. The precipitated reaction product is filtered off with suction and boiled with ethanol.

  He counts the 2-amino-3-carbethoxy-5,7-bis (3, 4,5-trimeth-) xyphenyl) - 4,5 - dihydro-7H-thieno [2,3-c] thiopyran from :: 202-2030
10 g of 2-amino-3-carbethoxy-5,7-bis (3,4,5-trimethoxy) henyl) -4,5-dihydric-7H-thienot2,3-c] thiopyran are added to j0 ml of formamide Nitrogen heated for 6 hours with stirring in an oil bath from 180 to 1900. After cooling, the reaction product is suction filtered and recrystallized from dimethylformamide-ethanol.

  The -hydroxy-6,8-bis (3,4,5-trimethoxyphenyl) -5,6-dihydro 8H-thiopyrano [4 ', 3': 4,5] thienof2,3-d] pyrimidine is obtained in this way F.



     255-2600.



   7 g of 4-hydroxy-6,8-bis (3, 4,5-trimethoxyphenyl) -5,6-di-hydro-8H-thiopyrano, 3 ': 4,5] thieno [2,3-d] pyrimidine are heated with 70 ml of phosphorus oxychloride in an oil bath of 1200 for 2 hours. The excess phosphorus oxychloride is evaporated off in vacuo, and ice water is added to the residue. This gives 4-chloro-6,8-bis (3,4,5-trimethoxyphenyl) -5,6-dihydro-8H-thiopyrano [4 ', -3': 4.5] thieno [2.3 -d] pyrimidine of F. 255-2600C (u.



  Dec.).



   Example 12
8 g of 4-chloro-6,8-bis (p-fluorophenyl) -5,6-dihydro-8H-thiopyranoC4 ', 3': 4.5] thiendC2,3-dJpyrimidine are dissolved in 100 ml of absolute toluene and warm heated to boiling with 7.0 g of p- diethylamino-ethylamine for 3 hours with stirring. It is then evaporated to dryness in vacuo and the residue is rubbed with 50% strength aqueous ethanol.

  Recrystallization of the product obtained from ethanol gives 4- (1,8-diethylamino-ethylamino) -6,8-bis (p-fluorophenyl) -5,6-dihydro-8H-thiopyranot4 ', 3 ': 4,5] thieno [2,3-d] pyrimidine of the formula
EMI11.1
 in the form of white crystals from F. 164 - 1680
By dissolving the base in the calculated amount of l-n ethanolic hydrochloric acid and adding isopropyl ether until crystallization occurs, the dihydrochloride from F.



  208 - 2100 received.



   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 material can eg can be produced as follows:
79 g of 1,5-bis (p-fluorophenyl) -penta-1,4-dien-3-one and 80 g of anhydrous sodium acetate are heated to the boil in 2 liters of 907% ethanol while stirring. By introducing a hydrogen sulfide gas stream for 6 hours and then gradually adding 2 liters of water with cooling, after recrystallization from ethanol, the 2,6-bis- (p-fluorophenyl) -2,3,5,6-tetrahydro-thiopyran- 4-on from F. 125 - 1260.



   30.4 g of 2,6-bis (p-fluorophenyl) -2,3,5,6-tetrahydro-thiopyran-4-one, 11.3 g of cyanoacetic ester, 3.2 g of powdered sulfur and 10 ml of morpholine are suspended in 100 ml of absolute ethanol and stirred for 4 hours in a bath of 500 and then for a further 8 hours at room temperature. After filtering off the reaction product with suction and recrystallization from absolute ethanol, 2-amino-3-carbethoxy-5,7-bis (p-fluorophenyl) -4,5-dihydro-7H-thieno [2,3-c] thiopyran vom F. 161-1620.



   26 g of 2-amino-3-carbethoxy-5,7-bis (p-fluorophenyl) -4,5-dihydro-7H-thienof2,3 -c] thiopyran are mixed with 130 ml of formamide under nitrogen for 4 hours while stirring in a Oil bath heated from 180 to 1900. The reaction product is suction filtered and recrystallized from ethanol.



  This gives 4-hydroxy-6,8-bis (p-fluorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4,5] thieno [2,3-d] pyrimidine vom F. 255-2600.

 

   10 g of 4-hydroxy 6,8 bis - (p-fluorophenyl) -5,6-dihydro -8H-thiopyrano [4 ', 3': 4.5] thieno [2,3-d] pyrimidine are mixed with 100 ml of phosphorus oxychloride Heated for 2 hours in an oil bath of 1200. The excess phosphorus oxychloride is then evaporated off in vacuo, and ice water is added to the residue. The precipitate obtained is filtered off with suction, triturated with ethanol and recrystallized from ethanol. This gives 4-chloro-6,8-bis (p -fluorophenyl) -5,6-dihydro-8H-thiopyrano t4 ', 3': 4,5] thieno [2,3-d] pyrimidine from F. 160-1610.



   Example 13
2.3 g of 4-chloro-6,8-bis (o-chlorophenyl) -5,6-dihydro-8H- -thiopyrano ', 3': 4,5] thieno [2,3-d] pyrimidine are in 150ml of absolute toluene dissolved warm and heated with 1.5 g of p-diethylamino-ethylamine for 3 hours with stirring to the boil. It is then evaporated to dryness in vacuo and the residue is triturated with water.



