EP1444234A2

EP1444234A2 - Deuterated pyrazolopyrimidinones and drugs containing said compounds

Info

Publication number: EP1444234A2
Application number: EP02779219A
Authority: EP
Inventors: Rudolf-Giesbert Alken
Original assignee: Turicum Drug Development AG
Current assignee: BDD Berolina Drug Development GmbH
Priority date: 2001-11-07
Filing date: 2002-11-07
Publication date: 2004-08-11
Also published as: NZ533385A; PL369654A1; WO2003039439A3; IL161790A0; DE10155018A1; JP2005509646A; HUP0401721A3; HUP0401721A2; US20050069276A1; KR20050044381A; IS7246A; RU2004117157A; WO2003039439A2; NO20042337L; CN1606557A; CA2470271A1; CZ2004639A3

Abstract

The invention relates to deuterated pyrazolopyrimidinones and drugs containing said compounds and to the use of said pyrazolopyrimidinones for inhibiting thrombocyte adhesion and aggregation, for the purpose of long-term improvement of memory performance and learning ability and for use in the treatment of heart diseases and cardiovascular diseases, hypertension, pulmonary hypertension, erectile dysfunction and obstructive respiratory diseases, such as for example bronchial asthma. The invention further relates to pharmaceutical compositions of deuterated pyrazolopyrimidinones and the physiologically acceptable salts thereof for inhibiting thrombocyte adhesion and aggregation, for the purpose of long-term improvement of memory performance and learning ability and for use in the treatment of heart diseases and cardiovascular diseases, hypertension, pulmonary hypertension, erectile dysfunction and obstructive respiratory diseases, such as for example bronchial asthma, combined with pharmaceutically acceptable adjuvants and/or additives.

Description

Deuterated pyrazolopyrimidinones and medicinal products containing these compounds

The invention relates to deuterated pyrazolopyrimidinones and medicaments containing these compounds.

Various pyrazolopyrimidinone derivatives are known to be effective and selective cGMP PDE5 inhibitors and are used, among others. for the treatment of cardiac and

Circulatory diseases, hypertension and erectile dysfunction are used. A well-known representative of this class of substances is sildenafil (US 5250534 AI, EP 463756 B1).

The object of the present invention is to provide pyrazolopyrimidinones which have improved pharmacokinetic and / or pharmacodynamic properties compared to the already known compounds.

Surprisingly, it has now been found that the deuterated pyrazolopyrimidinones according to the invention have significantly better pharmacokinetic and / or pharmacodynamic properties than the corresponding undeuterated compounds.

According to the invention, the object is therefore achieved by providing deuterated pyrazolopyrimidinones of the general formula I:

Formula I.

where R ^{1 is} independently H or D, R ^{2 is} C ₁ -C ₃ alkyl, -deuteroalkyl or -perdeuteroalkyl, R ^{3 is} H, D, C- _L- Cg-Al yl, -deuteroalkyl or -perdeuteroalkyl, R ⁴ independently of one another is H or D, R ^{5 is} H or D, R ^{6 is} H, D, C ₁ -C ₃ -alkyl, -deuteroalkyl or -perdeuteroalkyl, R ^{7 is} C ₁ -C ₃ -alkyl, -deuteroalkyl or - Perdeuteroalkyl means and wherein at least one of the radicals R ¹ to R ^{4 is} deuterium or contains deuterium.

Deuterated pyrazolopyrimidinones of the general formula I are preferred, where R ^{1 is} D, R ^{2 is} C ₁ -C ₃ alkyl,

-Deuteroalkyl or -perdeuteroalkyl means, R ^{3 is} C _α -C ₆ alkyl, -Deuteroalkyl or -perdeuteroalkyl means, R ⁴ independently of one another means H or D, R ^{5 is} H or D, R ^{6 is} C ₁ -C ₃ alkyl, Represents -deuteroalkyl or -perdeuteroalkyl and R ^{7 is} C ₁ -C ₃ -alkyl, -deuteroalkyl or -perdeuteroalkyl. Deuterated pyrazolopyrimidinones of the general formula I are particularly preferred, where R ^{1 is} independently H or D, R ^{2 is} perdeuteroethyl, R ^{3 is} C- _. -Cg-alkyl, -deuteroalkyl or -perdeuteroalkyl, R ^{4 is} independently H or D, R ^{s is} H or D, R ^{6 is} C ₁ -C ₃ -alkyl, -deuteroalkyl or -perdeuteroalkyl and R ^{7 is} C ₁ - C ₃ alkyl, -deuteroalkyl or -perdeuteroalkyl means.

Deuterated ones are particularly preferred

Pyrazolopyrimidinones of the general formula I, where R ^{1 is} independently H or D, R ^{2 is} C ₁ -C ₃ -alkyl, -deuteroalkyl or -perdeuteroalkyl, R ^{3 is} trideuteromethyl, R ^{4 is} independently H or D, R ^s H or D, R ^s Ci _j alkyl, or -Deuteroalkyl -Perdeuteroalkyl represents and R ⁷ is C ₁ -C ₃ alkyl, or -Deuteroalkyl -Perdeuteroalkyl.

Deuterated pyrazolopyrimidinones of the general formula I are advantageous, where R ^{1 is} independently H or D, R ^{2 is} C- _L -Cj-al yl, -deuteroalkyl or -perdeuteroalkyl, R ^{3 is} C- _L- Cg-alkyl, -deuteroalkyl or -Perdeuteroalkyl, R ^{4 is} D, R ^{5 is} H or D, R ^{s is} C ₁ -C ₃ alkyl, -deuteroalkyl or -perdeuteroalkyl and R ^{7 is} C- _^ -C _a -alkyl, -deuteroalkyl or -perdeuteroalkyl ,

Deuterated pyrazolopyrimidinones of the general formula I, where R ^{1 is} D, R ^{2 is} C ₁ -C ₃ alkyl, -deuteroalkyl or -perdeuteroalkyl, are particularly advantageous, R ³ -Deuteroalkyl or -perdeuteroalkyl, R ^{4 is} independently H or D, R ^{5 is} D, R ^{6 is} C ₁ -C ₃ alkyl, -Deuteroalkyl or -perdeuteroalkyl and R ⁷ -Deuteroalkyl or -perdeuteroalkyl means. Deuterated are also advantageous

Pyrazolopyrimidinones of the general formula I, where R ^{1 is} D, R ^{2 is} perdeuteroethyl, R ³ -Deuteroalkyl or -perdeuteroalkyl, R ^{4 is} independently H or D, R ^{5 is} H or D, R ^{6 is} trideuteromethyl and R ^{7 is} C ₁ -C ₃ alkyl, -deuteroalkyl or -perdeuteroalkyl.

