6-cyclylmethyl- and 6-alkylmethyl-substituted pyrazolopyrimidines, having pde9a inhibition properties

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) and their pharmaceutically acceptable salts which have PDE9A inhibition properties. In formula (I) R1 represents alkyl with 1-8 carbon atoms or cycloalkyl with 5-6 carbon atoms which, if necessary, can have up to three substitutes independently selected from: alkyl with 1-6 carbon atoms, hydroxy, halogen and trifluoromethyl, where the alkyl with 1-6 carbon atoms, if necessary, can be substituted with 1-3 substitutes independently selected from halogen and trifluoromethyl, R2 represents phenyl or aromatic mono- or bicyclic heteroaryl with 5-10 atoms in the ring and up to 5 heteroatoms selected from: sulphur, oxygen and/or nitrogen, where phenyl is substituted with 1-3 substitutes, and the heteroaryl, if necessary, can be substituted with 1-3 substitutes in each case independently selected from: alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, trifluoromethyl, trifluoromethoxy, amino, hydroxyl and halogen.

EFFECT: compounds can be used for preparing medicinal agents for enhancing perception, ability to concentrate, learning capability and memory enhancement.

9 cl, 1 dwg, 2 tbl, 78 ex

 

The invention relates to new 6-cyclemeter - and 6-alkylaryl-substituted pyrazolopyrimidines, method of their production and to their use to obtain drugs for improved understanding, better ability to concentrate, ability to learn and/or improve memory.

The inhibition of phosphodiesterase modulates the level. cyclic nucleotides 5'-3'-cyclic monophosphate (camp) or 5'-3'-cyclic guanosine monophosphate (cGMP). These cyclic nucleotides (camp and cGMP) are important secondary mediators and therefore play a Central role in the cellular cascade signal transduction. They activate again, inter alia, but not limited to, protein kinases. Activated by the camp protein kinase called protein kinase a (PKA), and activated the cGMP protein kinase called protein kinase G (PKG). Activated PKA or PKG again fosforilirovanii a number of cellular effector proteins (e.g. ion channels, receptors associated with G-protein, a structural protein). Thus, the secondary mediators of camp and cGMP can control various physiological processes in various organs. Cyclic nucleotides can also directly influence the effector molecules. So, you know, for example, that cGMP acts directly on ion channels and thus can influence the ü on cellular ion concentration (review in Wei et al., Prog. Neurobiol., 1998, 56: 37-64). A control mechanism to regulate the activity of camp and cGMP and thus again to control these physiological processes are phosphodiesterase (PDE). Phosphodiesterase hydrolyzing cyclic monophosphate to inactive monophosphate AMR and GMP. Meanwhile, described at least 21 gene PDE (Exp. Opin. Investig. Drugs 2000, 9, 1354-3784). These 21 phosphodiesterase gene based on the sequence homology can be divided into the 11 PDE families. (Nomenclatural standard see http://depts. washington. edu/pde/Nomenclature.html.). Separate PDE genes within the family differ-letter (for example, PDE1A and PDE1B). If within a gene are different splice variants, then specify additional numbers after the letter designation (for example, PDE1A1).

PDE9A person were cloned and sequenced in 1998. Amino acid identity relative to other PDE is a maximum of 34% (PDE8A) and a minimum of 28% (PDE5A). When Michaelis-Menten-constant (a measure Km) 170 nm PDE9A is similar with a high degree of cGMP. Thanks PDE9A is selective for cGMP (Km indicator for camp=230 μm). PDE9A not have any cGMP-domain communication, which may terminate allosteric regulation of enzymes by cGMP. In Western blot analysis, it was shown that PDE9A will expriment in humans, among other things, in the testes, brain, subtly the intestine, skeletal muscles, heart, lungs, thymus and spleen. Little expression was detected in brain, small intestine, heart, and spleen (Fisher et al., J. Biol. Chem., 1998, 273(25): 15559-15564). The gene for human PDE9A is located on chromosome 21q22.3 and contains 21 exons. Up to the present time identified alternative 4 Spleiβ options PDE9A (Guipponi et al., Hum. Genet, 1998, 103:386-392). Classical PDE-inhibitors do not inhibit human PDE9A. So IBMX, dipyridamole, SKF94120, rolipram and Vinpocetine in concentrations up to 100 μm do not show any inhibition of the isolated enzyme. For zaprinast proven value IC5035 microns (Fisher et al., J. Biol. Chem., 1998, 273(25): 15559-15564).

PDE9A mouse cloned and sequenced 1998 Soderling and others (J. Biol. Chem., 1998, 273(19): 15553-15558). It is like the human form, with such a high degree of cGMP at Km 70 nm. A mouse found particularly high expression in the kidney, brain, lungs and heart. PDE9A mouse at a concentration of less than 200 μm is also not inhibited IBMX; figure IC50for zaprinast is located at 29 μm (Soderling and other J. Biol. Chem., 1998, 273(19): 15553-15558). It was found that in the brain of the rat PDE9A much exprimarea in separate areas of the brain. These include Bulbus-olfactorius, mediated, cerebral cortex, basal gangli and basal anterior brain (Andreeva et. al., J. Neurosci., 2001, 21(22):9068-9076). In the processes of learning and memory VA the role play, in particular, the mediated, the cortex (cortical substance, Cortex and basal anterior brain.

As mentioned above, PDE9A is characterized by a particularly high degree of similarity cGMP. Therefore, PDE9A in contrast PDE2A (Km=10 μm; Martins et al., J. Biol. Chem 1982, 257:1973-1979), PDE5A (Km=4 μm; Francis et al., J. Biol. Chem, 1980, 255:620-626), PDE6A (Km=17 μm; Gillespie and Beavo, J. Biol. Chem, 1988, 263(17):8133-8141) and PDE11A (Km=0,52 μm; Fawcett et al., Proc. Nat. Acad. Sci., 2000, 97(7):3702-3707) are already active at low physiological concentrations. In contrast PDE2A (Murashima et al., Biochemistry, 1990, 29:5285-5292) catalytic activity of PDE9A not by increasing cGMP, as it does not have any GAF domains (cGMP-domain connection, through which the PDE activity of allosteric increases (Beavo et al., Current Opinion in Cell Biology, 2000, 12:174-179). Therefore, PDE9A inhibitors may lead to increased basal cGMP concentration.

In the international application WO 98/40384 described pyrazolopyrimidine characterized as inhibitors of PDE-1, 2 and 5, which can be used to treat cardiovascular and cerebrovascular diseases, and diseases of the urogenital region.

In patents Switzerland SN 396924, CH 396925, CH 396926, CH 396927, as well as in German patent DE 1147234 and DE 1149013 and in the United Kingdom patent GB 937726 described pyrazolopyrimidine diffuse coronary activity, which can be used for the ecene impaired circulation in the heart muscle.

In U.S. patent US 3732225 described pyrazolopyrimidine, which has anti-inflammatory and reducing the sugar content in the blood by the action.

In the German patent DE 2408906 described stolpersamuelson that can be used as antimicrobial and anti-inflammatory agents for the treatment of, for example, swelling.

The present invention relates to compounds of the formula:

where R1means alkyl with 1-8 carbon atoms, alkenyl with 2-6 carbon atoms, quinil with 2-6 carbon atoms or cycloalkyl with 3-8 carbon atoms, and alkyl with 1-8 carbon atoms may be substituted by oxo, alkyl with 1-8 carbon atoms, alkenyl with 2-6 carbon atoms, quinil with 2-6 carbon atoms or cycloalkyl with 3-8 carbon atoms, which optionally independently from each other, can be substituted by up to three radicals selected from the group of alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, hydroxycarbonyl, cyano, amino, nitro, hydroxy, alkylamino with 1-6 carbon atoms, halogen, trifluoromethyl, triptoreline, arylcarboxamide with 6-10 carbon atoms, alkylcarboxylic with 1-6 carbon atoms, alkylaminocarbonyl with 1-6 carbon atoms, alkoxycarbonyl with 1-6 carbon atoms, allumination with 6-10 carbon atoms, heteroarylboronic, heteroarylboronic is, alkylsulfonamides with 1-6 carbon atoms, alkylsulfonyl with 1 to 6 atomapi carbon, alkylthio with 1-6 carbon atoms,

thus

alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, alkylamino with 1-6 carbon atoms, arylcarboxamide with 6-10 carbon atoms, alkylcarboxylic with 1-6 carbon atoms, alkylaminocarbonyl 1-6 carbon atoms, alkoxycarbonyl with 1-6 carbon atoms, allumination with 6-10 carbon atoms, heteroarylboronic, heteroarylboronic, alkylsulfonamides with 1-6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, alkylthio with 1-6 carbon atoms optionally can be substituted by up to three radicals independently of one another, selected from the group hydroxy, cyano, halogen, trifluoromethyl, triptoreline, hydroxycarbonyl, and a group of the formula-NR3R4,

and

R3and R4independently of one another denote hydrogen or alkyl with 1-6 carbon atoms,

or

R3and R4together with the nitrogen atom to which they relate, mean from five - to eight-membered heterocyclyl,

