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Definitions

• the present invention relates to new chemical compounds which stimulate soluble guanylate cyclase, their preparation and their use as medicaments, in particular as medicaments for the treatment of cardiovascular diseases.
• Cyclic guanosine monophosphate is one of the most important cellular transmission systems in mammalian cells. Together with nitrogen monoxide (NO), which is released from the endothelium and transmits hormone-like and mechanical signals, it forms the NO / cGMP system.
• NO nitrogen monoxide
• the guanylate cyclases catalyze the biosynthesis of cGMP from guanosine triposphate (GTP).
• GTP guanosine triposphate
• the previously known representatives of this family can be divided into two groups according to both structural features and the type of ligand: the particulate guanylate cyclases that can be stimulated by natriuretic peptides and the soluble guanylate cyclases that can be stimulated by NO.
• the soluble guanylate cyclases consist of two subunits and most likely contain one heme per heterodimer, which is part of the regulatory center. This is of central importance for the activation mechanism. NO can bind to the iron atom of the heme and so the
• guanylate cyclase plays a decisive role in different physiological processes, in particular in the relaxation and proliferation of smooth muscle cells, platelet aggregation and adhesion and neuronal signal transmission as well as in diseases which are based on a disturbance of the above-mentioned processes.
• the NO / cGMP system can be suppressed in physiological conditions, which can lead, for example, to high blood pressure, platelet activation, increased cell proliferation, endothelial dysfunction, atherosclerosis, angina pectoris, heart failure, thromboses, stroke and myocardial infarction.
• a NO-independent treatment option for such diseases aimed at influencing the cGMP signal path in organisms is a promising approach due to the expected high efficiency and few side effects.
• WO 98/16507, WO 98/23619, WO 00/06567, WO 00/06568, WO 00/06569 and WO 00/21954 pyrazolopyridine derivatives are described as stimulators of soluble guanylate cyclase.
• These patent applications also describe pyrazolo-pyridines which have a pyrimidine residue in the 3-position.
• these new pyrazolopyridine derivatives are distinguished by a pyrimidine residue in the 3-position which has a certain substitution pattern, namely a cyclic lactam residue in the 5-position of the pyrimidine ring and, if appropriate, an amino group in the 4-position of the pyrimidine ring.
• the present invention relates to compounds of the formula (I)
• R 1 represents NH 2 or NHCO-d- ö -alkyl
• R 2 represents a radical of the formula R 3 NCOR 4 which is bonded to the rest of the molecule via the nitrogen atom
• R 3 and R 4 together with the amide group to which they are attached form a five- to seven-membered heterocycle which may be saturated or partially unsaturated, may optionally contain a further heteroatom from the group N, O, S and one to f nf more substituents from the group oxo, Ci- ö alkyl, hydroxy, hydroxy - ö alkyl which may have halogen or a C. 6 10 aryl ring or to a C 3 . 8- cycloalkyl ring, in which two carbon atoms are optionally connected to one another via an oxygen atom, can be fused;
• the present invention relates to compounds of the formula (I) in which
• R 1 represents NH 2 or NHCO-C 6 alkyl
• R 2 stands for a radical of the formula R 3 NCOR 4 , which via the nitrogen atom to the
• R 3 and R 4 together with the amide group to which they are attached form a saturated five- to seven-membered heterocycle form, which may optionally contain a further heteroatom from the group N, O, S and one to five further substituents from the group oxo, May include hydroxy, hydroxy-C M alkyl, halo or a C 6 - 10 -aryl or a C. 3 8- cycloalkyl ring, in which optionally two carbon atoms are connected to one another via an oxygen atom, can be fused;
• the present invention relates to compounds of the formula (I) in which
• R 1 represents NH 2 or NHCOCH 3 ;
• R 2 represents a radical of the formula R 3 NCOR 4 which is bonded to the rest of the molecule via the nitrogen atom,
• R 3 and R 4 together with the amide group to which they are attached form a saturated five- to seven-membered heterocycle which may optionally contain a further heteroatom from the group N, O, S and one to five further substituents from the group oxo , Cw-alkyl or to a phenyl ring or to a C 3 . 8 - cycloalkyl ring, in which two carbon atoms are optionally linked to one another via an oxygen atom, can be fused; and salts, isomers and hydrates thereof.