  The product thus obtained is recrystallized from ethanol. The 4-63-diethylamino-ethylamino) -6,8-bis (o-chlorophenyl) -5,6-dihydro-8H-thiopyrano ', 3': -4, Slthieno [2,3-d ] pyrimidine of the formula
EMI12.1
 in the form of white crystals from F. 240-2450
The 4-chloro-6,8-bis (o-chlorophenyl) -5,6-dihydro-8H thiopyrano [4 ', 3': 4,5] -thieno [2,3-dpyrimidine used as starting product can e.g. can be produced as follows:
80 g of 1,5-bis (o-chlorophenyl) -penta- 1, 4-dien-3-one and 65 g of anhydrous sodium acetate are heated to the boil in 3 liters of 90% ethanol with stirring.

  By introducing a hydrogen sulfide gas stream for 6 hours and then adding 2 liters of water while cooling, the 2,6-bis- (o-chlorophenyl) -2,3,5,6-tetrahydro-thiopyran- is obtained after recrystallization from ether 4-on from F. 120 - 1220
16.8 g of 2,6-bis (o-chlorophenyl) -2,3,5,6-tetrahydro-thiophyran-4-one, 5.65 g of cyanoacetic ester, 1.6 g of powdered sulfur and 5 ml of morpholine are stirred in 50 ml of absolute ethanol for 5 hours in a bath of 500 and then for 8 more hours at room temperature. After filtering off the reaction product with suction and recrystallizing it from ethanol, 2-amino-3-carbethoxy -5; 7-bis- (o-chlorophenyl) -4,5-dihydro-7H-thieno [2,3-c] thiopyran is obtained from F. 166 - 1670.



   5 g of 2-amino-3-carbäthoxy-5,7-bis (o -chlorophenyl) -4,5- -dihydro-7H-thieno [2,3-c] thiopyran are mixed with 50 ml of formamide under nitrogen for 4 hours Oil bath heated from 180 to 1900 with stirring. After filtering off the reaction product with suction and recrystallizing it from dimethylformamide-ethanol, 4-hydroxy-6,8-bis (o -chlorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4.5] thie is obtained - nol2,3-d] pyrimidine with a melting point of 290-3000 (u. decomp.).



     6 g of 4- hydroxy-6,8-bis (o-chlorophenyl) -5,6-dihydro- -8H-thiopyranof4 ', 3': 4,5] thieno [2,3-d] pyrimidine are mixed with 60 ml of phosphorus oxychloride Heated for 2 hours in the bath of 1200. The excess phosphorus oxychloride is evaporated off in vacuo and the residue is mixed with ice water. After recrystallization of the reaction product obtained in this way from benzene, the 4-chloro-6,8-bis (o-chlorophenyl) -5,6-dihydro-8H-thiopyranol4 ', 3': 4.5] thieno [2, 3-d] pyrimidine of m.p. 250-2520.



   Example 14
14g of 4-chloro-6,8-bis- (m-chlorophenyl) -5,6-dihydro-8H- -thiopyrano [4 ', 3': 4.5] thieno [2,3-dapyrimidine are dissolved in 400 ml of absolute toluene Dissolved warm and heated to boiling with 8.0 g of p-diethylamino-ethylamine for 3 hours with stirring. It is then evaporated to dryness in vacuo and the residue is triturated with water.



  Recrystallization of the product obtained from ethanol gives 4- (p-diethylamino-ethylamino) -6,8-bis (m-chlorophenyl) -5,6-dihydro-8H-thiopyranot4 ', -3': 4.5 ] thieno [2,3-d] pyrimidine of the formula
EMI12.2
 in the form of white crystals from F. 178 - 1800.



   By dissolving the base in the calculated amount of 1 -n ethanolic hydrochloric acid and adding isopropyl ether until crystallization occurs, the dihydrochloride from F.



     238 - 2400 (and decomp.) 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 material can e.g. can be produced as follows:
90 g of 1,5-bis (m-chlorophenyl) penta- 1, 4-dien-3-one and 80 g of anhydrous sodium acetate are heated to the boil in 3 liters of 90% ethanol with stirring. By introducing a hydrogen sulfide gas stream for 6 hours and then adding 2 liters of water with cooling, 2,6-bis- (m-chlorophenyl) -2,3,5,6-tetrahydro-thiopyrano-4 is obtained after recrystallization from ethyl acetate -on in the form of white crystals from F. 166 - 1670.



   16.8 g of 2,6-bis (m-chlorophenyl) -2,3,5,6-tetrahydro-thio pyran-4-one, 5.65 g of cyanoacetic ester, 1.6 g of powdered sulfur and 5 ml of morpholine suspended in 100 ml of absolute ethanol and stirred for 5 hours in a bath of 500 and then for 8 more hours at room temperature. After the reaction product has been filtered off with suction and recrystallized from ether, the 2-amino-3-carbethoxy -5,7-bis (m-chlorophenyl) -4,5-dihydro-7H-thie no [2,3-c] thiopyran from F. 145 - 1490.



