EP1104421A1

EP1104421A1 - 3-(4-amino-5-ethylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1h-pyrazolo 3,4-b]pyridine

Info

Publication number: EP1104421A1
Application number: EP99936550A
Authority: EP
Inventors: Alexander Straub; Achim Feurer; Chantal FÜRSTNER; Cristina Alonso-Alija; Johannes-Peter Stasch; Elisabeth Perzborn; Joachim Hütter; Klaus Dembowsky; Elke Stahl
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 1998-07-29
Filing date: 1999-07-16
Publication date: 2001-06-06
Also published as: JP2002521481A; DE19834045A1; WO2000006567A1; AU5160499A

Abstract

The present invention relates to 3-(4-amino-5-ethylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine of formula (I), to a method for the production thereof and to its utilization as medicament, especially as medicament in the treatment of cardiovascular diseases.

Description

3- (4-Amino-5-ethylpyrinididin-2-yl) -l- (2-fluorobenzyl) -lH-pyrazolo [3,4-b1pyridine

The present invention relates to the 3- (4-amino-5-ethylpyrimidin-2-yl) -l- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] pyridine of the formula (I),

a process for its preparation and its use as a medicament, in particular as a medicament for the treatment of cardiovascular diseases.

The compound can be prepared by using the amidine of formula (II)

with the enamine of formula (III)

implements.

The reaction takes place in a temperature range from 80 ° C to 120 ° C, preferably at 100 ° C.

The enamine of the formula (III) can act as solvent. But you can also work in common solvents such as toluene, dioxane and alcohols.

The reaction can be carried out at normal, elevated or reduced pressure (e.g. 0.5 to 5 bar). Generally one works at normal pressure.

The compound of formula (II) is new and therefore another object of the invention. It can be prepared by using the compound of formula (IV)

first in ethers with trifluoroacetic anhydride (TFAA) and in the presence of bases to give the compound of the formula (V)

implements

then the compound of the formula (VI) with sodium methoxide

in a next step by reaction with NH ₄ C1 and glacial acetic acid in alcohols in the corresponding amidine HCl salt of the formula (VII)

transferred and added in a last step with bases, preferably sodium carbonate. Suitable solvents for reacting the compound of the formula (IV) -> (V) are ethers, such as diethyl ether, dioxane or tetrahydrofuran and dimethylformamide; tetrahydrofuran is preferred.

Organic amines (trialkyl (C, -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 can be used. Pyridine is preferred.

The reaction takes place in a temperature range from 0 ° C to 40 ° C, preferably at room temperature.

The amide (IV) can be carried out, for example, by saponification of a corresponding ester as the starting compound with a base to give the acid, its conversion into the acid chloride by customary methods, for example using SOCl ₂ or POCl ₃ and subsequent reaction with ammonia.

The elimination of water from the amide (IV) to the nitrile (V) can be carried out with all conventional dehydrating agents. Trifluoroacetic anhydride (TFAA) is preferred according to the invention.

The conversion of the nitrile (V) into the imino ether (VI) can be carried out in acid, e.g. with HCl / alcohol mixtures, as well as in basic such as with methanol / sodium methoxide. It is usually carried out at 0 ° C to 40 ° C, for example at room temperature.

Suitable solvents for the reaction of the compound of formula (V) -> (VI)

Alcohols such as methanol or ethanol. Methanol is preferred. The reaction takes place in a temperature range from 0 ° C to 100 ° C, preferably at room temperature.

Alcohols such as methanol or ethanol are suitable as solvents for the reaction of the compound of the formula (VI) -> (VII). Methanol is preferred.

The reaction takes place in a temperature range from 0 ° C to 100 ° C, preferably at 65 ° C.

Inorganic or organic bases are suitable as bases for the reaction of the compound of the formula (VII) -> (II). These include, for example, 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. Sodium carbonate is preferred.

The pyrimidine is prepared by customary methods (see, for example, MG Hoffmann et al. In: Houben-Weyl, Methods of Organic Chemistry, 4th Edition, Volume E9b, Part 1, pp. 1-249; A. Weissenberger et al ., The Chemistry of heterocyclic compounds - Pyrimidines, 1962, 16; ibid 1970, 16, Suppl. 1, ibid 1985, 16, Suppl. 2; ibid 1994, 52).