Deuterated pyrazolopyrimidinones of the general formula I, in which R ^{1 is} D, R ^{2 is} perdeuteroethyl, R ³ are particularly advantageous -Deuteroalkyl or -perdeuteroalkyl, R ^{4 is} independently H or D, R ^{5 is} H or D, R ^{6 is} C _x -C ₃ alkyl, -Deuteroalkyl or -perdeuteroalkyl and R ^{7 is} perdeutero-n-propyl.

According to the invention the object is achieved by providing pyrazolopyrimidinones of the general formula I, namely

5- [2-d5-Ethoxy-5- (4-methylpiperazin-l-sulfonyl) phenyl] -1-methyl-3-n-propyl-l, 6-dihydropyrazolo [4, 3-d] pyrimidin-7- one .

5- [2-d5-Ethoxy-5- (4-methylpiperazin-l-sulfonyl) -3,4,6-trideuterophenyl] -l-methyl-3-n-propyl-l, 6- dihydropyrazolo [4,3- d] pyrimidin-7-one,

5- [2-d5-ethoxy-5- (4-trideuteromethylpiperazin-l-sulfonyl) -3,4,6-trideuterophenyl] -l-methyl-3-n-propyl-1,6-dihydropyrazolo [4,3- d] pyrimidin-7-one,

5- [2-d5-ethoxy-5- (dll-4-methylpiperazin-l-sulfonyl) -3,4,6-trideuterophenyl] -l-methyl-3-n-propyl-l, 6- dihydropyrazolo [4, 3-d] pyrimidin-7-one, - [2-d5-Ethoxy-5- (dll-4-methylpiperazin-l-sulfonyl) -, 4,6-trideuterophenyl] -l-trideuteromethyl-3-n-propyl-1,6-dihydropyrazolo [4,3- d] pyrimidin-7-one,

5- [2-d5-ethoxy-5- (dll-4-methylpiperazin-l-sulfonyl) -

3,4,6-trideuterophenyl] -1-trideuterometbyl-3-n-propyl-1,6-dihydropyrazolo [4,3-d] -6D-pyrimidin-7-one,

5- [2-d5-ethoxy-5- (dll-4-methylpiperazin-l-sulfonyl) -3,4,6-trideuterophenyl] -1-trideuteromethyl-3-n-d7-propyl ■ 1,6-dihydropyrazolo [ 4,3-d] pyrimidin-7-one,

5- [2-d5-ethoxy-5- (dll-4-methylpiperazin-l-sulfonyl) -3,4,6-trideuterophenyl] -l-trideuteromethyl-3-n-d7-propyl-1,6-dihydropyrazolo [ 4,3-d] -6D-pyrimidin-7-one,

5- [2-ethoxy-5- (4-trideuteromethylpiperazin-l-sulfonyl) phenyl] -l-methyl-3-n-propyl-l, 6- dihydropyrazolo [4, 3-d] pyrimidin-7-one,

5- [2-ethoxy-5- (4-trideuteromethylpiperazin-1-sulfonyl) phenyl] -l-trideuteromethyl-3-n-propyl-1, 6-dihydropyrazolo [4, 3-d] pyrimidin-7-one,

5- [2-ethoxy-5- (4-trideuteromethylpiperazin-l-sulfonylphenyl] -l-methyl-3-n-d7-propyl-l, 6- dihydropyrazolo [4, 3-d] pyrimidin-7-one,

5- [2-ethoxy-5- (4-trideuteromethylpiperazin-1-sulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydropyrazolo [4, 3-d] -6D-pyrimidine-7- on,

5- [2-ethoxy-5- (dll-4-methylpiperazin-l-sulfonyl) phenyl] -1-trideuteromethyl-3-n-propyl-1,6-dihydropyrazolo [4,3-d] pyrimidin-7-one . 5- [2-ethoxy-5- (dll-4-methylpiperazine-l-sulfonyl) phenyl] -1-methyl-3-n-d7-propyl-1,6-dihydropyrazolo [4,3-d] pyrimidine-7 -one

5- [2-ethoxy-5- (dll-4-methylpiperazin-l-sulfonyl) phenyl] -1-trideuteromethyl-3-n-d7-propyl-1,6-dihydropyrazolo [4,3-d] pyrimidine-7 -on and

5- [2-ethoxy-5- (dll-4-methylpiperazin-l-sulfonyl) phenyl] -1-trideuteromethyl-3-n-d7-propyl-l, 6-dihydropyrazolo [4,3-d] -6D- pyrimidin-7-one,

5- [2-d5-ethoxy-5- (piperazin-1-sulfonyl) phenyl] -1-methyl-3-n-propyl-l, 6-dihydropyrazolo [4, 3-d] pyrimidin-7-one,

5- [2-d5-ethoxy-5- (piperazin-1-sulfonyl) -3,4,6-trideuterophenyl] -l-methyl-3-n-propyl-l, 6- dihydropyrazolo [4, 3-d] pyrimidin-7-one,

5- [2-d5-Ethoxy-5- (2,2,3, 3, 5, 5, 6, 6-octadeuteropiperazin-l-sulfonyl) -3, 4, 6-trideuterophenyl] -l-methyl-3- n-propyl-1,6-dihydropyrazolo [4,3-d] pyrimidin-7-one,

5- [2-d5-ethoxy-5- (2,2, 3, 3, 5, 5, 6, 6-octadeuteropiperazin-l-sulfonyl) -3,4, 6-trideuterophenyl] -l-trideuteromethyl-3- n-propyl-1, 6-dihydropyrazolo [4, 3-d] pyrimidin-7-one,

5- [2-d5-ethoxy-5- (2,2,3,3,5,5,6,6-octadeuteropiperazine-l-sulfonyl) -3,4,6-trideuterophenyl] -l-trideuteromethyl-3- n-propyl-1,6-dihydropyrazolo [4, 3-d] -6D-pyrimidin-7-one,