     5 g of 2-amino -3-carbäthoxy-5,7-bis (m-chlorophenyl) -4,5-dihydro-7H-thieno [2,3-d] thiopyran are stirred with 50 ml of formamide under nitrogen for 4 hours heated in an oil bath from 180-1900. After the reaction product has been filtered off with suction and recrystallized from dimethylformamide-ethanol, 4-hydroxy-6,8-bis (m-chlorophenyl) 5,6-dihydro-8H-thiopyrano [4 ', 3': 4.5] -thieno is obtained [2,3-d] pyrimidine of m.p. 224-226.



   4 g of 4-hydroxy -6,8- bis - (m-chlorophenyl) -5,6-dihydro -8H-thiopyranol4 ', 3': 4,5] thieno [2,3-d] pyrimidine are mixed with 40 ml of phosphorus oxychloride Heated for 2 hours in an oil bath of 1200. The excess phosphorus oxychloride is then evaporated off in vacuo, and ice water is added to the residue. The precipitate obtained is filtered off with suction and washed with water. Recrystallization from benzene petroleum ether gives 4-chloro-6,8-bis (m-chlorophenyl) -5,6-dihydro-8H-thiopyra no [4 ', 3': 4.5] thieno [2, 3-d] pyrimidine of F. 214-2150.



   Example 15
3.6 g of 4-chloro-6,8-bis (2,4dichloro-phenyl) -5,6-dihydro-8H-thiopyranof4 ', 3': 4.5] thieno [2,3-d] pyrimidine are dissolved warm in 60 ml of absolute toluene and heated to boiling with 2.0 g of - diethylamino-ethylamine for 3 hours with stirring. It is then evaporated to dryness in vacuo and the residue is triturated with water.



  Recrystallization of the product obtained from benzene gives 4- (k-diethylamino-ethylamino) -6,8-bis (2,4-dichlorophenyl) -5,6-dihydro-8H-thiopyrano 14 ', 3': 4,5] thieno [2,3-d] pyrimidine of the formula
EMI13.1
 in the form of white crystals from F. 234 - 2420.



   The 4-chloro-6,8-bis- (2,4-dichlorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4.5] thienof2,3-d] pyrimidine used as the starting material can eg can be produced as follows:
29 g of 1,5 - bis - (2,4-dichlorophenyl) penta-1,4-dien-3-one and 25 g of anhydrous sodium acetate are heated to the boil in 1 liter of 90% ethanol with stirring.



  By introducing a hydrogen sulfide gas stream for 5 hours and adding 500 ml of water with cooling, 2,6-bis- (2,4-dichlorophenyl) -2,3,5,6-tetrahydro-thiopyran is obtained after recrystallization from ethyl acetate -4-on in the form of white crystals from F.



  167-1700.



   20.3 g of 2,6-bis - (2,4-dichlorophenyl) -2,3,5,6-tetrahydro-thiopyran-4-one, 5.65 g of cyanoacetic ester, 1.6 g of powdered sulfur and 5 ml Morpholine are suspended in 100 ml of absolute ethanol and stirred for 6 hours in a bath of 500 and then for 8 more hours at room temperature. The reaction product is suction filtered and recrystallized from ethanol. This gives 2-amino -3-carbethoxy-5,7-bis (2,4-dichlorophenyl) -4,5-dihydro-7H-thieno [2,3-c] thiopyran with a melting point of 140 to 1600.



   10 g of 2- amino -3-carbäthoxy-5,7-bis (2,4-dichlorophenyl) -4,5-dihydro-7H-thienot2,3-c] thiopyran are mixed with 100 ml of formamide under nitrogen for 6 hours Stir in an oil bath heated from 180-1900. After filtering off the reaction mixture with suction and boiling it with ethanol, 4-hydroxy-6,8-bis (2,4-dichlorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4.5] is obtained ] thieno [2,3 -d] pyrimidine, m.p. 2850 (u. decomp.).



   4g of 4-hydroxy-6,8-bis- (2,4-dichlorophenyl) -5,6-dihydro- -8H-thiopyrano [4 ', 3': 4,5] thieno [2,3 -d] pyrimidine heated with 40 ml of phosphorus oxychloride in an oil bath of 1200 for 2 hours. It is then evaporated to dryness in vacuo, and ice water is added to the residue.



  Recrystallization of the product thus obtained from ethyl acetate gives 4-chloro-6,8-bis- (2,4-dichlorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4.5 ] thieno [2,3-d] - pyrimidine of m. 245-2470.



   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 p-diethylamino-ethylamine at room temperature. The solution is immediately poured into 1/2 liter of water and the precipitate which has separated out is suction filtered. Recrystallization from ethanol gives the 4th (p-diethylamino-ethylamino) -6,8-bis (p-chlorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4 , 5] thieno [2,3-d] pyrimidine-7-oxide of the formula
EMI13.2
 in the form of white crystals from F. 205 - 2070.