• the present invention relates to compounds of the formula (I) in which
• R 1 represents NH 2 ;
• R 2 represents a radical of the formula R 3 NCOR 4 which is bonded to the rest of the molecule via the nitrogen atom,
• R 3 and R 4 together with the amide group to which they are attached form a five- to seven-membered heterocycle which can be saturated or partially unsaturated, can optionally contain a further heteroatom from the group N, O, S and one can have up to five further substituents from the group oxo, -CC 6 alkyl, hydroxy, hydroxy-Ci-e-alkyl, halogen or fused to a C 6 .io-aryhing;
• the present invention relates to compounds of the formula (I) in which
• R 1 represents NH 2 ;
• R 2 represents a radical of the formula R 3 NCOR 4 which is bonded to the rest of the molecule via the nitrogen atom, in which
• the present invention relates to compounds of the formula (I) in which
• R 1 represents NH 2 ;
• R 2 represents a radical of the formula R 3 NCOR 4 which is bonded to the rest of the molecule via the nitrogen atom,
• R 3 and R 4 together with the amide group to which they are attached form a five- or six-membered saturated heterocycle which may optionally contain a further oxygen atom and have one to five further substituents from the group oxo, C M -alkyl can or can be fused to a phenyl ring;
• Physiologically acceptable salts are preferred in the context of the present invention.
• Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids.
• Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids.
• 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 also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group.
• Sodium, potassium, magnesium or calcium salts as well as ammonium salts derived from ammonia, or organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine ,
• the compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers).
• the invention relates both to the enantiomers or diastereomers and to their respective mixtures.
• the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner, for example by chromatographic separation.
• Double bonds present in the compounds according to the invention can be in the eis or trans configuration (Z or E form).
• certain compounds can exist in tautomeric forms. This is known to those skilled in the art and such compounds are also within the scope of the invention.
• the compounds according to the invention can exist in the form of their hydrates, the number of water molecules bound to the molecule depending on the particular compound according to the invention.
• Alkyl generally represents a straight-chain or branched hydrocarbon radical having 1 to 20 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and isooctyl, nonyl, decyl, dodeyl, eicosyl.
• Alkylene generally represents a straight-chain or branched hydrocarbon bridge with 1 to 20 carbon atoms. Examples include methylene, ethylene, propylene, methylethylene, methylethylene, ethylethylene, ethylethylene, butylene, methylpropylene and methylpropylene. methylpropylene,
• Alkenyl generally represents a straight-chain or branched hydrocarbon radical having 2 to 20 carbon atoms and one or more, preferably one or two, double bonds. Examples include allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, isohexenyl, heptenyl, isoheptenyl, octenyl and isooctenyl.
• Alkynyl generally represents a straight-chain or branched hydrocarbon radical having 2 to 20 carbon atoms and one or more, preferably with one or two triple bonds. Examples include ethynyl, 2-butynyl, 2-pentynyl and 2-hexynyl.
• Acyl generally represents straight-chain or branched lower alkyl having 1 to 9 carbon atoms, which is bonded via a carbonyl group. Examples include: acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl and isobutylcarbonyl.
• Alkoxy generally represents a straight-chain or branched hydrocarbon radical having 1 to 14 carbon atoms which is bonded via an oxygen atom.
• Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy, octoxy or iso-octoxy.
• alkoxy and alkyloxy are used synonymously.
• Alkoxyalkyl generally represents an alkyl radical having up to 8 carbon atoms which is substituted by an alkoxy radical having up to 8 carbon atoms.
• Alkoxycarbonyl can, for example, by the formula
• Alkyl here generally represents a straight-chain or branched hydrocarbon radical having 1 to 13 carbon atoms.
• the following alkoxycarbonyl radicals may be mentioned for example: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.
