CH500226A - 4 amino alkylamino tetrahydro pyrido thieno pyrimidines - antimalarials amoebicides anti inflammatories and - Google Patents

Abstract

4',3':4,5 thieno 2,3-d pyrimidines substd. in the 4-position by an amino lower alkylamino group are new compounds, and are prepared by replacement of a halogeno, mercapto or ester group in the 4-position by an amino lower alkylamino group, using known methods. Useful as antimalarials, esp. for prophylactic use, also as amoebicides, anti-inflammatories and hypotensives. Starting material is prepared from the corresponding 4-OH compounds by known methods, such as PCl5, PCl3, P2S5, etc. Typically 4-chloro-7-methyl-5,6,7,8-tetrahydropyrido 4',3':4,5 thieno 2,3-d pyrimidine is treated with an excess of beta-diethylamino ethylamine to replace the chlorine atom.

Description

  

  
 



  Process for the preparation of new pyrirnidine derivatives
The invention relates to a process for the preparation of 5,6,7,8-tetrahydropyrido [4 ', 3': 4,5] thieno [2,3 -d] pyrimidines having the core of the formula
EMI1.1
 which have an amino lower alkylamino group in position 4, 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; h 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 having a maximum of 8 carbon atoms. Residues of this type interrupted by heteroatoms are mainly oxaalkylene, azaalkylene or thiaalkylene radicals.



  The following are to be mentioned in particular as substituents of the terminal amino group: methyl, ethyl, allyl, propyl, isopropyl, methallyl, straight or branched butyl, pentyl, hexyl or heptyl radicals connected at any point, 2- Hydroxyethyl or 3-hydroxypropyl radicals, 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-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-azapentylene- (1,5) -, 3- (hydroxy-lower alkyl) -3azapentylene- (1,5) -, such as 3 - (β-hydroxyethyl) -3-azapentylene- (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 2-5, especially 2-3, especially 2, carbon atoms, such as a Sithylene (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 and / or monounsaturated in the ring C-lower alkylamino, 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, the one on the pyrimidine nucleus seated nitrogen atom can also be further substituted by a lower alkyl radical and thus be tertiary.



   The new compounds can contain further substituents.



   For example, they can contain mono- or divalent, optionally substituted hydrocarbon radicals in the 6- and / or 8-position. Substituents in the 6- and / or 8-position include, in particular, alkyl radicals, such as lower alkyl radicals, especially those with 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, straight or branched, in any position linked butyl, pentyl or hexyl radicals, 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. B.



  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, the aromatic parts also can be substituted. 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.

  B. the lower alkoxy groups mentioned, such as methoxy, ethoxy, propoxy or butoxy groups, methylenedioxy groups, halogen atoms such as fluorine, chlorine or bromine atoms, trifluoromethyl groups, hydroxyl groups, nitro groups, amino groups or acyloxy groups or acylamino groups, in which the acyl radicals are especially 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 also, e.g. B. as indicated above for the aryl radicals, can be substituted.



   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. B. those mentioned have.



   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 are preferably substituted in the 7-position. As substituents, they primarily contain optionally substituted hydrogen radicals, in particular lower alkyl, alkenyl, cycloalkyl, cycloalkyl-alkyl radicals or phenyl or phenyl lower alkyl radicals, such as. B. the mentioned.



   The new compounds have valuable pharmacological properties, especially an antibacterial and anti-parasitic effect. In particular, they have an effect against plasmodia, e.g. B. Plasmodium berghei, as shown in animal experiments, e.g. with oral administration of 4ei00 to 300 mg / kg (administered on 4 consecutive days) to albino mice, shows. The new compounds are also effective against those strains of Plasmodia that are opposed to other anti-malarial agents such as 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.



  They also have such. B. in animal experiments, e.g. B. in the case of oral administration of 100-200 mg / kg to hamsters infected with E. histolytica, an amoebicidal effect can be shown and can be used accordingly. They also have an anti-inflammatory and antihypertensive 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
 wherein alk denotes a straight or branched lower alkylene radical which separates Ro from the nitrogen atom in the 4-position by 2-5, especially 2-3 carbon atoms, Ro stands for an amino group, especially a secondary or especially a tertiary amino group, e.g. a mono-lower alkylamino or, in particular, a di-lower alkylamino or a lower alkylene amino, oxaalkylenamino, azaalkyleneamine or thiaalkyleneamino group,

   such as an unsaturated and / or C-lower alkylated piperidino or pyrrolidino group, optionally in the ring, or an optionally C-lower alkylated morpholino, thiomorpholino, piperazino, N'-lower alkylpiperazino or N '- (hydroxy lower alkyl) piperazino group, such as N' -Methyl or N '- (ss-hydroxyethyl) piperazino group, Rl denotes a lower alkyl radical or, in particular, a hydrogen atom, R2, R2', R3 and R5, which can be the same or different, represent lower alkyl radicals, optionally, e.g.

  B. as indicated, substituted phenyl lower alkyl or phenyl radicals or represent hydrogen atoms, where preferably R2, and R3, hydrogen atoms, R2 and R3 each denotes one of the radicals, or R2 and R2, and / or R3 and R3, each together one optionally represent C-lower alkylated pentylene (1,5) or butylene (1,4) radical, R4 represents a lower alkyl radical or especially a hydrogen atom and R5 represents a lower alkyl radical, optionally one, for example As indicated, substituted phenyl lower alkyl, such as benzyl or phenylethyl, or in particular a hydrogen atom and Rn is an optionally substituted hydrocarbon radical, in particular a lower alkyl, alkenyl,

   Cycloalkyl or cycloalkyl-alkyl radical or a phenyl or phenyl-lower alkyl radical or hydrogen, and especially those compounds of the formula Ia in which R ,, Rt, R4, R6 and Rn have the meanings given, R2 and R3 are hydrogen atoms and R2 and R5, which can be identical or different, for optionally substituted by one, two or more lower alkyl radicals, trifluoromethyl groups and / or in particular lower alkoxy groups and / or especially halogen atoms, such as, for example 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 action against malaria
EMI3.1
 where Ph and Ph 'are phenyl radicals substituted by one, two or more lower alkoxy groups and / or halogen atoms, especially chlorine atoms, alk0 is a straight or branched lower alkylene radical which separates the two nitrogen atoms by 2 carbon atoms, Rn has the meaning given has and R, and R7 are lower alkyl radicals and in particular cis-4- (ss-diethylaminoethylamino) -6,8-bis (p-chlorophenyl) -7-methyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4,5] -thieno [2,3-d] pyrimidine and especially the cis4- (ss-dimethylaminoethylamino) -6,8-bis (p-chlorophenyl) -7-methyl5,6,7, 8-tetrahydropyrido [4 ', 3':

  : 4,5] thieno [2,3-d] pyrimidine, which, for example, in the form of its dihydrochloride in albino mice when administered orally on four consecutive days in a dose of 100 mg / kg each (based on the free base) a significant Has antimalarial activity. The last-mentioned compound also has an effect against chloroquine-resistant plasmodia in particular.



