MXPA01001411A - Substituted 4-amino-2-aryl-pyrimidines, their production and use and pharmaceutical preparations containing same - Google Patents

Abstract

The invention relates to compounds of formula (I) in which R1, R2, R3 and R4 have the meanings given in the claims. Said compounds are valuable active ingredients for the treatment and prophylaxis of diseases, for example cardiovascular diseases such as hypertension, angina pectoris, heartfailure, thrombosis and atherosclerosis. The compounds of formula (I) are able to modulate the body's production of cyclic guanosine monophosphate (cGMP) and are generally suitable for the treatment and prophylaxis of disorders associated with impaired cGMP balance. The invention further relates to methods for producing compounds of formula (I), their use in the treatment and prophylaxis of the above diseases and in the preparation of medicaments for such diseases, and to pharmaceutical preparations containing the compounds of formula (I).

Description

4-AMINO-2-ARILPIRIMIDINAS SUBSTITUTE, ITS PREPARATION, USE AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM The present invention relates to compounds of the formula I, wherein R1, R2, R3 and R4 have the meanings indicated below, which are valuable pharmaceutical active compounds for the therapy and prophylaxis of diseases, for example cardiovascular disorders such as high blood pressure, angina pectoris, heart failure, thrombosis or atherosclerosis . The compounds of the formula I have the ability to modulate the endogenous production of cyclic guanosine monophosphate (cGMP) and are generally suitable for the therapy and prophylaxis of disease states that are associated with an altered balance of cGMP. The invention also relates to processes for the preparation of compounds of the formula I, their use for the therapy and prophylaxis of the designated disease states and for the production of pharmaceuticals therefor, and pharmaceutical preparations containing the compounds of the invention. formula I. cGMP is an important intracellular messenger, which produces a number of pharmacological effects by modulating protein kinases dependent on cGMP, phosphodiesterases and ion channels. Examples are smooth muscle relaxation, inhibition of platelet activation and inhibition of smooth muscle cell proliferation and leukocyte adhesion. cGMP is produced by particulate and soluble guanylate cyclases as a response as a response to a number of extracellular and intracellular stimuli. In the case of particulate guanylate cyclases, the stimulus is essentially carried out by peptide signal substances such as the atrial peptide or the brain natriuretic peptide. Soluble guanylate cyclases (sGC), which are heterodimeric, cytosolic proteins, however, are essentially regulated by a family of enzymatically formed factors of low molecular weight. The most important stimulant is nitrogen monoxide (NO) or a closely related species. The importance of other factors such as carbon monoxide or the hydroxyl radical is still substantially unclear. The binding of NO to heme with pentacoordinated heme-nitrosyl complex formation is discussed as an activation mechanism of NO activation. The associated release of histidine that binds to iron in the state converts the enzyme into activated conformation. Active soluble guanylate cyclase, each is composed of a subunit - and a β-. Several subtypes of the subunits are described, which differ from each other with respect to sequence, specific tissue distribution and expression at various stages of development. The subtypes I HEAR! Y ? they are expressed primarily in the brain and lungs, whereas β2 is especially found in the liver and kidneys. Subtype 2 was detected in human fetal brain. The subunits designated 3 and ß3 were isolated from the human brain and are homologous to a: and ßx. More recent studies direct a subunit a2], which contains an insert in the catalytic domain. All subunits show great homology in the area of catalytic domain. Enzymes probably contain one heme per heterodimer, which is linked by β-Cis-78 and / or β-His-105 and is part of the regulatory center. The formation of guanylate cyclase activation factors can be decreased under pathological conditions or increased degradation thereof can be carried out as a result of the increased occurrence of free radicals. The resulting reduced activation of sGC leads, by attenuating the cell response mediated by respective cGMP, for example to an increase in blood pressure, to platelet activation or to increased cell proliferation and cell adhesion. As a result, the formation of endothelial dysfunction, atherosclerosis, high blood pressure occurs, stable and unstable angina pectoris, thrombosis, myocardial infarction, attack or erectile dysfunction. The pharmacological stimulation of sGC offers a possibility for the normalization of cGMP production and thus allows the treatment or prevention of diseases of this type. For the pharmacological stimulation of sGC, until now the compounds were used almost exclusively, whose action was based on an intermediate release of NO, for example organic nitrates. The disadvantage of this method of treatment lies in the development of tolerance and weakening of action and the higher dose that therefore becomes necessary. Various sGC stimulators that do not act by releasing NO were described in a series of publications by Vesely. The compounds, which are primarily hormones, plant hormones, vitamins or for example, natural substances such as lizard toxins, nevertheless consistently show only weak effects on the formation of cGMP in cell lysates (DL Vesely, Eur. J. Clin. Invest. 15 (1985) "jfitsx *, nßá? a?, i? á & ^ A, 258; DL Vesely, Biochem. Biophys. Res. Comm. 88 (1979) 1244.) Heme-free guanylate cyclase stimulation by protoporphyrin IX was detected by Ignarro. and collaborators (Adv. Pharmacol 26 (1994) 35) Pettibone et al. (Eur. J. Pharmacol. 116 (1985) 307) describes a hypotensive action for diphenyliodonium hexafluorophosphate and attributes this to a stimulus of sGC. shows a relaxing action in the aortas of isolated rats, equally active sGC according to Yu et al. (Brit. J. Pharmacol., 114 (1995) 1587), Ko et al. (Blood 84 (1994) 4226), Yu et al.

(Biochem J. 306 (1995) 787) and Wu et al. (Brit. J.