5- [2-d5-ethoxy-5- (2,2,3,3,5,5,6,6-octadeuteropiperazine-l-sulfonyl) -3,4,6-trideuterophenyl] -1-trideuteromethyl-3- n-d7-propyl-l, 6-dihydropyrazolo [4, 3-d] pyrimidin-7-one, 5- [2-d5-ethoxy-5- (2,2, 3, 3,5,5, 6, 6-octadeuteropiperazin-l-sulfonyl) -3, 4, 6-trideuteroρhenyl] -l-trideuteromethyl-3- n-d7-propyl-l, 6-dihydropyrazolo [4, 3-d] -6D-pyrimidin-7-one,

5- [2-ethoxy-5- (2,2,3,3, 5, 5, 6, 6-octadeuteropiperazine-l-sulfonyl) phenyl] -l-trideuteromethyl-3-n-propyl-l, 6-dihydropyrazolo [4, 3-d] pyrimidin-7-one,

5- [2-ethoxy-5- (2, 2,3,3,5,5,6, 6-octadeuteropiperazin-l-sulfonyl) phenyl] -l-methyl-3-n-d7-propyl-1,6 dihydropyrazolo [4, 3-d] pyrimidin-7-one,

5- [2-ethoxy-5- (2,2,3,3,5,5,6,6-octadeuteropiperazine-l-sulfonyl) phenyl] -l-trideuteromethyl-3-n-d7-propyl-1,6 dihydropyrazolo [4, 3-d] pyrimidin-7-one,

5- [2-ethoxy-5- (2,2,3,3,5,5,6,6-octadeuteropiperazine-l-sulfonyl) phenyl] -l-trideuteromethyl-3-n-d7-propyl-1,6 dihydropyrazolo [4,3-d] -6D-pyrimidin-7-pn,

5- [2-d5-ethoxy-5- (d9-piperazin-l-sulfonyl) -3, 4, 6-trideuterophenyl] -l-methyl-3-n-propyl-l, 6-dihydropyrazolo [4, 3- d] pyrimidin-7-one,

5- [2-d5-Ethoxy-5- (d9-piperazin-l-sulfonyl) -3,4,6-trideuterophenyl] -l-trideuteromethyl-3-n-propyl-l, 6- dihydropyrazolo [4,3- d] pyrimidin-7-one,

5- [2-d5-Ethoxy-5- (d9-piperazin-l-sulfonyl) -3,4,6-trideuterophenyl] -l-trideuteromethyl-3-n-propyl-l, 6- dihydropyrazolo [4,3- d] -6D-pyrimidin-7-one,

5- [2-d5-ethoxy-5- (d9-piperazin-l-sulfonyl) -3,4,6-trideuterophenyl] -l-trideuteromethyl-3-n-d7-propyl-l, 6- dihydropyrazolo [4, 3-d] pyrimidin-7-one, 5- [2-d5-ethoxy-5- (d9-piperazin-l-sulfonyl) -3, 4, 6-trideuterophenyl] -l-trideuteromethyl-3-n-d7-propyl-l, 6- dihydropyrazolo [4, 3-d] -6D-pyrimidin-7-one,

5- [2-ethoxy-5- (d9-piperazin-l-sulfonyl) phenyl] -1-trideuteromethyl-3-n-propyl-l, 6-dihydropyrazolo [4,3-d] pyrimidin-7-one,

5- [2-ethoxy-5- (d9-piperazin-l-sulfonyl) phenyl] -1-methyl-3-n-d7-propyl-l, 6-dihydropyrazolo [4, 3-d] pyrimidin-7-one .

5- [2-ethoxy-5- (d9-piperazin-l-sulfonyl) phenyl] -1-trideuteromethyl-3-n-d7-propyl-l, 6-dihydropyrazolo [4,3-d] pyrimidin-7-one .

5- [2-ethoxy-5- (d9-piperazin-l-sulfonyl) phenyl] -1- trideuteromethyl-3-n-d7-propyl-l, 6-dihydropyrazolo [4,3-d] -6D-pyrimidine- 7-one.

Preference is given to using the deuterated pyrazolopyrimidinones according to the invention and their physiologically tolerable salts for inhibiting platelet adhesion and aggregation, for long-term improvement in memory and learning ability, and for the treatment of cardiac and

Circulatory diseases, hypertension, pulmonary hypertension, erectile dysfunction and obstructive

Respiratory diseases such as Bronchial asthma.

Particularly preferred is the use of the deuterated pyrazolopyrimidinones according to the invention and their physiologically tolerable salts for the production of medicaments for the inhibition of platelet adhesion and aggregation, for the long-term increase in memory and learning ability, and for the treatment of cardiovascular diseases, hypertension, pulmonary hypertension, erectile dysfunction and obstructive respiratory diseases such as bronchial asthma.

Pharmaceuticals are particularly preferred

Compositions containing the deuterated pyrazolopyrimidinones according to the invention and their physiologically tolerable salts for inhibiting platelet adhesion and aggregation, for long-term improvement in memory performance and

Ability to learn and to treat cardiovascular diseases, hypertension, pulmonary hypertension, erectile dysfunction and obstructive respiratory diseases such as Bronchial asthma, in addition to pharmaceutically acceptable auxiliaries and / or additives.

The deuterated pyrazolopyrimidinones according to the invention are prepared on the basis of production processes for the non-deuterated compounds.

The synthesis of analog non-deuterated pyrazolopyrimidinones is described for example in US 5250534 AI, EP 463756 B1, EP 994115 A2 and EP 812845 B1. The processes carried out differ mainly in the time of the cyclization to the pyrimidinone system with respect to the introduction of the piperazine group.

The yield and purity of the products exceed that in

EP 812845 B1 synthesis described the other methods. This is based on a substituted pyrazole, which is linked to an ethoxybenzoic acid substituted by methylpiperazine and is cyclized in the last step to pyrazolopyrimidinone. The deuterated pyrazolopyrimidinones according to the invention are synthesized in relation to the reaction path in accordance with this patent specification, the reaction conditions being changed, if necessary, in order to avoid H / D exchange.

The starting point for the synthesis of the compounds according to the invention is ethyl 3-n-propylpyrazole-5-carboxylate, the preparation of which is analogous to Seki et al. [Che. Pharm. Bull., 32 (4), pp. 1568-1577, 1984]. Appropriately deuterated precursors are assumed for the synthesis of the derivative deuterated in the 3-position.

This pyrazole becomes analogous by N-methylation

US 5250534 or EP 463756 with dimethyl sulfate or deuterated dimethyl sulfate in the optionally deuterated l-methyl-3-n-propylpyrazole-5-carboxylic acid ester. The ester hydrolysis of this compound takes place in the presence of a deuterated carboxylic acid ester using deuterium chloride solution. The non-deuterated carboxylic acid ester is hydrolyzed alkaline analogously to US 5250534.