   The compounds of the general formula are also of importance
EMI3.2
 wherein R1, R2, R2, R3, R3, R4, R5 and Rn have the meanings given generally and preferably above, m is 1 or 2 and Rx is an N-lower alkyl-pyrrolidinyl-2- or -3-radical or an 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-5,6,7,8-tetrahydropyrido [4 ', 3': 4,5] thieno [2,3-d] -pyrimidine is used , in which Y is a radical which can be exchanged for an amino lower alkylamino group, is reacted with an amino lower alkylamine having at least one hydrogen atom on a nitrogen atom.



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



   A reactive esterified hydroxyl group is primarily 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. As ammonium groups, trialkylammonium, such as lower trialkylammonium groups, e.g. B. the trimethylammonium group to name. Mercapto groups are in particular free or etherified mercapto groups, such as lower alkyl mercapto, e.g. B. methyl mercapto or ethyl mercapto groups, or aralkyl mercapto, such as benzyl mercapto groups.

  A sulfonyl group is primarily a lower alkyl sulfonyl 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) -5,6,7,8 tetrahydropyrido [4 ', 3': 4,5] thieno- [2,3-d] pyrimidines which are on the nitrogen atom in 4- Position or on the nitrogen atom of the terminal amino group of the amino lower alkylamino group have at least one hydrogen atom, substitute these amino groups, for example by the substituents mentioned for the 4-amino lower alkylamino group.



   The substitution takes place e.g. by reaction with a reactive ester of a corresponding alcohol or by means of an epoxy. Reactive esters are especially 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 is carried out in the customary manner, advantageously in the presence of a basic condensing agent.



   The above-mentioned amino groups can also be substituted reductively, 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 is carried out in the usual way, for. B. 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 di-light metal hydride, e.g. an alkali metal-earth metal hydride such as sodium borohydride or lithium aluminum hydride.



   The reactions mentioned take place in the customary manner, advantageously under the conditions known for analogous reactions.



   In compounds obtained which contain free hydroxyl groups on an aromatic radical, these can be etherified or acylated. The acylation is carried out in the usual way, e.g. by reacting with carboxylic acids, advantageously in the form of their reactive functional derivatives, e.g. B. the one mentioned below.



  The etherification takes place in the usual way, e.g. B. by reacting with a reactive ester of an alkanol, preferably in the presence of a strong base.



   In compounds obtained which contain an acylated hydroxyl group, this can be cleaved to form the free hydroxyl group. Acylated hydroxyl groups are e.g. B. the above. The spin-off takes place e.g. hydrolytically, acidic or base-catalyzed depending on the expediency, e.g. B. with caustic soda.



   In compounds obtained which have alkoxy radicals on an aromatic ring, these can be converted into free hydroxyl groups in the customary manner.



  This conversion takes place z. B. by hydrolysis, especially by means of strong acids, such as. B. hydroiodic acid or hydrobromic acid and optionally in the presence of light metal halides, such as aluminum bromide or boron bromide, or with pyridine hydrochloride or aluminum chloride in pyridine.



   In compounds obtained which contain nitrable aryl radicals, these can be nitrated. The nitration is carried out in a manner known per se, for example by treatment with a mixture of concentrated sulfuric acid and concentrated nitric acid or with the mixed anhydride of nitric acid and a carboxylic acid, e.g. a lower alkanecarboxylic acid such as acetic acid.



   In compounds obtained which contain nitroaryl radicals, these can be reduced to aminoaryl radicals, e.g. B. with iron and hydrochloric acid or by means of catalytically excited hydrogen, such as hydrogen in the presence of a hydrogenation catalyst, e.g. B. a platinum, nickel or palladium catalyst such as platinum oxide, Raney nickel or palladium carbon.



   In compounds obtained which have amino groups on aromatic residues, these can be acylated. The acylation is carried out, for. B. by reacting with a carboxylic acid, preferably in the form of its reactive functional derivatives. Reactive functional acid derivatives are e.g. Acid halides, such as chlorides, esters, especially esters with lower alkanols, such as methanol or ethanol, or cyanomethyl esters, pure or mixed anhydrides, e.g. mixed anhydrides with carbonic acid monoalkyl esters, such as carbonic acid monoethyl or carbon isobutyl ester.



   In the acylamino compounds obtained, the acyl radicals can be split off in the customary manner, e.g. by hydrolysis, preferably in the presence of acidic or basic catalysts.



   In compounds obtained which contain a radical which can be split off by reduction in the 7-position, e.g. an α-aralkyl radical, such as a benzyl radical, can be split off reductively, e.g. by means of hydrogen in the presence of a hydrogenation catalyst.



   In compounds obtained which have a hydrogen atom in the 7-position, this can be exchanged for an optionally substituted hydrocarbon radical. This exchange takes place in a manner known per se, e.g. B. by reacting with a reactive ester of an appropriate alcohol, e.g. B. one of the above.

 

   The exchange can also take place by reaction with a corresponding oxo compound, such as an aldehyde or ketone, and simultaneous or subsequent reduction of the condensation product thus obtained. As reducing agents, e.g.



  those mentioned above for reductive substitution can be considered.



   The 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.

  Such acids may be mentioned, for example: hydrohalic acids, sulfuric acids, phosphoric acids, nitric acids, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, succinic, glycol, lactic, sipfel -, tartaric, citric, ascorbic, maleic, hydroxymaleic 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, such as. B. the picrates, can also be used to purify the free bases obtained by converting the free bases into salts, separating them and in turn frees the bases from the salts. As a result of the close relationships between the new compounds in 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 racemates in a known manner on the basis of the physico-chemical differences between the constituents, for example by chromatography and / or fractional crystallization.



   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. because of their different solubilities, decompose into the diastereomers, from which the antipodes can be released by the action of suitable agents. Optically active acids commonly used are e.g. B. the D- and L-forms of tartaric acid, di-o-toluyltartaric acid, malic acid, mandelic acid, camphorsulfonic 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. B. 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.



   For example, the 4-halo- or 4-mercapto-5,6,7,8-tetrahydropyrido [4 ', 3': 4,5] thieno [2,3zd] pyrimidines used as preferred starting materials can be obtained if the hydroxyl group is converted into a halogen atom or a mercapto group in a corresponding 4-hydroxy-5,6,7,8-tetrahydropyrido [4 ', 3': 4,5] thieno [2,3-d] pyrimidine.



   The conversion of the hydroxyl group into a halogen atom takes place in a manner known per se, e.g.



  by treatment with halides of sulfur or especially of phosphorus, e.g. B.



  Phosphorus pentachloride, phosphorus oxychloride, phosphorus trichloride, or corresponding bromides. The reaction is carried out in a customary manner, if appropriate in the presence of a tertiary base such as triethylamine or dimethylaniline.