• Cycloalkyl generally represents a cyclic hydrocarbon radical having 3 to 8 carbon atoms. Cyclopropyl, cyclopentyl and cyclohexyl are preferred. Examples include cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Cycloalkoxy in the context of the invention is an alkoxy radical whose hydrocarbon radical is a cycloalkyl radical. The cycloalkyl radical generally has up to 8 carbon atoms. Examples include: cyclopropyloxy and cyclohexyloxy. The terms "cycloalkoxy" and "cycloalkyloxy” are used synonymously.
• Aryl generally represents an aromatic radical having 6 to 10 carbon atoms.
• Preferred aryl radicals are phenyl and naphthyl.
• Halogen in the context of the invention represents fluorine, chlorine, bromine and iodine.
• heterocycle generally represents a saturated, unsaturated or aromatic 3- to 10-membered, for example 5- or 6-membered, heterocycle which can contain up to 3 heteroatoms from the S, N and / or O series and which in the case of a nitrogen atom can also be bound via this.
• Examples include: oxadiazolyl, thiadiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrrolidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,2,3 triazolyl, thiazolyl or oxazolyl, imol piperidyl.
• Thiazolyl, furyl, oxazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl and tetrahydrppyranyl are preferred.
• Heteroaryl (or “Hetaryl”) stands for an aromatic heterocyclic radical.
• the compound of formula (II) can be prepared according to the following reaction scheme:
• the compound of the formula (TI) is obtainable in a multistage synthesis from the sodium salt of the cyanobenzofruvic acid ethyl ester known from the literature (Borsche and Manteuffel, Liebigs. Ann. Chem. 1934, 512, 97). By reacting it with 2-fluorobenzylhydrazine under heating and in a protective gas atmosphere in an inert atmosphere
• Solvents such as dioxane give the 5-amino-1- (2-fluorobenzyl) -pyrazole-3-carboxylic acid ethyl ester, which cyclizes to the corresponding pyridine derivative by reaction with dimethylaminoacrolein in an acidic medium under a protective gas atmosphere and heating.
• This pyridine derivative l- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] pyri- Din-3-carboxylic acid ethyl ester is converted into a multistage sequence, consisting of converting the ester with ammonia into the corresponding amide, dehydration with a dehydrating agent such as trifluoroacetic anhydride to give the corresponding nitrile derivative, reaction of the nitrile derivative with sodium ethylate and a final reaction with ammonium chloride Transfer compound of formula (II).
• a haloacetonitrile such as, for example, bromoacetonitrile
• the acetonitrile derivative being used in equimolar amounts or in a slight excess, in the presence of an equimolar amount or in a slight excess of a base such as, for example, an alkali metal hydride, in particular sodium hydride, in an organic solvent, for example a cyclic ether, in particular Dioxane, or preferably in a mixture of organic solvents such as in particular a mixture of dioxane and dimethylformamide (DMF) in a ratio of 3: 1 to 5: 1, optionally in the presence of an equimolar amount or a slight excess of a lithium compound such as lithium bromide, preferably at normal pressure
• a haloacetonitrile such as, for example, bromoacetonitrile
• the acetonitrile derivative being used in equimolar amounts or in a slight excess, in the presence of an
• the compounds of formula (VIII) are e.g. available from Aldrich or Fluka (-
• the representation of 3-morpholinone is described, for example, in the patents US Pat. No. 5,349,045, US Pat. No. 3,966,766 and US Pat. No. 4, 156,683 and in J.Amer.Chem.Soc.
• 3,3,4,4-tetramethyl-pyrrolidin-2-one can, according to Justus Liebigs Ann. Chem. 1977; 8-19.
• Substituted 3-morpholinones are obtained by reaction of chlorocarboxylic acid chlorides with substituted 2-aminoethanols according to Tetrahedron Lett. 1995, 36, 3821-3824.
• 4,4-Dimethyl-l, 3-oxazolidin-2-one can be prepared from 2-amino-2-methylpropanol and diethyl carbonate according to Tetrahedron, 47, 1991, 2801-2820.