It is possible to start from the imino ether (VI) and to implement this, for example, with a suitable enamine such as (III). However, the imino ether (VI) can also first be converted into an amidine by means of ammonia or its salts, and this either as a free base (II) or as a salt (VII), if appropriate in the presence of one React base with enamines such as (III), acetals, enol ethers, aldehydes or enolates.

The enamines such as (III) can e.g. from C-H-acidic compounds such as acetonitrile derivatives by known methods by reaction with

Dimethylformamide derivatives such as e.g. Bis (dimethylamino) tert-butoxymethane, dialkoxy-dialkylamino-methanes can be produced.

The compound of formula (IV) can be prepared by the compound of formula (VIII)

with the compound of formula (IX)

in ethers, preferably dioxane and trifluoroacetic acid in the compound of the formula (X)

convicted, then by reaction with compound (XI)

(CH ₃ ) ₂ N - CH = CH-CHO (XI)

in inert solvents, preferably dioxane, the compound of formula (XII)

produces and in a last step ammonia optionally in methanol.

Instead of the sodium salt of enolate (VIII), it is also possible to use enol ethers, ketones or enamines.

If appropriate, the reaction of the compound of the formula (VIII) + (IX) -> (X) can also be carried out via intermediate compounds of the formulas (A) and (B),

B

at room temperature. The compound of formula (III) can be prepared by the compound of formula (XIII)

(CH ₃ ) ₂ N) ₂ - CH— O- (XIII)

with the compound of formula (XIV)

H ₅ C ₂ -CH ₂ -CN (XIV)

implemented at temperatures of 80 to 120 ° C.

The compounds of the formulas (XIII) and (XIV) are known and can be prepared by customary methods.

The compounds of the formulas (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) are new and can be prepared as described above.

The compound of formula (I) according to the invention shows an unforeseeable, valuable pharmacological spectrum of action.

The compound of the formula (I) according to the invention leads to vascular relaxation, platelet aggregation inhibition and to a reduction in blood pressure and to an increase in the coronary blood flow. These effects are mediated by direct stimulation of soluble guanylate cyclase and an intracellular increase in cGMP. In addition, the compound according to the invention enhances the action of substances which increase the cGMP level, such as EDRF (endothelium derived relaxing factor), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.

It can therefore be used in medicines for the treatment of cardiovascular diseases such as for the treatment of high blood pressure and heart failure, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, of arrhythmias, for the treatment of thromboembolic diseases and ischemia such as myocardial infarction, stroke, transitory and ischemic attacks , peripheral circulatory disorders, prevention of restenoses such as after thrombolysis therapies, percutaneously transluminal angioplasties (PTA), percutaneously transluminal coronary angioplasties (PTCA), bypass and for the treatment of arteriosclerosis and diseases of the genitourinary system such as prostate hypertrophy, female erectile dysfunction and erectile dysfunction.

The compound of formula (I) described in the present invention also represents an active ingredient for combating diseases in the central nervous system which are characterized by disorders of the NO / cGMP system. In particular, it is suitable for eliminating cognitive deficits, for improving learning and memory and for treating 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 dysfunctions and sleep disorders, as well as for the regulation of pathological disorders in the intake of food, luxury foods and addictive substances.

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 (apoplexia cerebri) such as stroke, cerebral ischemia and the skull Brain trauma. Likewise, the compound of formula (I) according to the invention can be used to combat painful conditions.

In addition, the compound of the formula (I) according to the invention has anti-inflammatory activity and can therefore be used as an anti-inflammatory agent.

In addition, the invention comprises the combination of the compound according to the invention with organic nitrates and NO donors.

Organic nitrates and NO donors within the scope of the invention are general

Substances that develop their therapeutic effect through the release of NO or NO species. Sodium nitroprusside, nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, molsidomine and SIN-1 are preferred.

The invention also includes combination with compounds that inhibit the degradation 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 pp. 150 to 155. These inhibitors potentiate the action of the compound according to the invention and increase the desired pharmacological effect.

