HK1054944A

HK1054944A - 2-aminoalkyl-thieno [2,3-d] pyrimidines

Info

Publication number: HK1054944A
Application number: HK03107347.2A
Authority: HK
Inventors: Jonas Rochus; Schelling Pierre; Christadler Maria; Beier Norbert
Original assignee: Merck Patent Gmbh
Priority date: 2000-06-29
Filing date: 2001-06-28
Publication date: 2003-12-19

Description

2-aminoalkyl thieno [2, 3-d ] pyrimidines

The invention relates to 2-aminoalkylthieno [2, 3-d ] of general formula (I)]PyrimidinesWherein R is¹To R⁶Have the meanings indicated in the text, and their use as medicaments, in particular as inhibitors of c-GMP phosphodiesterase.

Substances having c-GMP phosphodiesterase inhibitory properties have been known for many years. The substance acts to reduce if the level of cyclic-guanosine monophosphate (c-GMP) is pathologically increased. By virtue thereof, symptoms occurring in the case of elevated c-GMP levels, such as inflammation, and muscle relaxation, are inhibited or prevented. The c-GMP phosphodiesterase inhibitors are particularly useful in the treatment of cardiovascular diseases and sexual dysfunction.

Various molecular compounds are known to have c-GMP phosphodiesterase inhibitory properties.

On the one hand, quinazolines are described, for example, in j.med.chem.36, p.3765 ff (1993) and j.med.chem.37, p.7106 ff (1994).

On the other hand pyrazolopyrimidinones are also suitable, as described in WO 94/28902. The use of such substances for the treatment of impotence is also disclosed.

German patent application 19942474.8 discloses the use of pyrazolo [4, 3-d ] pyrimidines for the treatment of cardiovascular disorders and impotence.

Finally, German patent application 19644228.1 describes the use of thienopyrimidines of the general formula IIThe substituent R here¹To R⁴Are various alkyl, alkoxy, halogen or cycloalkyl groups, or hydrogen. X is cycloalkyl having 6 to 12 carbon atoms or straight-chain or branched alkylene having 1 to 10 carbon atoms, wherein one or two CH₂The radicals may be replaced by-CH ═ CH-radicals in which cycloalkyl and alkylene groups as defined above are replaced by-COOH, C (O) O (C)₁-C₆Alkyl), -C (O) NH₂、-C(O)NH(C₁-C₆Alkyl), -C (O) N (C)₁-C₆-alkyl groups)₂Or a-CN group is monosubstituted.

It is an object of the present invention to provide novel compounds for use as medicaments, in particular, as c-GMP phosphodiesterase inhibitors. This object is achieved by the compounds of the formula:wherein R is¹、R²Are identical or different and are, independently of one another, hydrogen or straight-chain or branched C₁-C₈-alkyl, or together with the carbon atom to which they are bonded form a 5-7 membered monounsaturated cycloalkenyl ring, R³、R⁴Are identical or different and are, independently of one another, hydrogen, hydroxy, straight-chain or branched C₁-C₈Alkyl radical, C₁-C₈Alkoxy or halogen, or together with the carbon atom to which they are bonded, form a 5-to 8-membered ring which may optionally contain one or more oxygen atoms in addition to carbon atoms, R⁵、R⁶May be identical or different and are, independently of one another, hydrogen, straight-chain or branched C₁-C₈Alkyl-which may be substituted by one or more hydroxy groups, C₁-C₈Alkoxy, amine, mono (C)₁-C₈Alkyl) amine, di (C)₁-C₈-alkyl) amine, nitrilo, N-morpholino, phenyl, benzodioxole or pyridyl-substituted-or C₄-C₇Cycloalkyl groups, or together with the nitrogen atom to which they are bonded, form a saturated heterocyclic ring, optionally containing one or more further nitrogen and/or oxygen atoms, and being interrupted by one or more C₁-C₈-alkyl, hydroxy, C₁-C₈-alkoxy, C₁-C₈-alkanol, C₁-C₆Oligo-hydroxyalkyl, amino, mono (C)₁-C₈-alkyl) amino, di (C)₁-C₈-alkyl) amino, -SO₂R⁷or-C (O) R⁷Radical substitution, R⁷Is C₁-C₈Alkyl radical, C₁-C₈-a fluoroalkyl group, a phenyl group, optionally substituted by an alkyl group, a halogen group or a nitrile group, or a benzodioxole group.