A mixture of fuming nitric acid and oleum can be used to nitrate the pyrazole carboxylic acid, as described in US 5250534 or EP 463756. In one embodiment of the invention, the nitration of the 1-position deuterated compound is described under mild conditions using nitric acid in the presence of ammonium heptamolybdate (Sana et al., Chem. Lett., Pp. 48-49, 2000).

The optionally deuterated l-methyl-4-nitro-3-n-propylpyrazole-5-carboxylic acid is reacted with Thionyl chloride and ammonium hydroxide solution converted into the 5-carboxamide (US 5250534 or EP 463756). From this, the 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide is obtained by reducing the nitro group, with reduction of a deuterated pyrazole analogously to Ram et al. [Tetrahedron Lett., Vol. 25 (32), pp. 3415-3418, 1984] the reaction with Pd / C is carried out in the presence of ammonium formate at room temperature.

In the second part of the synthesis, 2-ethoxybenzoic acid or deuterated 2-ethoxybenzoic acid is sulfochlorinated in the 5-position analogously to EP 812845 B1 and then reacted with optionally deuterated 4-methylpiperazine, so that 2-ethoxy-5- (4-methylpiperazine sulfonyl) ) benzoic acid or when using deuterated starting materials receives the corresponding deuterated compound.

The perdeuterated piperazine derivatives used according to the invention can be prepared analogously to known regulations for the preparation of the non-deuterated compounds (US 2905673, DE 2205597, DE 3836781).

3,3, 5, 5-tetradeutero-l-methylpiperazine is analogous to Shetty et al. [J. Labeled Compd. Radiopharm., Vol. 18 (11), pp. 1633-1640, 1981].

For the synthesis of 2, 2, 6, 6-tetradeutero-l-methylpiperazine and 2,2, 6, 6-tetradeutero-l- (trideuteromethyl) piperazine, analogously to Dischino et al. [J. Labeled Compd. Radiopharm., Vol. 25 (4), pp. 359-367, 1987] reacted N-benzylimidinodiacetic acid with urea and the l-benzyl-3, 5-piperazinedione formed with LiAlD to l-benzyl-3, 3, 5 , 5-tetradeuteropiperazine implemented. This then becomes a modification of the regulation reacted with methyl iodide or trideuteromethyl iodide and then debenzylated.

The subsequent linkage of the pyrazole derivative with the substituted benzoic acid takes place in the presence of N, N '-carbonyldiimidazole.

The cyclization of the system carried out in the last reaction step is carried out in tert-butanol with the addition of potassium tert-butanolate. The reaction product is by adding

Deuterium chloride solution is precipitated and the deuterated pyrazolopyrimidones according to the invention are isolated with a degree of deuteration of at least 98%.

Typical physiologically compatible inorganic and organic acids are, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid and benzoic acid. Other acids that can be used are described, for example, in Progress in Pharmaceutical Research, vol. 10, pages 224-225, Birkhäuser Verlag, Basel and Stuttgart, 1966, and Journal of Pharmaceutical Sciences, vol. 66, pages 1-5 (1977).

The acid addition salts are generally in a manner known per se by mixing the free base or its solutions with the corresponding acid or their solutions in an organic solvent, for example a lower alcohol such as methanol, ethanol, or n-propanol

Isopropanol or a lower ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone or an ether such as diethyl ether, tetrahydrofuran or dioxane. Mixtures of the solvents mentioned can also be used for better crystal deposition. In addition, physiologically compatible aqueous solutions of Acid addition salts of the compounds used according to the invention are prepared in an aqueous acid solution.

The acid addition salts of the invention

Connections can be carried out in a manner known per se, e.g. with alkalis or ion exchangers, are converted into the free base. Additional salts can be obtained from the free base by reaction with inorganic or organic acids, in particular those which are suitable for forming therapeutically usable salts. These or other salts of the new compound, e.g. the picrate can also be used to purify the free base by converting the free base into a salt, separating it and releasing the base from the salt.

The present invention also relates to pharmaceuticals for oral, buccal, sublingual, rectal, subcutaneous, intravenous or intramuscular application or for inhalation, which, in addition to conventional carriers and diluents, contain a compound of the general formula I or its acid addition salt as active ingredient.

The medicaments of the invention are produced in a known manner with the customary solid or liquid carriers or diluents and the commonly used pharmaceutical-technical auxiliaries in accordance with the desired type of application with a suitable dosage. The preferred preparations consist of a dosage form which is suitable for oral, buccal or sublingual application. Such forms of administration are, for example, tablets, chewable, lozenge or film-coated tablets, coated tablets, capsules, pills, powders, solutions or suspensions or depot forms. Of course, parenteral preparations such as injection solutions are also suitable. Suppositories may also be mentioned as preparations. Appropriate tablets can, for example, by

Mixing the active ingredient with known excipients, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or agents for achieving a depot effect such as carboxylpolymethylene, carboxylmethylcellulo - se, cellulose acetate phthalate or polyvinyl acetate can be obtained. The tablets can also consist of several layers.

Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents conventionally used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. The coated tablet can also consist of several layers, wherein the auxiliaries mentioned above for the tablets can be used.

Solutions or suspensions with the active ingredient used according to the invention can additionally taste-improving agents such as saccharin, cyclamate or sugar and e.g. Contain flavorings such as vanillin or orange extract. You can also

Contain suspension aids such as sodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoates. Capsules containing active ingredients can be produced, for example, by mixing the active ingredient with an inert carrier such as milk sugar or sorbitol and encapsulating it in gelatin capsules. Suitable suppositories can be produced, for example, by mixing them with carriers such as neutral fats or polyethylene glycol or their derivatives.

The preparation of the pharmaceutical preparations according to the invention is known per se and is described in the manuals known to the person skilled in the art, for example Hager's Handbuch (5.) 2, 622-1045; List et al., Pharmaceutical Forms, Stuttgart: Wiss. Verlagsges. , 1985; Sucker et al., Pharmaceutical Technology, Stuttgart: Thieme 1991; Ulimann's Encyclopedia (5th) A 19, 241-271; Voigt, Pharmaceutical Technology, Berlin: Ullstein Mosby 1995.

The following examples illustrate the invention.