R2means phenyl or heteroaryl, and phenyl is substituted by 1-3 radicals and heteroaryl may be substituted by 1-3 radicals selected in each case independently of one another, from alkyl groups with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, hydroxycu boil, cyano, trifluoromethyl, triptoreline, amino, nitro, hydroxy, alkylamino with 1-6 carbon atoms, halogen, arylcarboxamide with 6-10 carbon atoms, alkylcarboxylic with 1-6 carbon atoms, alkylaminocarbonyl with 1-6 carbon atoms, alkoxycarbonyl with 1-6 carbon atoms, allumination with 6-10 carbon atoms, heteroarylboronic, heteroarylboronic, alkylsulfonamides with 1-6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, alkylthio with 1-6 carbon atoms,

and

alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, alkylamino with 1-6 carbon atoms, arylcarboxamide with 6-10 carbon atoms, alkylcarboxylic with 1-6 carbon atoms, alkylaminocarbonyl with 1-6 carbon atoms, alkoxycarbonyl with 1-6 carbon atoms, allumination with 6-10 carbon atoms, heteroarylboronic, heteroarylboronic, alkylsulfonamides with 1-6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, and alkylthio with 1-6 carbon atoms optionally can be substituted by up to three radicals, independently of one another selected from the group hydroxy, cyano, halogen, trifluoromethyl, triptoreline, hydroxycarbonyl, and a group of the formula-NR3R4,

where

R3and R4have the above values,

and their salts, solvate and/or solvate salts.

Compounds p the invention are the compounds of formula (I) and their salts, the solvate and the solvate salts. Covered by formula (I) compounds mentioned in the following formula and their salts, solvate and solvate salts, and also covered by formula (I) compounds indicated in the following as examples of the invention and their salts, solvate, and a solvate of salt, as they are covered by formula (I), named subsequent connections already no mention of salt, solvate and solvate salts.

Compounds according to the invention, depending on their structure may exist in stereoisomeric forms (enantiomers, diastereomers). Therefore, the invention relates to the enantiomers or diastereomers and any mixtures. From such mixtures of enantiomers and/or diastereomers, the individual components can be isolated in a known manner.

In the framework of the invention, the salts are preferably physiologically acceptable salts of the compounds according to the invention.

Physiologically acceptable salts of the compounds of formula (I) include salts formed by the reaction of the accession of mineral acids, carboxylic acids and sulphonic acids. For example, salts of hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonate, econsultancy, toluenesulfonic acid, benzosulfimide, naphthalenedisulfonate, acetic acid, propionic acid, lactic key is lots tartaric acid, malic acid, citric fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds of formula (I) also include salts of conventional bases such as, mainly, alkali metal salts (e.g. sodium and potassium salts), salts of alkaline earth metals (e.g. calcium salts and magnesium), and ammonium salts formed with ammonia or organic amines with 1 to 16 carbon atoms, such as, mainly, ethylamine, diethylamine, triethylamine, ethyldiethanolamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, dehydroabietylamine, arginine, lysine, Ethylenediamine, methylpiperidin.

The solvate in the framework of the present invention means those forms of the compounds, which are in solid or liquid form through a coordination complex with the solvent molecules. Hydrates are a specific form of a solvate, which is a coordination bond with water.

In addition, the present invention also includes prodrugs of (precursors of drugs) of the compounds according to the invention. The term "prodrug" also includes compounds which themselves may be biologically active or inactive, od is ako during their stay in the body are converted into compounds according to the invention (for example, metabolically or hydrolytically).

In the framework of the present invention, unless specifically stated otherwise, the substituents have the following meanings:

Alkyl with 1-8 carbon atoms means not branched or branched alkyl radical with 1-8 carbon atoms, preferably with 1 to 6 carbon atoms, particularly preferably 1-5 carbon atoms. Preferred examples are methyl, ethyl, n-propyl, isopropyl, 2-butyl, 2-pentyl and 3-pentyl.

Alkenyl with 2-6 carbon atoms denotes unbranched or branched alkanniny radical with 2-6 carbon atoms, preferably from 2 to 4 carbon atoms, and especially preferably 2-3 carbon atoms. Preferred examples include vinyl, allyl, n-prop-1-EN-1-yl and n-but-2-EN-1-yl.

Quinil with 2-6 carbon atoms means not branched or branched alkynylaryl radical with 2-6 carbon atoms, preferably from 2 to 4 carbon atoms, and especially preferably 2-3 carbon atoms. Preferred examples include ethinyl, n-prop-1-in-2-yl, n-prop-1-in-3-yl and n-but-2-in-1-yl.

Alkoxy with 1-6 carbon atoms means remotemachine or branched CNS radical with 1-6 carbon atoms, preferably from 1-4 carbon atoms and, particularly preferably, from 1 to 3 carbon atoms. Preferred examples include methoxy, ethoxy, n-propoxy, is isopropoxy, trebucket, n-pentox and n-hexose.

C1-C6-alkoxycarbonyl means remotemachine or branched alkoxycarbonyl radical with 1-6 carbon atoms, preferably from 1-4 carbon atoms and, particularly preferably, from 1 to 3 carbon atoms. Preferred examples include methoxycarbonyl, etoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and trebutien.

C1-C6-alkylamino means remotemachine or branched mono - or dialkylamino radical with 1-6 carbon atoms, preferably from 1-4 carbon atoms, and especially preferably from 1 to 3 carbon atoms. Preferred examples include methylamino, ethylamino, n-propylamino, isopropylamino, trebutien, n-pentylamine and n-hexylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-trebutien, di-n-pentylamine, di-n-hexylamino, ethylmethylamino, isopropylacrylamide, n-butylacrylamide and n-hexisopodidae.

C1-C6-alkylcarboxylic means linked through the amino group alkylcarboxylic radical and the alkyl radical may be remotemachine or branched and can contain from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms and, particularly preferably, from 1 to 3 carbon atoms. Preferred examples of R is t methylcobalamine, ethylcarbodiimide, n-propylnitrosamine, isopropylcarbodiimide, trebucheeeeeet, n-intelcorporation and n-paxilonline.

With1-C6-alkylaminocarbonyl means attached through a carbonyl group, a mono - or valkiry radical, and alkyl radicals can be identical or different, remotemachine or branched and can contain in each case 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms and, particularly preferably, from 1 to 3 carbon atoms. Preferred examples include methylaminomethyl, ethylaminomethyl, n-propylaminosulfonyl, isopropylaminocarbonyl, trebucheeeeeet, n-intramyocardial, n-mexiletineciclovir, dimethylaminoethyl, diethylaminoethyl, di-n-propylaminoethyl, diisopropylaminoethanol, di-trebucheeeeeet, di-n-intramyocardial, di-n-mexiletineciclovir, ethylmethylamino, isopropylaminocarbonyl, n-butylethylenediamine and n-mexiletineciclovir. In addition, in the case dialkylamino radicals both alkyl radicals together with the nitrogen atom to which they are bound, may form a five - or eight-membered a heterocycle.

With6-C10-allumination means attached through a carbonyl group arylamino radical. Before occhialini examples include phenylenecarbonyl and naphthaleneboronic.

With6-C10-arylcarboxamide means attached through the amino group arylamino radical. Preferred examples include phenylenecarbonyl and naphthaleneboronic.

C1-C6-alkylsulfonamides means remotemachine or branched alkylsulfonyl radical with 1-6 carbon atoms, preferably from 1-4 carbon atoms and, particularly preferably, from 1 to 3 carbon atoms. Preferred examples include methylsulfonylamino, ethylsulfonyl, n-propyl-sulfonylamino, isopropylbenzylamine, trebuyuschayasya, n-pentylaniline and n-hexylaniline.

C1-C6-alkylsulfonyl means remotemachine or branched alkylsulfonyl radical with 1-6 carbon atoms, preferably from 1-4 carbon atoms and, particularly preferably, from 1 to 3 carbon atoms. Preferred examples include methylsulphonyl, ethylsulfonyl, n-propylsulfonyl, isopropylphenyl, treburilor, n-intercultural and n-hexylsilane.

C1-C6-alkylthio means remotemachine or branched alkyl radical with 1-6 carbon atoms, preferably from 1-4 carbon atoms and, particularly preferably, from 1 to 3 carbon atoms. Preferred examples include methylthio, ethylthio, n-propylthio, isopropylthio, trebur is LTI, n-pentylthio and n-hexylthio.

