DE10021069A1 - Substituted pyrazole derivative - Google Patents

Abstract

The invention relates to a substituted pyrazole derivative of formula (I), to a method for the production thereof, and to its use as a medicament, in particular, as a medicament for treating cardiovascular diseases.

Description

The present invention relates to a substituted pyrazole derivative, a process for its manufacture and its use as a medicament, especially as a medicament agent for the treatment of cardiovascular diseases.

It is already known that 1-benzyl-3- (substituted heteroaryl) fused pyrazole Derivatives inhibit platelet aggregation (cf. EP 667 345 A1).

WO 98/16223 discloses the use of 1-benzyl-3- (substituted-hetaryl) -con Densified pyrazole derivatives for the treatment of special diseases of the Cardiovascular system and the central nervous system.

WO 98/16507 discloses heterocyclylmethyl-substituted pyrazole derivatives and their Use in the treatment of cardiovascular diseases.

WO 98/23619 also discloses substituted pyrazole derivatives for the treatment of Cardiovascular diseases.

The present invention relates to a substituted pyrazole derivative of the formula (I)

and its isomers, hydrates and salts.

The compound of formula (I) according to the invention can also be in hydrate form or in Form of their salts. In general, here are salts with organic or called inorganic bases or acids.

In the context of the present invention, physiologically acceptable salts prefers. Physiologically acceptable salts of the compound according to the invention can salts of the substance according to the invention with mineral acids, carboxylic acids or Be sulfonic acids. Z are particularly preferred. B. salts with hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethane sulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, vinegar acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Physiologically acceptable salts can also be metal or ammonium salts compound of the invention. Z are particularly preferred. B. sodium, Potassium, magnesium or calcium salts, as well as ammonium salts, which are derived of ammonia, or organic amines such as ethylamine, di- or Triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, Arginine, lysine or ethylenediamine.

The compound according to the invention can be in stereoisomeric forms (enantiomers) exist. The invention relates to both the enantiomers and their mixture. The racemic forms can be standardized into the stereoisomerically uniform Separate components.

The compound of the formula (I) according to the invention exhibits an unforeseeable value full spectrum of pharmacological effects.  

In particular, it leads to vascular relaxation, platelet aggregation inhibition and to lower blood pressure and increase coronary blood flow. These effects are via direct stimulation of soluble guanylate cyclase and an intracellular increase in cGMP. In addition, the invention reinforces according compound of formula (I) the effect of substances that the cGMP Increase levels, such as EDRF (Endothelium derived relaxing factor), NO- Donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.

It can therefore be used in medicines to treat cardiovascular diseases such as for the treatment of high blood pressure and heart failure, stable and unstable angina, peripheral and cardiac vascular diseases, of arrhythmias, for the treatment of thromboembolic disorders and Ischemia such as myocardial infarction, stroke, transistoric and ischemic attacks, peripheral circulatory disorders, prevention of restenosis such as after thrombo lysis therapies, percutaneously transluminal angioplasties (PTA), percutaneously transluminal Coronary angioplasty (PTCA), bypass and for the treatment of arteriosclerosis, asthmatic diseases and diseases of the genitourinary system such as wise prostate hypertrophy, erectile dysfunction, female sexual dysfunction and Incontinence.

The compound of formula (I) described in the present invention also provides an active ingredient for combating diseases in the central nervous system, the are characterized by malfunctions of the NO / cGMP system. In particular, it is ge is suitable for eliminating cognitive deficits, for improving learning and memory benefits and for the treatment of Alzheimer's disease. It is also suitable for the treatment of diseases of the central nervous system such as anxiety, tension and depression, central nervous system-related sexual dysfunction and sleep disorders, as well as to regulate pathological disorders of food, enjoyment and Drug addiction.  

The active ingredient is also suitable for regulating cerebral blood flow and is therefore an effective means of fighting migraines.

It is also suitable for the prophylaxis and control of the consequences of cerebral infarction happen (apoplexia cerebri) such as stroke, cerebral ischemia and the skull Brain trauma. The compound of the formula (I) according to the invention can also be used Combating painful conditions can be used.

In addition, the invention comprises the combination of the invention Compound of formula (I) with organic nitrates and NO donors.