   The conversion of a hydroxyl group into a free mercapto group takes place in a manner known per se, e.g. by reacting with a sulfurizing agent such as phosphorus pentasulfide.



   In compounds obtained which have a halogen atom in the 4-position, such as chlorine or bromine, this can be exchanged for etherified hydroxyl groups or optionally etherified mercapto groups, especially by reacting with a compound of the formula HZ ', where Z' is an etherified hydroxyl group or means a free or etherified mercapto group. The compound of the formula HZ 'is preferably used in the form of its salts, such as metal salts, especially alkali metal salts, such as sodium or potassium 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 in the customary manner. The etherification takes place z. By reacting with reactive esters of corresponding alcohols, e.g. Esters with strong organic or inorganic acids such as hydrohalic acids, e.g. Chlorine, bromine or hydroiodic acid, sulfuric acid or arylsulphonic acids, such as benzene, p-bromobenzene or p-toluenesulphonic acid, where it is advantageous to work in the presence of bases such as alkali metal hydroxides, or the 4-mercapto compound in the form of its metal salts, e.g. B. alkali metal salts, such as sodium or potassium salts, are used.



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



   The 4-hydroxy-5,6,7,8-tetrahydropyrido [4 ', 3': 4, Sj-thieno [2,3-d] pyrimidines can be obtained by using a 2-amino-3-Z "-4, 5, 6,7-tetrahydro- thieno [2,3-c] pyridine, where Z" is a free or an oxo group having a functionally modified carboxyl group, eg means 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 (z. 13. Chloride), imino ether, anhydride, or a nitrile with the Provided that at least the radical Z ″ or the functionally modified carboxyl group of the carboxylic acid mentioned has a nitrogen atom.



   The 2-amino-3-Z "-4,5,6,7-tetrahydro thieno (2,3-c] pyridines, where Z" is a free carboxyl group or a functionally modified carboxyl group having an oxo group, can be obtained if a 4-piperidone with a compound of the general formula
EMI6.1
 wherein Z "has the meaning given, and at the same time or subsequently reacts with sulfur.



   The reaction is carried out in a conventional manner, advantageously in the presence of a solvent such as a polar solvent, e.g. B. a lower alkanol, such as methanol or ethanol, or dimethylformamide and preferably in the presence of a basic condensing agent such as an organic base such as diethylamine, triethylamine, piperidine or morpholine, at ordinary or slightly elevated temperature and, if desired, under a nitrogen atmosphere and / or in a closed vessel under pressure.



   Compounds with free carboxyl groups can be obtained in free form or in the form of their salts with bases. Obtained free acidic compounds can in the usual way, for. B. by reacting with appropriate basic agents, in the salts with bases, especially in therapeutically useful salts with bases, z. B. salts with organic amines, or metal salts are converted.



   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. Free compounds and salts can be converted into one another as described above.



   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 therapeutically usable salts mixed with a e.g. contain pharmaceutical organic or inorganic, solid or liquid carrier material suitable for enteral or parenteral administration.



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



   In the following examples the temperatures are given in degrees Celsius.

 

   example 1
4.8 g of 4-chloro-7-methyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4,5] thieno [2,3-d] pyrimidine are mixed with 25 mol of ß-diethylamino -äthylamine heated to 1000 for 5 hours with stirring. The reaction solution is evaporated to dryness. The partially crystalline residue is boiled with 300 ml of petroleum ether. The 4- (ß-diethylamino-ethylamino) -7-methyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4.5] -thieno [2.3 -d] pyrimidine of the formula
EMI6.2
 from F: 81-83. After recrystallization from petroleum ether, the melting point rises to 87-890.



   190 mg of the above base are dissolved in ethanol and treated with 0.6 ml of 2N ethanolic hydrochloric acid.



  After adding acetone, the precipitated crystals are filtered off with suction. This gives the dihydrochloride of 4- (B-diethylamino-ethylamino) -7-methyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4,5] thieno [2,3-d] pyrimidins from F: 259-2620.



   The 4-chloro: 7-methyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4,5] thieno [2,3-d] -pyrimidine used as starting material is prepared as follows:
50 ml of morpholine are added dropwise to 56.5 g of 1-methylpiperidone- (4), 42 g of cyanoacetamide and 17.5 g of sulfur in 150 ml of ethanol, while stirring. The mixture is then heated for 3 hours with an oil bath of 450. It is left to stand overnight, the reaction mixture is cooled with ice and the crystals are filtered off with suction.



  The 2-amino-3-carbamyl-6-methyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine of F: 187-190 is obtained in this way.



   12.6 g of the above amide are dissolved in hot ethanol, and 29 ml of 2.1 N ethanolic hydrochloric acid are added. After cooling, it is suctioned off and the hydrochloride of 2-amino-3-carbamyl-6-methyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine with a melting point of 2210 is obtained.



   36 g of 2-amino-3-carbamyl-6-methyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine are heated with 200 ml of formamide for 5 hours in a 175-180 oil bath. After cooling with ice, the precipitated crystals are suction filtered and washed with a little ethyl alcohol, acetone and ether.



  The 4-hydroxy-7-methyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4,5] thieno [2,3-d] pyrimidine of the formula is obtained
EMI7.1
 from F: 224-226.



   14.7 g of the above base are abs in 340 ml.



     Dissolved ethanol and mixed with 33.5 ml of 2N ethanolic hydrochloric acid. The precipitated crystals are sucked off, recrystallized from sithanol / water and the
Washed crystals with ethanol and ether. The 4-hydroxy-7-methyl-5,6,7,8 tetrahydropyrido [4 ', 3': 4,5] -thieno [2,3-d] pyrimidine hydrochloride hydrate is obtained from F: 3153170.



   13 g of 4-hydroxy-7-methyl-5, 6,7, 8-tetrahydropyrido [4 ', 3': 4,5thieno [2,3-d] pyrimidine hydrochloride hydrate are added to 200 ml of phosphorus oxychloride 2t / 2 Boiled under reflux for hours. The solid material is filtered off, dissolved in 400 ml of hot water and filtered. The filtrate is adjusted to pH = 7.5 with 2N sodium hydroxide solution, the precipitated crystals are filtered off with suction and recrystallized from methanol-water. This gives 4-chloro-7-methyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4,5] thieno [2,3-d] pyrimidine of the formula
EMI7.2
 from F: 112-114.



   15 g of the above base are dissolved in 200 ml of abs. Athanol and adds 31.4 ml of 2N ethanolic hydrochloric acid.



  After cooling, the precipitated crystals are filtered off with suction and washed with acetone. The monohydrochloride of 4-chloro-7-methyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4,5] thieno [2,3-d] pyrimidine of F: 3240 (decomposition) is thus obtained .