It has been found that 2-aminoalkylthieno [2, 3-d ] pyrimidines of formula (I) and their physiologically tolerable salts have advantageous pharmacological properties.

In particular, the molecules of formula (I) show a specific c-GMP phosphodiesterase inhibitory effect. These compounds are therefore particularly suitable for the treatment of disorders of the cardiovascular system and of dyspareunia in the form of erectile dysfunction.

The determination of the biological activity of the compounds (I) according to the invention is carried out, for example, according to the method described in WO 93/06104. In this method, the affinity of the compounds according to the invention for c-GMP and c-AMP phosphodiesterase is exploited by IC₅₀Value determination. IC herein₅₀The values are the inhibitor concentration required to produce 50% inhibition of enzyme activity. The phosphodiesterases used here can be isolated by known methods, as described, for example, in W.J. Thompson et al, biochem.10, p.311 ff (1971). The tests can be carried out, for example, by the modified W.J.Thompson and M.M.Appleman batch methods, described in biochem.18, p.5228 ff (1979).

The efficacy of the compounds of formula (I) according to the invention in the treatment of sexual dysfunction is demonstrated by the inhibition of phenylephrine-induced contraction of the hare cavernous preparation. In this method, the demonstration of the biological activity is advantageously carried out according to the method described in F.Holmquist et al, J.Urol., 150, p.1310-1350 (1993).

Advantageous results are obtained if compounds of the general formula (I) in which the radical R is used¹To R⁵Has the following meanings.

Radical R¹、R²Are different in that one is hydrogen and the other is linear or branched (C)₁-C₄) Alkyl, preferably methyl or ethyl, or R¹And R²Together form propylene, butylene or pentylene.

Radical R³And R⁴May be the same or different, located at the 3 and 4 positions of the phenyl ring; they are, independently of one another, hydrogen, straight-chain or branched (C)₁-C₆) Alkyl, straight or branched chain (C)₁-C₆) Alkoxy or halogen, or together form propylene, butylene, pentylene, ethyleneoxy, methyleneoxy or ethylenedioxy.

Radical R⁵And R⁶May be the same or different and are independently of one another hydrogen or C₁-C₆-alkyl which is unsubstituted or substituted by one or more hydroxy, methoxy, ethoxy, nitrile, methylamine, ethylamine, dimethylamine, diethylamine, pyridinyl, benzodioxole or N-morpholino groups, cyclopentyl or cyclohexyl, or R⁵、R⁶With the nitrogen atom to which they are bonded forming a piperidinyl or piperazinyl ring, optionally substituted by one or more hydroxy, hydroxycarbonyl, C₁-C₂Alkyl amines, -SO₂-R⁷or-C (O) -R⁷Is substituted by radicals in which R⁷Is C₁-C₃Alkyl radical, C₁-C₃-a fluoroalkyl group, a phenyl group substituted with one or more alkyl or nitrile groups, or a benzodioxole group.

The compounds according to the invention are suitable for use as medicaments, with the possibility of preparing human and veterinary medicaments.

In these uses, the compounds according to the invention are often in the form of their physiologically tolerable salts. Suitable salts are generally metal salts, such as alkali metal and alkaline earth metal salts, and ammonium salts, such as ammonia itself or salts of organic amines.

Another preferred form of salt of a compound according to the invention is an acid addition salt. They can be prepared by customary methods known to those skilled in the art, for example by reacting the compounds according to the invention with the respective acids in an inert solvent and subsequently isolating the salts, for example by evaporation. Examples of acids which form physiologically acceptable salts are, on the one hand, mineral acids, such as sulfuric acid, nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, or sulfamic acid.

On the other hand, organic acids also form suitable salts. They are, for example, formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid and ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene-mono-and disulfonic acid, and lauryl sulfuric acid.

When used as medicaments, the compounds according to the invention or their physiologically acceptable salts are formulated to give suitable pharmaceutical preparations. In this process, they are formulated into suitable dosage forms, which may be solid, liquid or semi-liquid, using at least one suitable carrier or one excipient. Such pharmaceutical formulations are a further aspect of the invention.