The following tests were carried out to determine the cardiovascular effects: In vitro tests on cells of vascular origin tested the influence on guanylate cyclase-dependent cGMP formation with and without NO donor. The anti-aggregatory properties have been demonstrated on human platelets stimulated with collagen. The vasodilatory effect was determined on rabbit aortic rings precontracted with phenylephrine. The hypotensive effects were examined in anesthetized and awake rats. Stimulation of soluble guanylate cyclase in primary endothl cells

Primary endothelial cells were removed from porcine aorta by treatment with collagenase solution. isolated. The cells were then cultured in culture medium at 37 ° C./5% CO ₂ until confluence was reached. For the investigations, the cells were passaged, sown in 24-well cell culture plates and subcultivated until they reached confluence (~ 2 × 10 ⁵ cells / well). The culture medium was aspirated to stimulate endothelial guanylate cyclase and the cells were washed once with Ringer's solution. After removal of the Ringer's solution, the cells were incubated in stimulation buffer with or without NO donor (sodium nitroprusside, SNP or DEA / NO 1 μM) for 10 minutes at 37 ° C./5% CO ₂ . The test substances (final concentration 1 μM) were then pipetted into the cells and incubated for a further 10 minutes. After the incubation period, the buffer solution was aspirated and 4 ° C stop buffer was added to the cells. The cells were then lysed at -20 ° C for 16 hours. The supernatants containing the intracellular cGMP were then removed and the cGMP concentrations were determined by the cGMP-SPA system (Amersham Buchler, Braunschweig). The results are shown in Table 1 below.

Table 1

Vascular relaxant effect in vitro

Rabbits are anesthetized and bled by the blow of the neck. The aorta is removed, adhering tissue is removed, divided into 1.5 mm wide rings and individually pretensioned in 5 ml organ baths with carbogen at 37 ° C. fumigated Krebs-Henseleit solution with the following composition (mM): NaCl: 119; KC1: 4.8; CaCl ₂ x 2 H ₂ O: 1; MgSO ₄ x 7 H ₂ O; 1.4; KH ₂ PO ₄ : 1.2; _NaHCO3: 25; Glucose: 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 a line recorder. 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. From this, the concentration is calculated which is required to reduce the level of the control value by 50% (IC ₅₀ ). The standard application volume is 5 μl, the DMSO portion in the bath solution corresponds to 0.1%. The results are shown in Table 2 below.

Table 2

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 measuring blood pressure is inserted into the femoral artery. The substances to be tested are administered orally in Transcutol, Cremophor EL, H ₂ O (10% / 20% / 70%) in a volume of 1 ml / kg. The results are shown in Table 3 below. Table 3

Effect on mean blood pressure in conscious, spontaneously hypertensive rats

Continuous blood pressure measurements over 24 hours were carried out on spontaneously hypertensive 200-250g free-moving female rats (MOL: SPRD). For this purpose, the animals were chronically implanted with pressure transducers (Data Sciences Inc., St. Paul, MN, USA) in the descending abdominal aorta below the renal artery and the associated transmitter was fixed in the abdominal cavity.

The animals were housed individually in Type III cages positioned at the individual recipient stations and were on a 12 hour light / dark

Rhythm adjusted. Water and feed were freely available.

To collect data, the blood pressure of each rat was recorded every 5 minutes for 10 seconds. The measuring points were combined for a period of 15 minutes and the mean value was calculated from these values.

The test compounds were dissolved in a mixture of Transcutol (10%), Cremophor (20%), H ₂ O (70%) and administered orally using a gavage in a volume of 2 ml / kg body weight. The test doses were between 0.3 and 30 mg / kg body weight. Inhibition of platelet aggregation in vitro

Blood from healthy volunteers of both sexes was used to determine platelet aggregation. 9 parts of blood were added to one part of 3.8% sodium citrate solution as an anticoagulant. The blood was at 900

Centrifuged rpm for 20min. The pH of the platelet-rich plasma obtained was adjusted to pH 6.5 using ACD solution (sodium citrate / citric acid / glucose). The platelets were then centrifuged and taken up in buffer and centrifuged again. The platelet precipitate was taken up in buffer and 2 mmol / 1 CaCl _{2 were} additionally added.