   The 4-chloro-6,8-bis - - chlorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4,5] -thieno [2,3-d] pyrimidine-7 used as starting product -oxide can for example can be produced as follows:
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, while stirring, a solution of 1.9 g of 85% strength m-chloroperbenzoic acid in 100 ml of methylene chloride is added within 45 minutes. The mixture is left to stir for a further 2 hours at room temperature and the reaction solution is then extracted 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. This gives 4-chloro-6,8-bis (p-chlorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4.5] thieno [2,3-d ] pyrimidine-7-oxide, mp 210-2150 (under decomposition).



   Example 17 3.5 g of 4 - C h l o r - 6.8 chloro-6,8-bis- (p-chlorophenyl) -5,6-dihydro-8H.



  -thiopyrano [4 ', 3': 4.5] thieno [2,3-d] pyrimidine-7,7-dioxide are dissolved in 200 ml of hot absolute toluene and 2.0 g of 4-diethylamino-ethylamine for 3 hours heated to the boil with stirring. You then steam in the Va.



  kuum to dryness and rub the residue with water until it solidifies. Recrystallization from ethanol gives 4- (A-diethylamino-ethylamino) -6,8-bis- (p-chlorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': -4.5 ] thieno [2,3-d] pyrimidine-7,7-dioxide of the formula
EMI14.1
 in the form of white crystals from F. 234-2360.



   The 4-chloro-6,8-bis - - chlorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4,5] -thieno [2,3-d] pyrimidine-7 used as starting material , 7-dioxide can, for example can be produced as follows:
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 4.4 g of 85% strength m-chloroperbenzoic acid are added while stirring. The mixture is left to stir for a further 3 hours at room temperature and the methylene chloride solution is then shaken thoroughly with 100 ml of 0.5 N sodium hydroxide solution. The methylene chloride solution is separated off, dried and evaporated to dryness in vacuo. The residue crystallizes on trituration with 50 ml of ethanol. The product thus obtained is briefly boiled in benzene.

  This gives 4-chloro-6,8-bis (p-chlorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4,5] thieno [2,3-d] pyrimidine- 7,7-dioxide in the form of white crystals from F. 280 - 2850 (u. Decomp.).



   Example 18
13.9 grams of cis -4-chloro-6,8-bis (p -chlorophenyl) -5,6-dihydro -8H-thiopyrano [4 ', 3: 4.5] thieno [2,3-d] pyrimidine are dissolved warm in 300ml of absolute toluene and heated to boiling with 8.6g of p-morpholinoethylamine for 3 hours while stirring. It is then evaporated to dryness in vacuo and the residue is triturated with water.



  Boiling the product obtained with ethanol gives the ice-4- (ss-morpholino-ethylamino) -6,8-bis- - chlorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4, 5] thieno [2,3-dipyrimidine of the formula
EMI14.2
 in the form of white crystals from F. 228 - 2300.



   Example 19
5.15 g of cis -4-chloro-6,8-bis- (p-fluorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4.51thieno [2.3: 4.5 ] thieno [2,3-d] pyrimidine are dissolved warm in 100 ml of absolute toluene and heated to boiling with 2.4 g, 13-dimethylaminoethylamine for 3 hours with stirring. It is then evaporated to dryness in vacuo and the residue is triturated with water.



  Recrystallization of the product obtained from absolute ethanol gives cis-4- (fi-dimethylamino-ethylamino) -6,8-bis- (p-fluorophenyl) -5,6-dihydro-8H-thiopyrano [4 '3': 4.5] thieno [2,3-d] pyrimidine of the formula
EMI14.3
 in the form of white crystals from F. 196 - 1970.



   The dihydrochloride of this compound melts at 2400 (and decomposition) and the bismethanesulfonate at 188 to 1900.



   Example 20
4.7 g of trans - 4-chloro-6,8-bis- (p-fluorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4.5] thieno [2,3-d] pyrimidine are dissolved warm in 150ml absolute toluene and heated to boiling with 2.3 g ** - dimethylaminoethylamine for 3 hours with stirring. It is then evaporated to dryness in vacuo and the residue is triturated with water.



  The product obtained is recrystallized from absolute ethanol. The trans-4- (8-dimethylamino-ethylamino) -6,8-bis (p-fluorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4.5] is obtained in this way ] thieno [2,3-dapyrimidirl of the formula
EMI15.1
 in the form of white crystals from F. 183 - 1840.



   The dihydrochloride of this compound melts at 2450 (dec.) And the bismethanesulfonate at 1400.



   The pure trans and cis forms of 4-chloro-6,8-bis (p-fluorophenyl) -5,6- -dihydro-8H-thiopyrano [4 '3': 4,5] thieno [2, 3-d] pyrimidines can be produced as follows:
27.5 g of a mixture of the two stereoisomers of 4-chloro-6,8-bis (p-fluorophenyl) -5,6-dihydro-8H-thiopyra- no [4 ', 3': 4.5] thieno [ 2,3-d] pyrimidines are dissolved in 80 ml of chloroform and drawn up on a chromatography column with 1.3 kg of Merck silica gel 0.05-0.2 mm.