Organic nitrates and NO donors within the scope of the invention are general Substances that have their therapeutic effect on the release of NO or NO species Make an impact. Sodium nitroprusside, nitroglycerin, isosorbide di are preferred nitrate, isosorbide mononitrate, molsidomine and SIN-1.

The invention also includes the combination with compounds that degrade inhibit of cyclic guanosine monophosphate (cGMP). These are in particular Inhibitors of phosphodiesterases 1, 2 and 5; Nomenclature according to Beavo and Reif snyder (1990) TiPS 11 p. 150 to 155. These inhibitors reduce the effect of Potentiated compound of the invention and the desired pharmacological Effect increased.

The compound of the formula (I) according to the invention can be prepared according to the following reaction scheme:

The production process according to the invention for the compound of formula (I) is characterized in that
the compound of formula (II)

with phenylazomalononitrile in the presence of a base and subsequent reaction with hydrogen in the presence of a catalyst to give the compound of the formula (III)

is implemented, and then by reaction with a hydroxyl protected 2-hydroxyacetaldehyde, reduction of the imino group obtained, Ab cleavage of the hydroxy protecting group and reaction with glyoxal in the compound of formula (I) is converted.  

The compound of formula (II) is in a multi-step synthesis from the literature known sodium salt of ethyl cyanobrenzenate (Borsche and Man devil, Liebigs. Ann. Chem. 1934, 512, 97). By implementing it with 2-fluorobenzylhydrazine under heating and in a protective gas atmosphere in an inert Solvents such as dioxane give 5-amino-1- (2-fluorobenzyl) pyrazole-3- carboxylic acid ethyl ester, which by reaction with dimethylaminoacrolein in acid Medium under a protective gas atmosphere and heating to the corresponding pyridine derivative cyclized. This pyridine derivative 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyri din-3-carboxylic acid ethyl ester is composed of a multi-step sequence consisting of Conversion of the ester with ammonia to the corresponding amide, dehydration with a dehydrating agent such as trifluoroacetic anhydride corresponding nitrile derivative, reaction of the nitrile derivative with sodium methylate and final reaction with ammonium chloride in the compound of formula (II) transferred.

The synthesis of phenylazomalondinitrile from aniline and malondinitrile by Diazotization is known from the literature ((L. F. Cavalieri, J. F Tanker, A. Bendich J. Am. Chem. Soc. 1949, 71.533).

The reaction of the compound of formula (II) with phenylazomalononitrile is carried out in the presence of a base. In general, inorganic or organic bases can be used as bases. These preferably include alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, or alkali metal or alkaline earth metal alcoholates such as sodium or potassium methoxide, sodium or potassium ethoxide or potassium, or organic butyl Amines (trialkyl (C ₁ -C ₆ ) amines) such as triethylamine, or heterocycles such as 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo- [5.4.0] undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. It is also possible to use alkali metals such as sodium and their hydrides such as sodium hydride as bases. Sodium methoxide is preferred.

Inert organic solvents are suitable as solvents. These include ethers, such as diethyl ether or tetrahydrofuran, DME, dioxane, alcohols such as methanol and Ethanol, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachlor methane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or Trichlorethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexa methylphosphoric triamide. It is also possible to use mixtures of the solvents put. Tetrahydrofuran, dimethylformamide, toluene, dioxane is particularly preferred or dimethoxyethane.

The reaction is carried out with heating to temperatures between 60 ° C and 110 ° C and Normal pressure carried out. The reaction mixture is left for about 5-24 hours react preferably 12 to 24 hours.

The compound of the formula (III) is then obtained by cleaving the azo group. Metals, in particular zinc, can be used as reducing agents in the presence of mineral acids such as hydrochloric acid, Na ₂ SO ₄ , boranes or hydrogen in the presence of a catalyst. The use of hydrogen in the presence of Raney nickel is preferred according to the invention.

The solvents mentioned above can be used as solvents. Dimethylformamide (DMF) is particularly preferred. The reaction is preferred as with heating, for example at 50-80 ° C, and a hydrogen pressure of 30 to 80 bar, preferably 50 to 70 bar. You leave the reactants respond about 24 hours.