Halogen means fluorine, chlorine, bromine and iodine. Preferred are fluorine, chlorine, bromine, especially fluorine and chlorine.

Heteroaryl means an aromatic mono - or bicyclic radical with 5 to 10 atoms in the ring and up to 5 heteroatoms from the series: sulfur, oxygen and/or nitrogen. Preferred are five - and six-membered heteroaryl containing up to four heteroatoms. Heteroaryl radical may be attached via a carbon atom or nitrogen. Preferred examples include thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, pyridyl, N-oxidability, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, benzofuranyl, benzothiophene, chinoline and ethenolysis.

Heteroarylboronic means attached through a carbonyl group heteroarylboronic radical. Preferred examples include tanyamiroshnik, parilamentary, pyrrolidinecarbonyl, thiazolidinediones, oxazolidinediones, imidazolidinethione, tetrachlorobenzoquinone, pyridineboronic, pyrimidinemethanol, pyridinylmethyl, indolylmethane, industriemechaniker, benzophenonetetracarboxylic, benzodiazepines.carbons, chinainternational and isojimaminamimachi.

Heteroarylboronic means connected through s is nogroup heteroarylboronic radical. Preferred examples include taylorsville, shrinkability, pyrrolidinedione, thiazolecarboxamide, oxazolidinedione, imidazolecarboxamide, tetrachloroaniline, pyridylcarbonyl, pyrimidinecarbonitrile, pyridinecarboxamide, indolealkylamine, indotricarbocyanine, benzogermanorbornadiene, benzothiazolesulfenamide, chinainternational, ethanolamine.

From three to eight-membered cycloalkyl means a saturated or partially unsaturated non-aromatic cycloalkyl radical with 3-8 carbon atoms, preferably 3-6 carbon atoms and, particularly preferably, from 5-6 carbon atoms in the cycle. Preferred examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl.

From 5 - to 8-membered tetracycl means a mono - or polycyclic heterocyclic radical with 5 to 8 carbon atoms in the cycle and up to three heteroatoms or heterogroup, preferably, with two heteroatoms or heterogroup from a number of: N, O, S, SO, SO2. Preferred is mono - or bicyclic a heterocycle. Especially preferred is a monocyclic heterocycle. Preferred heteroatoms are nitrogen and oxygen. Heterocyclic radical may be saturated or partially asystem. Preferred are saturated heterocyclic radicals. Especially preferred are a 5-7-membered heterocyclic radicals. Preferred examples include oxetan-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolyl, tetrahydrofuranyl, tetrahydrothieno, pyranyl, piperidinyl, tiopronin, morpholinyl, peligrosamente.

If radicals in the compounds according to the invention may be substituted and when unless specifically noted otherwise, preferably a substitution of up to three identical or different substituent.

Compounds according to the invention can also be in the form of tautomers, as shown below:

To another variant embodiment of the invention includes compounds of formula (I), in which

R1means alkyl with 1-8 carbon atoms, alkenyl with 2-6 carbon atoms, quinil with 2-6 carbon atoms or cycloalkyl with 3-8 carbon atoms, which are optionally, independently of one another can be substituted by up to three radicals selected from the group: alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, hydroxycarbonyl, cyano, amino, nitro, hydroxy, alkylamino with 1-6 carbon atoms, halogen, arylcarboxamide with 6-10 carbon atoms, alkylcarboxylic with 1-6 carbon atoms, alkylaminocarbonyl from 1-6 at the Mami carbon alkoxycarbonyl with 1-6 carbon atoms, allumination with 6-10 carbon atoms, heteroarylboronic, heteroarylboronic, alkylsulfonamides with 1-6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, alkylthio with 1-6 carbon atoms,

thus

alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, alkylamino with 1-6 carbon atoms, arylcarboxamide with 6-10 carbon atoms, alkylcarboxylic with 1-6 carbon atoms, alkylaminocarbonyl with 1-6 carbon atoms, alkoxycarbonyl with 1-6 carbon atoms, allumination with 6-10 carbon atoms, heteroarylboronic, heteroarylboronic, alkylsulfonamides 1-6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, alkylthio with 1-6 carbon atoms can be substituted by a radical selected from the group of hydroxy, cyano, halogen, hydroxycarbonyl, and a group of the formula-NR3R4,

and

R3and R4independently from each other denote hydrogen or alkyl with 1-6 carbon atoms,

or

R3and R4together with the nitrogen atom to which they are connected, means five to eight-membered heterocyclyl,

R2means phenyl or heteroaryl, and phenyl is substituted by 1-3 radicals and heteroaryl may optionally be substituted by 1-3 radicals selected in each case independently of one another, from the group: Ala is l with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, hydroxycarbonyl, cyano, trifluoromethyl, amino, nitro, hydroxy, alkylamino with 1-6 carbon atoms, halogen, arylcarboxamide with 6-10 carbon atoms, alkylcarboxylic with 1-6 carbon atoms, alkylaminocarbonyl with 1-6 carbon atoms, alkoxycarbonyl with 1-6 carbon atoms, allumination with 6-10 carbon atoms, heteroarylboronic, heteroarylboronic, alkylsulfonamides with 1-6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, alkylthio with 1-6 carbon atoms,

and

alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, alkylamino with 1-6 carbon atoms, arylcarboxamide with 6-10 carbon atoms, alkylcarboxylic with 1-6 carbon atoms, alkylaminocarbonyl with 1-6 carbon atoms, alkoxycarbonyl with 1-6 carbon atoms, allumination with 6-10 carbon atoms, heteroarylboronic, heteroarylboronic, alkylsulfonamides with 1-6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, and alkylthio with 1-6 carbon atoms optionally can be substituted by a radical selected from the group of hydroxy, cyano, halogen, hydroxycarbonyl, and a group of the formula-NR3R4,

where

R3and R4have the above meanings;

and also their salts, solvate and/or solvate salts.

Another variant implementation of the invention refers to is soedinenijam formula (I), in which

R1means alkyl with 1-5 carbon atoms or cycloalkyl with 3-6 carbon atoms, which optionally of which option from each other can be substituted by up to three radicals selected from the group: alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, trifluoromethyl, hydroxycarbonyl, cyano, amino, hydroxy, alkylamino with 1-4 carbon atoms, fluorine, chlorine, bromine, arylcarboxamide with 6-10 carbon atoms, alkylcarboxylic with 1-4 carbon atoms, alkylaminocarbonyl with 1-4 carbon atoms, alkoxycarbonyl with 1-4 carbon atoms, allumination with 6-10 carbon atoms, heteroarylboronic, heteroarylboronic, alkylsulfonamides with 1-4 carbon atoms, alkylsulfonyl with 1 to 4 carbon atoms, alkylthio with 1-4 carbon atoms,

moreover, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms optionally can be substituted by a radical selected from the group of hydroxy, cyano, fluorine, chlorine, bromine, hydroxycarbonyl, and a group of the formula-NR3R4,

thus

R3and R4independently from each other denote hydrogen or alkyl with 1-4 carbon atoms,

or

R3and R4together with the nitrogen atom to which they are connected, means five or six-membered heterocyclyl,

R2means phenyl, pyrimidyl, N-oxidability or pyridyl, and phenyl is substituted ha1-3 radical, and pyrimidyl, N-oxidability and pyridyl may optionally be substituted by 1-3 radicals selected in each case independently of one another, from the group: alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, hydroxycarbonyl, cyano, trifluoromethyl, amino, hydroxy, alkylamino with 1-4 carbon atoms, fluorine, chlorine, bromine, arylcarboxamide with 6-10 carbon atoms, alkylcarboxylic with 1-4 carbon atoms, alkylaminocarbonyl with 1-4 carbon atoms, alkoxycarbonyl with 1-4 carbon atoms, allumination with 6-10 carbon atoms, heteroarylboronic, heteroarylboronic, with alkylsulfonamides 1-4 carbon atoms, alkylsulfonyl with 1 to 4 carbon atoms, alkylthio with 1-4 carbon atoms,

and

alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms optionally can be substituted by a radical selected from the group of hydroxy, cyano, fluorine, chlorine, bromine, hydroxycarbonyl, and a group of the formula-NR3R4,

where

R3and R4have the values indicated above, and their salts, solvate and/or solvate salts.

Another variant embodiment of the invention relates to compounds of formula (I), in which

R1has the above meaning;

R2means phenyl, N-oxidability or pyridyl, and phenyl is substituted by 1-3 radicals and pyridyl and N-oxidability when is neobhodimosti can be substituted by 1-3 radicals, selected, in each case independently of one another, from the group: methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, ethoxy, fluorine and chlorine,

and their salts, solvate and/or solvate salts.

