DE10242941A1 - New 2-(pyrazolo-(3,4-b)-pyridinyl)-5-pyridinyl-4-pyrimidinylamine derivative, is a soluble guanylate cyclase stimulant useful e.g. for treating cardiovascular diseases, hypertension or ischemia - Google Patents

Abstract

2-(1-(2-Fluorobenzyl)-1H-pyrazolo-(3,4-b)-pyridin-3-yl)-5-(1-oxido-4-pyridinyl)-4-pyrimidinylamine (I) is new. Pyrazolo-pyridine compound of formula (I) and its isomers, salts and hydrates are new.

Description

The present invention relates to a substituted pyrazole derivative and its use as a medicament, in particular as a medicament for the treatment of cardiovascular diseases.

WO 00/06569 and WO 02/42301 disclose structurally similar ones Compounds as medicines, in particular for the treatment of cardiovascular diseases.

sowie deren Isomere, Salze und Hydrate.The present invention relates to a substituted pyrazole derivative of the formula (I)

and their isomers, salts and hydrates.

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

Within the scope of the present invention physiologically acceptable salts are preferred. physiological Safe salts of the compound according to the invention can be salts of the substance according to the invention with mineral acids, Carboxylic acids or sulfonic acids his. For example, particular preference is given to Salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or Benzoic acid.

Physiologically acceptable salts can as well Metal or ammonium salts of the compound of the invention. Especially preferred are e.g. Sodium, potassium, magnesium or calcium salts, and ammonium salts derived from ammonia or organic Amines such as ethylamine, di- or triethylamine, di- or Triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, Lysine or ethylenediamine.

Furthermore, the compounds of the invention in the form of their possible Hydrates occur.

The compound of the formula (I) according to the invention shows an unpredictable, valuable pharmacological spectrum of action and is therefore suitable for the treatment of diseases.

In particular, it leads to vascular relaxation, Inhibiting platelet aggregation and lowering blood pressure as well to an increase in coronary blood flow. These effects are about one direct stimulation of the soluble Guanylate cyclase and an intracellular increase in cGMP mediated. Moreover reinforced the compound of the invention of formula (I) the effect of substances that have the cGMP level increase, such as EDRF (Endothelium derived relaxing factor), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.

It can therefore be used in medicinal products Cardiovascular treatment Diseases such as those used to treat 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 like myocardial infarction, stroke, transistoric and ischemic attacks, peripheral circulatory disorders, prevention of restenoses such as after thrombolysis therapies, percutaneously transluminal Angioplasty (PTA), percutaneously transluminal coronary angioplasty (PTCA), bypass and for the treatment of arteriosclerosis, asthmatic Diseases and diseases of the genitourinary system such as prostate hypertrophy, erectile dysfunction, female sexual dysfunction, osteoporosis, Glaucoma, pulmonary hypertension, gastroparesis and incontinence are used become.

The compounds of the formula (I) described in the present invention are also active compounds for combating diseases in the central nervous system which are characterized by disorders of the NO / cGMP system. In particular, they are suitable for improving perception, concentration performance, learning performance, or memory performance after cognitive disorders, as they occur in particular in situations / diseases / syndromes such as “mild cognitive impairment”, age-associated learning and memory disorders, age-associated memory loss, vascular dementia, skull Brain trauma, stroke, dementia that occurs after strokes (“post stroke demen tia "), post-traumatic skull-brain trauma, general concentration disorders, concentration disorders in children with learning and memory problems, Alzheimer's disease, vascular dementia, dementia with Lewy bodies, dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoff psychosis.

They are also suitable for treatment diseases of the central nervous system such as anxiety, tension and depression, central nervous system conditional sexual dysfunction and sleep disorders, as well as for regulation pathological disorders the intake of food, beverages and addictive substances.

The active ingredients are also suitable also regulates cerebral blood flow and thus provides effective means of fighting of migraines represents.

They are also suitable for prophylaxis and combat the consequences of cerebral infarction (apoplexia cerebri) such as stroke, cerebral ischemia and traumatic brain injury. Likewise, the compounds of the invention of the formula (I) for combating of painful conditions become.

In addition, the compounds according to the invention have anti-inflammatory effects and can therefore be considered anti-inflammatory Means are used.

The invention also encompasses the combination of the compound of the formula (I) according to the invention with organic nitrates and NO domes.