Pharmacol. 116 (1995) 1973) detected a sGC stimulating activity of l-benzyl-3- (5-hydroxymethyl-2-furyl) indazole and demonstrated an antiproliferative and inhibitory action of platelet. Substituted pyrazoles and condensed pyrazoles having a stimulating action of sGC are described in EP-A-908456 and DE-A-19744027, substituted quinazolines having such an action in DE-A-19756388. Various 4-amino-2-arylpyrimidines are already known. For example EP-A-55693 describes pyrimidines substituted in the 2- position by a phenyl group and which are suitable as antidotes for the protection of crop plants against the phytotoxic action of herbicides. EP-A-136976 describes 2-phenylpyrimidines which are plant growth regulators. For certain 2-phenylpyrimidines which in position 4 can transport an amino group among others as a substituent, EP-A-555478 describes that they improve the learning power and the power of the memory. Surprisingly, it has now been found that the pyrimidines of the formula I according to the invention achieve strong activation of guanylate cyclase, considering that they are suitable for the therapy and prophylaxis of diseases associated with low level of cGMP. The present invention in this manner relates to compounds of the formula I wherein R 1 is alkyl with 1-8 carbon atoms which may be substituted by one or more substituents identical or different from the group consisting of hydroxyl, alkoxy with 1 to 4 carbon atoms, alkyl with 1 to 4 carbon atoms-S (O) m-, R5R6N and aryl, (cycloalkyl with 3 to 9 The carbon atoms may be substituted by one or more substituents that are identical or different from the group consisting of alkyl having 1 to 4 carbon atoms, hydroxyl and amino, or the radical of a saturated heterocyclic ring of 5. - 7-member, containing one or two hetero ring members identical or different from the group consisting of 0, NR7 and S (0) m and which may be substituted by one or more substituents identical or different from the group consisting of alkyl with 1 to 4 carbon atoms and arylalkyl with 1 to 4 carbon atoms; and R 2 is hydrogen, alkyl having 1 to 8 carbon atoms which may be substituted by one or more substituents identical or different from the group consisting of hydroxyl, alkoxy with 1 to 4 carbon atoms, alkyl with 1 to 4 carbon atoms S (O) m-, R5R6N and aryl, (C3-C9-cycloalkyl which may be substituted by one or more substituents identical or different from the group consisting of alkyl having 1 to 4 carbon atoms, hydroxyl and amino, or the radical of a saturated 5- to 7-membered heterocyclic ring, containing one or two hetero ring members identical or different from the group consisting of O, NR7 and S (0) m and which may be substituted by one or more identical substituents or different from the group consisting of alkyl with 1 to 4 carbon atoms and aryl-alkyl with 1 to 4 carbon atoms; or RXR2N is a radical, linked by a ring nitrogen atom, of a saturated 5-membered heterocyclic ring to 7-members, which in addition to the nitrogen atom carrying the radicals R1 and R2, can contain an additional member of hetero ring of the group consisting of O, NR7 and S (0) m and which may be substituted by one or more substituents identical or different from the group consists of alkyl with 1 to 4 carbon atoms, hydroxyl, alkoxy with 1 to 4 carbon atoms, R8R9N, hydroxycarbonyl, alkoxy with 1 to 4 carbon-carbonyl atoms and R8R9N-C0-; R3 is aryl; R4 is alkyl with 2 to 5 carbon atoms, trifluoromethyl or aryl; R5 and R6 are radicals identical or different from the group consisting of hydrogen and alkyl having 1 to 4 carbon atoms or the group R5R6N is a radical linked by a ring nitrogen atom, of a heterocyclic ring Saturated or unsaturated from 5 members to 7 members, which in addition to the nitrogen atom carrying the radicals R5 and R6, can additionally contain as an additional hetero ring member an oxygen atom, a S (0) group or a nitrogen atom and that can transport in atoms ring carbon one or more identical substituents or different from the group that I ccí? S-ester of alkyl having 1 to 4 carbon atoms, hydroxyl and amino and can carry on a ring nitrogen atom a radical R7; R7 is hydrogen, alkyl with 1 to 4 carbon atoms, aryl-alkyl with 1 to 4 carbon atoms, hydroxyalkyl with 1 to 4 carbon atoms, hydroxycarbonyl-alkyl with 1 to 4 carbon atoms, (alkoxy with 1 to 4 carbon atoms-carbonyl) -alkyl with 1 to 4 carbon atoms, R8R9N-CO-alkyl with 1 to 4 carbon atoms, R10- 10 S02- or aryl, where R7, if this group is present in a radical can not be carbocyclic aryl or aryl-alkyl with 1 to 4 carbocyclic carbon atoms; R8 and R9 are radicals identical or different from the group consisting of hydrogen and alkyl with 1 to 4 carbon atoms; R10 is alkyl with 1 to 4 carbon atoms, aryl or R8R9N; aryl is phenyl, naphthyl or heteroaryl, all of which may be substituted by one or more identical or different substituents, of the group consisting of halogen, alkyl having 1 to 4 carbon atoms, phenyl, CF3, N02, OH, -O- alkyl with 1 to 4 carbon atoms, -O-alkyl with 2 to 4 carbon atoms-O-alkyl with 1 to 4 carbon atoms, alkylenedioxy with 1 to 2 carbon atoms, NH2, -NH-alkyl ^^^^^^^^^^^^^^^^^^^ JJ ^^^^^^ with 1 to 4 carbon atoms, -N ((alkyl with 1 to 4 carbon atoms) carbon)) 2, -NH-CHO, -NH-CO-alkyl having 1 to 4 carbon atoms, -CN, -CO-NH2 / -CO-NH-alkyl having 1 to 4 carbon atoms, -CO-N ((alkyl having 1 to 4 carbon atoms)) 2, -CO-OH, -CO-O-alkyl having 1 to 4 carbon atoms, -CHO and -CO-alkyl having 1 to 4 carbon atoms; "heteroaryl" is the radical of a 5-membered or 6-membered monocyclic aromatic heterocycle or a 8-membered to 10 membered bicyclic aromatic heterocycle, each containing one or more ring hetero atoms identical or different from the group consisting of N , O and S; m is O, 1 or 2; in all their stereoisomeric forms and mixtures thereof in all proportions and their physiologically tolerable salts, compounds of the formula I are excluded wherein, simultaneously R is tert-butyl or trifluoromethyl, R is phenyl which may be substituted by one or two identical substituents or different, from the group consisting of halogen, OH, -O-R11 and CF3, RXR2N is R -NH-, (Rn) 2N- or R12 R13N- (CH2) p-NH-, p is 2 or 3, R11 is alkyl with 1 to 4 carbon atoms without saturated substitution and R12 and R13 are identical or different radicals, from the group consisting of hydrogen and R11 or the group R12 R13N is a radical * -B > fc-.J - «- feS-I linked by a ring nitrogen atom of a 5- or 6-membered saturated heterocyclic ring, which in addition to the nitrogen atom carrying the radicals R12 and R13, can additionally contain as hetero members. additional ring or oxygen atom, a sulfur atom or a nitrogen atom and which may be substituted by an aryl radical or by an aryl-alkyl radical having 1 to 4 carbon atoms, wherein the aryl group may be substituted by one or two identical or different substituents of the group consisting of halogen, OH, -0-R11 and CF3. If a number of times groups or substituents can occur in the compounds of formula 1, they can all independently have the indicated meanings and can each be identical or different. Alkyl radicals can be straight or branched chain. This also applies if they are contained in other groups, for example in alkoxy groups, alkoxycarbonyl groups or in amino groups, or if they are substituted. Examples of alkyl groups are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, the n-isomers of these radicals, isopropyl, isobutyl, isopentyl, sec-butyl, tert-butyl, neopentyl, 3,3-dimethylbutyl . The term alkyl herein is also expressly understood to mean, in addition to saturated alkyl radicals, unsaturated alkyl radicals, ie alkyl radicals containing one or more double bonds and / or one or more triple bonds, for example alkenyl radicals and alkynyl radicals. It will be appreciated that an unsaturated alkyl radical must contain at least two carbon atoms, an alkyl group with 1-8 carbon atoms, in this way for example they comprise alkyl radicals with 1-8 saturated carbon atoms and alkyl radicals with 2 to 8 unsaturated carbon atoms, an alkyl radical with 1 to 4 carbon atoms comprises alkyl radicals with 1 to 4 saturated carbon atoms and alkyl radicals with 2 to 4 unsaturated carbon atoms. Examples of unsaturated alkyl radicals are the vinyl radical, the 2-propenyl radical (allyl radical), the 2-butenyl radical, the 2-methyl-2-propenyl radical, the ethynyl radical, the 2-propynyl radical, (propargyl radical) or the 3-butynyl radical. If the alkyl radicals are substituted by one or more substituents, they are preferably substituted by one, two or three, in particular by one or two identical or different substituents. The substituents can be located on any desired carbon atoms of the alkyl radical. Cycloalkyl for example is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or cyclononyl, all can also be They are substituted as indicated, for example, by one or more alkyl radicals having 1 to 4 carbon atoms identical or different, in particular by methyl, and / or by hydroxyl. If the cycloalkyl radicals are substituted by one or more substituents, they are preferably substituted by one, two, three or four, in particular by one or two identical or different substituents. Examples of these substituted cycloalkyl radicals are 4-methylcyclohexyl, 4-tert-butylcyclohexyl, 4-hydroxycyclohexyl, 4-aminocyclohexyl or 2,3-dimethylcyclopentyl. The substituents can be located on any desired carbon atoms of the cycloalkyl radical. Carbocyclic aryl radicals such as phenyl radicals and naphthyl radicals and heteroaryl radicals can, if not otherwise stated, be unsubstituted or carry one or more for example one, two, three or four identical or different substituents, which can be located in any positions desired. If not stated otherwise, the substituents indicated in the definition of the aryl group, for example, can occur as substituents on these radicals. If nitro groups are present as substituents in the compounds of formula I, altogether only up to two nitrogen atoms may be present in the molecule. If an aryl radical such as, for example, a phenyl radical in turn transports a phenyl radical as a substituent, the benzene ring in the latter can also in turn be substituted or unsubstituted by one or more for example one, two, three or four identical or different radicals, for example by radicals of the group consisting of alkyl with 1 to 4 carbon atoms, halogen, hydroxyl, alkoxy with 1 to 4 carbon atoms, trifluoromethyl, cyano, hydroxycarbonyl, (alkoxy with 1 to 4 carbon atoms) carbonyl, aminocarbonyl, nitro, amino, alkylamino with 1 to 4 carbon atoms, di- (alkyl with 1 to 4 carbon atoms) amino and (alkyl with 1 to 4 carbon atoms) carbonyl-amino. In mono-substituted phenyl radicals, the substituent can be located in the 2-position, the 3-position or the 4-position, in disubstituted phenyl radicals the substituents can be located in the 2,3-position, 2,4-position, 2,5-position, position 2,6, position 3,4 or position 3,5. In tri-substituted phenyl radicals, the substituents can be located in the 2,3,4 position, the 2,3,5 position, the 2,3,6 position, the 2,4,5 position, the 2,4 position , 6 or the 3,4,5 position. Naphthyl can be 1-naphthyl or 2-naphthyl. In mono-substituted 1-naphthyl radicals, the substituent can be located in position 2, position 3, position 4, position 5, position 6, position 7 or position 8, in radicals 2- -.XM & & -., d2 & amp; amp; & amp; mono-substituted naphthyl in l * a position 1, position 3, position 4, position 5, position 6, position 7 or position 8. In poly-substituted naphthyl radicals, for example di- or tri-substituted naphthyl radicals, the substituents can also be located in all possible positions. If not stated otherwise, heteroaryl radicals, saturated heterocyclic ring radicals and ring radicals that are formed from two groups attached to a nitrogen atom together with this nitrogen atom, are preferably derived from heterocycles containing one, two , three or four identical or different ring hetero atoms, particularly preferably heterocycles containing one or two or three, in particular one or two, identical or different ring hetero atoms. If not stated otherwise, the heterocycles can be monocyclic or polycyclic, for example monocyclic, bicyclic or tricyclic. They are preferably monocyclic or bicyclic, in particular monocyclic. The individual rings preferably contain 5, 6 or 7 ring members. Examples of heterocyclic, monocyclic and bicyclic systems from which radicals occurring in the compounds of the formula I can be derived are pyrrole, furan, thiophene, imidazole, pyrazole, 1, 2, 3-triazole, 1,2,4-triazole, 1,3-dioxole, 1,3-oxazole, 1,2-oxazole, 1,3-thiazole, 1 , 2-thiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, pyran, thiopyran, 1,4-dioxin, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, 1,2-thiazine, 1 , 3-thiazine, 1,4-thiazine, 1, 2, 3-triazine, 1, 2,4-triazine, 1, 3, 5-triazine, 1,2,4,5-tetrazine, azepine, 1, 2 -diazepine, 1,3-diazepine, 1,4-diazepine, 1,3-oxazepine, 1,3-thiazepine, indole, benzothiophene, benzofuran, benzothiazole, benzimidazole, quinoline, isoquinoline, cinoline, quinazoline, quinoxaline, phthalazine, thienothiophenes , 1, 8-naphthyridine and other naphthyridines, pteridine, or phenothiazine, all in each case in saturated form (perhydrous form) or in partially unsaturated form (for example dihydro form and tetrahydro form) or in unsaturated form maximally, if the The involved forms are known and stable. Heterocycles that are suitable also include for example the saturated heterocycles pyrrolidine, piperidine, perhydroazepine (hexamethyleneimine), piperazine, morpholine, 1,3-thiazolidine and thiomorpholine. The degree of saturation of heterocyclic groups is indicated in the individual definitions. Unsaturated heterocycles for example may contain one, two or three double bonds in the ring system, 5-membered rings and 6-membered rings in the monocyclic and polycyclic heterocycles, in particular they may also be aromatic.