For the aggregation measurements, aliquots of the platelet suspension with the test substance were incubated at 37 ° C. for 10 min. The aggregation was then triggered by adding collagen in an aggregometer and using the turbidometric method according to Born (Born, G.V.R., J.Physiol. (London), .168, 178-195,

1963) at 37 ° C. The results are shown in Table 4 below.

Table 4

Measurement of the erection-promoting effectiveness of guanylate cyclase stimulators

To achieve a complete and persistent erection, the cavernous arteries and the entire erectile tissue architecture, which is formed from a network of smooth muscle cells and collagenous connective tissue, have to dilate maximally so that the corpus cavernosum is completely filled with blood can (Anderson K.-E. and Wagner G., "Physiology of Penile Erection.". Physiological Reviews 75, 191-236 (1995); Meinhardt W. Kropmann RF, Vermeig P, Lycclama a Nigelholt and Zwartendijk J. "The Influence of Medication on Erectile dysfunction. "Int. J. of Impotence Res. 9, 17-26 (1997). Relaxation of the smooth muscles is mediated by NO, which is associated with sexual stimulation of non-adrenergic, non-cholinergic nerve fibers and in the endothelial cells NO activates guanylate cyclase, the resulting increase in cGMP leads to dilation of the smooth muscles of the corpus cavernosum and thus to an erection. To test the effectiveness of the substance according to the invention, rabbits were used. The species rabbit became rabbit chosen because the neurophysiology, the hemodynamics and the control of the contraction and relaxation of the smooth muscles of the erectile tissue in rabbits and humans are very similar h are (Meyer MF, Taher H. Kräh H. Staubesand J., Becker AJ, Kircher M, Mayer B., Jonas U., Forsmann WG., Stief Ch.G. "Intracarvenous Application of SIN-1 in Rabbit and

Man: Functional and Toxcological Results. "Annais Urol. 27, 179-182 (1993); Taub HC, Lerner, SE, Melman A, Christ GJ" Relationship between contraction and relaxation in human and rabbit corpus cavernosum. " Urology 42, 698-671, (1993).

Method:

Adult male chinchilla rabbits with a weight of 3-5 kg are adapted for individual days after delivery. They have free access to water and can eat food for two hours a day. The animals are kept in a 10/14 hour day-night rhythm (light on, from 8:00 a.m.), the room temperature is 22-24 ° C.

The animals are weighed immediately before the start of the experiment. For intravenous administration, the substances according to the invention were dissolved in a mixture of Transcutol (GATTEFOSSE GmbH) diluted with 20% Cremophor (BASF) and water in a ratio of 3/7. Sodium nitroprusside was dissolved in 0.9% NaCl. The substance was injected into the ear vein at a volume of 0.5 ml / kg injected. For oral administration, the test substance was dissolved in a mixture of glycerin: water: polyethylene glycol 6: 10: 9.69 and applied in a volume of 1 ml / kg with the gavage.

The action of guanylate cyclase stimulators is enhanced by NO donors.

This was demonstrated with the addition of sodium nitroprusside.

The sodium nitroprusside was injected into the ear vein at a dose of 0.2 mg / kg simultaneously with the substance according to the invention. If the substance according to the invention was given orally, these animals were given sodium nitroprusside for 30 min. injected into the ear vein after oral administration. Appropriate controls with the solvent and with sodium nitroprusside alone were carried out.

Under resting conditions, the rabbit penis is not visible in the pubic region and completely covered by the penile skin. The erection is evaluated by measuring the length of the protruding penis with a caliper. The measurement will be 5, 10, 15, 30, 45, 60min. 120 and 180 min. carried out after administration of the substance. The effect is calculated as the product of the length of the penis not covered by fur in [mmjand the time that the erection lasts in [min.].

The intravenous injection of sodium nitroprusside takes about 10 minutes. persistent erection (110 [mm x min.]).

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, include the inventive

Compound of the formula (I) contains and process for the preparation of these preparations.

The active ingredient can optionally also be present in microencapsulated form in one or more of the above-mentioned carriers. The therapeutically active compound should be present in the pharmaceutical preparations listed above in a concentration of approximately 0.1 to 99.5, preferably approximately 0.5 to 95% by weight of the total mixture.