Organic nitrates and NO donors In general, substances within the scope of the invention are those which Release of NO or NO species unfold their therapeutic effect. Sodium nitroprusside, nitroglycerin, isosorbide dinitrate, Isosorbide mononitrate, molsidomine and SIN-1.

The invention also encompasses the combination of the compound of the formula (I) according to the invention with compounds that break down cyclic guanosine monophosphate inhibit (cGMP). These are in particular inhibitors of the phosphodiesterases 1, 2 and 5; Nomenclature according to Beavo and Reifsnyder (1990) TiPS 11 P. 150 to 155. These inhibitors, the effect of the compound of the invention potentiated and the desired pharmacological effect increased.

biological investigations

The biological effectiveness of the compound of Formula (I) is shown in the test below.

vasorelaxant 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 placed individually in 5 ml organ baths with 37 ° C warm, carbon-gassed Krebs-Henseleit solution of the following composition (mM) under prestress: NaCl: 119 ; KCl: 4.8; CaCl ₂ x 2 H ₂ O: 1.0; 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 subsequent 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% (ICsp). The standard application volume is 5 μl, the DMSO content in the bath solution corresponds to 0.1%.

The compound I according to the invention has an IC ₅₀ value of 286 nM.

Another subject of the present Invention are medicaments which contain the compound according to the invention, preferably together with one or more pharmacologically acceptable auxiliary substances or carriers included, and their use for the aforementioned purposes.

The active ingredient can be systemic and / or act locally. For this purpose, it can be applied in a suitable manner such as oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctival, topical or as an implant, for example a stent.

For the active substance can administer these administration routes in suitable administration forms be administered.

For oral application are known, the active ingredient quickly and / or modified delivery forms of application, such as tablets (not coated as well as coated Tablets, e.g. tablets coated with enteric coatings or Film-coated tablets), capsules, dragees, granules, pellets, powders, emulsions, Suspensions, solutions and aerosols.

Parenteral administration can be done by bypassing a resorption step (intravenous, intraarterial, intracardial, intraspinal or intralumbal) or by switching on absorption (intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). Administration forms suitable for parenteral administration include injection and Infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.

For the other application routes are e.g. Inhalation dosage forms (including powder inhalers, nebulizers), nasal drops / solutions, sprays; lingual, tablets or capsules to be administered sublingually or buccally, Suppositories, ear and eye preparations, vaginal capsules, aqueous Suspensions (lotions, shake mixes), lipophilic suspensions, ointments, creams, milk, pastes, powder or implants, for example stent.

The active ingredients can be in a manner known per se in the listed Application forms are transferred. This is done using inert non-toxic, pharmaceutical suitable auxiliaries. Which includes et al excipients (e.g. micro crystalline cellulose), solvents (e.g. liquid polyethylene glycols), Emulsifiers (e.g. sodium dodecyl sulfate), dispersants (e.g. Polyvinylpyrrolidone), synthetic and natural biopolymers (e.g. albumin), Stabilizers (e.g. antioxidants such as ascorbic acid), dyes (e.g. inorganic pigments such as iron oxides) or taste and / or Odors. The active ingredient can optionally in a or more of the above-mentioned carriers also in microencapsulated Form.

The therapeutically effective compound of the formula (I) is intended in the pharmaceutical preparations listed above in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture may be present.

The pharmaceutical preparations listed above can except the compound of the invention of the formula (I) also contain other active pharmaceutical ingredients.

In general, it has both proven beneficial in both human and veterinary medicine, the active ingredient according to the invention in total amounts from about 0.01 to about 700, preferably 0.01 to 100 mg / kg body weight 24 hours each, possibly in the form of several individual doses, for Achieving the desired Deliver results. A single dose contains the active ingredient according to the invention preferably in amounts from about 0.1 to about 80, in particular 0.1 up to 30 mg / kg body weight.

The invention is explained below a preferred embodiment explained in more detail to which however, they are not restricted is. Unless otherwise stated, all refer below Quantities in percent by weight.

Starting Compounds:

I. Synthesis of 3- (dimethylamino) -2- (1-oxido-4-pyridinyl) -2-propenenitrile (E / Z mixture)

IA) 4 - [(Dimethylamino) methylene] pyridine acetonitrile (E / Z mixture)

4-pyridylacetonitrile 7.52 g (63.7 mmol) and teri-butoxybis (dimethylamino) methane 11.09 g (63.7 mmol) be at 100 ° C for 2 h touched. This releases the dimethylamine and t-butanol by means of a vacuum pump discharged to the atmosphere by a slight vacuum flow.