   The compounds prepared as follows can also be used for condensation to form the pyrimidine ring:
To a suspension of 226 g of 1-methylpiperidone (4), 226 g of cyanoacetate and 70 g of sulfur in 600 ml of abs. Ethanol is added dropwise with stirring to 200 ml of morpholine in such a way that the temperature does not exceed 600. The mixture is then stirred for a further 3 hours at an internal temperature. After cooling, the crystals are suction filtered. This is dissolved in chloroform, petroleum ether is added and the precipitated crystals are sucked off. The 2-amino-3-carbethoxy-6-methyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine of F: 101-102 is obtained in this way.



   0.287 g of the above base are dissolved in 4 ml of ethanol and treated with 1.2 ml of ethanolic hydrochloric acid.



  After cooling, the precipitated crystals are filtered off with suction. The hydrochloride of 2-amino-3-carbethoxy-6-methyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine of F: 243-245 is obtained in this way.



   12 g of 2-amino-3-carbethoxy-6-methyl-4,5,6,7-th hydro-thieno [2,3-c] pyridine are heated under reflux for 30 minutes with 70 ml of methanol and 70 mol of 2N sodium hydroxide solution. It is concentrated in vacuo, neutralized with 2N hydrochloric acid and the precipitated crystals are filtered off with suction. The 2-amino-3-carboxy-6-methyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine of F: 1690 (decomposition) is obtained in this way.



   Example 2 17 coarse cis-4-chloro-6,8-bis (p-chlorophenyl) 7-methyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4,5] thieno- [ 2,3-d] pyrimidine hydrochloride are introduced into 70 ml of ß-diethylamino-ethylamine. The mixture is refluxed for 15 minutes and then evaporated to dryness. The residue is digested with 95% strength ethanol and the crystals are filtered off with suction. The cis-4- (ss-diethylamino-ethylamino) -6,8-bis (p-chlorophenyl) -7-methyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4,5] thieno [2,3-d] pyrimidine of the formula
EMI8.1
 from F: 177-1790. After recrystallization from methylene chloride-ethanol, the melting point is 179-1810.



   540 mg of the above base are suspended in 5 ml of methanol with heating and treated with 1.1 ml of 2N ethanolic hydrochloric acid. Crystallization sets in on addition of ether. The crystals are suction filtered and recrystallized from ethanol-ether. The dihydrochloride of cis-4- (p-diethylaminoethylamino) -6.8 bis (p-chlorophenyl) -7-methyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4 is obtained in this way , 5] - thieno [2,3-d] pyrimidine of F: 240: 2450 (dec.).



   The cis -4-chloro-6,8-bis (p-chlorophenyl) -7methyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4.5] thieno [2,3 -d] pyrimidine is made as follows:
30 g of glacial acetic acid in 50 ml of abs are added dropwise to 61 mol of 8.2 N ethanolic methylamine solution at a temperature of -200. Ethanol. A mixture of 29 g of acetone and 140.5 g of p-chlorobenzaldehyde is added to the methylaminoacetole solution with good cooling, and it is then stirred for 7 hours at room temperature.



  The crystals which have precipitated out are used, washed with ethanol and 1-methyl-2,6-bis (p-chlorophenyl) piperidone (4) of F: 142 "is obtained.



   150 ml of morpholine are added to a suspension of 500 g of 1-methyl 2,6-bis (p-chlorophenyl) piperidone (4>, 126 g of cyaflacetamide and 48 g of sulfur in 3 liters of absolute ethanol) and the mixture is boiled 2 Hours of stirring under reflux. After cooling, the crystals are filtered off with suction and washed with ethanol and ether. This gives cis-2-amino-3-carbamyl-5,7-bis (p-chlorophenyl) 6- methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine of the formula
EMI8.2
 from F: 236 ".



   179 g of cis-2-amino-3-carbamyl-5,7-bis (p-chlorophenyl) -6-methyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine are mixed with 1030 ml of acetic anhydride and 1030 ml of ethyl ortho-formate were boiled under reflux for 10 hours. It is then concentrated to dryness, the residue is boiled for 10 minutes with 1.5 l of ethanol and, after cooling, the crystals are filtered off with suction.



  This gives 4-hydroxy-6,8-bis (p-chlorophenyl) -7-methyl5,6,7,8-tetrahydropyrido [4 ', 3': 4,5] thieno [2,3- d] pyrimidine of the formula
EMI8.3
 from F: 301-3040.



      15g of 4-hydroxy-6,8-bis (p-chlorophenyl) -7-methyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4.5] thieno [2,3-d ] pyrimidine are refluxed for 3l / 2 hours with 450 ml of phosphorus oxychloride. After standing for 12 hours at room temperature, the precipitated crystals are suction filtered and washed with acetone and petroleum ether.

 

  The crude hydrochloride of 4-chloro-6, 8-bis (p-chlorophenyl) -7-methyl 5,6,7,8-tetrahydropyrido [4 ', 3': 4.5] -thieno is obtained in this way [2,3] pyridine.



  To release the base, the hydrochloride is mixed with water and an equal volume of saturated soda solution, extracted with chloroform, the chloroform solution is evaporated and the residue is rubbed with a little abs. Ethanol. This gives the free base of the formula
EMI9.1
 from F: 148-1500.



   Example 3
19.5 g of cis -4-chloro-6,8-bis-phenyl-7methyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4.5] thieno [2,3-d] pyrimidine boiled under reflux for 15 minutes with 100 ml of ß-diethylamino-ethylamine. It is then evaporated to dryness in vacuo, and 50 ml of abs are added. Ethanol is added, the crystals are suctioned off and recrystallized from methylene chloride-petroleum ether. The cis-4- (ß-diethylamino-ethylamino) -6,8 bis-phenyl-7-methyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4.5] thieno is obtained in this way [2,3-d] pyrimidine of the formula
EMI9.2
 from F: 172-173.5.



   The cis-4-chloro-6,8bis-phenyl-7-methyl 5,6,7,8-tetrahydropyrido4 ', 3': 4,5] -thieno [2,3-d] pyrimidine used as starting material manufactured as follows:
60 g of glacial acetic acid in 100 ml of absolute ethanol are added dropwise to 134 ml of 8.2N ethanolic methylamine solution at a temperature of -20 ". 212 g of benzaldehyde and 58 g of acetone are added to this methylamine acetate solution with good cooling. The mixture is stirred for a further hour at 0 and 2 hours at room temperature The precipitated crystals are filtered off with suction, washed well with ethanol and recrystallized from methylene chloride-ether, thus obtaining 1-methyl-2,6-bis-phenylpiperidone- (4) of F: 15im153 ".



   To a suspension of 13 g of 1-methyl-2,6: bisphenyl-piperidone- (4), 4.2 g of cyanoacetamide and 1.8 g of sulfur in 100 ml of abs. Ethanol is added to 5 ml of morpholine and refluxed for 11/2 hours. After cooling, the precipitated crystals are filtered off with suction, washed with cold ethanol and recrystallized from chloroform-petroleum ether. The cis-2-amino-3-carbamyl-5,7-bis-phenyl-6-methyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine of F: 203- is thus obtained 205.