In addition to the compound of the formula (I) according to the invention, the pharmaceutical preparations listed above can also contain further active pharmaceutical ingredients.

In general, it has proven to be advantageous in both human and veterinary medicine to use the active ingredient (s) according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg / kg of body weight per 24 hours, optionally in the form multiple doses to achieve the desired results. A single dose contains the active ingredient (s) according to the invention preferably in amounts of about 1 to about 80, in particular 3 to 30 mg / kg of body weight.

The present invention is illustrated below with the aid of non-restrictive preferred examples. Unless otherwise stated, all quantities refer to percentages by weight.

Examples

Abbreviations:

RT: room temperature

EE: ethyl acetate

MCPBA: m-chloroperoxybenzoic acid

B ABA: n-butyl acetate / n-butanol / glacial acetic acid / phosphate buffer pH 6

(50: 9: 25.15; original phase)

Eluents for thin layer chromatography:

T 1 E 1: toluene - ethyl acetate (1: 1) Tl EtOHl: toluene - methanol (1: 1)

C 1 E 1: cyclohexane - ethyl acetate (1: 1)

C 1 E2: cyclohexane - ethyl acetate (1: 2)

Output connections

Example 1A

3-dimethylamino-2-ethyl acrylonitrile

100 ml (84.4 g; 0.48 mol) of bis (dimethylamino) tert-butoxymethane and 180 ml (2.07 mol, 142.9 g) of n-butyronitrile are stirred in an open flask at 100 ° C. for 48 hours . It is then evaporated in vacuo and the residue is distilled in a high vacuum. 42.7 g (71% of theory) of the title compound are obtained.

* ^ Po 08-0093 ⁼ 53-46 C

Example 2A

5-Amino-1 - (2-fluorobenzyl) -1 H-pyrazole-3-carboxylic acid ethyl ester

100 g (0.613 mol) of sodium salt of ethyl cyanobrenzenate (representation analogous to Borsche and Manteuffel, Liebigs Ann. 1934, 512, 97) are mixed with 111.75 g (75 ml, 0.98 mol) of trifluoroacetic acid while stirring well under argon in 2.5 l of dioxane at room temperature Stirred for 10 min, a large part of the

Educt goes into solution. Then add 85.93 g (0.613 mol) of 2-fluorobenzylhydrazine and boil overnight. After cooling, the precipitated crystals of sodium trifluoroacetate are filtered off with suction, washed with dioxane and the solution is further reacted raw. Example 3A

Ethyl l- (2-fluorobenzyl) -IH-pyrazolo [3,4-b] pyridine-3-carboxylate

61.25 ml (60.77 g, 0.613 mol) of dimethylaminoacrolein and 56.28 ml (83.88 g, 0.736 mol) of trifluoroacetic acid are added to the solution from Example 2A and the mixture is boiled under argon for 3 days. The solvent is then evaporated in vacuo, the residue is poured into 2 liters of water and extracted three times with 1 liter of ethyl acetate. The combined organic phases are with

Dried 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

Rf (SiO ₂ , TlEl): 0.83

Example 4A

l- (2-fluorobenzyl) -IH-pyrazolo [3,4-b] pyridine-3-carboxamide

10.18 g (34 mmol) of the ester from Example 3A 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.

Rf (SiO ₂ , TlEl): 0.33

Example 5A

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

36.1 g (133 mmol) of l- (2-fluorobenzyl) -IH-pyrazolo [3,4-b] pyridine-3-carboxamide from Example 4A 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 within 10 min, the temperature rising to 40 ° C. The mixture is stirred overnight at room temperature. The mixture is then poured into 11 water and extracted three times with 0.5 l of ethyl acetate each time. The organic phase is washed with saturated sodium bicarbonate solution and with 1N HCl, dried with MgSO4 and evaporated.