The following variant embodiment of the invention relates to compounds of formula (I), in which

R1means alkyl with 1-5 carbon atoms or cycloalkyl with 5-6 carbon atoms, which optionally can be substituted by up to three radicals selected, independently from each other, from the group: alkyl with 1-4 carbon atoms, fluorine, trifluoromethyl, hydroxy, phenylcarbonylamino, alkylcarboxylic with 1-4 carbon atoms, alkylaminocarbonyl with 1-4 carbon atoms or phenylenecarbonyl, and

R2means phenyl, N-oxidability or pyridyl, and phenyl is substituted by 1-3 radicals and pyridyl and N-oxidability may optionally be substituted by 1-3 radicals selected in each case independently of one another, from the group: methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, ethoxy, fluorine and chlorine,

and their salts, solvate and/or solvate salts.

Another variant embodiment of the invention relates to compounds of formula (I), in which

R1means alkyl with 1-5 carbon atoms or cycloalkyl with 5-6 carbon atoms, which optionally can be substituted by up to three radicals selected, independently researched the performance from each other, from the group: alkyl with 1-4 carbon atoms, fluorine, trifluoromethyl, hydroxy, phenylcarbonylamino, alkylcarboxylic with 1-4 carbon atoms, alkylaminocarbonyl with 1-4 carbon atoms or phenylenecarbonyl, and

R2means phenyl, N-oxidability or pyridyl, and phenyl is substituted with radicals and pyridyl and N-oxidability optionally independently from each other may be substituted by a radical selected from the group: methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, ethoxy, fluorine and chlorine,

and their salts, solvate and/or solvate salts.

In addition, a method of preparing compounds according to the invention of formula (I), characterized in that either [A] compounds of the formula:

in which R2has the above value,

through interaction with the compound of the formula:

in which

R1has the above value, and

Z denotes chlorine or bromine,

in an inert solvent and in the presence of a base is first converted into compounds of the formula:

in which

R1and R2have the above values,

and then in an inert solvent in the presence of a base is subjected to cyclization in the compounds of formula (I);

or

[In] the compounds of formula (II) when direct cycles the tion in (I) is subjected to interaction with the compound of the formula:

in which

R1has the above value, and

R5means methyl or ethyl,

in an inert solvent in the presence of a base,

or

[C] compounds of the formula:

in which

R2has the above value,

first, through interaction with the compound of the formula (IIIa) in an inert solvent and in the presence of a base transform into compounds of the formula:

in which

R1and R2have the above values,

and the second stage is subjected to cyclization to the compound (I) in an inert solvent and in the presence of bases and oxidizing agents

and the compounds of formula (I), if necessary with appropriate solvents (i) and/or bases (ii) or acids turn in their solvate, salt and solvate salts.

For the first stage of the method [A] and [C] suitable inert organic solvents which do not change under the reaction conditions. These include, preferably, ethers, such as diethyl ether, dioxane, tetrahydrofuran or dimethyl ether glycol or toluene or pyridine. You can also use a mixture of these solvents. Especially preferred are tetrahydrofuran, toluene or pyridine.

As pillars of the deposits suitable in General, hydrides of alkali metals, such as sodium hydride or cyclic amines, such as piperidine, pyridine, dimethylaminopyridine (DMAP) or alkylamines followed with 1-4 carbon atoms, such as triethylamine.

Preferred are sodium hydride, pyridine and/or dimethylaminopyridine.

The base is usually used in an amount of from 1 mol to 4 mol, preferably from 1.2 mol to 3 mol, in each case, per 1 mol of the compounds of General formula (II) or (V).

According to one variant, the interaction is carried out in pyridine, to which is added a catalytic amount of dimethylaminopyridine (DMAP). If necessary, it can also be even and toluene.

The reaction temperature usually varies within wide limits. Typically operate at a temperature in the range of (-20)°C to (+200)°C, preferably from 0°C to (+100)°C.

As solvent for the cyclization in the second stage methods [A] and [C] suitable organic solvents. These include, preferably, alcohols, such as methanol, ethanol, propanol, isopropanol, n-butanol or tertbutanol or ethers, such as tetrahydrofuran or dioxane, or dimethylformamide or dimethyl sulfoxide. Particularly preferably used alcohols such as methanol, ethanol, propanol, isopropanol or tertbutanol. Possible is also to use mixtures of the mentioned solvents.

As grounds for cyclization in the second stage methods [A] and [C] are suitable customary inorganic bases. These include hydroxides of alkali metals or alkaline earth metals, such as sodium hydroxide, potassium hydroxide or barium hydroxide, or carbonates of alkali metals such as sodium carbonate or potassium or sodium bicarbonate or alkali metal alcoholate, such as methanolate sodium or potassium or tertbutanol potassium. Especially preferred are potassium carbonate, sodium hydroxide, and tertbutanol potassium.

When carrying out the cyclization base is used usually in an amount of from 2 mol to 6 mol, preferably from 3 mol to 5 mol, in each case, per 1 mol of the compounds of General formula (IV) or (VI).

As oxidants for cyclization in the second stage of the method [S] are suitable, for example, hydrogen peroxide or sodium borate. Preferred is hydrogen peroxide.

The cyclization of the methods [A], [B] and [C] is usually carried out at a temperature ranging from 0°C to +160°C, preferably at the boiling point of a solvent.

The cyclization is usually carried out at atmospheric pressure. However, it is also possible to carry out the method at elevated or reduced pressure (for example, in the range from 0.5 to 5 bar).

As solvent for the JV is soba [In] suitable above for the second stage methods [A] and [C] alcohols, moreover, preferred is ethanol.

As grounds for the way [In] suitable hydrides of alkali metals, such as sodium hydride or potassium or an alkali metal alcoholate, such as methanolate sodium, ethanolate sodium, isopropylate sodium or trebuchet potassium. Preferred is sodium hydride.

The base is used in an amount of from 2 mol to 8 mol, preferably from 3 mol to 6 mol, in each case, per 1 mol of the compounds of General formula (II).

The compounds of formula (II) are known and can be obtained, for example, by first condensing dinitrile ethoxymethylenemalonic acid with hydrazine derivatives of the formula (VII):

where

R2has the above value,

in an inert solvent in personnally formula (V), and then to expose them to interact with one of the above oxidizing agents, preferably with hydrogen peroxide in the presence of ammonia (cf., for example, A. Miyashita et al., Heterocycles 1990, 31, 1309ff).

Compounds of formulas (IIIa), (IIIb) and (VII) are commercially available, known from the literature and can be obtained by analogy with the known literature methods.

The method according to the invention can be illustrated, for example, by the following formula scheme:

Scheme

Other methods of obtaining pyrazolo[3,4-d]pyrimidine-4-ones are known and can also be used for the synthesis of compounds according to the invention (see, for example, .Schmidt et al., Helvetica Chimica Acta 1962, 189, 1620ff.).

Compounds according to the invention show unexpected full range of pharmacological and pharmacokinetic activity. In particular, they are characterized by inhibition of PDE9A.

Therefore, they are suitable as pharmaceuticals for the treatment and/or prevention of diseases of humans and animals.

The term "treatment" in the context of the present invention includes prevention.

It has been unexpectedly found that the compounds according to the invention is suitable to obtain drugs to enhance, improve concentration, improve the ability to learn or improve memory.

Due to its pharmacokinetic properties of the compounds according to the invention can be used alone or in combination with other drugs to enhance, improve concentration, improve the ability to learn or improve memory.

Compounds according to the invention are particularly suitable for improving perception, improve concentration, improve the ability to learn or improve memory after cognitive impairments, such as crust is surrounding especially when situations/diseases/syndromes, such as "mild cognitive ability, age disability learning and memory, age-related memory loss, vascular (vascular) dementia, traumatic brain injury, paralysis, dementia, post-paralysis (post-shock dementia"), post-traumatic dementia, General concentration disturbances, impaired concentration in children with problems in learning and memory, Alzheimer's disease, dementia with Lewy-particles, dementia with degeneration of the frontal lobe, including the syndrome Picca, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, oligotrophication lateral sclerosis (ALS), Huntington's disease, multiple sclerosis, thalamic degeneration, dementia of Creutzfeld-Jakob disease, HIV-dementia, schizophrenia with dementia or psychosis Korsakoff.

Activity in vitro of the compounds according to the invention can be illustrated by the following biological tests.

PDE-inhibition.