   145 g of cis-2-amino-3-carbamyl-5,7-bis phenyl-6methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine are mixed with 1000 mol of ortho formate and 1000 ml of acetic anhydride boiled under reflux for 4 hours. It is then evaporated to dryness, the residue is stirred with 400 ml of abs. Ethanol, sucks the crystals and recrystallizes from dimethylformamide. 4-Hydroxy-6,8-bis-phenyl-7-methyl 5,6,7,8-tetrahydropyrido4 ', 3': 4,5] thieno [2,3-d] pyrimidine of the formula is obtained in this way
EMI9.3
 from F: 288-291.



      104g of 4-hydroxy-6,8-bis-phenyl-7-methyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4,5] thieno [2,3-d] pyrimidine are mixed with 1500 ml of phosphorus oxychloride boiled under reflux for 4 hours. The reaction solution is then evaporated to dryness and the residue is stirred up with 800 g of ice water. The solid material is filtered off with suction, stirred up with ethanol and the crystals are suctioned off. The crystals are finely pulverized and suspended in water. Saturated soda solution is added to this suspension and extracted with chloroform. The chloroform solution is dried and evaporated. The residue is crystallized from a little abs. Ethanol.

  The cis-4-chloro-6,8-bis-phenyl-7-methyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4.5] - thieno [2,3- d] pyrimidine from F. 156-1570.



   Example 4
4g cis -4-chloro-6,8-bis-phenyl-7-methyl 5,6,7,8-tetrahydropyrido [4 ', 3': 4.5] -thieno [2,3-d] pyrimidine are refluxed with 20 ml of ß-dimethylaminoäthyiamin for 15 minutes. It is then evaporated to dryness in vacuo and recrystallized from methanol. The cis-4- (ss-dimethylamino-ethylamino) -6,8-bis-phenyl-7-methyl-5,6,7,8-tetrahydepyrido [4 ', 3': 4.5] is obtained in this way. thieno [2,3-d] pyrimidm of the formula
EMI10.1
 from F: 190-1910.



   Example 5
20g cis-4-chloro-6, 8-bis (p-chlorophenyl) 7-methyl-5,6,7,8-tetrahydropyrido4 ', 3': 4,5] thieno [2,3-d] pyrimidine are refluxed for 10 minutes in 70 ml of diimethylamino-ethylamine. It is then evaporated to dryness. The residue is digested in 95% ethanol and the precipitated crystals are filtered off with suction. After recrystallization from methylene chloride-ethanol, cis-4- (ss-dimethyl-aminoethylamino) -6,8-bis (p-chlorophenyl) -7-methyl-5,6,7,8 tetrahydropyrido [4 ', 3': 4.5] thieno [2,3-d] pynmidine of the formula
EMI10.2
 from F. 180-182.



   Example 6
10 g of cis -4-chloro-6,8-bis (p-chlorophenyl) 7-methyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4,5lthieno [2,3-d ] pyrimidine are dissolved in 35 ml of s-morpholino-ethylamine and heated to an internal temperature of 1450 for 15 minutes. After cooling, the reaction solution is mixed with 50 ml of 95% strength ethanol and the crystals which have precipitated out are suction filtered. After recrystallization from methylene chloride-petroleum ether, the cis-4- (ss-morpholinoethylamino) -6,8-bis (p-chlorophenyl) -7-methyl-5,6,7,8-tetrahydropyrido [4 ', 3 ': 4.5] thieno t2,3-d] pyrimidine of the formula
EMI10.3
 from F. 196-1970.



   Example 7
8g of cis-chloro-6,8-bis (p-chlorophenyi) - 7-methyl-5, 6,7,8-tetrahydropyrido [4 ', 3': 4.5] thieno [2,3-d ] pyrimidine are heated to 1450 for 15 minutes in a preheated oil bath with 30 ml of N, N, N'-triethylethylenediamine.



  After cooling, 40 ml of ethanol are added and the crystals which have precipitated out are filtered off with suction. The cis-4- [N - (- diethylaminoethyl) - äthylamino] -6,8bis- (p-chlorophenylX 7-methyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4, 5] thienot2,3-d] pyrimidine of the formula
EMI11.1
 from F. 153-1540.



   Example 8
By reacting 4-chloro-7-isopropyl-5,6,7,8-tetrahydropyrido C4 ', 3': L, / ethieno [2,3-d] pyrimidine with β-dimethylaminoethylamine in a manner analogous to that in Described in the preceding examples, 4- (ss-dimethylaminoethylamino) -7-isopropyl 5,6,7,8-tetrahydropyrido [4 ', 3': 4,5j-thieno2,3-d] pyrimidine of the formula is obtained
EMI11.2

The 4-chloro-7-isopropyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4,5] thieno [2,3-d] pyrimidine used as a starting material can be obtained as follows.



   10 ml of morpholine are added dropwise with stirring to a suspension of 14.1 g of 1-isopropyl-piperidone- (4), 8.4 g of cyanoacetamide and 3.5 g of sulfur in 30 ml of absolute ethanol, and the mixture is then stirred at 400 for 3 hours and 4 hours at 600 continue.



  After cooling, the reaction product is mixed with 250 ml of water and extracted with chloroform.



  The chloroform solution is washed with water, dried over sodium sulfate and evaporated. The residue obtained in this way is boiled up with 400 ml of ether, the ether solution is filtered and concentrated strongly, with 2-amino-3-carbamyl-6-isopropyl-4,5,6,7-tetrahydro-thieno [2,3- c] pyridine precipitates, which, after recrystallization from ether-petroleum ether, melts at 112-114.



   By reacting this amide in a manner analogous to that described in the preceding examples with formamide, 4-hydroxy-7-isopropyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4.5] thieno [2 , 3-d] pyrimidine.



   The conversion of this compound into the hydrochloride and reaction of the latter with phosphorus oxychloride in a manner analogous to that described in the preceding examples gives the 4-chloro-7-isopropyl-5,6,7,8-tetrahydroyrido [4 ', 3': 4,5jthieno [2,3d] pyriinidine, which can be converted into the hydrochloride in the usual way.

 

   The above-described 2-amino-3-carbamyl-6-benzyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine can also be obtained by hydrolysis of the corresponding 3-cyano compound. This can e.g. can be made as follows.



   To 28.2 g of 1-isopropyl-piperidone- (4), 13.2 g of malondinitrile and 7 g of sulfur in 60 ml of absolute ethanol are added dropwise 20 ml of morpholine with stirring.



  After adding the morpholine, stirring is continued at 40 for 3 hours. The precipitated crystals are suction filtered and recrystallized from isopropanol. This gives 2-amino-3-cyano-6-isopropyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine with a melting point of 174-1750.