Suitable carriers here are the customary organic and inorganic substances known to the person skilled in the art and are selected according to the intended administration, i.e. enteral, parenteral or topical administration. Typical examples of this type of material are water, vegetable oils, benzyl alcohol, alkylene glycols, polyethylene glycols, triacetin, gelatin, carbohydrates (e.g. lactose or starch), magnesium stearate, talc and petroleum jelly. In the choice of the above-mentioned carriers, care must of course be taken that they do not react with the substances according to the invention.

Oral administration forms are preferred administration forms according to the invention, examples being precisely tablets, pills, coated tablets, capsules, powders, granules, syrups, juices and drops.

Suppositories are used in particular in the case of rectal administration, solutions, preferably oily or aqueous solutions, are used in the case of parenteral administration, and suspensions, emulsions and implants are also used.

Examples of topical application include ointments, creams and powders.

Another possibility consists in freeze-drying the compounds according to the invention. The lyophilized product can then be used, for example, to prepare an injection.

The preparations of the substances according to the invention can be sterilized and/or can contain excipients, for example lubricants, preservatives, stabilizers and wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants and flavorings. Examples of such substances are vitamins.

The dosage of the substance according to the invention is preferably from 1 to 500mg, in particular from 5 to 100mg, per dosage unit. In this case the daily dosage unit is from 0.02 to 10mg/kg body weight. Although it is true that the individual doses may vary from patient to patient, and that each individual patient may vary depending on various factors. Such factors are, for example, the efficacy of the particular compound employed, the age, body weight, general health, sex, food intake during administration, time and route of administration, rate of excretion, drug combination and severity of the particular condition.

The compounds of the formula (I) according to the invention are prepared by reacting the corresponding 2-halomethylthio [2, 3-d ] thiopheno [ IIa ] compounds of the general formula]The reaction of pyrimidines with the appropriate alkylamines of formula (III) is prepared as shown in the following reaction scheme (1).In the formulae (IIa) and (III), the substituent R¹To R⁶Have the meanings indicated for formula (I). Hal is a halogen atom, preferably chlorine.

The reaction according to equation (1) is carried out at a temperature of-30 to 150 ℃, preferably 0 to 120 ℃. In this case the reaction can be carried out in the substance without the use of a solvent, or with the use of a suitable solvent. Suitable solvents are generally customary solvents known to the person skilled in the art. Examples are hydrocarbons such as hexane, petroleum ether, benzene, toluene and xylene; chlorinated hydrocarbons such as trichloroethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform and dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; glycol ethers such as ethylene glycol monomethyl ether, ethylene glycol dimethyl ether; ketones such as acetone and butanone; amides such as acetamide, dimethylacetamide, N-methylpyrrolidone, and dimethylformamide; nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide; nitro compounds such as nitromethane and nitrobenzene; esters, such as ethyl acetate; and mixtures of the above solvents. Dimethylformamide and/or N-methylpyrrolidone are preferably used as solvents.

After completion of the reaction, the material obtained is worked up in a customary manner, for example by extraction with an organic solvent after treatment with water, and the compound is isolated in a customary manner, for example by distillation of the solvent. Generally, the resulting residue is purified by recrystallization.

2-halomethylthio [2, 3-d ] pyrimidines of the formula (IIa) can be prepared by reacting the corresponding 4-chlorothienopyrimidine with a suitable, optionally substituted benzylamine. The applicant's German patent application 19644228 gives a description of a similar reaction in which the pyrimidine ring is substituted by a group X, as defined above for formula (II), instead of reacting with a halomethyl function. The reaction conditions disclosed therein may be applied to the materials of the present invention.

4-chlorothienopyrimidines can be obtained in a manner known from the literature, see, for example, Houben-Weyl, Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart.

The invention will now be illustrated in detail in the following examples. The temperatures are stated here in degrees Celsius and the abbreviations have the meaning known to the person skilled in the art. In this case all products are treated after the reaction is complete: water is added to adjust the pH of the solution between about 2 and 10, depending on the product obtained. Then, extraction is carried out with ethyl acetate or dichloromethane, and the organic phase is separated and dried. The solvent is then distilled off and the residue obtained is purified by chromatography on silica gel and/or by crystallization.