Heterocyclic radicals can be linked by any ring carbon atom. Nitrogen heterocycles, for example pyrrole, imidazole, pyrrolidine, piperidine, hexamethyleneimine, 1,3-thiazolidine, morpholine, thiomorpholine, piperazine, etc., can also be attached via any convenient ring nitrogen atom, in particular if the nitrogen heterocycle involved is linked to a carbon atom. For example, a thienyl radical may be present as a 2-thienyl radical or a 3-thienyl radical, a radical radical such as a 2-furyl or 3-furyl radical, a pyridyl radical such as a 2-pyridyl radical, a radical 3 -pyridyl or 4-pyridyl, a piperidine radical such as a 1-piperidinyl radical (= piperidino radical), 2-piperidinyl radical, 3-piperidinyl radical or 4-piperidinyl radical, radical (thio) morpholino as a 2- (thio) morpholinyl radical, radical 3- (thio) morpholinyl or 4- (thio) morpholinyl radical (= radical) (uncle) morpholino). A radical derived from 1,3-thiazole can be attached via position 2, position 3, position 4 or position 5, a radical derived from imidazole can be attached via position 1, position 2, position 4 or the position 5. If not stated otherwise, the heterocyclic groups may be unsubstituted or may carry one or more, for example one, two, three or four identical or different substituents. The substituents on the heterocycles can be located in any of the desired positions, for example in a 2-thienyl radical or a 2-furyl radical in the 3-position and / or in the 4-position and / or in the 5-position, in a radical 3-thienyl or 3-furyl radical in position 2 and / or in position 4 and / or in position 5, in a 2-pyridyl radical in position 3 and / or in position 4 and / or in position 5 and / or in position 6, in a radical 3 -pyridyl in position 2 and / or in position 4 and / or in position 5 and / or in position 6, in a radical 4 -pyridyl in the position 2 and / or in position 3 and / or in position 5 and / or in position 6. If not stated otherwise, substituents that may occur for example are substituents indicated in the definition of the aryl group, in the case of saturated or partially unsaturated heterocycles as additional substituents also the oxo group and the thioxo group. Substituents on a heterocycle can also be substituents on a carbocycle and can also form a ring, additional rings can thus be fused to a ring system such as for example cyclopenta-fused, cyclohexa-fused or benzo-fused rings, can be present. If not stated otherwise, possible substituents on a substitutable nitrogen atom of a heterocycle, by examples are unsubstituted and substituted 1 to 4 carbon alkyl radicals, aryl radicals, acyl radicals, such as -CO-alkyl having 1 to 4 carbon atoms or -CO-aryl, or sulfonyl radicals such as -S02-alkyl with 1 to 4 carbon atoms or -S02-aryl. Suitable sulfur heterocycles may also be present as S-oxides or S, S-dioxides, ie they may contain the group S (= 0) or the group S (= 0) 2 instead of a sulfur atom. Suitable nitrogen heterocycles may also be present as N-oxides or as quaternary salts with an anion derived from a physiologically tolerable acid as an anti-ion. Pyridyl radicals can be present, for example, as pyridine N-oxides. Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine. The present invention includes all stereoisomeric forms of the compounds of the formula I. Asymmetric centers contained in the compounds of the formula I all independently of each other, may have the S or the R configuration. The invention includes all possible enantiomers and diastereomers, as well as mixtures of two or more stereoisomeric forms, for example mixtures of enantiomers and / or diastereomers, in all proportions. The invention in this manner refers to enantiomers in enantiomerically pure form, both as antipodes of gJSsafcftá-dextrorotatory as levorotatory, in the form of racemates and in the form of mixtures of the two enantiomers in all proportions. In the presence of cis / trans isomerism, for example in double bonds cycloalkyl groups, the invention relates both to the cis form and the trans form and mixtures of these forms in all proportions. Individual stereoisomers can be prepared if desired, by resolution of mixing of usual methods, for example by chromatography or crystallization, by the use of stereochemically homogeneous starting materials in the synthesis or by stereoselective synthesis. If appropriate, the derivatization can be carried out before separation of the stereoisomers. The separation of a mixture of stereoisomers can be carried out in the stage of the compounds of the formula I or in the step of an intermediate in the course of the synthesis. . If mobile hydrogen atoms are present, the present invention also includes all tautomeric forms of the compounds of the formula I. If the compounds of the formula I contain one or more acidic or basic groups, the invention also relates to corresponding physiologically or toxicologically tolerable salts, in particular the pharmaceutically useful salts. Thus, the compounds of formula I containing acidic groups can be present in these compounds and can be used according to the invention, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts. Examples of these salts are sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines, for example ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of formula I that contain one or more basic, ie protonatable, groups may be present and may be used According to the invention, in the form of their acid addition salts with physiologically tolerable inorganic or organic acids, for example as salts with hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, acid methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, acid pimelic, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, etc. If the compounds of the formula I simultaneously contain acidic and basic groups in the molecule, in addition to the salt forms profiled or established by SM38Í? £ S% É. J? «? * r ^^^ J ^ -fcatafii-j the invention, also include salts of metals or betaines (zwitterions). Salts of the compounds of formula I can be obtained by customary processes known to the person skilled in the art, for example by combination with an organic or inorganic acid or base, in a solvent or dispersant, or in an alternate form of other salts by exchange of anions or exchange of cations. The present invention also includes salts of the compounds of the formula I which due to the low physiological tolerability are not directly suitable for use in pharmaceutical products, but are suitable for example as intermediates for chemical reactions or for the preparation of physiologically tolerable salts. The present invention also includes all solvates of compounds of the formula I, for example hydrates or adducts with alcohols, and also derivatives of the compounds of the formula I such as for example esters and amides and prodrugs and active metabolites. Preferably R1 is alkyl with 1 to 8 carbon atoms which may be substituted by one or more identical or different substituents, from the group consisting of hydroxyl, alkoxy with 1 to 4 carbon atoms, alkyl with 1 to 4 carbon atoms -S (O) m-, R5 R6N and aryl, 25 o (cycloalkyl with 3 to 9 carbon atoms that can *% * • «. ^. * - »~? A- ~ ** MIA ^? ^. .2-., »*. ^. * -. * & **. ** iM! t &GßtííS & & amp; & KÍL. '2 &?' "J A.. . J ^^ i ^? ^ ^ ¡& .2 ^ ¡i ^ i ^^ &amp? A? S ^ > "." -, is substituted by one or more substituents identical or different from the group consisting of alkyl having 1 to 4 carbon atoms, hydroxyl and amino, preferably R2 is hydrogen, alkyl having 1 to 8 carbon atoms which may be substituted by one or more substituents identical or different from the group consisting of hydroxyl, alkoxy with 1 to 4 carbon atoms, alkyl with 1 to 4 carbon atoms-S (0) m-, R5R6N and aryl, or (cycloalkyl) to 9 carbon atoms to be substituted by one or more substituents identical or different from the group consisting of alkyl having 1 to 4 carbon atoms, hydroxyl and amino.It is particularly preferred if R 1 is alkyl with 1 to 8 carbon atoms or cycloalkyl with 3 to 9 carbon atoms and R2 is hydrogen or if R1 and R2 are identical or different, alkyl having 1 to 8 carbon atoms, wherein all radicals may be unsubstituted or substituted, as indicated. if R1 is (cyclone oalkyl with 3 to 9 carbon atoms, which may be substituted by one or more substituents identical or different from the group consisting of alkyl with 1 to 4 carbon atoms, hydroxyl and amino, and R 2 is hydrogen. If R1 is cycloalkyl (with 3 to 9 carbon atoms) which may be substituted by one or more substituents identical or different from the group consisting of alkyl with 1 to 4 carbon atoms, hydroxyl '• *?' £ & js s2s and amino, or the radical of a saturated 5-membered, 6-membered or 7-membered heterocyclic ring containing one or two hetero ring members identical or different from the group consisting of 0, NR ^^ S ( 0) ra and which may be substituted by one or more substituents identical or different from the group consisting of alkyl with 1 to 4 carbon atoms and aryl-alkyl with 1 to 4 carbon atoms, then R2 is preferably hydrogen. An alkyl radical representing R1 or R2 is preferably an unsubstituted or substituted 1 to 4 carbon alkyl radical. A cycloalkyl radical (with 3 to 9 carbon atoms) represents R1 or R2 is preferably a cycloalkyl radical with 3 to 7 carbon atoms unsubstituted or substituted. In addition to the aforementioned preferred meanings of R1 and R2, it is further preferred if the group RR2N is a radical, linked via a ring nitrogen atom, of a 5-membered, 6-membered or 7-membered saturated heterocyclic ring which in addition to the nitrogen atom that carries the radicals R1 and R2, additionally an additional oxygen ring, an S (0) group or a nitrogen atom carrying a radical R7 can be additionally heteroarylated as a member and can be replaced by one or more identical or different substituents, of the group consisting of alkyl with 1 to 4 carbon atoms, hydroxyl, alkoxy with 1 to 4 carbon atoms, R8R9N, hydroxycarbonyl, alkoxycarbonyl with 1 to 4 atoms and R8R9N-CO-. A radical representing RXR2N of a heterocyclic ring is preferably derived from a saturated 5-membered or 6-membered heterocyclic ring, particularly preferably from piperidine, morpholine, thiomorpholine (and its S-oxide and S, S-dioxide) or piperazine , all may be substituted as indicated, most particularly preferably unsubstituted piperidine, morpholine or thiomorpholine (and its S-oxide and S, S-dioxide) or N-methylpiperazine. The aryl group representing R3 is preferably unsubstituted or substituted phenyl, particularly preferably substituted phenyl, very particularly preferably phenyl, which is substituted by one or two substituents of those indicated above for aryl. Especially preferably, R 3 is phenyl which is substituted by one or two identical or different substituents, of the group consisting of halogen and alkyl having 1 to 4 carbon atoms, even more preferably phenyl which is substituted by chlorine or methyl. The substituent on a mono-substituted phenyl group representing R 3 is preferably in the para position. R 4 is preferably alkyl having 2 to 5 carbon atoms, trifluoromethyl or unsubstituted phenyl or substituted, particularly preferably straight or branched chain with 3 to 4 carbon atoms, for example n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. Aryl is preferably phenyl or a 5-membered or 6-membered monocyclic heteroaryl, having one or two, in particular a hetero-atom of the group consisting of N, O and S, which may be substituted as indicated, particularly preferably unsubstituted or substituted phenyl or unsubstituted pyridyl, thienyl or furyl, very particularly preferably unsubstituted or substituted phenyl or unsubstituted pyridyl. Preferred compounds of the formula I are those in which one or more of the radicals contained have the preferred meanings, the present invention refers to all combinations of definitions of preferred substituents. The present invention also includes, of all preferred compounds of formula I, all their stereoisomeric forms and mixtures thereof in all proportions and their physiologically tolerable salts. The present invention also relates to processes for the preparation of the compounds of the formula I, which are explained below and by which the compounds according to the invention are obtained. s ^^ S ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ fc ^^^^^^^^^^^^^^ The compounds of the formula I can be prepared by first reacting an amidine of the formula II in a manner known per se, with a 3-oxo-propionic acid ester of the formula ## STR3 ## III which carries a radical R4 in the 3-position, to give a 4-hydroxypyrimidine of the formula IV. R in formula III, for example, is alkyl with 1 to 4 carbon atoms such as methyl or ethyl. The hydroxypyrimidine of formula IV is then activated, for example, by conversion to a 4-halopyrimidine. For example, the compound of formula IV can be converted to 4-chloropyrimidine of formula V by reaction with phosphorus halide such as phosphorus oxychloride. By reaction of the compound of the formula V (or of another reactive derivative of the hydroxypyrimidine) with the desired amine of the formula VI, the compound of the formula I according to the invention is then obtained with replacement of the chlorine by the amino group. Suitable solvents for this replacement reaction are for example water, alcohols such as methanol, ethanol or isopropanol, ethers such as tetrahydrofuran or dioxane, amides such as dimethylformamide (DMF) or N-methylpyrrolidone (NMP), or hydrocarbons or halogenated hydrocarbons such as benzene, toluene, xylene, chlorobenzene or dichlorobenzene. "" ^ á IV V The reactions for the synthesis of the compounds of the formula I can be carried out over a wide range of temperatures. Reaction temperatures of 20 ° C to 150 ° C are preferred. The reactions can be accelerated by the addition of suitable bases such as, for example, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium alkoxides, triethylamine or pyridine, in the first and in the last stages additionally also by an excess of amidine. Formula II or amidine of formula VI. Instead of the free amidines of the formula II, the corresponding amidinium salts can also be used. In this case, it is particularly convenient to carry out the ., -? I?.?. ¡: ¿¿:,. ^^^ ¿a2¿ * ,. 2? , ^ j ^., - first stage with addition of bases. The intermediates of formulas IV and V and the final compounds of formula I can be separated from the respective reaction mixture by customary processes such as crystallization, sublimation, chromatography or distillation and, if desired, purified, however depending on the circumstances of the individual case, intermediaries can react more also without isolation of intermediaries. Still further, functional groups in the obtained compounds can be converted. For example, thioether groups can be converted to sulfones or sulfoxides, by oxidation with a peroxy compound such as 3-chloroperbenzoic acid or monoperoxyphthalic acid or hydrogen peroxide, or carboxylic acid ester groups can be hydrolyzed in the carboxylic acids. All reactions for the synthesis of the compounds of the formula I are well known per se by the person skilled in the art and can be carried out under standard conditions, according to or analogously to literature procedures as described for example in Houben-Weyl, "Methoden der Organischen Chemie" [Methods of Organic Chemistry], Thieme-Verlag, Stuttgart, or in "Organic Reactions" (Organic Reactions), John Wiley & amp; amp;; Sons, New York. Depending on the conditions of the individual case, it may also be advantageous or necessary to avoid side reactions in the synthesis of the compounds of the formula I, to temporarily block certain functional groups by the introduction of protecting groups and then subsequently release them again or use groups functional first in the form of precursors, of which the desired functional group is then produced at a later stage. These synthesis strategies and protective groups or precursors suitable for the case individual, are known by the person with skill in the specialty. The starting amidines of the formula II or their salts, the oxo-esters of the formula III and the amines of the formula VI are obtained commercially or can be prepared by or in analogy to known processes. The compounds of the formula I according to the invention achieve an increase in the concentration of cGMP by the activation of soluble guanylate cyclase (sGC) and are therefore valuable agents for the therapy and prophylaxis of diseases associated with a low level or Reduced cGMP or are caused by this level or for whose therapy or prophylaxis an increase in the level of cGMP present is desired. The activation of sGC by the compounds of formula I can be investigated for example in the activity assay described below.