Flash chromatography (dichloromethane / ethyl acetate 50: 1 → 20: 1) gives the title compound.
Yield: 10.2 g (93%)
R _f value: 0.29 (dichloromethane / ethyl acetate 20: 1)
¹ H-NMR: (300 MHz, D ₆ -DMSO), δ = 3.25 (s, 6H, 2 × CH ₃ ), 7.25 (d, 2H, Ar-H), 7.80 (s, 1H, Ar-H) , 8.33 (d, 2H, Ar-H).
MS: (ESI pos.), M / z = 174 ([M + H] ⁺ )

IB) 3- (Dimethylamino) -2- (1-oxido-4-pyridinyl) -2-propenenitrile (E / Z mixture)

55.0 g (302 mmol) of 4 - [(dimethylamino) methylene] pyridine acetonitrile (E / Z mixture) from Example 1A are dissolved in 2200 ml of trichloromethane and 112 g (452 mmol) of meta-chloroperbenzoic acid are added at room temperature. The temperature rises to 34 ° C. The mixture is left to rest at room temperature for 3 hours. It is then extracted twice with 1 normal sodium hydroxide solution. The aqueous phase is extracted once with ethyl acetate. The aqueous phase is evaporated to dryness on a rotary evaporator and the residue is stirred with 800 ml of dichloromethane / methanol 3: 1. The precipitate is then suction filtered and 250 ml of Di chloromethane / methanol washed. The filtrate is evaporated to dryness on a rotary evaporator and the residue is purified by chromatography on silica gel (dichloromethane / methanol / concentrated aqueous ammonia solution 9: 1: 0.1).
Yield: 12.3 g (22%)
¹ H-NMR: (300 MHz, D ₆ -DMSO), 6 = 3.23 (s, 6 H, 2 × CH ₃ ), 7.24 (d, 2 H, Ar-H), 7.69 (s, 1 H, Ar -H), 8.04 (d, 2H, Ar-H).
LC / MS: retention time: 0.9 min;
MS: (ESI pos.), M / z = 190 ([M + H] ⁺ ).
Instrument: Micromass Quattro LCZ, HP1100; Column: Symmetry C18, 50 mm × 2.1 mm, 3.5 μm; Eluent A: water + 0.05% formic acid, eluent B: acetonitrile + 0.05% formic acid; Gradient: 0.0 min 90% A → 4.0 min 10% A → 6.0 min 10% A; Oven: 40 ° C; Flow: 0.5 ml / min; UV detection: 208-400 nm.

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

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

100 g (0.613 mol) sodium salt of cyanopyruvate (Representation analogous to Borsche and Manteuffel, Liebigs Ann. 1934, 512, 97) are under vigorous stir under argon in 2.5 1 dioxane at room temperature with 111.75 g (75 ml, 0.98 mol) of trifluoroacetic acid added and stirred for 10 minutes, being a big one Part of the educt goes into solution. Then 85.93 g (0.613 mol) of 2-fluorobenzylhydrazine are added and heated under reflux overnight. After cooling the precipitated crystals of sodium trifluoroacetate are suctioned off, washed with dioxane and the solution further implemented raw.

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

The solution obtained from II A) is mixed with 61.25 ml (60.77 g, 0.613 mol) of dimethylaminoacrolein and 56.28 ml (83.88 g, 0.736 mol) of trifluoroacetic acid and heated under reflux under argon for three 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 dried with magnesium sulfate and concentrated on a rotary evaporator. 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 , toluene / ethyl acetate 1: 1): 0.83

II C) 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboxamide

10.18 g (34 mmol) of the ester obtained in Example II B) are placed in 150 ml of methanol saturated with ammonia at 0-10 ° C. The mixture is stirred for two days at room temperature and then concentrated in vacuo.
Rf (SiO ₂ , toluene / ethyl acetate 1: 1): 0.33

II D) 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 II C) 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 ° C. The mixture is stirred overnight at room temperature. The mixture is then poured into 1 l of 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 1 normal hydrochloric acid, dried with magnesium sulfate and concentrated on a rotary evaporator.
Yield: 33.7 g (100% of theory)
Mp: 81 ° C
Rf (SiO ₂ , toluene / ethyl acetate 1: 1): 0.74

II E) (2-fluorobenzyl) -1H-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 gives 36.45 g (144.5 mmol) of 3-cyano-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine (from Example II D) added. You stir 2 hours at room temperature and sets the solution obtained directly for the next Level.