Example 1

A solution of 2g of 4- (3-chloro-4-methoxybenzylamino) -2-chloromethyl-5, 6, 7, 8-tetrahydrobenzothieno [2, 3-d ] pyrimidine in 10ml of DMF is treated with 5ml of 3-aminopropanol and heated at 80 ℃ for 1 hour. Then diluted with water and extracted with ethyl acetate. The crystalline product obtained after the usual work-up was dissolved in HCl alcoholic solution and treated with diethyl ether until cloudy. 2.1g of 4- (3-chloro-4-methoxybenzylamino) -2- (3-hydroxypropylaminomethyl) -5, 6, 7, 8-tetrahydrobenzothieno [2, 3-d ] pyrimidine are obtained in the form of its dihydrochloride salt.

M.p.＝225℃

Example 2

The reaction was carried out as described in example 1, using the equivalent amount of diethanolamine instead of 3-aminopropanol.

After treatment with the respective acids, 4- (3-chloro-4-methoxybenzylamino) -2- (bis-2-hydroxyethylaminomethyl) -5, 6, 7, 8-tetrahydrobenzothieno [2, 3-d ] pyrimidine is obtained in the form of its hydrochloride.

M.p.＝180℃

Example 3

The reaction was carried out as described in example 1, using the equivalent amount of 4-piperidinol instead of 3-aminopropanol.

After treatment with the respective acids, 4- (3-chloro-4-methoxybenzylamino) -2- (4-hydroxypiperidinomethyl) -5, 6, 7, 8-tetrahydrobenzothieno [2, 3-d ] pyrimidine is obtained in the form of its dihydrochloride salt.

M.p.＝119℃

Example 4

The reaction was carried out as described in example 1, using the equivalent amount of 3-methoxypropylamine instead of 3-aminopropanol.

After treatment with the respective acids, 4- (3-chloro-4-methoxybenzylamino) -2- (3-methoxypropanaminomethyl) -5, 6, 7, 8-tetrahydrobenzothieno [2, 3-d ] pyrimidine is obtained in the form of its dihydrochloride salt.

M.p.＝116℃

Example 5

The reaction was carried out as described in example 1, using the same amount of 2-hydroxyethylamine instead of 3-aminopropanol.

After treatment with the respective acids, 4- (3-chloro-4-methoxybenzylamino) -2- (2-hydroxyethylaminomethyl) -5, 6, 7, 8-tetrahydrobenzothieno [2, 3-d ] pyrimidine is obtained in the form of its dihydrochloride salt.

M.p.＝225℃

Example 6

The reaction was carried out as described in example 1, using the same amount of N, N-dimethyltrimethylene diamine instead of 3-aminopropanol.

After treatment with the respective acids, 4- (3-chloro-4-methoxybenzylamino) -2- (N, N-dimethylaminopropylaminomethyl) -5, 6, 7, 8-tetrahydrobenzothieno [2, 3-d ] pyrimidine is obtained in the form of its 1, 5-fumarate salt.

M.p.＝180℃

Example 7

The reaction was carried out as described in example 1, using the same amount of N-hydroxyethylpiperazine instead of 3-aminopropanol.

After treatment with the respective acids, 2- {4- [4- (3-chloro-4-methoxybenzylamino) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-2-ylmethyl ] piperazin-1-yl } ethanol is obtained in the form of its dihydrochloride salt.