'^ Faith?.,. 'S ¿¿', fo «^" ^ ¡Zj ^ Diseases and pathological conditions that are associated with a low level of cGMP, where the increase in the level of cGMP is desired and for whose therapy and prophylaxis the compounds of the formula I can be used, for example, cardiovascular disorders such as endothelial dysfunction, diastolic dysfunction, atherosclerosis, high blood pressure, stable and unstable angina pectoris, thrombosis, restenosis, myocardial infarction, attack, heart failure or hypertension. pulmonary, or for example erectile dysfunction, bronchial asthma, chronic renal failure and diabetes. Compounds of the formula I can be further used in the therapy of cirrhosis of the liver and to improve the capacity of restricted learning or memory power. The compounds of the formula I and their physiologically tolerable salts can thus be used in animals, preferably in mammals, and in particular in humans, as pharmaceuticals by themselves, in mixtures with one another or in the form of preparations pharmaceuticals. The present invention therefore also relates to the compounds of the formula I and their physiologically tolerable salts for use as pharmaceuticals, their use for the normalization of a disturbed cGMP equilibrium and in particular their use in the therapy and prophylaxis of the syndromes previously mentioned, and their use for the production of medicines. The present invention further relates to pharmaceutical preparations (or pharmaceutical compositions) containing an effective dose of at least one compound of formula I and / or its physiologically tolerable salt as an active constituent and a pharmaceutically tolerable carrier, i.e. one or more usual pharmaceutically tolerable vehicles and / or excipients (or additives). The pharmaceutical products according to the invention can be administered orally, for example in the form of pills, tablets, film-coated tablets, coated tablets, granules, hard and soft gelatin capsules, aqueous or alcoholic solutions, syrups, emulsions or suspensions. , or rectally for example in the form of suppositories. Administration can however also be carried out parenterally, for example subcutaneously, intramuscularly or intravenously in the form of injection solutions or infusion solutions. Further possible administration forms for example are percutaneous or topical application, for example in the form of ointments, tinctures, sprays or transdermal therapeutic systems or administration by inhalation in the form of nasal sprays or aerosol mixtures, for example microcapsules, implants or rods .