Yield: 33.7 g (100% of theory)

M.p .: 81 ° CR _f (SiO ₂ , T1E1): 0.74

Example 6A

(2-fluorobenzyl) - 1 H-pyrazolo [3, 4-b] pyridine-3-carboximidic 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-l- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] pyridine from Example 5A was added. The mixture is stirred for 2 hours at room temperature and the solution obtained is used directly for the next step. Example 7A

1 - (2-fluorobenzyl) 1 H-pyrazolo [3, 4-b] pyridine-3-carboxamidine

The above solution of (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboximidic acid methyl ester in methanol from Example 6A is combined with 33.76 g (32.19 ml, 562 mmol) glacial acetic acid and 9.28 g (173 mmol) Ammonium chloride was added and the mixture was stirred under reflux overnight. The solvent is evaporated in vacuo, the is triturated

Residue well with acetone and sucks off the precipitated solid. 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 , TlEtOHl): 0.08

Manufacturing examples

example 1

3 - (4-Amino-5-ethylpyrimidin-2-yl) - 1 - (2-fluorobenzyl) 1 H-pyrazolo [3, 4-b] pyridine

16 g of the compound of Example 1A are pipetted into 8 g of the compound of Example 7A in a test tube. The mixture is homogenized in an ultrasonic bath, evacuated and kept in an oil bath at 100 ° C with good swiveling, the vacuum still being applied. After 30 seconds, the mixture begins to bubble up slightly, the amidine dissolving. After 1 min everything is clear and the bubbling stops. The temperature is raised to 125 ° C. for 15 minutes and the reaction is allowed to continue at 100 ° C. for about 12 hours. The mixture solidifies after cooling. The mixture is stirred with a little toluene, the crystals are filtered off and washed with ether. The mother liquor is spun in and chromatographed on SiO ₂ with toluene / ethyl acetate 1: 1.

The residue is recrystallized from 250 ml of boiling acetonitrile, the residue which is insoluble in the boiling point is treated again with 100 ml of boiling acetonitrile and filtered. 2.8g crystallize from the combined filtrates. The mother liquors are spun in, the residue is treated with ether and suction filtered. This gives a total of 4.2 g (40.6% of theory) of the target compound. M.p .: 204 ° C

R _f (SiO ₂ , TlEl): 0.2

'H NMR (d ₆ -DMSO, 200 MHz): d = 1.15 (t, 3H, CH CH ₂ ), 2.45 (q, 2H, CH ₃ CH ₂ ), 5.8

(s, 2H, CH ₂ (2-F-Ph), 6.95 (broad s, 2H, NH ₂ ), 7.1 - 7.4 (m, 5H, 2-F-Ph, H5), 8.1 (s,

IH, 6-pyrimidinyl), 8.64 (dd, IH), 8.95 (dd, IH).

MS (DCI.NH3): 349 (100%, M + H).

Claims

claims

Compound of formula (I)

2. A process for the preparation of the compound according to claim 1, characterized in that the amidine of the formula (II)

with the enamine of formula (III)

implements.

3. Medicament containing at least the compound of claim 1.

4. Medicament containing at least the compound of claim 1 in combination with organic nitrates or NO donors.

5. Medicament containing at least the compound of claim 1 in combination with compounds that inhibit the breakdown of cyclic guanosine monophosphate (cGMP).

6. Use of the compound according to claim 1 for the manufacture of a medicament.

7. Use of the compound according to claim 1 for the manufacture of a medicament for the treatment of cardiovascular diseases.

8. Use of the compound according to claim 1 for the manufacture of a medicament for the treatment of thromboembolic disorders and / or ischemia.

9. Use of the compound according to claim 1 for producing a

Medicines used to treat hypertension.

10. Use of the compound according to claim 1 for the manufacture of a medicament for the treatment of sexual dysfunction.

11. Use of the compound according to claim 1 for the manufacture of a medicament with anti-inflammatory properties.

17. Use according to any one of claims 6 to 11, wherein the compound according to claim 1 in combination with organic nitrates or NO donors or in combination with compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP) is used.

18. l- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] pyridine-3-carboxamidine of the formula (II)

19. A process for the preparation of the compound according to claim 18, characterized in that the compound of the formula (IV)

first in ethers with trifluoroacetic anhydride (TFAA) and in the presence of bases to the compound of formula (V)

implements

then the compound of the formula (VI) with sodium methoxide

transferred and mixed with bases in a last step.