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

The solution of (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboximidic acid methyl ester in methanol obtained from Example II E) is mixed with 33.76 g (32.19 ml, 562 mmol) glacial acetic acid and 9.28 g (173 mmol ) Added ammonium chloride and stirred under reflux overnight. The solvent is evaporated in vacuo, the residue is triturated well with acetone and the precipitated solid is filtered off with suction.
¹ H NMR (d ₆ -DMSO, 200 MHz): δ = 5.93 (s, 2H); 7.1-7.5 (m, 4H); 7.55 (dd, 1H); 8.12 (dd, 1H); 8.30 (dd, 1H); 9.5 (bs, 4H exchangeable) ppm.
MS (EI): m / z = 270.2 (M-HCl)

embodiment

2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -5- (1-oxido-4-pyridinyl) -4-pyrimidinylamin

19.0 g (70.6 mmol) 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboximidamide (starting compound II) and 13.4 g, (70.6 mmol) 3- (dimethylamino) -2- ( 1-oxido-4-pyridinyl) -2-propenenitrile (E / Z mixture) (starting compound I) are heated under reflux in 500 ml of xylene. After 3, 6 and 9 hours, a further 19.0 g (70.6 mmol) of 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboximidamide (starting compound II) are added. The mixture is then refluxed for a further 15 hours. After cooling to room temperature, the precipitate formed is suction filtered and washed with toluene and then with a little methanol. The precipitate is digested in 250 ml of dimethyl sulfoxide at 90 ° C. Insoluble constituents are filtered off and the filtrate is chromatographed on silica gel with dichloromethane / methanol / conc. aqueous ammonia solution 20: 1: 0 → 10: 1: 0 → 5: 1: 0.1 cleaned. The product-containing fractions are evaporated to dryness on a rotary evaporator, and the residue is stirred with a little ethyl acetate and suction filtered. After washing with a little ethyl acetate and drying, 8.7 g of the product are obtained. A further 0.29 g of product can be obtained if the precipitate remaining after digestion with dimethyl sulfoxide is slurried in 150 ml of dimethyl sulfoxide at 60 ° C. and purified chromatographically on silica gel in the same way as described above.
Yield: 8.99 g (30.7%)
Retention time: 3.76 min
Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60mm × 2mm, 3.5μm; Eluent: A = 5 ml HClO4 / l H2O, B = ACN; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 6.5 min 90% B; Flow: 0.75 ml / min, temp .: 30 degrees C, detection UV 210 nm.
¹ H NMR: (300 MHz, D ₆ -DMSO), δ = 5.82 (s, 2H, CH ₂ ), 7.06-7.27 (m, 5H, Ar-H, NH ₂ ), 7.30-7.41 (m, 2H , Ar-H), 7.53 (d, 2H, Ar-H), 8.25-8.29 (m, 3H, Ar-H), 8.63 (dd, 2H, Ar-H), 9.05 (dd, 1 H, Ar- H).
MS: (ESI pos.), M / z = 414 ([M + H] ⁺ ).

Claims (9)

Compound of formula (I)

and their isomers, salts and hydrates. Compounds of formula (I) as defined in claim 1 for Treatment of diseases. Medicament containing at least one compound of the formula (I) as defined in claim 1 and at least one other Excipient. Medicament containing at least one compound of the formula (I) as defined in claim 1 in combination with organic Nitrates or NO donors. Medicaments containing at least one compound of the formula (I) as defined in claim 1 in combination with compounds, which inhibit the breakdown of cyclic guanosine monophosphate (cGMP). Use of compounds of formula (I) as in claim 1 defined in the manufacture of medicinal products for treatment of cardiovascular diseases. Use of compounds of formula (I) as in claim 1 defined, for the manufacture of medicaments for the treatment of Hypertension. Use of compounds of formula (I) as in claim 1 defined, for the manufacture of medicaments for the treatment of thromboembolic disorders and ischemia. Use according to any one of claims 6 to 8, wherein compounds of formula (I) as defined in claim 1 in combination with organic Ni occurred or NO donors or in combination with compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP) can be used.