The present administration form depends, for example, on the disease to be treated and its severity. The pharmaceutical preparations usually contain 0.2 to 500 mg, preferably 1 to 200 mg, of active compound of the formula I and / or their physiologically tolerable salts; depending on the nature of the preparation and the intended use, the amount of active compound contained may also be greater. The pharmaceutical preparations may be produced in a manner known per se. For this, one or more compounds of formula I and / or their physiologically tolerable salts, are combined with one or more solid and liquid pharmaceutical carriers and / or additives and, if desired, in combination with other pharmaceutically active compounds having therapeutic or prophylactic action , in a convenient administration form or dosage form, which can then be used as a pharmaceutical product in human or veterinary medicine. The pharmaceutical preparations normally contain 0.5 to 90 weight percent of the compounds of the formula I and / or their physiologically tolerable salts. For the production, for example of pills, tablets, coated tablets and hard gelatine capsules, it is possible to use lactose, starch, for example corn starch, or starch derivatives, talc, stearic acid or its salts, etc. Vehicles for soft gelatin capsules and suppositories are for example fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. Suitable vehicles for the preparation of solutions, for example injection solutions, or of emulsions or syrups, are for example water, physiological saline solution, alcohols such as ethanol, glycerol, polyols, sucrose, invert sugar, glucose, mannitol, vegetable oils. , etc. The compounds of the formula I and their physiologically tolerable salts can also be lyophilized and the lyophilizates obtained can be used, for example for the production of injection preparations or infusion preparations. Suitable carriers for microcapsules, implants or rods, for example, are copolymers or glycolic acid and lactic acid. In addition, of the active compounds and vehicles, the pharmaceutical preparations may additionally contain customary excipients or additives, for example fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweetening agents, colorants, flavors, flavorings, Thickening agents, diluents, buffering substances, solvents, solubilizers, agents pass to achieve a deposition effect, salts to alter the osmotic pressure, coating agents or antioxidants.

The dose of the active compound of formula I which is administered and / or of one of its physiologically tolerable salts depends on the individual case and will be adjusted to the individual conditions as is usual for optimal action. In this way, it depends on the nature and severity of the disease to be treated, sex, age, weight and response of the individual of the human or animal to be treated, the potency and duration of action of the compounds used or whether the therapy is acute or chronic or prophylaxis is carried out, or if additional active compounds are administered in addition to the compounds of formula 1. In general, a daily dose of about 0.01 to 100 mg / kg, preferably 0.1 to 10 mg / kg, in Particularly 0.3 to 5 mg / kg (in each case mg per kg of body weight) is appropriate in the case of administration to an adult of approximately 75 kg of weight to achieve the desired action. The daily dose can be administered in a single dose or in particular in the case of administration, of relatively large amounts, divided by an amount for example two, three or four individual doses, if appropriate, depending on the individual behavior, it may be necessary to divert towards or down of the indicated daily dose. The compounds of the formula I activate the soluble guanylate cyclase. Considering this property, apart from as active pharmaceutical compounds in human medicine and veterinary medicine, they can also be used as a scientific tool or as an aid for biochemical investigations where an effect on guanylate cyclase of this type is intended, and also for diagnostic properties, for example in In vitro diagnosis of cell or tissue samples. In addition, the compounds of the formula I and their salts, as already mentioned above, can serve as intermediates for the preparation of additional active pharmaceutical compounds. The following examples illustrate the invention without restricting it. EXAMPLES Example 1 2- (4-Chlorophenyl) -4-hydroxy-6-isopropylpyrimidine A mixture of 19.1 g of 4-chlorobenzamidine hydrochloride, 15.8 g of ethyl 4-methyl-3-oxopentanoate, 11.2 g of potassium tert-butoxide and 200 ml of ethanol, heated at reflux for 2 hours. After cooling to room temperature, the solid is filtered off with suction, washed with water and with a little ethanol and dried at 40 ° C under vacuum. Yield: 12.5 9. P.f .: 164 ° C. The following were prepared analogously: Example 2 2- (4-Chlorophenyl) 4-hydroxy-6-trifluoromethylpyrimidine; p.f. : 258 ° C. Example 3 2- (4-Chlorophenyl) -6-tert-butyl-4-hydroxypyrimidine; p.f. : 193 ° C. Example 4 2- (4-Chlorophenyl) 4-hydroxy-6-phenylpyrimidine; p.f .: 306 ° C. Example 5 2- (4-methylphenyl) -4-hydroxy-6-isopropylpyrimidine; p.f .: 164 ° C. Example 6 2- (3,5-Dichlorophenyl) -4-hydroxy-6-isopropylpyrimidine; p.f. : 203 ° C. Example 7 2- (4-Aminocarbonylphenyl) 4-hydroxy-6-isopropylpyrimidine; p.f. : 294 ° C. Example 8 4-Chloro-2- (4-chlorophenyl) -6-isopropylpyrimidine. The mixture of 12 g of 2- (4-chlorophenyl) -4-hydroxy-6-isopropylpyrimidine and 35 ml of phosphorus oxychloride is heated at 90 ° C for 3 hours with stirring. Most of the excess phosphorus oxychloride is removed by vacuum distillation, and the residue is added to 100 ml of ice-water and stirred. The solid white precipitate that It is separated by filtration with suction and dried under vacuum at room temperature. Yield: 11.4 g P.f. : 74 ° C 5 The following were prepared analogously Example 9 4-Chloro-2- (4-chlorophenyl) -6-trifluoromethylpyrimidine; mp .: 76 ° C Example 10 10 4-Chloro-2- (4-chlorophenyl) -6-tert-butylpyrimidine; mp .: 93 ° C Example 11 4-Chloro-2- (4-chlorophenyl) -6-phenylpyrimidine; p.f .: 127 ° C. Example 12 4-Chloro-2- (4-methylphenyl) -6-isopro-pyrimidine; p.f .: 15 oil Example 13 4-Chloro-2- (3,5-dichlorophenyl) -6-isopropylpyrimidine; mp .: 59 ° C Example 14: 4-Chloro-2- (4-cyanophenyl) -6-isopropylpyrimidine from m.p. 114 ° C is obtained in an analogous reaction starting from 2- (4-aminocarbonylphenyl) 4-hydroxy-6-isopropylpyrimidine. Example 15 2- (4-Chlorophenyl) -6-isopropyl-4- ((2,2,6,6-tetramethylpiperidin-4-yl) amino) -pyrimidine dihydrochloride.

A mixture of 534 mg of 4-chloro-2- (4-chlorophenyl) -6-isopropylpyrimidine and 1.8 g of 4-amino-2, 2, 6, 6-tetramethylpiperidine is heated at 150 ° C for 2 hours with stirring. After cooling, 20 ml of water are added and the mixture is stirred at room temperature. The white precipitate was filtered off with suction, dried under vacuum and recovered 20 ml of ethyl acetate. By addition of hydrogen chloride, the title compound is precipitated, filtered off with suction and dried under vacuum.

Performance: 0.8 g. M.p .: 359 ° C Example 16 2- (4-Chlorophenyl) -6-isopropyl-4-morpholinopyrimidine A mixture of 267 mg of 4-chloro-2- (4-chlorophenyl) -6-isopropylpyrimidine and 522 mg of morpholine is heat at 130 ° C for 2 hours. After cooling, 20 ml of water is added, the mixture is stirred and the solid is filtered off with suction and dried at 50 ° C under vacuum. Yield: 0.28 g. P.f. : 123 ° C The following compounds of the formula I are prepared analogously to Examples 15 and 16. If an acid is specified in the "pf" column, the compound is obtained in the form of the acid addition salt with the specified acid. The "2 HCl" specification means The compound is obtained as a dihydrochloride.

Ex. R4 R3 RXR2N P f.