   15.5 g of the above base are dissolved in hot ethanol, 70 ml of 1-n are added. ethanolic hydrochloric acid. The precipitated crystals are suction filtered and recrystallized from ethanol-water. The hydrochloride of 2-amino-3-cyano-6-isopropyl-4,5,6,7 tetrahydro-thieno [2,3-c] pyridine with a melting point of 2222230 is obtained in this way.



   Example 9
By reacting 4-chloro-7-isobutyl-5, 6,7, 8-tetrahydropyrido [4 ', 3': 4,5] thieno (2,3-d] pyrimidine with β-pyrrolidinoethylamine in a manner analogous to that Described in the preceding examples, 4- (ss-pyrrolidinoät.hylamino) -7-isobutyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4,5] thieno- 2,3- d] pyrimidine of the formula
EMI12.1

The 4-chloro-7-isobutyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4,5] thieno [2,3-d] pyrimidine used as a starting material can be obtained as follows.



   To a suspension of 31 g of 1-isobutyl-piperidone- (4), 13.2 g of malononitrile and 7 g of sulfur in 60 ml of absolute ethanol, 20 ml of morpholine are added dropwise with stirring and then stirred for a further 3 hours at a temperature of 400 .



  After cooling, the reaction product is filtered off with suction. This is dissolved hot in absolute ethanol and mixed with ethanolic hydrochloric acid. After cooling with ice water, the crystals are filtered off with suction and recrystallized from ethanol. The 2-amino-3-cyano-6-isobutyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine hydrochloride hydrate with a melting point of 208-209 is obtained in this way.



   By hydrolysing this nitrile to the corresponding amide and reacting the latter with formamide in a manner analogous to that described in the preceding examples, 4-hydroxy7-isobutyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4 is obtained , 5] thieno [2,3-d] pyrimidine.



   The conversion of this compound into the hydrochloride and reaction of the latter with phosphorus oxychloride in a manner analogous to that described in the preceding examples gives 4-chloro-7-isobutyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4 , 51thieno [2,3-d] pyrimidine, which can be converted into the hydrochloride in the usual way.



   The compounds prepared as follows can also be used for condensation to form the pyrimidine ring:
To a suspension of 18.5 g of 1-isobutyl-piperidone- (4), 13.5 g of ethyl cyanoacetate and 4.17 g of sulfur in 30 ml of absolute ethanol, 17 ml of morpholine are added dropwise with stirring and then a further 3 Hours at 400 The reaction mixture is introduced into water and the precipitated crystals are filtered off with suction and recrystallized from ethanol-water. 15 g of the crystals thus obtained are dissolved warm in absolute ethanol and 53 ml of 1-n. Ethanolic hydrochloric acid is added, the hydrochloride of 2-amino-3-carbethoxy-6-isobutyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine of m. 205-206 precipitating.



   Example 10
By reacting 4-chloro-7-sec-butyl-4,5,6,7-tetrahydropyrido [4 ', 3': 4,5] thieno [2,3-d] pyrimidine with e-piperidinopentylamine in analogous In a manner as described in the preceding examples, 4- (e-piperidinopentylamino) -7-sec.butyl5,6,7,8-tetrahydropyrido (4 ', 3': 4.5] thieno [2,3- d] pyrimidine of the formula
EMI12.2
  
The 4-chloro-7-sec-butyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4,5] thieno [2,3-d] -pyrimidine used as starting material can be obtained as follows can be obtained.



   10 ml of morpholine are added dropwise with stirring to a suspension of 15.5 g of 1-sec-butyl-piperidone- (4), 8.4 g of cyanoacetamide and 3.5 g of sulfur in 30 ml of absolute ethanol. The mixture is then stirred for a further 3 hours at 402 and 4 hours at 600.



  After cooling, 300 ml of water are added.



  After a while, a resinous product and yellowish crystals separate out. The crystals are separated and dissolved in ether. The ether solution is purified with animal charcoal, filtered and petroleum ether is added, whereupon the 2-amino-3-carbamyl-6-sec-butyl-4,5,6,7 tetrahydro-thieno [2,3-c] pyridine from F . 127-129 is eliminated.



   By reacting this amide in a manner analogous to that described in the preceding examples with formamide, 4-hydroxy-7-sec.-butyl-5, 6,7,8-tetrahydropyrido [4 ', 3': 4.5] is obtained thieno [2,3-d] pyrimidine.



   The conversion of this compound into the hydrochloride and reaction of the latter with phosphorus oxychloride in a manner analogous to that described in the preceding examples gives the 4-chloro-7-sec-butyl-5,6,7,8-tetrahydropyrido [4 ', 3 ': 4,5] thieno [2,3-d] pyrimidine, which can be converted into the hydrochloride in the usual way.



   The compound prepared as follows can also be used for condensation to form the pyrimidine ring:
To a suspension of 31 g of l-sec-butyl-piperidone (4), 22.6 g of ethyl cyanoacetate and 7 g of sulfur in 60 ml of ethanol are added dropwise with stirring 20 ml of morpholine and then another 15 Minutes at 40 ". The reaction solution is poured into water and the supernatant water is decanted from the separated oil. Crystallization begins when a little methanol is added.

  The crystals are suctioned off and dissolved in ethanol-water. 20 g of the base thus obtained are dissolved in hot ethanol and mixed with 35.5 ml of 2-n. Ethanolic hydrochloric acid is added, whereupon the hydrochloride of 2-amino-3-carbethoxy-6-sec.butyl-4,5,6,7 tetrahydro-thieno [2,3-c] pyridine crystallizes out with a melting point of 195-197.



   The above-described 2-amino-3-carbamyl-6-sec-butyl-4,5,6,7 tetrahydro-thieno [2,3-c] pyridine can also be obtained by hydrolysis of the corresponding 3-cyano compound. This can e.g. B. be prepared as follows.



   10 ml of morpholine are added dropwise with stirring to a suspension of 15.5 g of 1-sec-butyl-piperidone- (4), 6.6 g of malononitrile and 3.5 g of sulfur in 30 ml of absolute ethanol. After the addition, stirring is continued for 3 hours at a temperature of 400.



  After cooling, the precipitated material is suctioned off and dissolved in 2-n. Hydrochloric acid and extracted with chloroform. The acidic aqueous phase is made alkaline and extracted with chloroform. The dried chloroform solution is evaporated. The residue obtained in this way is recrystallized from chloroform, petroleum ether and water.

  The 2-amino-3-cyano-6-sec-butyl-4,5,6,7 tetrahydro-thieno [2,3-c] pyridine with a melting point of 124-1260 is obtained in this way
Example 11
By reacting 4-chloro-7-benzyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4,5] thieno [2,3-d] pyrimidine with γ-dimethylaminopropylamine in a manner analogous to that in Described in the preceding examples, 4- (r-dimethylamino-propylamino) -7-benzyl 5,6,7,8-tetrahydropyrido [4 ', 3': 4,5] -thieno2,3-d) pyrimidine is obtained the formula
EMI13.1

The 4-chloro-7-benzyl-5,6,7,8-tetrahydropyrido [4 ', 3: 4,5] thieno [2,3-d] pyrimidine used as a starting material can be obtained as follows.