The following compounds are obtained analogously: 1- {4- [4- (3-chloro-4-methoxybenzylamino) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-2-ylmethyl ] piperazin-1-yl } -2, 2, 2-trifluoroacetone 1- {4- [4- (3-chloro-4-methoxybenzylamino) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-2-ylmethyl ] piperazin-1-yl } ethanone (3-chloro-4-methoxybenzyl) [2- (4-methanesulfonylpiperazin-1-ylmethyl) -5, 6, 7, 8-tetrahydrobenzo [4 ], 5] thieno [2, 3-d ] pyrimidin-4-yl ] amine 1- [4- (3-chloro-4-methoxybenzylamino) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-2-ylmethyl ] piperidin-3-ol (3-chloro-4-methoxybenzyl) (2- { [ (pyridin-2-ylmethyl) amino ] methyl } -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-4-yl) amine 1-benzo [1, 3] dioxol-5-yl-1- {4- [4- (3-chloro-4-methoxybenzylamino) -5, 6, 7, 8-Tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-2-ylmethyl ] piperazin-1-yl } methanone 4- (1- {4- [4- (3-chloro-4-methoxybenzylamino) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-2-ylmethyl ] piperazin-1-yl } formyl) benzonitrile (3-chloro-4-methoxybenzyl) {2- [4- (toluene-4-sulfonyl) piperazin-1-ylmethyl ] -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-4-yl } amine 4- {4- [4- (3-chloro-4-methoxybenzyl) Benzylamino) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-2-ylmethyl ] piperazine-1-sulfonyl } benzonitrile (2- { [ (benzo [1, 3] dioxol-5-ylmethyl) amino ] methyl } -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-4-yl) (3-chloro-4-methoxybenzyl) amine 3- { [4- (3-chloro-4-methoxybenzylamino) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-2-ylmethyl ] amino } propan-1, 2-diol (3-chloro-4-methoxybenzyl) {2- [ (2-morpholin-4-ylethylamino) methyl ] -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-4-yl } amine 3- {4- [4- (3-chloro-4-methoxybenzylamino) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-2-ylmethyl ] piperazin-1-yl } propane-1, 2-diol (3-chloro-4-methoxybenzyl) [2- (4-dimethylaminopiperidin-1-ylmethyl) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-4-yl ] amine 6- { [4- (3-chloro-4-methoxybenzylamino) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-2-ylmethyl ] amino } hex-1-ol (3-chloro-4-methoxybenzyl) (2-cyclohexylaminomethyl-5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-4-yl) amine 1- { [4- (3-chloro-4-methoxybenzylamino) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-2-ylmethyl ] (2-hydroxypropyl) amino } propan-2-ol 3- { [4- (3-chloro-4-methoxybenzylamino) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-2-ylmethyl ] (2-cyanoethyl) amino } propionitrile (2S, 3S, 4S, 5R) -6- { [4- (3-chloro-4-methoxybenzylamino) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-2-ylmethyl ] methylamino } hex-1, 2, 3, 4, 5-pentaol

The following examples relate to pharmaceutical formulations:

example A: injection vial

100g of the active compound of the formula (I) and 5g of disodium hydrogen phosphate are adjusted to pH 6.5 in 3L of double distilled water with 2N hydrochloric acid, are dispensed into injection vials, are freeze-dried under sterile conditions and are sealed aseptically. Each injection vial contained 5mg of active compound.

Example B: suppository

20g of the active compound mixture of the formula (I) are fused with 100g of soya lecithin and 1400g of cocoa butter, poured into moulds and cooled. Each suppository contains 20mg of active compound.

Example C: solutions of

1g of active compound of the formula (I), 9.38g of NaH₂PO₄.2H₂O、28.48gNa₂HPO₄.12H₂O and 0.1g benzalkonium chloride are dissolved in 940ml double distilled water to prepare a solution. The solution was adjusted to pH 6.8, 1L was made up and sterilized by radiation. The solution may be used in the form of eye drops.

Example D: ointment formulation

500g of active compound of the formula (I) are mixed with 99.5g of petroleum gel under sterile conditions.

Example E: tablet formulation

A mixture of 1kg of active compound of the formula (I), 4kg of lactose, 1.2kg of potato starch, 0.2kg of talc and 0.1kg of magnesium stearate is compressed in the customary manner to tablets, each tablet containing 10mg of active compound.

Example F: coated tablet

Similarly to example E, tablets are compressed and then coated in a customary manner with tablets of sucrose, potato starch, talc, tragacanth and colorant.

Example G: capsule preparation

2kg of active compound of the formula (I) are filled in customary manner into hard gelatin capsules, each containing 20mg of active compound.

Example H: ampoule (CN)

1kg of a 60L double distilled water solution of the active compound of the formula (I) are sterile-filtered, dispensed into ampoules, freeze-dried under sterile conditions and sealed sterile. Each ampoule contains 10mg of active compound.

Example I: inhalation spray

14g of active compound of formula (I) are dissolved in 10ml of isotonic NaCl solution and the solution is filled into commercially available aerosol containers with a pump mechanism. The solution may be sprayed into the mouth or intranasally. One spray (about 0.1ml) corresponds to a dose of about 0.14 mg.