The compound of formula (III) is protected with a hydroxyl-protected 2-hydroxy implemented acetaldehyde and then reduced the resulting imino group. As Protecting groups for the hydroxyl function come the conventional, the expert  known hydroxyl protecting groups in question. The use of a is preferred Silyl protecting group, especially the t-butyldimethylsilyl protecting group.

The solvents mentioned above can be used as solvents. Methanol is particularly preferred. The reaction is preferably at room temperature and normal pressure.

The imino group obtained by this reaction is preferably ent in situ speaking secondary amino group reduced. For this, the specialist reducing agents known for this reaction, such as alkali metal hydrides, for example Lithium aluminum hydride or sodium borohydride or sodium cyanoborohydride, alkali metals such as sodium in ethanol or hydrogen in the presence of a catalyst be used. The reduction with sodium cyano is preferred according to the invention borohydride in the presence of a dehydrating agent such as molecular sieve. The Reduction is preferably carried out at room temperature and is after about 2 to 8 hours, preferably completed after about 3 to 5 hours.

From the hydroxyl-protected ethanolamine derivative thus obtained, the invention according compound of formula (I) by deprotection of the hydroxyl group and get final reaction with glyoxal. The choice of deprotectant is depending on the selected protective group. In the case of those preferred according to the invention Silyl protecting groups can preferably fluoride compounds such as tetrabutylammo nium fluoride among conventional for these reactions and known to those skilled in the art Conditions are used.

The reaction with glyoxal, preferably in the form of its hydrate, is under protection gas atmosphere, for example under nitrogen or a noble gas such as argon guided. The reaction is carried out at room temperature for about 12 to 24 hours guided. As a solvent for these last steps also come the ge above called solvents in question, with tetrahydrofuran (THF) is particularly preferred.  

Instead of glyoxal, acetal compounds thereof - optionally in Presence of acids - can be used.

The invention is explained in more detail below by a preferred exemplary embodiment explained, but to which it is not limited. Unless otherwise indicated, all quantities below refer to percentages by weight.

Examples Abbreviations

RT: room temperature
EE: ethyl acetate
MCPBA: m-chloroperoxybenzoic acid
BABA: n-butyl acetate / n-butanol / glacial acetic acid / phosphate buffer pH 6
(50: 9: 25.15; original phase)

Solvent for thin layer chromatography

T1 E1: toluene-ethyl acetate (1: 1)
T1 EtOH1: toluene-methanol (1: 1)
C1 E1: cyclohexane-ethyl acetate (1: 1)
C1 E2: cyclohexane-ethyl acetate (1: 2)

1. Preparation of 5-amino-1- (2-fluorobenzyl) pyrazole-3-carboxylic acid ethyl ester

100 g (0.613 mol) sodium salt of ethyl cyanobenzofruenate (representation analogous to Borsche and Manteuffel, Liebigs Ann. 1934, 512, 97) are under good Stir under argon in 2.5 l dioxane at room temperature with 111.75 g (75 ml, 0.98 mol) of trifluoroacetic acid were added and the mixture was stirred for 10 min, a large part of the Educt goes into solution. Then 85.93 g (0.613 mol) of 2-fluorobenzylhydrazine are added  and cook over night. After cooling, the precipitated crystals of the Sucked off sodium trifluoroacetate, washed with dioxane and the solution continues raw implemented.

2. Preparation of 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboxylic acid ethyl ester

The solution obtained from 1. is mixed with 61.2 ml (60.77 g, 0.613 mol) of dimethylamino acrolein and 56.28 ml (83.88 g, 0.736 mol) of trifluoroacetic acid and boiled under argon for 3 days. The solvent is then evaporated in vacuo, the residue is poured into 2 l of water and extracted three times with 1 l of ethyl acetate. The combined organic phases are dried with magnesium sulfate and evaporated. It is chromatographed on 2.5 kg of silica gel and eluted with a toluene / toluene-ethyl acetate = 4: 1 gradient. Yield: 91.6 g (49.9% of theory over two stages).
Mp 85 ° C
R _f (SiO ₂ , T1E1): 0.83