  It is eluted with a mixture of 4 parts of isopropyl ether and 1 part of chloroform, the fractions being continuously monitored by means of thin-layer chromatography. The trans-4-chloro -6,8-bis- (p-fluorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': -4.5] is obtained from the first usable fractions by crystallization from benzene ] thieno [2,3-d] pyrimidine from 191-1920. Cis-4-chloro-6,8-bis (p-fluorophenyl) -5 is obtained from the following fractions by crystallization from a lot of isopropyl ether, 6-dihydro-8H-thiopyrano. [4 ', 3': 4,5] thieno [2,3-d] -pyrimidine from 193-1940.



   Example 21
4.8 g of 2 - methyl-4-chloro.6,8-bis (p-chlorophenyl) -5,6-di- hydro-8H-thiopyrano [4 ', 3': 4.5] thieno [2, 3-d] pyrimidine is dissolved warm in 300 ml of absolute toluene and stirred with 2.0 g of p-dimethylamino-ethylamine for 3 hours in a 1200 oil bath. It is then evaporated to dryness in vacuo and the residue is triturated with water.



  Recrystallization of the product obtained from ethyl alcohol gives 2-methyl-4-q3-dimethylamino-ethylamino) -6,8-bis (p-chlorophenyl) 5,6-dihydro-8H.



     -thiopyrano [4 ', 3': 4.5] thieno [2,3-d] pyrimidine of the formula
EMI15.2
 in the form of crystals from F. 176-177t. The mixture of stereoisomers can be separated into the pure trans compound from F. 175 - 177 (sinters from 1600) and into the pure cis compound from F. 187 - 1890 by fractional crystallization from ethanol.



   The 2-methyl-4-chloro-6,8-bis (p-chlorophenyl) -5,6-dihydro-8H-thiopyrano- [4 ', 3': 4,5] thieno, 3-d ] pyrimidine can, for example can be produced as follows:
22 g of 2-amino-3-carbamyl-5,7-bis (p-chlorophenyl) -4,5- -dihydro-7H-thieno [2,3-c] thiopyran are mixed with 100 ml of acetic anhydride in an oil bath for 6 hours heated by 1500. The reaction solution is then poured into 1 liter of water and stirred until a solid precipitate forms. This is filtered off and dried. The product thus obtained is dissolved in 5 parts by volume of chloroform and then applied to a chromatography column with 50 times the amount of silica gel Merck 0.05-0.2 mm.

  It is eluted with a mixture of 19 parts of chloroform and 1 part of ethyl acetate and the fractions obtained are continuously monitored by thin-layer chromatography. The 2-methyl-4-hydroxy-6,8-bis - (p-chlorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4.5] can be obtained from the middle fractions by crystallization. Isolate thieno [2,3-d] pyrimidine of m. 249-2510.



   5 g of 2-methyl-4-hydroxy-6,8-bis (p-chlorophenyl) -5,6-di-hydro-8H-thiopyrano [4 ', 3': 4,5] thieno [2,3- d] pyrimidine u.



  1.5 ml of N, N-dimethylaniline are heated with 50 ml of phosphorus oxychloride in an oil bath of 1200 for 15 hours. The excess phosphorus oxychloride is then evaporated off in vacuo and the residue is treated with ice water while cooling. The solid precipitate obtained in this way is filtered off with suction and dried. The product obtained is then dissolved in a little chloroform and drawn up on a chromatography column with 40 times the amount of silica gel Merck 0.05-0.2 mm. It is eluted with chloroform and the fractions obtained are continuously monitored by means of thin-layer chromatography. The 2-methyl-4-chloro -6,8-bis (p-chlorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': -4.5 ] thieno [2,3-djpyrimidine, which, when recrystallized from isopropyl ether, shows a F. of 170-1720.

 

   Example 22
To a boiling solution of 12.0 g of ethylenediamine in 150 ml of absolute toluene, a solution of 4.6 g of cis-4-chloro 6,8bis (pchlorphenyl) -5,6-dihydrn-8H-ffiiopyrano [ 4 ', 3': -4.5] thieno [2,3-d] pyrimidine in 100 ml of absolute toluene.



  The mixture is then heated to boiling for 2 hours. The reaction solution is evaporated to dryness in vacuo and the residue is made to crystallize by adding water. Recrystallization from absolute ethanol gives cis-4-q3- -aminoethylamino) -6,8-bis (p-chlorophenyl) -5,6-dihydro- -8H-thiopyrano [4 ', 3': 4, Sjthieno [2,3-d] pyrimidine of the formula
EMI16.1
 in crystals from F. 200 - 2020.



   By dissolving in an excess of ethanolic hydrochloric acid in the heat, the dihydrochloride of F. 267-2700 is obtained on cooling.



   Example 23
21.5 g of cis-4-chloro-6,8-phenyl- (p-chlorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4.5] thieno [2,3- d] pyrimidine are dissolved warm in 400 ml of absolute toluene and heated to boiling with 10.0 g of j3- (dimethylamino) ethylamine for 3 hours while stirring. It is then evaporated to dryness in vacuo and the residue is rubbed with 50% ethanol. Recrystallization from absolute ethanol thus gives cis-4- (ss-dimethylamino-ethylamino) -6,8-phenyl- (p-chlorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3' : 4,5] thieno [, 3-d] pyrimidine in crystals of m. 145-1480.