Recombinant PDE1C (GenBank/EMBL Accession Number: NM_005020, Loughney et al., J. Biol. Chem. 1996 271, 796-806), PDE2A (GenBank/EMBL Accession Number: NM_002599, Rosman et al., Gene 1997 191, 89-95), PDE3B (GenBank/EMBL Accession Number: NM_000922, Miki et al., Genomics 1996, 36, 476-485), PDE4B (GenBank/EMBL Accession Number: NM_002600, Obernolte et al., Gene. 1993, 129, 239-247), PDE5A (GenBank/EMBL Accession Number: NM_001083, Loughney et al., Gene 1998, 216, 139-147), PDE7B (GenBank/EMBL Accession Number: NM_018945, Hetman et al., Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 472-476), PDE8A (GenBank/EMBL Accession Number: AF-056490, Fisher t al., Biochem. Biophys. Res. Commun. 1998 246, 570-577), PDE9A (Fisher et al., J. Biol. Chem, 1998, 273 (25): 15559-15564), PDE10A (GenBank/EMBL Accession Number: NM_06661, Fujishige et al., J Biol. Chem. 1999, 274, 18438-45), PDE11A (GenBank/EMBL Accession Number: NM_016953, Fawcett et al., Proc. Natl. Acad. Sci. 2000, 97, 3702-3707) were exprimarea through pFASTBAC baculovirus expression system (GibcoBRL) in Sf9 cells.

Subjects substances to determine their activity in vitro to PDE9A dissolved in 100% dimethyl sulfoxide (DMSO) and serially diluted. Usually get a series of dilutions from 200 μm to 1.6 μm (final concentration in the test: from 4 μm up to 0.032 μm). Every 2 ál of diluted solutions of substances placed in the wells of microtiter plates (Isoplate; Wallac Inc., Atlanta, GA). Immediately after this, add 50 µl of the diluted solution of the above drug PDE9A. Dilution of the drug PDE9A chosen so that during subsequent incubation get less than 70% of the substance (typical dilution: 1:10 000; the dilution buffer: 50 mm Tris/HCl pH 7.5, 8.3 mm MgCl2, 1.7 mm EDTA, 0.2% BSA). The substrate [8-3H]guanosine-3',5'-cyclophosphate (1 MXI/μl; Amersham Pharmacia Biotech., Piscataway, NJ) diluted 1:2000 buffer for testing (50 mm Tris/HCl pH 7.5, 8.3 mm MgCl2, 1.7 mm EDTA) to a concentration of 0.0005-MXI/µl. Add 50 ál (0,025 MXI) diluted substrate finally start the enzymatic reaction. The tested compounds are incubated at room temperature for 60 minutes and stop the reaction by adding 25 μl dissolved in the buffer for testing PDE9A inhibitor (for example, inhibitor from the sample receiving 1, final concentration 10 μm). Then immediately add 25 μl of the suspension of yttrium scintillation of beads with a concentration of 18 mg/ml (Yttrium Scintillation Proximity Beads, Amersham Pharmacia Biotech., Piscataway, NJ). Microtiter tablets sealed with tape and incubated for 60 minutes at room temperature. Then the tablets was measured within 30 seconds per well in a scintillation counter (Wallac Inc. Atlanta, GA). Figure IC50determine, through the graphical dependence of the concentration of substances from inhibition in percent.

Representative examples of the inhibitory effect of the compounds according to the invention in relation to PDE9A are shown in Table 1 by means of indicators IC50.

Table 1
Example No.Figure IC50nm
238
512
115
3412
37-160
3813
39-130

Activity in vitro of the tested substances on recombinant PDE3B, PDE4B, PDE7B, PDE8A, PDE10A and PDE11A determined as described above for PDE9A Protocol testing with the following adaptations: as the substrate used [5',8-3H]adenosine-3',5'-cyclophosphate (1 MXI/µl; Amerscham Pharmacia Biotech., Piscataway, NJ). In addition of the inhibitor solution to terminate the reaction, there is no need. Instead, after incubation of the substrate and PDE continue to add beads yttrium, as already described above, and thanks to terminate the reaction. To determine the relative activity of recombinant PDE1C, PDE2A and PDE5A in addition to the Protocol, proceed as follows. For PDE1C additionally added to the reaction mixture calmodulin 10-7M and calcium chloride (3 mm). PDE2A when testing stimulate the addition of 1 μm with GMP and tested with BSA-concentration of 0.01%. As substrates for PDE1C and PDE2A use [5',8-3H]adenosine-3',5'-cyclophosphate (1 MXI/ µl; Amerscham Pharmacia Biotech., Piscataway, NJ), and for PDE5A -[8-3H]-guanosine-3',5'-cyclophosphate (1 MXI/µl; Amerscham Pharmacia Biotech., Piscataway, NJ).

Long-lasting potentiation.

Long-lasting potentiation is considered a correlate of learning and memory. To determine does PDE9 inhibition effect on long potentiated the e, can be used the following method.

The mediated rat is placed at an angle of about 70° with respect to the cutting blade (Chopper). The mediated cut with a distance of 400 μm. Slice taken from the knife by a very soft, highly moistened brush (wool marten) and transferred into a glass vessel with carbenicillin refrigerated liquid nutrient medium (124 mm sodium chloride, of 4.9 μm KCl,1.3 mm of semihydrate magnesium sulfate, 2.5 mm of anhydrous calcium chloride, 1.2 mm of monocalciumphosphate, 25.6 mm sodium bicarbonate, 10 mm glucose, pH 7.4). During the measurement, the slices are heated in the chamber below the liquid level 1-3 mm in height. The flow velocity of 2.5 mm/min Pre-treatment gas is carried out at reduced pressure (about 1 ATM), as well as through the microchannels in the pre-chamber. The chamber sections are connected with the advanced camera so that you can support minicircles. To implement minicircles through the microchannels using a stream of carbon. Svezhepriobretenny sections hippocampus subjected accommodation in the chamber for slices at 33°C for at least one hour.

The intensity of the excitation is chosen so that the focal ekstaticheski postsynaptic potential (fEPSP) was 30% of the maximum anticatholicism posts opticheskogo potential (EPSP). Through a monopolar stimulating electrode consisting of lacquered high-quality special steel (instrumental), and two-phase generator excitation constant current to a small quantity (AM-System 2100) locally excite collateral generator with a voltage of 1-5 V, pulse width polarity 0.1 MS, total 0.2 MS pulse). Through glass electrodes (borosilicate glass with filament 1-5 Mω, diameter 1.5 mm, the diameter of the syringes 3-20 µm)filled with a standard liquid nutrient medium of the layer Stratum radiatum, register ekstaticheski postsynaptic potential (fEPSP). Measuring the field potential is relative to the chlorinated reference electrode made of silver, on the edge of the camera to slice through the DC amplifier. The filtering capacity of the field passes through a low pass filter (5 KHz). For statistical analysis of the experiment determine the slope (the gradient of the potential) fEPSP (fEPSP-gradient). Recording, analysis and management of the experiment carried out by automatic software (PWIN), developed in the field of neurophysiology. Education average value of the index fEPSP-gradient for each time value for each time point) and the graph is realized by means of software EXCEL, moreover, the corresponding record macro automates the recording of data (results).

SUPERLINE slices of hippocampus through a 10 μm solution of the compounds according to the invention leads to a significant increase in LTP.

The activity in vivo of the compounds according to the invention can be, for example, is shown as follows.

The test of social identification.

Test social identification is a test of learning ability and memory. It evaluates the ability of rats to distinguish between known and unknown members of the species. Therefore, this test is suitable for testing the action of the compounds according to the invention to improve learning ability and memory.

Adult rats contained in the group, for 30 minutes prior to the start of the test are placed in separate cells for testing. Four minutes before testing experimental animal is transferred to a Supervisory Boxing. After this period of adaptation to the experimental animal is placed young animal and measured 2 minutes of absolute time during which an adult animal examines young animal (experiment 1). Measure all clearly aimed at young animal behavior, i.e. ANO-genital examination, prosecution, and care of the skin in which the adult animal is at a distance from the young animal is not more than 1 cm, then a young belly the second take, adult animal is treated with a compound of the invention or dissolving it in an inactive substance, and then return to his cell for maintenance. After a period of exposure 24 hours the test is repeated (experiment 2). Reduction of time for social interaction in comparison with experiment 1 shows that adult rat remembers a young animal.

Adult animals administered intraperitoneally injection or after a set period of time (e.g. one hour) before experiment 1, either directly after the experience of 1 or inactive solvent (10% ethanol, 20% solutol, 70% physiological saline) or 0.1 mg/kg, 0.3 mg/kg 1.0 mg/kg or 3.0 mg/kg of the compounds according to the invention, dissolved in 10% ethanol, 20% solutol, 70% physiological salt solution. Processed inactive solvent rats do not show any decrease in the time of social interaction in experiment 2 compared with experiment 1. Therefore, they do not remember what had once been in contact with young animals. It was unexpectedly found that the second attempt after treatment with compounds according to the invention a time of social interaction is significantly reduced in comparison with the processing of an inactive solvent. This means that rats treated with the stuff, I remember a young animal, and therefore, the compounds according to the invention have esteem, improves learning ability and memory.