Example 1 Preparation of l-trideuteromethyl-3-n-propylpyrazole-5-carboxylic acid ethyl ester

Analogously to the preparation of the non-deuterated compound, 18.3 g of 3-n-propylpyrazole-5-carboxylic acid ethyl ester are reacted with 13.5 g of dδ-dimethyl sulfate for 2.5 hours at 90 ° C. The mixture is then dissolved in dichloromethane, washed with an aqueous sodium carbonate solution, the organic phase is separated off and dried and, after removal of the solvent, is purified by column chromatography. 14.2 g of ethyl l-trideuteromethyl-3-n-propylpyrazole-5-carboxylate are obtained as a colorless oil. Yield: 71% calculated: C: 60.28%; H: 9.61%; N: 14.06% found:

C: 60.35%; H: 9.70%; N: 14.05% ^X H NMR (200 MHz, CDC1 ₃ ): δ 1.10 (3H, t); 1.35 (3H, t); 1.73 (2H, m); 4.21 (2H, q); 6.80 (1H, s).

Example 2

Preparation of 4D-1-trideuteromethyl-3-n-propylpyrazole

5-deuterocarbonsäure

The hydrolysis of the carboxylic acid ester is in

Deuterium chloride solution carried out by suspending 9.96 g of 1-trideuteromethyl-3-n-propylpyrazole-5-carboxylic acid ethyl ester in deuterium chloride solution and for

Reflux for 15 hours. After

Working up, 5.7 g of reaction product are isolated as ivory crystals. Yield: 66%

Melting point: 147-151 ° C calculated:

C: 55.47%; H: 9.89%; N: 16.17% found: C: 55.60%; H: 9.82%; N: 16.12%

^X H NMR (200 MHz, d6-DMSO): δ 0.87 (3H, t); 1.60 (2H,);

2.49 (2H, t).

Example 3

Preparation of l-trideuteromethyl-4-nitro-3-n-propylpyrazole-5-carboxylic acid

The pyrazole carboxylic acid is nitrated by means of

Nitric acid in the presence of ammonium heptamolybdate. 8.66 g of 4D-1-trideuteromethyl-3-n-propyl-5-pyrazole deuterocarboxylic acid are dissolved in dichloromethane and, after adding 3.15 ml of 70% nitric acid and 61.75 g of ammonium heptamolybdate, the mixture is heated to reflux for 6 hours. The reaction mixture is filtered, the solvent is removed and the solid obtained purified by column chromatography. 8.43 g of product are obtained as a white solid. Yield: 78% Melting point: 122-126 ° C calculated:

C: 44.44%; H: 6.52%; N: 19.44% found:

C: 44.37%; H: 6.49%; N: 19.38%

^X H NMR (200 MHz, CDC1 ₃ ): δ 0.92 (3H, t); 1.65 (2H, m); 2.51 (2H, t); 10.6 (1H, s).

Example 4

Preparation of l-trideuteromethyl-4-nitro-3-n-propylpyrazole-5-carboxamide

In a manner known per se, 10.85 g of 1-trideuteromethyl-4-nitro-3-n-propylpyrazole-5-carboxylic acid are added to 50 ml of thionyl chloride and the mixture is heated under reflux for 3 hours. The excess thionyl chloride is distilled off in vacuo

The residue was taken up in acetone and carefully added to an ice-cooled aqueous ammonium hydroxide solution to which ice had been added. The precipitated reaction product is filtered off and 7.85 g of the carboxamide is obtained as a light yellow solid. Yield: 73% Melting point: 137-141 ° C calculated: C: 44.64%; H: 7.02%, N: 26.03% found:

C: 44.72%; H: 7.08%; N: 26.10%

^X H NMR (200 MHz, CDCI3): δ 0.93 (3H, t); 1.64 (2H,);

2.51 (2H, t); 6.70 (2H, s). Example 5

Preparation of 4-amino-l-trideuteromethyl-3-n-propylpyrazole-5-carboxamide

10.8 g of the nitro compound are dissolved in dry methanol under argon and 2.5 g of 10% Pd-C are added to the solution. The reaction mixture is mixed with 14.5 g of anhydrous ammonium formate and at

Room temperature stirred for 30 minutes. The catalyst is filtered off and washed with dry methanol. The filtrate is concentrated, the residue is mixed with water and the product is shaken out with dichloromethane. The organic phase is after

Drying concentrated and 7.5 g of 4-amino-1-trideuteromethyl-3-n-propylpyrazole-5-carboxamide are obtained as a white solid.

Yield: 81%

Melting point: 96-98 ° C calculated:

C: 51.87%; H: 9.25%; N: 30.25% found:

C: 51.93%; H: 9.22%; N: 30.19%

^X H NMR (200 MHz, CDC1 ₃ ): δ 0.93 (3H, t); 1.64 (2H, m);

2.51 (2H, t); 4.60 (2H, s); 6.70 (2H, s).

Example 6

Preparation of 1, 3, 4, 6-tetradeutero-5-chlorosulfonyl-2-d5-ethoxybenzoic acid

Analogously to the process for the preparation of the non-deuterated compound, 17.7 g of melted d10-2-ethoxybenzoic acid are added to an ice-cooled mixture of 7.5 ml of thionyl chloride and 28.2 ml of chlorosulfonic acid, with stirring, the temperature of the reaction mixture being kept below 25 ° C. The reaction mixture is stirred for 18 hours at room temperature, then carefully poured into an ice-water mixture and stirred for another hour. The product which separates out is separated off, dried and recrystallized from a hexane / toluene mixture. 20.45 g of light yellow solid are obtained. Yield 75%

Melting point: 111-114 ° C calculated:

C: 39.63%; H: 6.28%; found: C: 39.88%; H: 6.20%

¹³ C NMR (200 MHz, d6-DMSO): δ 15.10 (sept); 64.70 (quint); 114.20 (t); 118.30 (s); 128.4 (t); 131.70 (t); 136.20 (s); 171.30 (s).

Example 7

Preparation of 2-d5-ethoxy-5- (4-dll-methylpiperazin-l-sulfonyl) -3,4, 6-trideuterobenzoic acid

The preparation is carried out in a manner known per se, at 10 ° C. to give a suspension of 27.3 g 1,3,4,6-

Tetradeutero-5-chlorosulfonyl-2-d5-ethoxybenzoic acid in

95 ml of water 25.8 g of dl2-4-methylpiperazine are added with stirring. The temperature of the reaction mixture is kept below 20 ° C. during the addition. The solution is cooled to 10 ° C. and stirred at this temperature for a further 2 hours. The solid which precipitates is filtered off, washed with ice water and dried.