   By dissolving the base in the calculated amount of 1 -n ethanolic hydrochloric acid in the warmth and adding isopropyl ether until crystallization occurs, the dihydrochloride has a melting point of 223-2250 (with decomposition).



   Example 24
14.9 g of trans -4-chloro-6,8-phenyl- (p-chlorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4.5] thieno [2,3-d] pyrimidine are dissolved in 500 ml of warm toluene and heated to boiling with 6.8 g of p- (dimethylamino) ethylamine for 3 hours with stirring. It is then evaporated to dryness in vacuo and the residue is triturated with 50% strength ethanol. Recrystallization from absolute ethanol gives the trans-4 - (; p-dimethylamino -ethylamino) -6,8-phenyl- (p-chlorophenyl) -5,6-dihydro-8H -thiopyrano [4 ', 3': 4,5] thieno [2,3-d] pyrimidine in crystals from F. 186-1880.



   By dissolving the base in the calculated amount of 1-n ethanolic hydrochloric acid in the warmth and adding isopropyl ether until crystallization occurs, the dihydrochloride has a melting point of 238-2400 (with decomposition).



   The trans- or used as the starting product. cis -4-chloro-6,8-phenyl - (p-chlorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4.5] thieno [2,3-d] pyrimidine can e.g. can be produced as follows:
To a solution of 10 g of sodium hydroxide in a mixture of 150 ml of water and 80 ml of ethanol, a mixture of 18 g of p-chlorobenzaldehyde and 10.6 g of benzaldehyde and 50 ml of absolute ethanol is added with stirring within 20 minutes. The mixture is stirred for one hour at room temperature, the precipitate formed is filtered off with suction and washed thoroughly with water. Recrystallization from ethanol gives l-phenyl-5- (p-chlorophenyl) -penta-1,4-dien-3-one in yellow crystals from F.



  145-1500.



   100 g of 1-phenyl-5- (p-chlorophenyl) -penta 1, 4-dien-3-one and 100 g of anhydrous sodium acetate are heated to the boil in 3 liters of 90% ethanol with stirring.



  By passing in a hydrogen sulfide gas stream for 6 hours and then adding 2 liters of water while cooling, 2-phenyl-6- (p-chlorophenyl) -2,3,5,6-tetrahydro-thiopyran-4 is obtained after recrystallization from ethanol -on in white crystals from F. 122 - 1240.



   30.2 g of 2-phenyl-6 - (p-chlorophenyl) -2,3,5,6-tetrahydro-thiopyran-4-one, 11.3 g of cyanoacetic ester, 3.2 g of powdered sulfur and 10 ml of morpholine are in Suspended 150 ml of absolute ethanol and stirred in a 500 bath for 6 hours. After standing overnight, the mixture is evaporated to dryness in vacuo and the residue is made to crystallize by trituration with ethanol. After suction filtration and recrystallization from ethanol, the 2-amino-3-carbethoxy -5,7-phenyl- (p-chlorophenyl) -4,5-dihydro-7H-thieno [2,3-c] thiopyran of F. 125 is obtained - 1300.



   10 g of 2-amino-3-carbethoxy-5,7-phenyl- (p-chlorophenyl) -4,5-dihydro-7H-thieno [2,3-d] thiopyran are mixed with 100 ml of formamide under nitrogen for 6 hours in one heated oil bath from 185-1900. After cooling, the reaction product is suction filtered and recrystallized from 100 ml of absolute ethanol. This gives 4-hydroxy-6,8-phenyl - (p-chlorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4,5] thieno [2,3-d] pyrimidine from F. 215-2180.



   5.5 g of 4 - hydroxy-6,8-phenyl- (p-chlorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4.5] thieno [2,3 -d] pyrimidine are heated with 55 ml of phosphorus oxychloride for 2 hours in a 1200 oil bath. The excess phosphorus oxychloride is then evaporated off in vacuo, and ice water is added to the residue. The precipitate obtained is filtered off with suction, washed with water and, after drying, boiled with 50 ml of absolute ethanol. The product obtained is dissolved in chloroform-isopropyl ether 1: 2 and drawn up on a chromatography column with 150 times the amount of silica gel. It is eluted with a mixture of 9 parts of isopropyl ether and 1 part of chloroform and the separation is continuously monitored by means of thin-layer chromatography.

  In this way, boiling gives trans-4-chloro-6,8-phenyl- (p -chlorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4.5] thie no, 3 -d] pyn.midin from F. 154-1560 and the corresponding cis-stereoisomer from F. 184-1860.



   Example 25
19 g of cis -4- chloro-6,8- (p-chlorophenyl) - (p-fluorophenyl) -5,6- dihydro-8H-thiopyrano [4 ', 3': 4,5] thieno [2,3- d] pyrimidine are dissolved warm in 400 ml of absolute toluene and heated to boiling with 8.3 g of p- (dimethylamino) ethylamine while stirring. It is then evaporated to dryness in vacuo and the residue is triturated with 50% strength ethanol. Recrystallization of the solid product thus obtained from ethanol gives the cis-4- (8-dimethylamino-ethylamino) -6,8- (p-chlorophenyl) - (p-fluorophenyl) -5,6-dihydro-8H- thiopyrano [4 ', 3': 4,5] thieno [2,3- -djpyrimidine in crystals from F. 197-1990.