• the compounds of the formula (V) can be obtained from the compounds of the formula (IX) by reaction with an excess, for example a 2 to 3-fold excess of a formic acid derivative, such as, for example, a formic acid ester, such as ethyl formate, in an organic solvent, for example a cyclic ether , preferably tetrahydrofuran (THF), in the presence of an excess, for example a 2 to 3-fold excess of a base, for example an alkali metal base, preferably KOfBu, preferably in the case of normal pressure and stirring the reaction solution for several hours, for example 1 to 2 hours, at room temperature, and subsequent reaction with an amount of acetic acid corresponding to the amount of base used and subsequent reaction with an acetic acid derivative such as acetyl chloride or acetic anhydride with cooling and subsequent stirring, preferably at normal pressure for a few
• a formic acid derivative such as, for example, a formic acid ester, such as ethyl formate
• Minutes to several hours for example 30 minutes to 2 hours, can be obtained at room temperature.
• the compounds of the formula (11) can be reacted with compounds of the formula (DI) or (IV) or (V) in an organic solvent such as, for example, a hydrocarbon, preferably an aromatic hydrocarbon, in particular xylene or toluene, optionally in the presence of a base, for example an organic base such as an amine, preferably triethylamine, preferably at normal pressure and stirring the reaction solution for several hours, for example 12 hours, at elevated temperature, for example 80-130 ° C., preferably 100-130 ° C., in particular 120 ° C. , to the compounds of formula (I) according to the invention.
• the reactants can be used in equimolar amounts, or one of the reactants is used in a triple excess.
• the compounds of the general formula (T) according to the invention show an unforeseeable, valuable pharmacological spectrum of activity.
• the compounds of the general formula (I) according to the invention lead 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.
• the compounds of general formula (I) according to the invention enhance the action of substances which increase the cGMP level, such as, for example, EDRF (endothelium derived relaxing factor), NO donors, protopoyrin IX, arachidonic acid or phenylhydrazine derivatives.
• cardiovascular diseases such as, for example, 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, transistoric and Ischemic attacks, peripheral circulatory disorders, prevention of restenoses such as after thrombolysis therapies, percutaneous franslurninal angioplasties (PTA), percutaneous transluminal coronary angioplasties (PTCA), bypass and for the treatment of arteriosclerosis, asthmatic diseases and diseases of the urogenital system, such as the prostate erectile dysfunction, such as the sexual genital system, prostate erectile dysfunction, such as the sexual genital system, prostate erectile dysfunction, for example, erectile dysfunction, female genital prostate system - Function, osteoporosis, gastroparesis and incontinence are used.
• cardiovascular diseases such as, for example, for the treatment of high blood pressure and heart failure, stable
• the compounds of general formula (I) described in the present invention also represent active substances for combating diseases in the central nervous system which are characterized by disorders of the NO / cGMP system.
• 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-related learning and memory disorders, age-associated memory loss, vascular dementia, skull Brain trauma, stroke, dementia that occurs after a stroke ("post stroke dementia”), 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 corsakoff Psychosis. They are also suitable for the treatment of
• Central nervous system disorders such as anxiety, tension and depression conditions, central nervous system-related sexual dysfunctions and sleep disorders, as well as for the regulation of pathological disorders in the intake of food, beverages and addictive substances.
• the active ingredients are also suitable for regulating cerebral blood flow and are therefore effective means of combating migraines.
• Formula (I) can be used to combat painful conditions.
• the compounds according to the invention have anti-inflammatory activity and can therefore be used as anti-inflammatory agents.
• the invention comprises the combination of the compounds of the general formula (I) according to the invention with organic nitrates and NO donors.
• Organic nitrates and NO donors in the context of the invention are generally substances which are therapeutic via the release of NO or NO species
• the invention also includes combination with compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP). These are in particular
• Digitizer (DAS-1802 HC, Keithley Instruments Munich) digitized and registered in parallel on a line recorder.
• DAS-1802 HC Digitizer-HC, Keithley Instruments Munich
• phenylephrine is added cumulatively to the bath in increasing concentration.
• 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 reached 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 ⁇ l, the DMSO content in the bath solution corresponds to 0.1%.
• Table 1 The results are shown in Table 1 below:
• Rats are anesthetized, heparinized and the liver perfused in situ through the portal vein.
• the primary rat hepatocytes are then obtained ex vivo from the liver using collagenase solution.
• 2 '10 hepatocytes per ml were incubated with the same concentration of the compound to be examined at 37 ° C.