Claims

1. A compound of formula (I)Wherein R is¹、R²Are identical or different and are, independently of one another, hydrogen or straight-chain or branched C₁-C₈-alkyl, or together with the carbon atom to which they are bonded form a 5-7 membered monounsaturated cycloalkenyl ring, R³、R⁴Are identical or different and are, independently of one another, hydrogen, hydroxy, straight-chain or branched C₁-C₈Alkyl radical, C₁-C₈Alkoxy or halogen, or bound theretoTogether form a 5-to 8-membered ring which may optionally contain one or more oxygen atoms in addition to carbon atoms, R⁵、R⁶May be identical or different and are, independently of one another, hydrogen, straight-chain or branched C₁-C₈Alkyl-which may be substituted by one or more hydroxy groups, C₁-C₈Alkoxy, amine, mono (C)₁-C₈Alkyl) amine, di (C)₁-C₈-alkyl) amine, nitrilo, N-morpholino, phenyl, benzodioxole or pyridyl-substituted-or C₄-C₇Cycloalkyl groups, or together with the nitrogen atom to which they are bonded, form a saturated heterocyclic ring, optionally containing one or more further nitrogen and/or oxygen atoms, and being interrupted by one or more C₁-C₈-alkyl, hydroxy, C₁-C₈-alkoxy, C₁-C₈-alkanol, C₁-C₆Oligo-hydroxyalkyl, amino, mono (C)₁-C₈-alkyl) amino, di (C)₁-C₈-alkyl) amino, -SO₂R⁷or-C (O) R⁷Radical substitution, R⁷Is C₁-C₈Alkyl radical, C₁-C₈-a fluoroalkyl group, a phenyl group, optionally substituted by an alkyl group, a halogen group or a nitrile group, or a benzodioxole group.

2. A compound according to claim 1, characterized in that

R¹、R²Are different, one of them being hydrogen and the other being chosen from linear or branched (C)₁-C₄) Alkyl, or preferably methyl or ethyl, or R¹And R²Together form propylene, butylene or pentylene,

R³and R⁴Are identical or different and are located in the 3-and 4-positions of the phenyl ring; they are, independently of one another, hydrogen, straight-chain or branched (C)₁-C₆) Alkyl, straight or branched chain (C)₁-C₆) Alkoxy or halogen, or together form propylene, butylene, pentylene, ethyleneoxy, methyleneoxy or ethylenedioxy,

radical R⁵And R⁶Are identical or different and are each independently of the other hydrogen or C₁-C₆-alkyl which is unsubstituted or substituted by one or more hydroxy, methoxy, ethoxy, nitrile, methylamine, ethylamine, dimethylamine, diethylamine, pyridinyl, benzodioxole or N-morpholino groups, cyclopentyl or cyclohexyl, or R⁵、R⁶With the nitrogen atom to which they are bonded forming a piperidinyl or piperazinyl ring, optionally substituted by one or more hydroxy, hydroxycarbonyl, C₁-C₂Alkyl amines, -SO₂-R⁷or-C (O) -R⁷Is substituted by radicals in which R⁷Is C₁-C₃Alkyl radical, C₁-C₃-a fluoroalkyl group, a phenyl group substituted with one or more alkyl or nitrile groups, or a benzodioxole group.

3. 4- (3-chloro-4-methoxybenzylamino) -2- (3-hydroxypropylaminomethyl) -5, 6, 7, 8-tetrahydrobenzothieno [2, 3-d ] pyrimidine,

4- (3-chloro-4-methoxybenzylamino) -2- (bis-2-hydroxyethylaminomethyl) -5, 6, 7, 8-tetrahydrobenzothieno [2, 3-d ] pyrimidine,

4- (3-chloro-4-methoxybenzylamino) -2- (bis-4-hydroxypiperidinomethyl) -5, 6, 7, 8-tetrahydrobenzothieno [2, 3-d ] pyrimidine,

4- (3-chloro-4-methoxybenzylamino) -2- (3-methoxypropanaminomethyl) -5, 6, 7, 8-tetrahydrobenzothieno [2, 3-d ] pyrimidine,

4- (3-chloro-4-methoxybenzylamino) -2- (2-hydroxyethylaminomethyl) -5, 6, 7, 8-tetrahydrobenzothieno [2, 3-d ] pyrimidine,

4- (3-chloro-4-methoxybenzylamino) -2- (N, N-dimethylaminopropylaminomethyl) -5, 6, 7, 8-tetrahydrobenzothieno [2, 3-d ] pyrimidine,

1- {4- [4- (3-chloro-4-methoxybenzylamino) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-2-ylmethyl ] piperazin-1-yl } -2, 2, 2-trifluoroacetone,