   By dissolving the base in the calculated amount of 1-n ethanolic hydrochloric acid in the warmth and adding isopropyl ether until crystallization occurs, the dihydrochloride has a melting point of 2450 (with decomposition).



   Example 26
14.9 g of trans-4-chloro-6,8- (p-chlorophenyl) - (p-fluorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4.5] thieno [2, 3-d] - pyrimidine is dissolved in 500 ml of absolute toluene and heated to boiling with 6.6 g of p- (dimethylamino) ethylamine for 3 hours while stirring. It is then evaporated to dryness in vacuo, and water is added to the residue. Trituration of the resulting resin with ethanol and recrystallization from absolute ethanol gives trans-4- (8-dimethylaminoethylamino) -6,8- (p-chlorophenyl) - (p-fluorophenyl) -5,6-dihydro-8H - thiopyrano [4 ', 3': 4,5] thieno [2,3-d] pyrimidine in crystals from F. 186-1880.



   By dissolving the base in the calculated amount of 1-n ethanolic hydrochloric acid in the warmth and adding isopropyl ether until crystallization occurs, the dihydrochloride has a melting point of 2350 (with decomposition).



   The trans- or used as the starting product. cis -4-chloro-6,8- (p-chlorophenyl) - (p-fluorophenyl) -5,6-dihydro -8H - thiopyrano [4 ', 3': 4.5] thieno [2,3-d] pyrimidine can, for example can be produced as follows:
To a solution of 10 g of sodium hydroxide in a mixture of 150 ml of water and 80 ml of ethanol, a mixture of 18 g of p-chlorobenzalacetone and 12.4 g of p-fluorobenzaldehyde in 50 ml of ethanol is added with stirring within 20 minutes. The mixture is stirred for one hour at room temperature, then the precipitate formed is filtered off with suction and washed thoroughly with water. Recrystallization from ethanol gives l- (p-chlorophenyl) -5 - (p-fluorophenyl) -penta-1,4-dien-3-one in yellow crystals with a melting point of 163-1650.



   100 g of l- (p-chlorophenyl) -5 - (p-fluorophenyl) -penta-1,4-dien-3-one and 100 g of anhydrous sodium acetate are heated to the boil in 3 liters of 90% ethanol with stirring. By introducing a stream of hydrogen sulfide gas for 6 hours and then adding 3 liters of water while cooling, after
Recrystallization from ethanol the 2- (p-chlorophenyl) -6 - (p-fluorophenyl) -2,3,5,6-tetrahydro-thiopyran-4-one from F.



      124-1260.



   43 g of 2- (p-chlorophenyl) -6- (p-fluorophenyl) -2,3,5,6-tetra-hydro-thiopyran-4-one, 15.2 g of cyanoacetic ester, 4.3 g of powdered sulfur and 13 ml of morpholine are suspended in 200 ml of absolute ethanol and stirred for 6 hours in a bath of 500 and then allowed to stand for 10 hours at room temperature. One steams in
Vacuum to dryness and bring the oily residue to solidify by rubbing with water. After recrystallization from ethanol, the 2-amino-3-carbäthoxy-5,7- (p-chlorophenyl) - (p-fluorophenyl) -4,5- dihydro-7H-thieno [2,3-c] thiopyran from F. 168 1700.



   10 g of 2-amino -3-carbethoxy-5,7. (P-chlorophenyl) - (p -fluorophenyl) -4,5-dihydro-7H-thieno [2,3-c] thiopyran are mixed with 100 ml of formamide under nitrogen Heated for 6 hours in an oil bath from 185 to 1900. After cooling, the reaction product is suction filtered and recrystallized from 100 ml of ethanol. This gives 4-hydroxy -6,8- (p-chlorophenyl) - (p-fluorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4.5] thieno [2,3- dApyrimidine from F. 228 to 2300.



   40 g of 4-hydroxy -6,8- (p-chlorophenyl) - (p-fluorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4.5] thieno [2,3-djpyrimidine heated with 400 ml of phosphorus oxychloride for 2 hours in an oil bath of 1200. The excess phosphorus oxychloride is then evaporated off in vacuo, and ice water is added to the residue. The solid precipitate is filtered off with suction, washed with water and, after drying, rubbed with 200 ml of ethanol. The product obtained in this way is dissolved in 10 times the volume of chloroform-isopropyl ether 1: 2 and drawn up on a chromatography column with 150 times the amount of silica gel. It is eluted with a mixture of 4 parts of isopropyl ether and 1 part of Cholroform and the separation is continuously monitored by means of thin-layer chromatography.

 

  Trituration of the corresponding eluates with absolute ethanol thus gives trans-4-chloro-6,8- (p-chlorophenyl) - (p-fluorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3' : - 4,5] thieno [2,3-d] pyrimidine of m. 157-1600 and the corresponding cis stereoisomer of m. 149-1530.