 

   50 ml of morpholine are added dropwise to a suspension of 95 g of 1-benzyl-piperidone (4), 42 g of cyanoacetamide and 16 g of sulfur in 200 ml of absolute ethanol and the mixture is then stirred at a bath temperature of 600 for a further 4 hours. After cooling, the reaction solution is poured into 1000 ml of water, whereupon a resinous precipitate separates out. The supernatant water is decanted and the residue is mixed with water and 2-n. Hydrochloric acid. The undissolved powdery material is suction filtered and boiled with methanol. The insoluble portion obtained is the hydrochloride of 2-amino-3-carbamyl-6-benzyl-4,5,6,7 tetrahydro- * ieno [2, 3 ic] pyridine of F. 2260 (decomp.).

  Further hydrochloride can be obtained from the filtrate by adding ether.



   By reacting this amide in a manner analogous to that described in the preceding examples with formamide, 4-hydroxy-7-benzyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4.5] thieno [ 2,3-d] pyrimidine.



   The conversion of this compound into the hydrochloride and reaction of the latter with phosphorus oxychloride in a manner analogous to that described in the preceding examples gives the 4-chloro-7-benzyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4,5] thieno [2,3-d] pyrimidine, which can be converted into the hydrochloride in the usual way.



   The compounds prepared as follows can also be used for condensation to form the pyrimidine ring:
To a suspension of 18.9 g of 1-benzyl-piperidone- (4), 11.3 g of ethyl cyanoacetate and 3.5 g of sulfur in 30 ml of absolute ethanol are added dropwise 10 ml of morpholine with stirring and then stirred for a further 3 hours a temperature of 400. After cooling in ice water, the reaction product crystallizes out. It is filtered off with suction and recrystallized from isopropanol. This gives 2-amino-3-carbethoxy-6-benzyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine with a melting point of 112113.50.



   15.8 g of the above base are dissolved in hot ethanol and mixed with 50 ml of 1-n. ethanolic hydrochloric acid added. The precipitated product is filtered off with suction and recrystallized from ethanol. The hydrochloride of 2-amino-3-carbethoxy-6-benzyl-4,5,6,7 tetrahydrothiene [2,3-c] pyridine with a melting point of 219-222 "is obtained in this way.



      15.8 g of 2-amino-3-carbethoxy-6-benzyl-4,5,6,7 tetrahydro-thieno [2,3-c] pyridine are dissolved in 70 ml of methanol and 70 ml of 2-n. Sodium hydroxide solution boiled under reflux for 3 hours. It is then reduced to half and with 2-n. Hydrochloric acid acidified. The resulting material is filtered off with suction, stirred up with 100 ml of ethanol and suction filtered. The 2-amino-3-carboxy-6-bezyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine hydrochloride of F. 2000 (decomp.) Is obtained in this way.



   The 2-amino-3-carbamyl-6-benzyl-4,5,6,7-tetrahydro-thieno2,3-c] pyridine described above can also be obtained by hydrolysis of the corresponding 3-cyano compound. This can e.g. B. be prepared as follows.



   To a suspension of 18.9 g of 1-benzyl-piperidone- (4), 6.6 g of malondinitrile and 3.5 g of sulfur in 30 ml of ethanol, 10 ml of morpholine are added dropwise with stirring and then stirred for a further 15 minutes at 40 ° The reaction product which has crystallized out is recrystallized from isopropanol. This gives 2-amino-3-cyano-6-benzyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine with a melting point of 1521530
15 g of the above base are dissolved in hot ethanol and mixed with 51 ml of 1-n. Ethanolic hydrochloric acid is added, whereupon the hydrochloride of 2-amino-3-carbethoxy-6-benzyl-4,5,6,7 tetrahydro-thieno [2,3-c] pyridine of mp 240-241 (decomp.) crystallizes out.



   Example 12
2.4g of 2,7-dimethyl-4-hydroxy-6,8-diphenyl-5,6,7,8-tetrahydropyrido [4'.3 ': 4.5] thieno [2,3-d] pyrimidine are refluxed for 4 hours with stirring in 50 ml of phosphorus oxychloride and 0.5 ml of triethylamine. It is then concentrated completely in vacuo, the residue is taken up in methylene chloride and poured into ammoniacal ice water. The methylene chloride layer is separated off and the aqueous phase is back-extracted with methylene chloride. The collected extracts are dried and evaporated. The residue thus obtained, which is the 2,7-dimethyl-4-chloro-6,8-diphenyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4.5] thieno [2.3 .d] -pyrimidm is refluxed with 15 ml of dimethylaminoethylamine for 10 minutes.

  It is then evaporated in vacuo and water is added to the residue. The precipitated crystals are suction filtered, dissolved in absolute ethanol and treated with an excess of ethanolic hydrochloric acid. After the addition of ether, the precipitated crystals are suction filtered and recrystallized from ethanol-ether.



  This gives 2,7-dimethyl-4- (ss-dimethylaminoethylamino) -6,8-diphenyl-5,6,7,8-tetrahydropyrido [4 ', 3': 4.5] -thieno [2 , 3-d] pyrimidine dihydrochloride of the formula
EMI14.1
 from F. 2150 (decomp.).



   The 2,7-dimethyl-4-hydroxy-6,8-diphenyl-5,6,7,8-tetrahydropyrido (4 ', 3': 4,5] thieno [2,3-d] used as starting material pyrimidine can be made as follows.



   72.7 g of 2-amino-3-carbamyl-5,7-diphenyl-6-methyl 4,5,6,7-tetrahydro-thieno [2,3-c] pyridine are refluxed with 500 ml of acetic anhydride for 6 hours . It is cooled to 0 and the precipitated crystals are filtered off with suction. The substance is chromatographically separated on a 1 kg silica gel column (silica gel Merck 0.05-0.2 mm) with chloroform / ethyl acetate 9: 1. The middle fractions were combined and recrystallized from methylene chloride-petroleum ether. This gives 2,7-dimethyl-4-hydrocy-6,8-diphenyl 5,6,7,8-tetrahydropyrido [4 ', 3': 4,5] thieno 2,3-d] pyrimidine vom F. 255-2560.



   Other starting materials in which the free or esterified carboxyl group can be converted into the carbamyl group in the usual manner can, for. B. be manufactured as follows:
To 12 g of 2-amino-3-carbethoxy-6-methyl-4,5,6,7-tetrahydro-thieno [2,3 -c] pyridine in 30 ml of glacial acetic acid, 10 ml of acetyl chloride are added with stirring and then stirred at 70 " The reaction solution is concentrated, the residue is absorbed in water and the aqueous solution is adjusted to pH = 9 with saturated sodium carbonate solution. The precipitated material is filtered off with suction and recrystallized from chloroform-petroleum ether. The 2-acetylamino- 3-carbethoxy-6-methyl-4,5,6,7-tetrahydro thieno [2,3-cpyridine, mp 140-1420.