Do not . (° C) 17 CF3 4-Chlorophenyl (3-phenylpropyl) amino oil 18 CF3 4-Chlorophenyl (2-Ethylthioethyl) amino 114 (HCl) 19 CF3 4-Chlorophenyl (l-benzylpiperidin-4-yl) amino 128 (2 HCl) CF3 4-Chlorophenyl 4- (2-hydroxyethyl) iperazine 119 21 Isopropyl 2-Pyridyl Benzylamino 150 22 Isopropyl 2 -Pirazinyl Tiomorpholino 107 23 Isopropyl 4-Methylphenyl (3-Methoxypropyl) - Amino-24-Isopropyl 4-Methylphenyl-Cyclopentylamino-66-Isopropyl-4-Methylphenyl (trans-4-Hydroxycyclohexyl) amino Oil 26 Isopropyl 4-Chlorophenyl (3-methoxypropyl) - Amino 27-Isopropyl 4-chlorophenyl 4-methylpiperazino 292 (2HC1) oil 28 Isopropyl 4-Chlorophenyl Piperidino 75 29 Isopropyl 4-Chlorophenyl Pyrrolidine 215 (HCl) Isopropyl 4-Chlorophenyl Thiomorpholino 215 (Hcl) Ex. R4 R3 RR2N P.f. No. (° C) 31 Isopropyl 4-Chlorophenyl (2- (3-Methoxyphenyl) -213 ethyl) -amino (HCl) 32 Isopropyl 4-Chlorophenyl Butylamino Oil 33 Isopropyl 4-Chlorophenyl Diethylamino Oil 34 Isopropyl 4-Chlorophenyl Dibutylamino 165 ( HCl) 35 Isopropyl 4-Chlorophenyl Dipropylamino 176 (HCl) 36 Isopropyl 4-Chlorophenyl Diallylamino 118 37 Isopropyl 4-Chlorophenyl Di (2-methoxyethyl) amino 127 (HCl) 38 Isopropyl 4-Chlorophenyl Perhydroazepin-1-yl 68 39 Isopropyl 4- Chlorophenyl Benzylamino 108 40 Isopropyl 4-Chlorophenyl (2-Methoxyethyl) amino 152 (HCl) 41 Isopropyl 4-Chlorophenyl (2-Ethylmercaptoethyl) - 148 amino (HCl) 42 Isopropyl 4-Chlorophenyl (3-Morpholinopropyl) 245 amino (2HC1) 43 Isopropyl 4-Chlorophenyl N- (Ethyl) -N- (benzyl) - Amine 44 Isopropyl 4-chlorophenyl 4-Aminocarbonylpipe-189 ridino oil Ex. R4 R3 RXR2N P.f. No. (° C) 45 Isopropyl 4-Chlorophenyl 1,3-thiazolidin-3-yl 77 46 Isopropyl 4-Chlorophenyl 4- (Dimethylaminosul- 150 phonyl) -piperazine 47 Isopropyl 4-Chlorophenyl 4-Benzylpiperazine 265 (2HC1) 48 Isopropyl 4-Chlorophenyl 4- ((Isopropylamino-133 carbonyl) -methyl) piperazine 49 tert-Butyl 4-chlorophenyl 4-methylpiperazino 122 50 tert-Butyl 4-chlorophenyl (2-methoxyethyl) amino 94 51 tert-Butyl 4-chlorophenyl (3 - Pyridylmethyl) amino 143 52 tert-butyl 4-chlorophenyl Morpholino 136 53 tert-Butyl 4-chlorophenyl 4- (dimethylaminosul-168 phonyl) -piperazino 54 tert-Butyl 4-chlorophenyl (2, 2, 6, 6-Tetramethyl- 142 piperidin-4-yl) amino 55 Phenyl 4-Chlorophenyl Morpholino 193 56 Phenyl 4-Chlorophenyl 4-Methylpiperazino 167 57 Phenyl 4-Chlorophenyl (3-pyridylmethyl) amino 130 58 Phenyl 4-Chlorophenyl (3- (Imidazol-1-yl) - 154 propyl) amino 59 Phenyl 4-chlorophenyl (2- (3-methoxyphenyl) ethyl) -103 amino (HCl) Ex. R4 R3 RXR2N P.f. No. (° C) 60 Phenyl 4-Chlorophenyl 4-Carboxy-l, 3-thiazo-113-lyrin-3-yl 61-Isopropyl 2-thienyl-pyrrolidino-74-62-Isopropyl 4-thienyl-cis-2, 6-Dimethylmorpholino 103 63 Phenyl 4-Chlorophenyl Diethylamino 132 64 Phenyl 4-Chlorophenyl Butylamino 95 (HCl) 65 Phenyl 4-Chlorophenyl Thiomorpholino 175 66 tert-Butyl 4-Chlorophenyl Tiomorpholino 119 67 Isopropyl 4 -Pyridyl Butylamino 101 68 Isopropyl 4-Pyridyl (3-Phenylpropyl) amino Resin 69 Phenyl 4-Chlorophenyl Dipropylamino 72 70 Isopropyl 4-Chlorophenyl Cyclopropylamino Oil 71 CF3 4-Chlorophenyl (3-pyridylmethyl) amino 181 72 Isopropyl 4-Chlorophenyl 3, 3-Dimethylpiperidino Oil 73 CF3 4-Chlorophenyl 4 Methylpiperazine 108 74 CF3 4-Chlorophenyl Morpholino 184 75 tert-Butyl 4-Chlorophenyl Perhydroazepin-1-yl 151 76 tert-Butyl 4-Chlorophenyl 4-aminocarbonyl-164 piperidino 77-isopropyl 3,5-dichlorophenyl (trans-4-hydroxy) 174 hexil cycle) -amino Ex. R4 R3 R: R2N P.f.

No. (° C) 78 Isopropyl 3,5-Dichlorophenyl (2-hydroxyethyl) -88 amino-79-isopropyl-3,5-dichlorophenylbutylamino-190 (HCl) 80 Isopropyl 3, 5-Dichlorophenyl Diethylamino Oil 81 Morpholine 138 Isopropyl 3,5-Dichlorophenyl 82 Isopropyl 3, 5-Dichlorophenyl. Thiomorpholino-130-83-isopropyl-3, 5-dichlorophenyl-4-methylpiperazino. 84 Isopropyl 3, 5-Dichlorophenyl Dipropylamino Oil 85 Isopropyl 4 -Methylphenyl Dipropylamino Oil 86 Isopropyl 4-Methylphenyl Diethylamino 180 (HCl) 87 Isopropyl 4-Methylphenyl (3-Hydroxypropyl) -86 amino 88 Isopropyl 4-Methylphenyl Butylamino Oil 89 Isopropyl 4-Methylphenyl Morpholino 95 90 Isopropyl 4 -Methylphenyl Tiomorpholino 107 91 Isopropyl 4-Methylphenyl 4-Methylpiperazino 70 92 Isopropyl 4-Chlorophenyl N- (Ethyl) -N- (Butyl) - Amino-93-Isopropyl 4-Chlorophenyl N- (Methyl) -N- (Butyl) -amino-Ex. R4 R3 ^ R2N P.f. No. * (° C) 94 Isopropyl 4-Chlorophenyl 4- (2-Pyridyl) - 166 Piperazine 5 95 CF3 4-Chlorophenyl 4- (2-Pyridyl) - 174 Piperazine 96 Isopropyl 4-Chlorophenyl cis / trans-2, 6 - Dimethyl alcohol-Morpholino 97 Isopropyl 4-Methylphenyl cis-2,6-dimethyl- Oil 10 Morpholino 98 Isopropyl 4-Methylphenyl Di (2-methoxyethyl) - Amine 99-Isopropyl 4-methylphenyl 4-Aminocarbonyl-192-piperidino 15-100-Isopropyl 4 -Methylphenyl Perhydroazepin-1-yl Oil 101 tert-Butyl 4-Chlorophenyl cis-2,6-Dimethyl-117 morpholino 102 tert-Butyl 4-Chlorophenyl (3-methoxypropyl) -Omino Amino 20 103 tert-Butyl 4-Chlorophenyl Di ( 2-methoxyethyl) - Amino 104-Isopropyl 4-chlorophenyl-cis-2, 6-dimethyl-114 morpholino-105-Isopropyl 4-chlorophenyl (2-diisopropylamino-219-ethyl-ethyl) -amino (2 Hcl) oil tto &j? aSJb &amp? ai * - *! Ex. R4 R3 RXR2N P.f.