1- {4- [4- (3-chloro-4-methoxybenzylamino) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-2-ylmethyl ] piperazin-1-yl } ethanone,

(3-chloro-4-methoxybenzyl) [2- (4-methanesulfonylpiperazin-1-ylmethyl) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-4-yl ] amine,

1- [4- (3-chloro-4-methoxybenzylamino) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-2-ylmethyl ] piperidin-3-ol,

(3-chloro-4-methoxybenzyl) (2- { [ (pyridin-2-ylmethyl) amino ] methyl } -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-4-yl) amine,

1-benzo [1, 3] dioxol-5-yl-1- {4- [4- (3-chloro-4-methoxybenzylamino) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-2-ylmethyl ] piperazin-1-yl } methanone,

4- (1- {4- [4- (3-chloro-4-methoxybenzylamino) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-2-ylmethyl ] piperazin-1-yl } formyl) benzonitrile,

(3-chloro-4-methoxybenzyl) {2- [4- (toluene-4-sulfonyl) piperazin-1-ylmethyl ] -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-4-yl } amine,

4- {4- [4- (3-chloro-4-methoxybenzylamino) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-2-ylmethyl ] piperazine-1-sulfonyl } benzonitrile,

(2- { [ (benzo [1, 3] dioxol-5-ylmethyl) amino ] methyl } -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-4-yl) (3-chloro-4-methoxybenzyl) amine,

3- { [4- (3-chloro-4-methoxybenzylamino) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-2-ylmethyl ] amino } propane-1, 2-diol,

(3-chloro-4-methoxybenzyl) {2- [ (2-morpholin-4-ylethylamino) methyl ] -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-4-yl } amine,

3- {4- [4- (3-chloro-4-methoxybenzylamino) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-2-ylmethyl ] piperazin-1-yl } propane-1, 2-diol,

(3-chloro-4-methoxybenzyl) [2- (4-dimethylaminopiperidin-1-ylmethyl) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-4-yl ] amine,

6- { [4- (3-chloro-4-methoxybenzylamino) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-2-ylmethyl ] amino } hex-1-ol,

(3-chloro-4-methoxybenzyl) (2-cyclohexylaminomethyl-5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-4-yl) amine,

1- { [4- (3-chloro-4-methoxybenzylamino) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-2-ylmethyl ] (2-hydroxypropyl) amino } propan-2-ol,

3- { [4- (3-chloro-4-methoxybenzylamino) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-2-ylmethyl ] (2-cyanoethyl) amino } propionitrile,

(2S, 3S, 4S, 5R) -6- { [4- (3-chloro-4-methoxybenzylamino) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-d ] pyrimidin-2-ylmethyl ] methylamino } hex-1, 2, 3, 4, 5-pentaol,

or one of their physiologically acceptable salts.

4. A medicament comprising a compound according to claim 1 or 2 or one of its physiologically acceptable salts.

5. A medicament comprising a compound selected from the group consisting of:

4- (3-chloro-4-methoxybenzylamino) -2- (3-hydroxypropylaminomethyl) -5, 6, 7, 8-tetrahydrobenzothieno [2, 3-d ] pyrimidine,

or one of their physiologically acceptable salts.

6. Use of a compound according to one of claims 1 to 3 or one of its physiologically acceptable salts for the preparation of a c-GMP phosphodiesterase inhibitory drug.

7. Use of a compound according to one of claims 1 to 3 or one of its physiologically acceptable salts for the preparation of a medicament for cardiovascular diseases.

8. Use of a compound according to one of claims 1 to 3 or one of its physiologically acceptable salts for the preparation of a medicament for sexual dysfunction.

9. Use according to one of claims 6 to 8, characterized in that a compound selected from the group consisting of:

or one of their physiologically acceptable salts.

10. Process for the preparation of a compound according to one of claims 1 to 3, characterized in that 2-halomethylthioeno [2, 3-d ] of the general formula (IIa)]PyrimidinesWherein the substituent R¹To R¹Having the meaning indicated in claim 1, with alkylamines of the general formula (III),

HNR⁵R⁶III wherein the substituent R⁵And R⁶Having the meaning indicated in claim 1, and optionally purifying the resulting material.

11. Process for the preparation of a medicament, characterized in that a compound according to one of claims 1 to 3 or one of its physiologically acceptable salts is brought into a suitable dosage form with at least one suitable excipient or carrier.