Another object of the present invention is the use of compounds according to the invention for the treatment and/or prophylaxis of diseases, especially the previously mentioned diseases.

Another object of the present invention is the use of compounds according to the invention for obtaining a medicinal product for the treatment and/or prophylaxis of diseases, especially of the aforementioned diseases.

The next object of the present invention is a method of treatment and/or prophylaxis of diseases, especially of the aforementioned diseases using active number of compounds according to the invention.

Another object of the present invention is a drug containing at least one compound according to the invention and at least one or more other biologically active substances, in particular for the treatment and/or prophylaxis of the aforementioned diseases.

Compounds according to the invention can provide a system and/or local action. With this purpose, use them appropriately, for example, orally, parenterally, pulmonale, nasal, lingual, sublingual, buccal, rectal, dermal, transdermal, conjunctival, otiono or as implant or stent.

For this connection on izobreteny is given in the relevant forms.

For oral use of suitable known from the prior art existing forms, quickly and/or modificirovana releasing compounds according to the invention containing the compounds according to the invention in crystalline and/or amortiziruemoe and/or soluble form, such as tablets (with shell or without shell, for example, are resistant to gastric juice or slowly soluble or insoluble membrane that controls the release of the compounds according to the invention.), quickly disintegrating in the mouth tablets or films/wafers, films/lyophilizate, capsules (for example hard or soft gelatin capsules), pills, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral use may occur without the stage of resorbtive (for example, intravenously, intraarterially, intracardiac, intraspinal or intralumbalno) or including resorption (intramuscularly, subcutaneously, intradermally, percutaneous or intraperitoneal). For parenteral use are suitable, inter alia, forms such as solutions for injection and infusion in the form of solutions, suspensions, emulsions, liofilizatow or sterile powders.

For other ways to use suitable, for example, inhalation dosage forms (inter alia powder inhalers, resplit what?), nasal drops, solutions, sprays; lingual, sublingual or buccal used for tablets, films/wafers or capsules, suppositories, ear and eye structures, vaginal capsules, aqueous suspensions (lotions, agitated mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as patches), milk, pastes, foams, powder-powder, implants, and stents.

Compounds according to the invention can be converted in the common shapes. It can be produced in a known manner by mixing with inert non-toxic pharmaceutically acceptable excipients. Among other things, to such excipients include carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycol), emulsifiers and dispersants or wetting (for example, sodium dodecylsulfate, oleate policeservice), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g. antioxidants such as ascorbic acid), colorants (e.g. inorganic pigments such as iron oxides) and correctors of taste and smell.

Another object of the invention is a drug containing at least one is a compound according to the invention, usually together with one or more other inert non-toxic pharmaceutically acceptable auxiliary substances, as well as use it for that purpose.

Usually to achieve effective action is sufficient for parenteral application be consumed daily from about 0.001 to 10 mg/kg of body weight. For oral use daily consumed quantity (dose) ranges from about 0.005 to 3 mg/kg of body weight.

Despite this, if necessary, may require deviation from these quantities, depending on body weight, route of administration, individual tolerance in relation to the active substance, the type of composition and the time or interval of time, after which carry out the application. Therefore, in some cases it may be sufficient to manage with less than the abovementioned minimum amount (dose), at the same time, in other cases, called the upper bound should be increased. In the case of large doses may be recommended to divide them up during the day for several servings.

In the following text and examples, unless otherwise indicated, the percentage data are mass percent, the parts are mass parts, and the ratio of the solvents, the ratio upon dilution and concentration the liquid in the fluid is STI" in each case refers to the volume.

Reduction.

BSAalbumin calf serum
DCthin-layer chromatography
DCIdirect chemical ionization (in MS)
DMSOthe sulfoxide
d.Th.theoretical yield of product
EDTAethylenediaminetetraacetic acid
ESIelectrospray ionization (in MS)
Fp. (TPL)melting point
h (h)hour(s)
HPLChigh-performance liquid chromatography at elevated pressure
LC-MSliquid chromatography with mass spectroscopy
min)minute(s)
MSmass spectroscopy
NMR nuclear resonance spectroscopy
Rtthe exposure time (in HPLC)
TrisTris-(hydroxymethyl)aminomethan

LC-MS methods:

Method 1

Instrument type MS: Micromass ZQ; instrument Type HPLC: TSP P4000, TSP AS300, TSP UV3000; column: Grom-Sil 120 ODS-4 HE, 50×2 mm, 3.0 mm; eluent A: water + 250 μl of 50%formic acid/l, eluent b: acetonitrile + 250 μl of 50%formic acid/l; gradient: 0.0 to min 0% B → 0,2 min 0% B → a 2.9 min 70% B → 3,1 min 90% B → 4.5 min 90% B; oven: 50°C.; flow: 0.8 ml/min; UV detection: 210 nm.

Method 2

Instrument: Micromass Platform LCZ with HPLC with filler (Agilent) Serie 1100; column: Grom-Sil 120 ODS-4 HE, 50 mm × 2.0 mm, 3 μm; eluent A: 1 l water + 1 ml 50%formic acid/l, eluent B: 1 l acetonitrile + 1 ml 50%formic acid; gradient: 0.0 to min 100% A → 0.2 to min 100% A → a 2.9 min 30% A → a 3.1 min 10% A → 4.5 min 10% And; oven: 55°C.; flow: 0.8 ml/min; UV detection: 208-400 nm.

Method 3

Instrument type MS: Micromass ZQ; instrument Type HPLC: Waters Alliance 2790; column: Grom-Sil 120 ODS-4 HE, 50×2 mm, 3.0 mm; eluent b: acetonitrile + 0.05% of formic acid, eluent A: water + 0.05% of formic acid; gradient: 0.0 to min 5% B → a 2.0 min 40% B → 4.5 min 90% B → a 5.5 min 90% B; oven: 45°C.; flow: 0,0 min 0.75 ml/min → 4.5 min 0.75 ml/min → 5,5 min 1.25 ml/min; UV detection: 210 nm.

Method 4

Instrument: Micromass Quattro LCZ with HPLC Agilent Serie 1100; column: Grom-Sl 120 ODS-4 HE, 50 mm × 2.0 mm, 3 μm; eluent A: 1 l water + 1 ml 50%formic acid, eluent B: 1 l of acetonitrile + 1 ml 50%formic acid; gradient: 0.0 to min 100% A → 0.2 to min 100% A → a 2.9 min 30% A → a 3.1 min 10% A → 4.5 min 10% A; oven: 55°C.; flow: 0.8 ml/min; UV detection: 208-400 nm.

Source connection:

Example 1A.

5-amino-1-(2,6-dimetilfenil)-1H-pyrazole-4-carbonitrile.

3.0 g (17.3 mmol) of the hydrochloride of 2,6-dimethylphenylimino suspended from 2.1 g (17.3 mmol) of dinitrile ethoxymethylenemalonic acid in 40 ml of ethanol and mixed with 7.3 ml (52,1 mmol) of triethylamine. The reaction mixture is heated with reflux for 3 hours, forming a clear solution. After cooling to room temperature, it is mixed with diethyl ether. Drop down in the precipitated chloride of triethylamine filtered. The solvent is removed in vacuo, and the residue washed with preparative HPLC (YMC Gel ODS-AQ S-5/15 μm; eluent A: water, eluent b: acetonitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95%).

Obtain 2.3 g (62% of theoretical) of product in the form of yellow crystals.

LC-MS (method 1): Rt=2,77 minutes

MS (ESI pos): m/z=213 (M+H)+.

Example 2A.

5-amino-1-(2,3-dimetilfenil)-1H-pyrazole-4-carbonitrile.

Analogously to Example 1A from 3 g a (17.4 mmol) of the hydrochloride of 2,3-dimethylphenylimino, 2,12 g a (17.4 mmol) of dinitrile etexilate is enmalikova acid and 7.3 ml (52,1 mmol) of triethylamine gain of 2.08 g (56% of theoretical) of the desired product.

LC-MS (method 1): Rt=2,79 minutes

MS (ESI pos): m/z=213 (M+H)+.

Example 3A.

5-amino-1-(4-were)-1H-pyrazole-4-carbonitrile.

Analogously to Example 1A from 3 g (of 18.9 mmol) of the hydrochloride of 4-methylphenylhydrazine, 2.3 g (of 18.9 mmol) of dinitrile ethoxymethylenemalonic acid and 7.9 ml (of 56.7 mmol) of triethylamine obtain 2.16 g (57% of theoretical) of the desired product.