26.75 g of crude product are obtained, which after removal of a

Sample that is used to secure the structure is processed immediately.

Yield: 77%

Melting point: 192-196 ° C calculated:

C: 48.39%; H: 11.30%; N: 8.06% found:

C: 48.27%; H: 11.25%; N: 8.00% ¹³ C NMR (200 MHz, CDC1 ₃ ): δ 14.90 (sept); 39.20 (quint); 46.00-46.40 (m); 56.10-56.50 (m); 113.70 (t); 115.90 (s); 127.60 (t); 131.70 (t); 129.50 (s); 162.90 (s); 171.30 (s).

Example 8

Preparation of 4- [2-d5-ethoxy- (4-dll-methylpiperazin-l-sulfonyl) -3,4, 6-trideuterobenzamido] -1-trideuteromethyl-3-n-propylpyrazole-5-carboxamide

The compound is prepared analogously to the preparation process for the non-deuterated compound, in that 27.3 g of 2-d5-ethoxy-5- (4-dll-methylpiperazin-1-ylsulfonyl) -3, 4, 6-trideuterobenzoic acid with 17. 9 g of N, N'-carbonyldiimidazole in ethyl acetate are mixed with one another and reacted with one another for 30 minutes at 55 ° C. and then for 2 hours with heating to reflux. 16.7 g of 4-amino-1-trideuteromethyl-3-n-propylpyrazole-5-carboxamide are added to this reaction mixture and the mixture is stirred for 72 hours at room temperature. The solid which settles out is isolated. The product is processed without further purification, a sample is taken only to secure the structure and this is recrystallized from aqueous methanol. 29.6 g of product are obtained. Yield: 85% Melting point: 202-205 ° C calculated: C: 51.34%; H: 10.57%; N: 16.33% found:

C: 51.43%; H: 10.49%; N: 16.28%

¹³ C NMR (200 MHz, CDC1 ₃ ): δ 13.90-14.30 (m); 22.10 (quint); 25.40 (quint); 32.90 (sept); 39.00 (sept); 46.30-46.70 (m); 56.70-57.10 (m); 63.90 (quint); 115.20 (T); 120.10 (s); 122.60 (s); 125.70 (t); 130.80-131.20 (m); 141.30 (s); 158.7 (s); 164.20 (s); 171.10 (s).

Example 9

Preparation of 5- [2-d5-ethoxy-5- (dll-4-methylpiperazin-1-sulfonyl) -3,4, 6-trideuterophenyl] -l-trideuteromethyl-3-n-propyl-1, 6-dihydropyrazolo [ 4, 3-d] -6D-pyrimidin-7-one ^' In a manner known per se, 12.9 g of 4- [2-d5-ethoxy- (4-dll-methylpiperazin-l-yl-sulfonyl) -3, 4, 6-trideuterobenza ido] -l-trideuteromethyl-3-n-propylpyrazole-5-carboxamide suspended in tert-butanol and mixed with 3.37 g of potassium tert-butanolate. The mixture is heated to reflux for 8 hours, cooled to room temperature and water is added. The resulting solution is added dropwise with aqueous deuterium chloride solution. The precipitated reaction product is granulated at pH 7 and 10 ° C. for 1 hour, then filtered off, washed with water and dried. 10.36 g of product are isolated. Yield: 83% Melting point: 186-188 ° C calculated: C: 53.09%; H: 10.72%; N: 16.89% found:

C: 53.21%; H: 10.83%; N: 16.75%, 0

13C-NMR (200 MHz, CDC1 ₃ ): δ 13.90-14.30 (m); 22.80 (quint); 25.20 (quint); 32.80 (sept); 39.00 (sept); 46.30-46.70 (); 56.70-57.10 (m); 65.80 (quint); 106.50 (s); 115.20 (t); 119.30 (s); 124.00 (t); 128.30 (t);

131.60 (s); 134.30 (s); 148.50 (s); 161.30 (s); 163.20 (s); 171.80 (s).

Claims

Patent claims

1. Deuterated pyrazolopyrimidinones of the general formula I

where R ¹ is independently H or D,

R ² means C ₁ -C ₃ -alkyl, -deuteroalkyl or -perdeuteroalkyl,

R ³ H, D, C ₁ -C ₆ -alkyl, -deuteroalkyl or

-Perdeuteroalkyl is,

R ⁴ independently means H or D,

R ^s H or D,

R ⁶ H, D, C ₁ -C ₃ alkyl, deuteroalkyl or

-Perdeuteroalkyl represents,

R ⁷ means C ₁ -C ₃ -alkyl, -deuteroalkyl or -perdeuteroalkyl and where at least one of the radicals R ¹ to

R ⁴ is deuterium or contains deuterium.

2. Deuterated pyrazolopyrimidinones according to claim 1, characterized in that R ¹ D is ,

R ² means C ₁ -C ₃ -alkyl, -deuteroalkyl or -perdeuteroalkyl,

R ³ is Ci-Cg-alkyl, -deuteroalkyl or -perdeuteroalkyl,

R ⁴ independently means H or D, R ⁵ is H or D,

R ^s _L -G _j represents -Al yl, -deuteroalkyl or -perdeuteroalkyl and R ⁷ represents C ₁ -C ₃ -alkyl, -deuteroalkyl or -perdeuteroalkyl.

3. Deuterated pyrazolopyrimidinones according to claim 1, characterized in that R ¹ is independently H or D,

R ² perdeuteroethyl means,

^R3 -deuteroalkyl or -perdeuteroalkyl,

R ⁴ independently represents H or D, R ^s is H or D,

R ⁶ represents C ₁ -C ₃ alkyl, deuteroalkyl or perdeuteroalkyl and

R ⁷ means C ₁ -C ₃ alkyl, deuteroalkyl or perdeuteroalkyl.

4. Deuterated pyrazolopyrimidinones according to claim 1, characterized in that

R ¹ is independently H or D,

R ² means C ₁ -C ₃ -alkyl, -deuteroalkyl or -perdeuteroalkyl,

R ³ is trideuteromethyl,

R ⁴ independently means H or D,

R ⁵ is H or D,

R ^s represents C ₁ -C ₃ alkyl, deuteroalkyl or perdeuteroalkyl and R ⁷ means C ₁ -C ₃ alkyl, deuteroalkyl or perdeuteroalkyl.