   15 g of the above bases are dissolved in 125 ml of absolute ethanol and 53 ml of 1-n. ethanolic hydrochloric acid added. On addition of ether and while cooling with ice, the hydrochloride of 2-acetylamino-3-carbethoxy-6-methyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine with a melting point of 204-2060 crystallizes out.

 

   7g of 2-acetylamino-3-carbethoxy-6-methyl4,5,6,7-tetrahydrothieno [2,3-c] pyridine are mixed with 35 ml of 2-n. Sodium hydroxide solution and 35 ml of methanol were refluxed for 30 minutes. The mixture is then concentrated in a water jet vacuum and 35 ml of 2N are added to the residue. Hydrochloric acid. After some time, the 2-acetylamino-3-carboxy-6-methyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine with a melting point of 215-218 crystallizes out.



   15 g of the above product are mixed with 40 ml of aqueous 2-n. Hydrochloric acid stirred up. First a clear solution, then crystallization sets in. The sucked-off balls are recrystallized from water. The hydrochloride of 2-acetylamino-3-carboxy-6-methyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine with a melting point of 274 is obtained in this way.

 

Claims (1)

PATENT CLAIM Process for the preparation of 5,6,7,8-tetrahydropyrido ', 3': 4, S] thieno [2,3-d] pyrimidines having the core of the formula EMI15.1 which have an amino lower alkylamino group in the 4-position, and their salts, characterized in that a 4-Y-5,6,7,8-tetrahydropyrido [4 ', 3': 4,5] thieno [2,3- d] pyrimidine, in which Y denotes a radical which can be exchanged for an amino lower alkylamino group, is reacted with an amino lower alkyl amine having at least one hydrogen atom on a nitrogen atom. SUBCLAIMS 1. The method according to claim, characterized in that one starts 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 in a compound obtained whose amino lower alkylamino group has at least one hydrogen atom on the nitrogen atom in the 4-position 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 means a reactive ester or an epoxide or substituted by reductive alkylation. 5. The method according to claim, characterized in that in a compound obtained which has a residue which can be split off by reduction in the 7-position, this is split off by reduction. 6. The method according to claim, characterized in that in a compound obtained which has a hydrogen atom in the 7-position, this is exchanged for an optionally substituted hydrocarbon radical by reacting with a reactive ester or by reductive alkylation. 7. The method according to claim, characterized in that optionally obtained isomer mixtures are separated. 8. The method according to claim, characterized in that optionally obtained racemates are separated into the optical antipodes. 9. The method according to claim, characterized in that the free compounds obtained are converted into their salts. 10. The method according to claim, characterized in that the salts obtained are converted into the free compounds. 11. The method according to claim or one of the dependent claims 1-10, characterized in that a compound of the formula EMI16.1 wherein alk denotes a lower alkylene radical which separates Ro from the nitrogen atom in the 4-position by 2-3 carbon atoms, Ro denotes a mono-lower alkyl amino group, a di-lower alkylamino group or a piperidine or pyrrolidino group which is optionally unsaturated and / or C-lower alkylated in the ring or an optionally C-lower alkylated morpholino, thiomorpholino, piperazino, N'-lower alkylpiperazino or N '- (hydroxy-lower alkyl) piperazino group, Rl denotes a lower alkyl radical or a hydrogen atom, R2 and Ra are lower alkyl radicals, optionally substituted phenyl or phenyl lower alkyl radicals or hydrogen atoms, R4 is a lower alkyl radical or a hydrogen atom, R5 is a hydrogen atom, a lower alkyl radical or an optionally substituted phenyl lower alkyl radical and Rn is a lower alkyl radical, an optionally substituted phenyl radical or phenyl lower alkyl radical or hydrogen, or prepares a salt thereof. 12. The method according to claim or one of the subclaims 1-10, characterized in that a compound of the formula EMI16.2 wherein alk denotes a lower alkylene radical which separates Ro from the nitrogen atom in the 4-position by 2 to 3 carbon atoms, Ro stands for a di-lower alkylamino group, an optionally mono-lower alkylated piperidino or pyrromidino group or an optionally C-lower alkylated morpholino, thiomorpholino, N'-lower alkylpiperazino or N '- (hydroxy-lower alkyl) -piperazino group, R2 and R5 represent phenyl radicals optionally substituted by lower alkyl radicals, trifluoromethyl groups, lower alkoxy groups and / or halogen atoms, R5 represents a hydrogen atom or a lower alkyl radical and Rn represents a lower alkyl radical or an optionally substituted phenyl or phenyl lower alkyl radical, or a salt thereof . 13. The method according to claim or one of the dependent claims 1-10, characterized in that a compound of the formula EMI16.3 wherein alk is a lower alkylene radical which separates Ro from the nitrogen atom in the 4-position by 23 carbon atoms, Ro stands for a di-lower alkylamino group, an optionally C-lower alkylated piperidino or pyrrolidino group or an optionally C-lower alkylated morpholino, thiomorpholino, N'-lower alkylpiperazino or N '- (hydroxy-lower alkyl) -piperazino group, R2 and R3 are optionally substituted by chlorine atoms, bromine atoms and / or lower alkoxy groups Phenyl radicals, R5 stands for a hydrogen atom or a lower alkyl radical and Rn stands for a lower alkyl radical or an optionally substituted phenyl or phenyl lower alkyl radical, or prepares a salt thereof. 14. The method according to claim or one of the dependent claims 1-10, characterized in that a compound of the formula EMI16.4 where Ph and Ph 'are phenyl radicals substituted by one, two or more halogen atoms, especially chlorine atoms, alk is a straight or branched lower alkylene radical which separates the two nitrogen atoms by 2 carbon atoms, Rn is an optionally substituted phenyl or phenyl lower alkyl radical or in particular a lower alkyl radical, and R6 and R6 mean lower alkyl radicals, or prepares a salt thereof. 15. The method according to claim or one of the dependent claims 1-10, characterized in that a compound of the formula EMI17.1 wherein alk 'stands for the ethylene (1,2) or propylene (1,3) radical, R' and R "mean methyl or ethyl radicals, Hal and Hal 'stand for halogen atoms and R11 means a lower alkyl radical, or make a salt from it. 16. The method according to claim or emem aer dependent claims 1-10, characterized in that the 4- (ss-diethylaminoäthylamino) -6,8-bis (p-chlorophenyl) -7-methyl-5,6,7,8 -tetrahydropyrido [4 ', 3': 4, Sjthleno [2,3-d] pyrimidine or a salt thereof.