• the decrease in the substrate to be examined over time was determined bioanalytically (HPLC / UV, HPLC / fluorescence or LC / MSMS) at 5 times in each case in the period from 0-15 min after the start of incubation.
• the clearance was calculated from this using the cell number and liver weight.
• the substance to be examined is administered intravenously as a solution to rats via the tail vein. Blood is drawn from the rats at specified times, this is heparinized and plasma is obtained therefrom by conventional measures. The substance is bioanalytically quantified in plasma. The pharmacokinetic parameters are calculated from the plasma concentration-time curves thus determined using conventional non-compartmental methods used for this.
• the present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain the compounds of the general formula (I) according to the invention and processes for the preparation of these preparations.
• the active ingredient can optionally also be present in microencapsulated form in one or more of the carriers mentioned above.
• the therapeutically active compounds of the general formula (I) are said to be present in the pharmaceutical preparations listed above in a concentration of about
• 0.1 to 99.5 preferably from about 0.5 to 95% by weight of the total mixture may be present.
• the active ingredient (s) according to the invention in total amounts of about 0.01 to about 700, preferably 0.01 to 100 mg / kg body weight per 24
• a single dose contains the active ingredient (s) according to the invention preferably in amounts of about 0.1 to about 80, in particular 0.1 to 30 mg / kg body weight,
• Packing material Symmetry C 18, 50x2.1 mm, 3.5 ⁇ m.
• Front injector temp. 250 ° C
• Example II a 3- (dimethylamino) -2- (3-oxo-4-morpholinyl) -2-propenitrile (E / Z mixture)
• Example V c) are dissolved in 330 ml of THF and mixed with 27 g (341 mmol) of pyridine. 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 MgSO 4 and evaporated in a rotary evaporator. Yield: 33.7 g (100% of theory) mp: 81 ° CR f (SiO 2 , TlEl): 0.74
• KOtBu (379 mg, 3.55 mmol, 2.2 equivalents) was suspended in THF and within 10 min with a solution of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) acetonitrile (0.30 g, 1.6 mmol) from Example VI a) and ethyl formate (0.29 ml, 0.26 g, 3.6 mmol, 2.2 equivalents) in THF. After 2 h at room temperature, the mixture was cooled to 0 ° C.
• the mixture was filtered through a short silica gel frit with dichloromethane / methanol as the eluent.
• the eluent was dried over sodium sulfate and evaporated to dryness on a rotary evaporator at 40 ° C. That in 57 percent.
• the resulting crude product was used directly in the next reaction.
• Example VII The preparation was carried out analogously to Example VII from (2-oxo-l, 3-thiazolidin-3-yl) acetonitrile from Example Villa, ethyl formate and acetic anhydride.
• the substance was called
• decan-3,5-dione (obtainable from maleinimide and furan by Diels-Alder reaction, e.g. according to Padwa, A .; Dimitroff, M .; Waterson, A.G; Wu, T .; J Org Chem
• the mixture was chromatographed twice over silica gel with dichloromethane / methanol (1st gradient 200: 1/50: 1/20: 1, 2nd gradient 100: 1/50: 1) and then by preparative HPLC (column: Kromasil 100 C 18 5 ⁇ m 250x20 mm No. 101131R, flow: 25 ml / min, temp. 50 ° C, gradient water / acetonitrile at 0 min: 55/45, at 14 min 55/45) further cleaned.
• the reaction can be carried out with equal success in xylene at 120-140 ° C or in acetic acid at 120 ° C. It is also possible to add Lewis acids, e.g. Zinc (II) acetate, scandium (III) trifluoromethanesulfonate, manganese (II) acetate, cobalt (II) acetate, yttrium (III) trifluoromethanesulfonate, boron trifluoride-diethyl ether complex.
• Lewis acids e.g. Zinc (II) acetate, scandium (III) trifluoromethanesulfonate, manganese (II) acetate, cobalt (II) acetate, yttrium (III) trifluoromethanesulfonate, boron trifluoride-diethyl ether complex.
• the purification can also be carried out chromatographically on silica gel (dichloromethane /

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