5. Deuterated pyrazolopyrimidinones according to claim 1, characterized in that

R ¹ is independently H or D,

R ^{2 is} C ₁ -C ₃ -alkyl, -deuteroalkyl or -perdeuteroalkyl, R ³ is Ci-Cg-alkyl, -deuteroalkyl or -perdeuteroalkyl,

R ⁴ D means

R ^s H or D,

R ^s represents C ₁ -C ₃ alkyl, deuteroalkyl or perdeuteroalkyl and

R ⁷ means C ₁ -C ₃ alkyl, deuteroalkyl or perdeuteroalkyl.

6. Deuterated pyrazolopyrimidinones according to claim 1, characterized in that

R ¹ D is,

R ² means C ₁ -C ₃ -alkyl, -deuteroalkyl or -perdeuteroalkyl,

R ³ is C _x -C ₆ -alkyl, -deuteroalkyl or -perdeuteroalkyl,

R ⁴ independently means H or D,

R ^s D is,

^RS represents C ₁ -C ₃ alkyl, deuteroalkyl or perdeuteroalkyl and R ⁷ represents C ₁ -C ₃ alkyl, deuteroalkyl or perdeuteroalkyl.

7. Deuterated pyrazolopyrimidinones according to claim 1, characterized in that R ¹ is D,

R ² perdeuteroethyl means, R ³ is C- _L -Cg-alkyl, -deuteroalkyl or -perdeuteroalkyl,

R ⁴ independently represents H or D, R ⁵ is H or D, R ^δ represents trideuteromethyl and

R ⁷ means C _x -C ₃ -alkyl, -deuteroalkyl or -perdeuteroalkyl.

8. Deuterated pyrazolopyrimidinones according to claim 1, characterized in that

R ¹ D is,

R ² perdeuteroethyl means,

R ³ Ci-Cg-alkyl,. -Deuteroalkyl or -Perdeuteroalkyl, R ⁴ independently represents H or D,

R ⁵ is H or D,

R ⁶ represents C ₁ -C ₃ alkyl, deuteroalkyl or perdeuteroalkyl and

R ⁷ means perdeutero-n-propyl.

9. 5-[2-d5-Ethoxy-5-(4-methylpiperazine-l-sulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydropyrazolo[4,3-d]pyrimidine-7 -on.

10. 5-[2-d5-Ethoxy-5-(4-methylpiperazine-l-sulfonyl)-3,4,6-trideuterophenyl]-1-methyl-3-n-propyl-1,6-dihydropyrazolo[4, 3-d] pyrimidin-7-one.

11. 5-[2-d5-Ethoxy-5-(4-trideuteromethylpiperazine-l-sulfonyl)-3, 4, 6-trideuterophenyl] -1-methyl-3-n-propyl-1, 6-dihydropyrazolo [4, 3-d] pyrimidin-7-one.

12. 5-[2-d5-Ethoxy-5-(dll-4-methylpiperazine-l-sulfonyl)-3,4,6-trideuterophenyl]-1-methyl-3-n-propyl-1,6-dihydropyrazolo[ 4, 3-d]pyrimidin-7-one.

13. 5-[2-d5-Ethoxy-5-(dll-4-methylpiperazine-l-sulfonyl)-3,4,6-trideuterophenyl]-1-trideuteromethyl-3-n-propyl-1,6-dihydropyrazolo[ 4, 3-d] pyrimidin-7-one.

14. 5-[2-d5-Ethoxy-5-(dll-4-methylpiperazine-1-sulfonyl)-3,4,6-trideuterophenyl]-1-trideuteromethyl-3-n-propyl-1,6-dihydropyrazolo[ 4 , 3-d] -6D-pyrimidin-7-one

15. 5-[2-d5-Ethoxy-5-(dll-4-methylpiperazine-l-sulfonyl)-3, 4, 6-trideuterophenyl]-1-tideuteromethyl-3-n-d7-propyl-1,6 -dihydropyrazolo [4,3-d]pyrimidin-7-one.

16. 5-[2-d5-Ethoxy-5-(dll-4-methylpiperazine-l-sulfonyl)-3,4,6-trideuterophenyl]-1-trideuteromethyl-3-n-d7-propyl-1,6- dihydropyrazolo [4, 3-d]-6D-pyrimidin-7-one.

17. 5-[2-Ethoxy-5-(4-trideuteromethylpiperazin-1-sulfonyl)phenyl]-l-methyl-3-n-propyl-1, 6-dihydropyrazolo[4, 3-d]pyrimidin-7-one .

18. 5-[2-Ethoxy-5-(4-trideuteromethylpiperazin-1-sulfonyl)phenyl] -1-trideuteromethyl-3-n-propyl-1, 6-dihydropyrazolo[4, 3-d]pyrimidin-7-one .

19. 5-[2-Ethoxy-5-(4-trideuteromethylpiperazine-l-sulfonyl)phenyl]-l-methyl-3-n-d7-propyl-l, 6-dihydropyrazolo[4, 3-d]pyrimidine-7 -on.

20. 5-[2-Ethoxy-5-(4-trideuteromethylpiperazine-1-sulfonyl)phenyl] -1-methyl-3-n-propyl-1,6-dihydropyrazolo[4, 3-d] -6D-pyrimidine- 7-on.

21. 5-[2-Ethoxy-5-(dll-4-methylpiperazine-l-sulfonyl)phenyl] -l-trideuteromethyl-3-n-propyl-l, 6-dihydropyrazolo[4, 3-d]pyrimidine-7 -on.

22. 5-[2-Ethoxy-5-(dll-4-methylpiperazine-1-sulfonyl)phenyl] -l-methyl-3-n-d7-propyl-l, 6-dihydropyrazolo[, 3-d]pyrimidine- 7-o .

23. 5-[2-Ethoxy-5-(dll-4-methylpiperazine-l-sulfonyl)phenyl]-1-trideuteromethyl-3-n-d7-propyl-1,6-dihydropyrazolo[4,3-d]pyrimidine -7-o .

1. 5-[2-Ethoxy-5-(dll--methylpiperazine-1-sulfonyl)phenyl]-l-trideuteromethyl-3-n-d7-propyl-1, 6-dihydropyrazolo[4, 3-d]-6D -pyrimidin-7-one.

25. 5-[2-d5-Ethoxy-5-(piperazin-1-sulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-one .