LC-MS (method 2): Rt=3.0V min MS (ESI pos): m/z=199 (M+H)+.

Example 4A.

5-amino-1-(2,6-dichlorophenyl)-1H-pyrazole-4-carbonitrile.

Analogously to Example 1A from 3 g (14.1 mmol) of the hydrochloride of dichloropyridazine, 1.7 g (14.1 mmol) of dinitrile ethoxymethylenemalonic acid and 5.8 ml (42,2 mmol) of triethylamine after purification on a chromatographic column to obtain 2.9 g (83% of theoretical) of the desired product.

LC-MS (method 3): Rt=2,8 minutes

MS (ESI pos): m/z=253 (M+H)+.

1H-NMR (300 MHz; DMSO-d6): δ = 6,82 (s, 2H), to 7.59 (m, 2H), 7,69 (m, 1H), 7,80 (s, 1H) h/mlnc

Example 5A.

5-amino-1-(2,5-dichlorophenyl)-1H-pyrazole-4-carbonitrile.

Analogously to Example 1A from 3 g (about 16.9 mmol) of 2,5-dichloropyridazine, 2.0 g (to 16.9 mmol) of dinitrile ethoxymethylenemalonic acid and 7.1 ml (50.8 mmol) of triethylamine obtain 2.2 g (51% of theoretical) of the desired product.

LC-MS (method 2): Rt=3,2 minutes

MS (ESI pos): m/z=253 (M+H)+.

Example 6A.

Amino-1-(2-nitrophenyl)-1H-pyrazole-4-carbonitrile.

Analogously to Example 1A from 3 g (15.8 mmol) of the hydrochloride of 2-nitrophenylhydrazine, of 1.93 g (to 16.9 mmol) of dinitrile ethoxymethylenemalonic acid and 6.6 ml (47,6 mmol) of triethylamine gain of 1.9 g (53% of theoretical) of the desired product.

LC-MS (method 2): Rt=2,8 minutes

MS (ESI pos): m/z=230 (M+H)+.

1H-NMR (300 MHz; DMSO-d6): δ = 6.87 in (s, 2H), 7,72 (m, 1H), to 7.77 (s, 1H), 7,78 (m, 1H), 7,88 (m, 1H), 8,16 (dd, 1H) h/mlnc

Example 7A.

5-amino-1-(3-forfinal)-1H-pyrazole-4-carbonitrile.

Analogously to Example 1A from 4 g (24.6 mmol) of the hydrochloride of 3-forfamilies, 3 g (24.6 mmol) of dinitrile ethoxymethylenemalonic acid and 103 ml (73.8 mmol) of triethylamine receive 1.5 g (31% of theoretical) of the desired product.

LC-MS (method 2): Rt=2,9 minutes

MS (ESI pos): m/z=203 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ = for 6.81 (s, 2H), 7,28 (m, 1H), was 7.36 (m, 2H), EUR 7.57 (m, 1H), 7,80 (s, 1H) h/mlnc

Example 8A.

5-amino-1-(2-were)-1H-pyrazole-4-carbonitrile.

10.2 g (64,4 mmol) of the hydrochloride of 2-methylphenylhydrazine from 7.8 g (64,4 mmol) dinitrile ethoxymethylenemalonic acid are suspended in 100 ml of methanol and mixed with 26,9 ml (193.3 M. mmol) of triethylamine. The reaction mixture is heated during the night with reflux (backward flow), forming a clear solution. Immediately thereafter the solvent is distilled off with igenom pressure and purify the crude product through column chromatography (silica gel, the solvent dichloromethane). Obtain 10.8 g (85% of theoretical) of the desired product.

LC-MS (method 2): Rt=3,10 minutes

MS (ESI pos): m/z=199 (M+H)+.

Example 9A.

5-amino-1-(2-ethylphenyl)-1H-pyrazole-4-carbonitrile.

Analogously to Example 1A from 3.0 g in (17.0 mmol) of the hydrochloride of 2-ethylphenethylamine, 2,12 g in (17.0 mmol) of dinitrile ethoxymethylenemalonic acid and 7.1 ml (51,1 mmol) of triethylamine get 3,05 g (83,5% of theoretical) of the desired product.

TPL=130°C

MS (ESI pos): m/z=213 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 1,0 (t, 3H), 2,35 (q, 2H), 6,4 (s, 2H), 7,2-7,5 (m, 4H), and 7.7 (s, 1H), h/mlnc

Example 10A.

5-amino-1-(2-triptoreline)-1H-pyrazole-4-carbonitrile.

Analogously to Example 1A from 4.8 g (25,9 mmol) of the hydrochloride of 2-triftormetilfullerenov, and 3.16 g (25,9 mmol) dinitrile ethoxymethylenemalonic acid and 7.2 ml (of 51.7 mmol) of triethylamine get 5,02 g (76,9% of theoretical) of the desired product.

TPL=190°C

MS (ESI pos): m/z=253 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 6.6 (s, 2H), 7.5 (d, 1H), 7.7-8.0 (m, 4H) h/mlnc

Example 11A.

5-amino-1-(2-forfinal)-1H-pyrazole-4-carbonitrile.

Analogously to Example 1A from 5.0 g (30,8 mmol) of the hydrochloride of 2-forfamilies, of 3.27 g (to 26.7 mmol) of dinitrile ethoxymethylenemalonic acid and 11.3 ml (81,3 mmol) of triethylamine recip who have 5,13 g (88% purity, 84% of theoretical) of the desired product.

MS (ESI pos): m/z=203 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 6.7 (s, 2H), 7.3-7.6 (m, 4H), 7.8 (s, 1H) h/mlnc

Example 12A.

5-amino-1-(2-chlorophenyl)-1H-pyrazole-4-carbonitrile.

Analogously to Example 1A from 5.0 g (27,1 mmol) of the hydrochloride of 2-chlorophenylhydrazone, and 3.31 g (27,1 mmol) dinitrile ethoxymethylenemalonic acid and 11.3 ml (81,3 mmol) of triethylamine get with 4.64 g (78% of theoretical) of the desired product.

TPL=135°C

MS (ESl pos): m/z=219 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 6.6 (s, 2H), 7.45-7.75 (m, 4H), 7.8 (s, 1H) h/mlnc

Example 13A.

5-amino-1-(2-pyridinyl)-1H-pyrazole-4-carbonitrile.

Analogously to Example 1A from 3.0 g (to 26.7 mmol, 97% purity) 2-hydrazinopyridazine, 3,26 g (to 26.7 mmol) of dinitrile ethoxymethylenemalonic acid and 7.4 ml (53,3 mmol) of triethylamine obtain 2.3 g (46,6% of theoretical) of the desired product.

TPL=193°C

MS (ESI pos): m/z=186 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 7.35 (m, 1H), 7.8-8.12 (m, 3H), 8.15 (s, 2H), 8.5 (m, 1H) h/mlnc

Example 14A.

5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carbonitrile.

Analogously to Example 1A from 4.1 g (18 mmol) of the hydrochloride of methoxyphenylhydrazine, 2,19 g (18 mmol) of dinitrile ethoxymethylenemalonic acid and 10 ml (71,9 mmol) of triethylamine obtain 3.5 g (88% of theoretical is about) of the desired product.

TPL=129°C

MS (ESI pos): m/z=215 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 3.8 (s, 3H), 6.3 (s, 2H), 7.05 (t, 1H), 7.2 (d, 1H), 7.25 (d, 1H), 7.5 (t, 1H), 7.7 (s, 1 H) h/mlnc

Example 15A.

Amide 5-amino-1-(2,6-dimetilfenil)-1H-pyrazole-4-carboxylic acid.

2 g (9.4 mmol) of 5-amino-1-(2,6-dimetilfenil)-1H-pyrazole-4-carbonitrile (Example 1A) are dissolved in 25 ml of ethanol and mixed with 20 ml of 30%hydrogen peroxide and 40 ml of 25%aqueous ammonia. Stirred at room temperature overnight, and then immediately thicken the solution on a rotary evaporator to approximately 15 ml of the resultant oily emulsion accept in dichloromethane. Washed repeatedly with water and saturated sodium thiosulfate solution. After drying over sodium sulfate to remove the solvent in vacuo. The residue purified by preparative HPLC (YMC Gel ODS-AQ S-5/15 μm; eluent A: water, eluent b: acetonitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95%). Obtain 0.88 g (40% of theoretical) of product as a colorless solid.

LC-MS (method 2): Rt=2,6 minutes

MS (ESl pos): m/z=231 (M+H)+.

Example 16A.

Amide 5-amino-1-(2,3-dimetilfenil)-1H-pyrazole-4-carboxylic acid.