No. (° C) 106 Isopropyl 4-Chlorophenyl 4- (2-Hydroxyethyl) -227 Piperazine 107 Isopropyl 4-Chlorophenyl (1-Benzylpiperidin-250 4 -yl) amino (2HC1) 108 Phenyl 4-Chlorophenyl cis / trans-2,6-Dimethyl-187 morpholino 109 Phenyl 4-Chlorophenyl (3-Methoxypropyl) amino Oil 110 Phenyl 4-Chlorophenyl Di (2-methoxyethyl) amino Oil 111 Phenyl 4-chlorophenyl 4-Aminocarbonylpipe-204 Ridino 112 Phenyl 4-Chlorophenyl Perhydroazepin-1-yl 126 113 Isopropyl 4-Cyanophenyl (4-Hydroxybutyl) amino 93 114 Isopropyl 4-Cyanophenyl (3-methoxypropyl) amino 70 115 Isopropyl 4-Cyanophenyl Butylamino 89 116 Isopropyl 4-Cyanophenyl Cyclopentylamino 141 117 Isopropyl 4-Cyanophenyl (4-hydroxycyclohexyl) - 101 amino 118 Isopropyl 4-cyanophenyl (3-pyridylmethyl) amino 149 119 Isopropyl 4-Cyanophenyl Dipropylamino 80 120 Isopropyl 4-Cyanophenyl Perhydroazepinyl-117 121 Isopropyl 4-Cyanophenyl Morpholine 224 122 Isopropyl 4-Cyanophenyl 4-Methylpiperazino 152 123 Isopropyl 2-Methylthiazol-4-yl Dipropylamino Oil Ex. R4 R3 RRN P.f. No. (° C) 124 Isopropyl 4-Chlorophenyl Cyclopentylamino 82 125 Isopropyl 4-Chlorophenyl (trans-4-hydroxy-138-clohexyl) -amino 126-Isopropyl 4-chlorophenyl (trans-4-amino-128-clohexyl) -amino-127-Isopropyl 4 -Chlorophenyl (cis / trans4-Hydroxycycium-cyclohexyl) amino-128-Isopropyl-4-chlorophenyl (4-methylcyclohexyl) - amino-129-isopropyl-4-chlorophenyl-N- (cyclohexyl) -N-88 (methyl) amino-130-isopropyl-4-chlorophenyl ( 2-Isopropyl-5-methylcyclohexyl) amino-131-Isopropyl 4-chlorophenyl (trans-2-Hydroxy-cyclohexyl) -amino-132-tert-butyl-4-chlorophenyl ester Cyclopentylamino-89-133-tert-butyl-4-chlorophenyl (trans-4-hydroxy) 173 cyclohexyl) -amino 134 CF 3 4-Chlorophenyl Cyclopentylamino 99 135 Phenyl 4-Chlorophenyl (trans-4-Hydroxy-95 cyclohexyl) -amino 136 Isopropyl 4-Chlorophenyl 4-Hydroxypiperidine 121 E j. R4 R3 RXR2N P f. Do not . (° C) 137 Isopropyl 4-Chlorofenil (4-Hydroxybutyl) - Amino acid 138 Isopropyl 4-Chlorofenil (Benzimidazol-2-yl-112-methyl) -amino 139 Isopropyl 4-Chlorophenyl Cyclobutylamino 70 140 Isopropyl 4-Chlorophenyl Ciclononylamino Oil 141 Isopropyl 4-Chlorophenyl 3-diethylamino- Carbonyl-piperidino oil 142 Isopropyl 4-chlorophenyl ((R) -1-phenylethyl) - amino-143-isopropyl 4-chlorophenyl ((S) -1-phenylethyl) -amino oil Example 144 2- ( 4-chlorophenyl) -6-isopropyl -4 - (1 -oxot iomorfol ino) -pyrimidine 0.25 g of 2- (4-chlorophenyl) -6-isopropyl-4-thiomorpholinopyrimidine are dissolved in 1 ml of glacial acetic acid and treated with 0.068 ml of a hydrogen peroxide solution with 35% concentration. After 2 hoursThe mixture is diluted with 20 ml of water and the product is extracted with ethyl acetate. The ethyl acetate phase is extracted twice by shaking with 10 ml of water and the organic phase is concentrated after drying over sodium sulfate. sodium. The residue is recrystallized from isopropanol. Yield: 0.189. P.f. : 171 ° C. The following sulfoxides and sulphones were prepared analogously: Example 145 2- (4-Chlorophenyl) -6- isopropyl -4 - (1,1-dioxo-thiomorpholine) pyrimidine; p.f .: 226 ° C. EXAMPLE 146 2- (4-Chlorophenyl) -6-isopropyl-4- (l -oxo-1,3-thiazolidin-1-yl) pyrimidine; mp .: 128 ° C. Example 147 2- (4-Chlorophenyl) -4- ((2-ethylsulfinylethyl) -amino) -6-isopropylpyrimidine; mp .: 103 ° C Example 148 6-Isopropyl-2- (4-methylphenyl) 4- (1-oxothiomorpholin) -pyrimidine; mp .: 152 ° C Example 149 2- (3,5-Dichlorophenyl) -6-isopropyl-4- (1-oxothiomorpholin) -pyrimidine; mp: 187 ° C Pharmacological Investigations Activation of soluble guanylate cyclase The activation of soluble guanylate cyclase (sGC), which catalyzes the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP) and pyrophosphate, by the compounds according to the invention is quantified with the aid of an enzyme immunoassay (EIA) of Amersham. For this, the test substances were first incubated with sGC in microtiter plates and then the amount of resulting cGMP is determined, sGC used has been isolated from bovine lung (see "Methods in Enzymology", Methods 195). p 377). The test solutions (100 μl per well) contain 50 mM triethanolamine (TEA) buffer (pH 7.5), 3 mM MgCl 2, reduced glutathione (GSH), 0.1 mM GTP, 1 mM 3 -isobutyl-1-methylxanthine (IBMX), suitably diluted enzyme solution and the test substance or in the control experiments, the solvent. The test substances were dissolved in dimethyl sulfoxide (DMSO) and the solution was diluted with DMSO / water, so that the final concentration c of the test substance in the test batch was 50 μM. The concentration of DMSO in the test lot was 5% (v / v). The reaction was initiated by the addition of sGC. The reaction mixture was incubated at 37 ° C for 15 to 20 minutes and then stopped by cooling with ice and addition of stop reagent (50 mM EDTA, pH 8.0). An aliquot of 50 μl is recovered and used for the determination of cGMP content using the acetylation protocol of the Amersham cGMP EIA team. The absorption of the samples was measured at 450 nm (reference wavelength 620 nm) in a microtiter plate reading apparatus. The concentration of cGMP was determined by a calibration curve, which is obtained under the same experimental conditions. The activation of sGC by a test substance is indicated as an n-fold stimulus of the basal enzymatic activity found in the control experiments (with solvent instead of the test substance) (calculated according to the stimulus formula n) -sometimes = [cGMp] test substance / [cGMP] control). The following results were obtained: Compound of the n-fold stimulus Example No. a c = 50 μM 23 > 8 25 28 29 > 4 30 > 4 32 > 4 33 > 16 34 > 4 35 > 16 36 > 8 38 > 8 43 > 4 44 > 4 45 > 4 n-fold stimulus compound Example No. a c = 50 μM 52 > 8 63 > 8 66 > 4 69 > 4 77 30 79 > 4 80 > 16 81 > 4 82 > 4 84 > 16 85 > 16 86 > 16 88 > 8 89 > 8 90 > 16 97 > 16 98 > 8 99 > 4 100 > 8 112 > 8 124 > 16 125 32 133 > 16 * m ^^^^^^^^^^^^^^^^^ Compound of n-fold stimulus Example No. a c = 50 M 137 > 16

Claims (12)