26. 5-[2-d5-Ethoxy-5-(piperazine-1-sulfonyl)-3,4,6-trideuterophenyl] -1-methyl-3-n-propyl-1, 6-dihydropyrazolo[, 3-d ] pyrimidin-7-one.

27. 5-[2-d5-ethoxy-5-(2,2,3,3,5,5,6,6-octadeuteropiperazine-1-sulfonyl)-3,4,6-trideuterophenyl]-l-methyl- 3-n-propyl-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-one.

28. 5-[2-d5-ethoxy-5-(2,2,3,3,5,5,6,6-octadeuteropiperazine-1-sulfonyl)-3,4,6-trideuterophenyl]-l-trideuteromethyl- 3-n-propyl-l, 6-dihydropyrazolo[4, 3-d]pyrimidin-7-one.

29. 5-[2-d5-Ethoxy-5-(2, 2, 3, 3, 5, 5,6, 6-octadeuteropiperazine-1-sulfonyl)-3,4,6-trideuterophenyl]-1-trideuteromethyl- 3-n-propyl-1,6-dihydropyrazolo[4, 3-d]-6D-pyrimidin-7-one.

30. 5-[2-d5-Ethθxy-5-(2,2,3,3,5,5,6,6-octadeuteropiperazine-1-sulfonyl) -3,4,6-trideuterophenyl] -1-trideuteromethyl- 3-n-d7-propyl-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-one.

31. 5-[2-d5-Etnoxy-5-(2,2,3,3,5,5,6,6-octadeuteropiperazine-1-sulfonyl) -3,4,6-trideuterophenyl] -1-trideuteromethyl- 3-n-d7-propyl-1,6-dihydropyrazolo[4,3-d]-6D-pyrimidin-7-one.

32. 5-[2-Ethoxy-5-(2,2,3,3,5,5,6, 6-octadeuteropiperazine-1-sulfonyl)phenyl]-l-trideuteromethyl-3-n-propyl-l, 6 - dihydropyrazolo [4, 3-d]pyrimidin-7-one.

33. 5-[2-Ethoxy-5-(2,2,3,3, 5,5, 6,6-octadeuteropiperazine-1-sulfonyl)phenyl] -1-methyl-3-n-d7-propyl-1 ,6-dihydropyrazolo[4,3-d]pyrimidin-7-one.

34. 5-[2-Ethoxy-5-(2,2, 3, 3, 5, 5, 6, 6-octadeuteropiperazine-1-sulfonyl)phenyl] -1-trideuteromethyl-3-n-d7-propyl-

1, 6-dihydropyrazolo[4, 3-d]pyrimidin-7-one.

35. 5-[2-Ethoxy-5-(2,2,3,3,5,5,6, 6-octadeuteropiperazine-1-sulfonyl)phenyl]-1-trideuteromethyl-3-n-d7-propyl-1 , 6-dihydropyrazolo[4, 3-d]-6D-pyrimidin-7-one.

36. 5-[2-d5-ethoxy-5-(d9-piperazine-l-sulfonyl)-3,4,6-trideuterophenyl]-1-methyl-3-n-propyl-1,6-dihydropyrazolo[4, 3-d] pyrimidin-7-one.

37. 5-[2-d5-ethoxy-5-(d9-piperazine-l-sulfonyl)-3,4,6-trideuterophenyl] -1-trideuteromethyl-3-n-propyl-1,6-dihydropyrazolo [4, 3-d]pyrimidin-7-one.

38. 5-[2-d5-ethoxy-5-(d9-piperazine-l-sulfonyl)-3, 4, 6-trideuterophenyl] -l-trideuteromethyl-3-n-propyl-l, 6-dihydropyrazolo [4, 3-d]-6D-pyrimidin-7-one.

39. 5-[2-d5-ethoxy-5-(d9-piperazine-l-sulfonyl)-3,4,6-trideuterophenyl]-1-trideuteromethyl-3-n-d7-propyl-1,6-dihydropyrazolo[ 4, 3-d] pyrimidin-7-one.

40. 5-[2-d5-ethoxy-5-(d9-piperazine-l-sulfonyl)-3,4,6-trideuterophenyl]-1-trideuteromethyl-3-n-d7-propyl-1,6-dihydropyrazolo[ 4, 3-d] -6D-pyrimidin-7-one.

41. 5-[2-Ethoxy-5-(d9-piperazin-l-sulfonyl)phenyl] -1-trideuteromethyl-3-n-propyl-l, 6-dihydropyrazolo[4,3-d]pyrimidin-7-one .

42. 5-[2-Ethoxy-5-(d9-piperazine-l-sulfonyl)phenyl] -1-methyl-3-n-d7-propyl-1, 6-dihydropyrazolo[4,3-d]pyrimidine-7 -on.

43. 5-[2-Ethoxy-5-(d9-piperazine-l-sulfonyl)phenyl] -1-trideuteromethyl-3-n-d7-propyl-1,6-dihydropyrazolo[4, 3-d]pyrimidine-7 -on.

44. 5-[2-Ethoxy-5-(d9-piperazine-l-sulfonyl)phenyl] -1-trideuteromethyl-3-n-d7-propyl-1,6-dihydropyrazolo[4, 3-d] -6D- pyrimidin-7-one.

45. Use of the deuterated pyrazolopyrimidinones according to one of claims 1 to 44 and their physiologically tolerated salts for inhibiting platelet adhesion and aggregation, for long-term increase in memory performance and learning ability and for the treatment of cardiac and circulatory diseases, hypertension, pulmonary Hypertension, erectile dysfunction and obstructive respiratory diseases such as bronchial asthma.

46. Use of the deuterated pyrazolopyrimidinones according to the invention according to one of claims 1 to 44 and their physiologically tolerated salts for the production of drugs for the inhibition of platelet adhesion and aggregation, for the long-term increase in memory performance and learning ability and for the treatment of cardiac and circulatory diseases, hypertension, pulmonary hypertension, erectile dysfunction and obstructive respiratory diseases such as bronchial asthma.

47. Pharmaceutical compositions containing deuterated pyrazolopyrimidinones according to one of claims 1 to 44 and their physiologically tolerated salts for inhibiting platelet adhesion and aggregation, for long-term increase in memory performance and learning ability and for the treatment of cardiac and circulatory diseases, hypertension, pulmonary hypertension, erectile Dysfunction and obstructive respiratory diseases such as bronchial asthma, in addition to pharmaceutically acceptable auxiliaries and/or additives.