3. Preparation of 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboxamide

10.18 g (34 mmol) of the ester obtained in Example 2 are placed in 150 ml of methanol saturated with ammonia at 0-10 ° C. The mixture is stirred at room temperature for two days and then concentrated in vacuo.
R _f (SiO ₂ , T1E1): 0.33

4. Preparation of 3-cyano-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine

36.1 g (133 mmol) of 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboxamide from Example 3 are dissolved in 330 ml of THF and 27 g (341 mmol) of pyridine are added. Then 47.76 ml (71.66 g, 341 mmol) of trifluoroacetic anhydride are added over the course of 10 minutes, the temperature rising to 40.degree. The mixture is stirred overnight at room temperature. Then the mixture is poured into 1 l of water and extracted three times with 0.5 l of ethyl acetate. The organic phase is washed with saturated sodium bicarbonate solution and with 1N HCl, dried with MgSO ₄ and evaporated.
Yield: 33.7 g (100% of theory)
Mp: 81 ° C
R _f (SiO ₂ , T1E1): 0.74

5. Preparation of (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboximide acid methyl ester

30.37 g (562 mmol) of sodium methylate are dissolved in 1.5 l of methanol and 36.45 g are added (144.5 mmol) 3-cyano-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine (from Example 4) added. The mixture is stirred for 2 hours at room temperature and the resulting solution is placed directly for the next level.  

6. Preparation of 1- (2-fluorobenzyl) 1H-pyrazolo [3,4-b] pyridine-3-carboxamidine (Compound II)

The solution of (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboximidic acid methyl ester in methanol obtained from Example 5 is combined with 33.76 g (32.19 ml, 562 mmol) of glacial acetic acid and 9.28 g (173 mmol) of ammonium chloride added and stirred under reflux overnight. The solvent is evaporated off in vacuo, the residue is triturated well with acetone and the precipitated solid is filtered off with suction. It is added to 2 l of water, 31.8 g of sodium carbonate are added with stirring and the mixture is extracted three times with a total of 1 l of ethyl acetate, the organic phase is dried using magnesium sulfate and evaporated in vacuo.
Yield 27.5 g (76.4% of theory over two stages)
M.p .: 86 ° C
R _f (SiO ₂ , T1EtOH1): 0.08

7. Preparation of 2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] - 5 - [(E) -phenyldiazenyl] -4,6-pyrimidinediamine

A solution of 21.92 g (71.7 mmol) of 1- (2-fluorobenzyl) 1H is added to a stirred solution pyrazolo [3,4-b] pyridine-3-carboxamidine in toluene from Example 6 3.87 g of sodium methanolate and then 12.2 g (71.7 mmol) phenylazomalononitrile (L.F. Cavalieri, J.F. Tanker, A. Bendich J. Am. Chem. Soc., 1949, 71, 533). You stir overnight at 110 ° C and let cool. The solid that precipitates becomes suction filtered and washed with ethanol. After drying, 23 g (73% d. Th.) Of the target connection.  

8. Preparation of 2- [1- (2-fluorobenzyl) -1H-p azolo [3,4-b] pyridin-3-yl] - 4,5,6-pyrimidine triamine trihydrochloride (compound (III)

5 g (11.38 mmol) of 2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -5 - [(E) - phenyldiazenyl] -4,6-pyrimidinediamine Example 7 are with 800 mg 50 percent. Raney nickel in water in 60 ml DMF for 22 hours at 65 bar hydrogen pressure and 62 ° C hydrogenated. It is suctioned off from the catalyst over Kieselguhr, the solution is evaporated in vacuo and stirred with 5 N HCl. The precipitated yellow-brown precipitate is suctioned off and dried. 3.1 g (59.3% of theory) of the target compound are obtained. The free base is obtained by shaking out with dilute NaHCO ₃ solution and extracting with ethyl acetate. The solid which is insoluble in both phases is filtered off with suction. The ethyl acetate phase also contains small amounts of the free base.