1. CLAIMS 1. A compound of formula I, wherein R 1 is alkyl having 1 to 8 carbon atoms, which may be substituted by one or more substituents identical or different from the group consisting of hydroxyl, alkoxy with 1 to 4 carbon atoms, alkyl with 1 to 4 carbon atoms- S (O) m-, R5R6N and aryl, cycloalkyl with 3 to 9 carbon atoms, which may be substituted by one or more substituents identical or different from the group consisting of alkyl with 1 to 4 carbon atoms, hydroxyl and amino, or the radical of a 5-membered saturated 7-membered heterocyclic ring, containing one or two hetero ring members identical or different from the group consisting of O, NR7 and S (0) m, and which may be substituted by one or more substituents identical or different from the group consisting of alkyl having 1 to 4 carbon atoms and aryl-alkyl having 1 to 4 carbon atoms; and R 2 is hydrogen, alkyl having 1 to 8 carbon atoms which may be substituted by one or more identical substituents or different, from the group consisting of hydroxyl, alkoxy with 1 to 4 carbon atoms, alkyl with 1 to 4 carbon atoms-S (0) m-, R5R6N and aryl, cycloalkyl with 3 to 9 carbon atoms, which may be substituted by one or more substituents identical or different from the group consisting of alkyl having 1 to 4 carbon atoms, hydroxyl and amino, or the radical of a saturated 5-membered to 7-membered heterocyclic ring, containing one or two members of hetero ring, identical or different, from the group consisting of 0, NR7 and S (0) m and which may be substituted by one or more substituents identical or different from the group consisting of alkyl with 1 to 4 carbon atoms and arylalkyl with 1 to 4 carbon atoms-; or RR2N is a radical, linked by a ring nitrogen atom, of a saturated 5-membered to 7-membered heterocyclic ring, in addition to the nitrogen atom carrying the radicals R1 and R2, may contain an additional hetero ring member of the group consisting of O, NR7 and S (0) m and which may be substituted by one or more substituents identical or different from the group consisting of alkyl having 1 to 4 carbon atoms, hydroxyl, alkoxy with 1 to 4 carbon atoms, R8R9N, hydroxycarbonyl, alkoxycarbonyl with 1 to 4 carbon atoms and R8R9N-CO-; R3 is phenyl which may be substituted by one or more substituents identical or different from the group consisting of halogen, alkyl having 1 to 4 carbon atoms, phenyl, CF3, N02, OH, -O-alkyl having 1 to 4 carbon atoms , -O-alkyl having 2 to 4 carbon atoms-O-alkyl having 1 to 4 carbon atoms, alkylenedioxy having 1 to 2 carbon atoms, NH2, -NH-alkyl having 1 to 4 carbon atoms, N ( (alkyl having 1 to 4 carbon atoms)) 2, -NH-CHO, -NH-CO-alkyl having 1 to 4 carbon atoms, -CN, -CO-NH2, -CO-NH-alkyl with 1 to 4 carbon atoms, -CO-N ((alkyl having 1 to 4 carbon atoms)) 2, -COOH, -CO-0-alkyl having 1 to 4 carbon atoms, -CHO and -C 0-10 alkyl with 1 to 4 carbon atoms; R4 is alkyl having 2 to 5 carbon atoms, trifluoromethyl or phenyl which may be substituted by one or more substituents identical or different from the group consisting of halogen, alkyl having 1 to 4 carbon atoms, phenyl, CF3, N02, OH, -O-alkyl 15 with 1 to 4 carbon atoms, -O-alkyl with 2 to 4 carbon atoms-O-alkyl with 1 to 4 carbon atoms, alkylenedioxy with 1 to 2 carbon atoms, NH2, -NH-alkyl with 1 to 4 carbon atoms, N ((alkyl having 1 to 4 carbon atoms)) 2, -NH-CHO, -NH-CO-alkyl having 1 to 4 carbon atoms Carbon, -CN, -CO-NH2, -CO-NH-alkyl with 1 to 4 carbon atoms, -CO-N ((alkyl with 1 to 4 carbon atoms)) 2, -COOH, -CO-O -alkyl with 1 to 4 carbon atoms, -CHO and -CO- alkyl with 1 to 4 carbon atoms; R5 and R6 are radicals identical or different from the group consisting of hydrogen 25 and alkyl with 1 to 4 carbon atoms or the group R5R6N is a radical, linked by means of a ring nitrogen atom, of a 7-membered saturated or unsaturated 5-membered heterocyclic ring, which in addition to the nitrogen atom carrying the radicals R5 and R6, can additionally contain as an additional hetero ring member a oxygen atom, a group S (0) m or a nitrogen atom that can carry in carbon atoms of the ring one or more substituents identical or different from the group consisting of alkyl with 1 to 4 carbon atoms, hydroxyl 10 and amino and can transport in a ring nitrogen atom, a radical R7; R7 is hydrogen, alkyl of 1 to 4 carbon atoms, aryl-alkyl of 1 to 4 carbon atoms-, hydroxy-alkyl of 1 to 4 carbon atoms, hydroxycarbonyl-alkyl of 1 to 4 carbon atoms, 15 (alkoxycarbonyl with 1 to 4 carbon atoms) - (alkyl with 1 to 4 carbon atoms) -, R8R9N-CO-alkyl with 1 to 4 carbon atoms, R10-SO2- or aryl, where R7, if group is present in a piperazino radical represents R1 R2 N, can not be carbocyclic aryl or aryl-alkyl with 1 to 4 20 carbocyclic carbon atoms; R8 and R9 are radicals identical or different from the group consisting of hydrogen and alkyl with 1 to 4 carbon atoms; R10 is alkyl with 1 to 4 carbon atoms, aryl or R8R9N; Aryl is phenyl, naphthyl or heteroaryl, which can all be substituted 25 by one or more identical or different substituents of the a group consisting of halogen, alkyl having 1 to 4 carbon atoms, phenyl, CF3, N02, OH, -O-alkyl having 1 to 4 carbon atoms, -O-alkyl having 2 to 4 carbon atoms-O-alkyl with 1 to 4 carbon atoms, alkylene dioxy with 1 to 2 carbon atoms, NH2, -NH-alkyl with 1 to 4 carbon atoms, -N ((alkyl with 1 to 4 carbon atoms)) 2, -NH- CHO, -NH-CO-alkyl having 1 to 4 carbon atoms, -CN, -C0-NH2, -CO-NH-alkyl having 1 to 4 carbon atoms, -CONC (alkyl having 1 to 4 carbon atoms) ) 2, -CO-OH, -C0-0- alkyl having 1 to 4 carbon atoms, -CHO and -CO-alkyl having 1 to 4 carbon atoms; "heteroaryl" is the radical of a 5-membered or 6-membered monocyclic aromatic heterocycle or of an 8-membered to 10 membered bicyclic aromatic heterocycle, each of which contains one or more ring hetero atoms identical or different from the group consisting of N, O and S; m is 0, 1 or 2; in all their stereoisomeric forms and mixtures thereof in all proportions and their physiologically tolerable salts, compounds of the formula I are excluded wherein simultaneously R 4 is tert-butyl or trifluoromethyl, R 3 is phenyl which may be substituted by one or two substituents identical or different from the group consisting of halogen, OH, -O-R11 and CF3, RXR2N is R11 -NH-, (Rn) 2N- or R12R13N- (CH2) p-NH-, p is 2 or 3, R11 is alkyl with 1 to 4 carbon atoms unsubstituted and R12 and R13 ^^^^^^^^ g ^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^ j ^^^^^^^^^^^^^^ are identical or different radicals of the group consisting of hydrogen and R11 or the group R12R13N is a radical linked by a ring nitrogen atom, of a ring 5-membered or 6-membered saturated heterocyclic group, which in addition to the nitrogen atom carrying the radicals R12 and R13 may additionally contain as an additional hetero ring member an oxygen atom, a sulfur atom or a nitrogen atom and it may be substituted by an aryl radical or by an aryl alkyl radical having 1 to 4 carbon atoms, wherein the aryl group may be substituted by one or two substituents identical or different from the group consisting of halogen, OH, -0-R11 and CF3.
2. 2. A compound of formula I in accordance 15 with claim 1, characterized in that R1 is alkyl with 1 to 8 carbon atoms, which may be substituted by one or more substituents identical or different from the group consisting of hydroxyl, alkoxy with 1 to 4 carbon atoms, alkyl with 1 to 4 carbon atoms-S (O) m-, R5R6N 20 and aryl, or is a cycloalkyl with 3 to 9 carbon atoms which may be substituted by one or more substituents identical or different from the group consisting of alkyl having 1 to 4 carbon atoms, hydroxyl and amino; and R2 is hydrogen, alkyl having 1 to 8 carbon atoms which can 25 being replaced by one or more identical substituents or ^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^ t ^^ ¡¡A? ^^^^^^^^ í ^^^^^^ different from the group consisting of hydroxyl, alkoxy with 1 to 4 carbon atoms, alkyl with 1 to 4 carbon atoms- S (0) m-, R5R6N and aryl, or is a cycloalkyl with 3 to 9 carbon atoms which may be substituted by one or more other substituents identical or different from the group consisting of alkyl with 1 to 4 carbon atoms, hydroxyl and not me; or RXR2N is a radical, linked by a ring nitrogen atom, of a saturated 5-membered, 6-membered or 7-membered heterocyclic ring, which in addition to the atom Nitrogen transporting the radicals R1 and R2 can additionally contain as an additional hetero ring member, an oxygen atom, a group S (0) or a nitrogen atom carrying a radical R7 and which can be substituted by one or more identical substituents or 15 different from the group consisting of alkyl with 1 to 4 carbon atoms, hydroxyl, alkoxy with 1 to 4 carbon atoms, R8R9N, hydroxycarbonyl, alkoxycarbonyl with 1 to 4 carbon atoms and R8R9N-CO-; in all its stereoisomeric forms and mixtures of all proportions 20 or its physiologically tolerable salts.
3. 3. A compound of formula I according to claim 1 and / or 2, characterized in that R1 is alkyl with 1 to 4 carbon atoms, which may be substituted by one or more identical substituents or 25 different from the group consisting of hydroxyl, alkoxy with ^^ ¡^ g ^^^^^^^^^^^^^^^^^^^^ g ^^^^^^^^^^^^^^^^^^^^ gg ^^^^^^^^^^^^ ß ^ íj ^^ fc ^^^^^ S ^^^^^^^^ jM 1 to 4 carbon atoms, alkyl with 1 to 4 atoms carbon-S (0) m-, R5R6N and aryl, or cycloalkyl with 3 to 9 carbon atoms which may be substituted by one or more substituents identical or different from the group consisting of alkyl having 1 to 4 carbon atoms, hydroxyl and amino, and R2 is hydrogen, or R1 and R2 are identical or different alkyl having 1 to 4 carbon atoms which may be substituted by one or more substituents identical or different from the group consisting of hydroxyl, alkoxy with 1 to 4 carbon atoms , alkyl having 1 to 4 carbon atoms-S (O) m-, R5R6N and aryl; in all its stereoisomeric forms and their mixtures in all proportions or their physiologically tolerable salts.
4. 4. A compound of formula I according to one or more of claims 1 to 3, characterized in that R1 is cycloalkyl with 3 to 9 carbon atoms, which may be substituted by one or more substituents identical or different from the group consisting of of alkyl having 1 to 4 carbon atoms, hydroxyl and amino, and R2 is hydrogen; in all its stereoisomeric forms and mixtures thereof in all proportions or their physiologically tolerable salts.
5. 5. A compound of the formula I according to claim 1 and / or 2, characterized in that RXR2N- is an unsubstituted or substituted radical of the group that ¿^^^ £ ^ ^ gg ^ ^ ^^^^^^^^^^ consists of piperidino, morpholino and thiomorpholino (and their S-oxide and S, S-dioxide) and piperazino; in all its stereoisomeric forms and mixtures thereof in all proportions or their physiologically tolerable salts.
6. 6. A compound of formula I according to one or more of claims 1 to 5, characterized in that R3 is substituted phenyl; in all its stereoisomeric forms and their mixtures in all proportions or their physiologically tolerable salts.
7. 7. A compound of formula I according to one or more of claims 1 to 6, characterized in that R4 is alkyl with 3 to 4 carbon atoms; in all its stereoisomeric forms and their mixtures in all proportions or their physiologically tolerable salts.
8. 8. A process for the preparation of compounds of the formula I according to one or more of claims 1 to 7, characterized in that it comprises activating a 4-hydroxypyrimidine of the formula IV and then reacting it with an amine of the formula VI, twenty 10 VI wherein R1, R2, R3 and R4 have the meanings indicated in claims 1 to 7. A compound of the formula I according to one or more of claims 1 to 7 and / or its physiologically tolerable salts, for use as a pharmaceutical product. A pharmaceutical preparation containing one or more compounds of the formula I according to one or more of claims 1 to 7 and / or their physiologically tolerable salts and a pharmaceutically tolerable carrier. 11. A compound of formula I in accordance with one or more of claims 1 to 7 and / or its salts You? &? & ^^? Át ^ it ^ m ^ iá &&& s? Tt? Saí ia? ~. A ^^ > **** am? i ** r. physiologically tolerable to use as activators of soluble guanylate cyclase. 12. A compound of formula I according to one or more of claims 1 to 7 and / or its physiologically tolerable salts, for use in the therapy or prophylaxis of cardiovascular disorders, endothelial dysfunction, diastolic dysfunction, atherosclerosis, high blood pressure, angina pectoris, thrombosis, restenosis, myocardial infarction, attack, 10 heart failure, pulmonary hypertension, erectile dysfunction, bronchial asthma, chronic renal failure, diabetes or cirrhosis of the liver or to improve the restricted learning capacity or power of memory.