 

Claims (1)

PATENT CLAIM Process for the preparation of 5,6-dihydro-8H-thio pyrano [4 ', 3': 4,5] thieno [2,3-d] pyrimidines of the formula EMI17.1 which have an aryl radical in at least one of the 6 and 8 positions and can be further substituted in the 2, 5, 6 and 8 positions, and in which n is 0, 1 or 2 and Rz is an amino lower alkylamino group, and their salts, characterized that one is a 4-Y-5,6-dihydro-8H-thiopyrano [4 ', 3': 4,5] thie no [2,3-d] pyrimidine of the formula EMI17.2 which has an aryl radical in at least one of the 6 and 8 positions and can be further substituted in the 2, 5, 6 and 8 positions, and in which n is zero, 1 or 2, and Y is a radical which can be exchanged for an amino lower alkylamino group, with an amino lower alkylamine of the formula RzH, in which Rz has the meaning given. SUBCLAIMS 1. The method according to claim, characterized in that one starts out from a compound in which Y is a reactive esterified or etherified hydroxyl group, an ammonium group, a mercapto group or a sulfonyl group. 2. The method according to claim, characterized in that one starts from a compound in which Y is a halogen atom or an etherified mercapto group. 3. The method according to claim, characterized in that one starts from a compound in which Y is a chlorine atom or the methyl mercapto group. 4. The method according to claim, characterized in that one starts from compounds in which n is 0. 5. The method according to claim, characterized in that in a compound obtained whose amino lower alkylamino group has at least one hydrogen atom on the nitrogen atom in position 4 or on the nitrogen atom of the terminal amino group, the amino group (s) having at least one hydrogen atom on the nitrogen atom by reaction substituted with a reactive ester of an alcohol or an epoxide or by reductive alkylation. 6. The method according to claim, characterized in that the S-unsubstituted compounds obtained are oxidized to ien S-oxides or monoxides to the dioxides. 7. The method according to claim or one of the dependent claims 1 to 6, characterized in that compounds of the formula EMI18.1 where n is 2, 1 or 0, alk is a lower alkylene radical which separates Ro from the nitrogen atom in the 4-position by 2 to 5 carbon atoms, Ro is an amino group, a mono-lower alkylamino or di-lower alkylamino group or a lower alkylenamino, oxaalkylenamino , Azaaikylenamino or thiaalkyleneamino group, R1 represents a lower alkyl radical or a hydrogen atom, one of the radicals R2 and R3 represents an optionally substituted phenyl radical and the other represents a lower alkyl radical, an optionally substituted phenyl or phenyl-lower alkyl radical, an optionally substituted pyridyl radical or a hydrogen atom , R2 'and R3' denote hydrogen atoms, or either R2 and Ra 'or R3 and R3' together each form an optionally lower-alkylated pentylene (1,5) or butylene (1,4) radical and one of the other two radicals represents a Hydrogen atom and the other represents an optionally substituted phenyl radical, R4 represents a lower alkyl radical or a hydrogen atom and R3 represents a hydrogen atom or a lower alkyl radical, or prepares a salt thereof. 8. The method according to claim or one of the dependent claims 1 to 6, characterized in that compounds of the formula EMI18.2 where n is 2, 1 or 0, alk is a lower alkylene radical which separates Ro from the nitrogen atom in the 4-position by 2 to 5 carbon atoms, Ro is a di-lower alkylamino group, an optionally 3-unsaturated and / or C- lower alkylated piperidino or pyrrolidino group or an optionally C-lower alkylated morpholino, thiomorpholino, N'-lower alkylpiperazino or N '- (hydroxy-lower alkyl) piperazine group, R2 and R3 represent optionally by fluorine, chlorine atoms, Bromine atoms and / or lower alkoxy groups are substituted phenyl radicals and R3 is a hydrogen atom or a lower alkyl radical, or a salt thereof is produced. 9. The method according to claim or one of the dependent claims 1 to 5, characterized in that compounds of the formula EMI18.3 where Ph and Ph 'are phenyl radicals substituted by one, two or more lower alkoxy groups and / or halogen atoms, alk0 is a straight or branched lower alkylene radical which separates the two nitrogen atoms by 2 to 5 carbon atoms and R6 and R7 are lower alkyl radicals, or make a salt from it. 10. The method according to claim or one of the dependent claims 1 to 5, characterized in that compounds of the formula EMI19.1 wherein alk 'represents the ethylene (1,2) or propylene (1,3) radical, Re and R7 represent methyl or ethyl radicals and Hal and Hal' represent fluorine, chlorine or bromine atoms, or a Makes salt from it. 11. The method according to claim or one of the dependent claims 1 to 5, characterized in that the 4- (p-diethylaminoethylamino) -6,8-bis (p-chlorophenyl) -5,6-dihydro-8H-thiopyrano [4 ', 3': 4,5] thienoL2,3- -d] pyrimidine or a salt thereof. 12. The method according to claim or one of the dependent claims 1 to 6, characterized in that the isomer mixtures obtained are separated. 13. The method according to claim or one of the dependent claims 1 to 6, characterized in that the racemate mixtures or racemates obtained are cleaved into the optical antipodes. 14. The method according to claim or one of the dependent claims 1 to 6, characterized in that the free bases obtained are converted into their salts. 15. The method according to claim or one of the dependent claims 1 to 6, characterized in that the salts obtained are converted into the free bases.