9. Preparation of N5- (2 - {[tert-butyl (dimethyl) silyl] oxy} ethyl) -2- [1- (2-fluoro benzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -4,5,6-pyrimidinetriamine

6 g (17.13 mmol) of 2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] 4,5,6-pyrimidinetriamine from Example 8 are dissolved in 200 ml of methanol and adds 3.28 g (18.84 mmol) of t-butyldimethylsilyloxyacetaldehyde. Then 30 g molecular sieve, and after 10 minutes 1.35 g (22.26 mmol) sodium cyanoborohydride and 4 ml glacial acetic acid are added and the mixture is stirred for 5 hours at room temperature. Decant from the molecular sieve, add 35 g of silica gel and evaporate in vacuo. The residue is chromatographed on an SiO ₂ column using toluene / ethyl acetate = 5: 1 → ethyl acetate. After a pre-fraction (R _f [SiO ₂ , toluene / ethyl acetate = 1: 1] = 0.67; bis (TBDMS-oxyethyl) compound), 3.3 g (37.9% of theory) of a yellow solid are obtained as the main fraction
R _f (SiO ₂ , toluene / ethyl acetate = 1: 1): 0.27 and 0.22 (double stain, very bright in the UV).

10. Preparation of 3-amino-5- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine- 3-yl] -10-oxa-1,4,6,8-tetraazatricyclo [7.3.1.02.7] trideca-2,4,6-trien-13-ol (Compound I)

1.5 g (2.95 mmol) of N5- (2 - {[tert-butyl (dimethyl) silyl] oxy} ethyl) -2- [1- (2- (2-fluorobenzyl) -1H-pyrazolo [3,4- b] pyridin-3-yl] -4,5,6-pyrimidinetriamine from Example 9 in 20 ml of tetrahydrofuran (THF), adds 2.68 ml (2.95 mmol) of a 1.1 M solution of tetrabutylammonium fluoride in THF and stirred for 2 hours at room The thin layer chromatogram shows complete conversion to a new main product, 2 - ({4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-yl] -5-pyrimidinyl} amino) ethanol (R _f [SiO ₂ , ethyl acetate] = 0.12; educt: 0.7).
¹ H-NMR (300 MHz, DMSO): δ = 2.85 (m, 2H, CH ₂ ), 3.15 (m, 1H), 3.45 (m, 2H), 4.8 (t, 1H), 5.8 (s, 2H, CH ₂ Ph), 6.15 (s, 4H, 2 NH ₂ ), 7.1 (m, 2H), 7.2 (m, 1H), 7.31 (m, 2H), 8.6 (dd, 1H, pyrazolopyridine H6), 9.05 (dd , 1H, pyrazolopyridine H4).

Then, while stirring under argon, 693 mg (0.69 ml, 2.95 mmol) of a 40 percent. aqueous glyoxal hydrate solution and stir overnight. Complete sales of two new main products can be seen in the HPLC. The solution is evaporated in vacuo and eluted on an RP-8 column with a gradient of acetonitrile / water = 10/90 → 90/10. The second fraction contains the desired compound. It is freed from the acetonitrile portion in vacuo and the precipitated product is suctioned off from the aqueous solution and washed with ether. 150 mg of a pale yellow powder are obtained.
1H-NMR (400 MHz, CD ₃ CN, exchange with MeOH): δ = 3.0 (m, 1H), 3.18 (m, 1H), 3.22-3.34 (m, 2H), 4.5 (s, 1H), 4.8 ( d, 1H), 5.8 (s, 2H, CH ₂ ), 5.95 (d, 1H, exchange, OH), 6.2 (broad s, 2H, exchange, NH ₂ ), 7.11 (m, 2H, 2-fluorobenzyl), 7.22 (m, 2H, fluorobenzyl), 7.34 (dd, 1H, pyrazolopyridine H5), 8.05 ppm (1H, d, exchange, OH), 8.6 (dd, 1H, pyrazolopyridine H6), 9.05 (dd, 1H, pyrazolopyridine H4) .

Biological studies 1. Stimulation of the recombinant soluble guanylate cyclase (sGC) in vitro

The studies on the stimulation of recombinant soluble guanylate cyclase (sGC) by the compound of the invention was according to the following Literature performed method described in detail: M. Hoenicka, E. M. Becker, H. Apeler, T. Sirichoke, H. Schroeder, R. Gerzer and J.-P. Stasch: Purified soluble guanylyl cyclase expressed in a baculovirus / Sf9 system: stimulation by YC- 1, nitric oxide, and carbon oxide. J. Mol. Med. 77 (1999) 14.

The activation of the sGC by a test substance is called n-fold stimulation of the Basal activity specified.

Table 1

2. Vascular relaxant effect in vitro

Rabbits are anesthetized and bled by the blow of the neck. The aorta is removed, adherent tissue is removed, divided into 1.5 mm wide rings and individually pretensioned in 5 ml - organ baths with 37 ° C warm, carbogen-gassed Krebs-Henseleit solution of the following composition (mM): NaCl: 119 ; KCl: 4.8; CaCl ₂ × 2 H ₂ O: 1; MgSO ₄ x 7 H ₂ O: 1.4; KH ₂ PO ₄ : 1.2; _NaHCO3: 25; Gliteosis: 10. The contraction force is recorded with Statham UC2 cells, amplified and digitized via A / D converter (DAS-1802 HC, Keithley Instruments Munich), and recorded in parallel on line recorders. To create a contraction, phenylephrine is added cumulatively to the bath in increasing concentration. After several control cycles, the substance to be examined is examined in increasing doses in each further run and the level of the contraction is compared with the level of the contraction achieved in the last previous run. This is used to calculate the concentration required to reduce the control value by 50% (IC ₅₀ ).
Compound (I): IC ₅₀ = 1200 nM

3. Blood pressure measurements on anesthetized rats

Male Wistar rats with a body weight of 300-350 g are anesthetized with thiopental (100 mg / kg ip). After tracheotomy, a catheter for blood pressure measurement is inserted into the femoral artery and a catheter for substance administration into the femoral vein. The substance to be tested is administered intravenously in Transcutol / Cremophore / EL / H ₂ O (10% / 10% / 80%) in a volume of 1 ml / kg. Compound (I) induces a dose-dependent and long-lasting lowering of blood pressure in rats. After intravenous administration of 0.1 mg / kg and 0.3 mg / kg, a maximum drop in blood pressure of -17 mm and -41 mm Hg was observed.

Claims (13)

1. Compound of formula (I)
and their isomers, hydrates and salts. 2. A process for the preparation of the compound according to claim 1, characterized in that the compound of formula (II)
with phenylazomalononitrile in the presence of a base and subsequent reaction with hydrogen in the presence of a catalyst to give the compound of the formula (III)
is reacted, and this is subsequently converted into the compound of the formula (I) by reaction with a hydroxyl-protected 2-hydroxyacetaldehyde, reduction of the imino group obtained, removal of the hydroxyl protective group and reaction with glyoxal. 3. Medicament containing the compound of formula (I) according to claim 1. 4. A process for the manufacture of medicaments, characterized in that the compound of formula (I) according to claim 1, optionally with usual auxiliaries and additives in a suitable application form leads. 5. Medicament containing the compound of formula (I) according to claim 1 in Combination with organic nitrates or NO donors. 6. Medicament containing the compound of formula (I) according to claim 1 in Combination with compounds that break down cyclic guanosine inhibit monophosphate (cGMP). 7. Use of the compound of formula (I) according to claim 1 for the preparation of drugs.   8. Use of the compound of formula (I) according to claim 1 in the Her Provision of medicines for the treatment of cardiovascular diseases. 9. Use according to claim 8, wherein the compound of formula (I) in com combination with organic nitrates or NO donors or in combination with Compounds that breakdown cyclic guanosine monophosphate (cGMP) inhibit is used. 10. Use of the compound of formula (I) according to claim 1 in the Her Provision of medicines for the treatment of thromboembolic disease kung and ischemia. 11. Use according to claim 10, wherein the compound of formula (I) in com combination with organic nitrates or NO donors or in combination with Compounds that breakdown cyclic guanosine monophosphate (cGMP) inhibit is used. 12. Use of the compound of formula (I) according to claim 1 in the Her Provision of drugs to treat sexual dysfunction. 13. Use according to claim 12, wherein the compound of formula (I) in com combination with organic nitrates or NO donors or in combination with Compounds that breakdown cyclic guanosine monophosphate (cGMP) inhibit is used.