Analogously to Example 15A of 1.5 g (7.1 mmol) of 5-amino-1-(2,3-dimetilfenil)-1H-pyrazole-4-carbonitrile (Example 2A) in a mixture of 25 ml of ethanol,10 ml of 30%hydrogen peroxide and 40 ml of 25%aqueous ammonia to obtain 1.29 g (70% of theoretical) of the desired product.

LC-MS (method 2): Rt=2,7 minutes

MS (ESI pos): m/z=231 (M+H)+.

Example 17A.

Amide 5-amino-1-(4-were)-1H-pyrazole-4-carboxylic acid.

Analogously to Example 15A 2 g (10.1 mmol) of 5-amino-1-(4-were)-1H-pyrazole-4-carbonitrile (Example 3A) in a mixture of 25 ml of ethanol, 20 ml of 30%hydrogen peroxide and 40 ml of 25%aqueous ammonia are of 1.02 g (47% of theoretical) of the desired product.

LC-MS (method 2): Rt=2,7 minutes

MS (ESI pos): m/z=217 (M+H)+.

Example 18A.

Amide 5-amino-1-(2,6-dichlorophenyl)-1H-pyrazole-4-carboxylic acid.

Analogously to Example 15A 2 g (7.9 mmol) of 5-amino-1-(2,6-dichlorophenyl)-1H-pyrazole-4-carbonitrile (Example 4A) in a mixture of 25 ml of ethanol, 10 ml of 30%hydrogen peroxide and 40 ml of 25%aqueous ammonia to obtain 1.6 g (74% of theoretical) of the desired product by crystallization from the reaction solution.

LC-MS (method 2): Rt=2,5 minutes

MS (ESI pos): m/z=271 (M+H)+.

Example 19A.

Amide 5-amino-1-(2,5-dichlorophenyl)-1H-pyrazole-4-carboxylic acid.

Analogously to Example 15A 2 g (7.9 mmol) of 5-amino-1-(2,5-dichlorophenyl)-1H-pyrazole-4-carbonitrile (Example 5A) in a mixture of 25 ml of ethanol, 18 ml of 30%hydrogen peroxide and 40 ml of 25%aqueous ammonia are 2,02 g (94% of theoretical) of the desired product by crystallization from the reaction solution.

LC-MS (method 2): Rt=2,8 m is N.

MS (ESI pos): m/z=271 (M+H)+.

Example 20A.

Amide 5-amino-1-(2-nitrophenyl)-1H-pyrazole-4-carboxylic acid.

Analogously to Example 15A of 1.5 g (6.5 mmol) of 5-amino-1-(2-nitrophenyl)-1H-pyrazole-4-carbonitrile (Example 6A) in a mixture of 25 ml of ethanol, 16 ml of 30%hydrogen peroxide and 40 ml of 25%aqueous ammonia to obtain 1.4 g (86% of theoretical) of the desired product by crystallization from the reaction solution.

LC-MS (method 2): Rt=2,3 minutes

MS (ESI pos): m/z=248 (M+H)+.

Example 21A.

Amide 5-amino-1-(2-AMINOPHENYL)-1H-pyrazole-4-carboxylic acid.

1.28 g (5,27 mmol) of amide 5-amino-1-(2-nitrophenyl)-1H-pyrazole-4-carboxylic acid (Example 20A) are placed in 30 ml of ethyl ether, acetic acid and mixed with 5.8 g (from 25.8 mmol) chloride dihydrate divalent tin at 70°C for 16 hours. After cooling at room temperature the solution was adjusted to pH 9-10 by saturated solution of sodium bicarbonate. Drop down in the sediment salt tin filtered through diatomaceous earth. The filtrate is extracted with ethyl ether acetic acid. The combined organic phases are washed with a saturated solution of sodium chloride. After drying over sodium sulfate to remove the solvent in vacuo. Get 0,82 g (72% of theoretical) of the desired product.

LC-MS (method 4): Rt=3,0 minutes

MS (ESI pos): m/z=218 (M+H)+ .

1H-NMR (300 MHz, DMSO-d6): δ = 5.04 (s, 2H), 6.00 (s, 2H), 6.66 (m, 1H), 6.89 (m, 1H), 7.03 (m, 2H), 7.92 (s, 1H) h/mlnc

Example 22A.

Amide 5-amino-1-(3-forfinal)-1H-pyrazole-4-carboxylic acid.

Analogously to Example 15A of 1.3 g (6.4 mmol) of 5-amino-1-(3-forfinal)-1H-pyrazole-4-carbonitrile (Example 7A) in a mixture of 25 ml of ethanol, 10 ml of 30%hydrogen peroxide and 40 ml of 25%aqueous ammonia to obtain 1.1 g (75% of theoretical) of the desired product by crystallization from the reaction solution.

LC-MS (method 2): Rt=2,6 minutes

MS (ESI pos): m/z=221 (M+H)+.

Example 23A.

Amide 5-amino-1-(2-were)-1H-pyrazole-4-carboxylic acid.

40,0 g (201,8 thousand cub. mmol) 5-amino-1-(2-were)-1H-pyrazole-4-carbonitrile (Example 8A) is mixed with 300 ml of 96%sulfuric acid under ice cooling. Immediately thereafter heated to 40°C. and stirred at this temperature for 2 hours. After cooling, add up to a volume of 2 l of ice water and carefully neutralized with 50%sodium hydroxide solution. After three times of extraction with ethyl ether acetic acid (each time 2 l) and the combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and the solvent is distilled off under reduced pressure. Get 36,0 g (82% of theoretical) of product (purity >90%), which without additional is sustained fashion cleanup use in subsequent reactions.

LC-MS (method 1): Rt=2,14 minutes

MS (ESI pos): m/z=217 (M+H)+.

Example 24A.

Amide 5-amino-1-(2-ethylphenyl)-1H-pyrazole-4-carboxylic acid.

Analogously to Example 15A of 2.75 g (12.8 mmol) of 5-amino-1-(2-ethylphenyl)-1H-pyrazole-4-carbonitrile (Example 9A) in a mixture of 106 ml of ethanol, 27 ml of 30%hydrogen peroxide and 133 ml of 25%aqueous ammonia are 2.58 g (87% of theoretical) of the desired product after chromatography with silica gel (solvent dichloromethane with 0-10% methanol).

TPL=147°C.

MS (ESI pos): m/z=231 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 1.0 (t, 3H), 2.4 (q, 2H), 5.95 (s, 2H), 6.3 (breites d, 2H), 7.2-7.5 (m, 4H), 7.8 (s, 1H) h/mlnc

Example 25A.

Amide 5-amino-1-(2-triptoreline)-1H-pyrazole-4-carboxylic acid.

Analogously to Example 15A of 5.0 g (to 19.8 mmol) 5-amino-1-(2-triptoreline)-1H-pyrazole-4-carbonitrile (Example 10A) in a mixture of 195 ml of ethanol, 49 ml of 30%hydrogen peroxide and 244 ml of 25%aqueous ammonia are 4,01 g (87% of theoretical) of the desired product after chromatography with diatomaceous earth (solvent dichloromethane with 0-10% methanol).

TPL=186°C.

MS (ESI pos): m/z=271 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 6.1 (s, 2H), 7.0 (breites d, 2H), 7.45-8.0 (m, 5H) h/mlnc

Example 26A.

Amide 5-amino-1-(2-forfinal)-1H-pyrazole-4-carboxylic acid.

Analogously to Example 15 is from 5.0 g (21.9 mmol, 89% purity) of 5-amino-1-(2-forfinal)-1H-pyrazole-4-carbonitrile (Example 11A) in a mixture of 173 ml of ethanol, 43 ml of 30%hydrogen peroxide and 216 ml of 25%aqueous ammonia are to 3.89 g (81% of theoretical) of the desired product after chromatography with silica gel (solvent dichloromethane with 0-10% methanol).

TPL=181°C.

MS (ESI pos): m/z=221 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 6.2 (s, 2H), 7.0 (breites d, 2H), 7.3-7.6 (m, 4H), 7.9 (s, 1H) h/mlnc

Example 27A.

Amide 5-amino-1-(2-chlorophenyl)-1H-pyrazole-4-carboxylic acid.

Analogously to Example 15A of 4.6 g (21,0 mmol) 5-amino-1-(2-chlorophenyl)-1H-pyrazole-4-carbonitrile (Example 12A) in a mixture of 159 ml of ethanol, 39 ml of 30%hydrogen peroxide and 198 ml of 25%aqueous ammonia are 3,93 g (79% of theoretical) of the desired product after chromatography with silica gel (solvent dichloromethane with 0-10% methanol).

TPL=166°C.

MS (ESI pos): m/z=237 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 6.1 (s, 2H), 7.0 (breites d, 2H), 7.4-7.7 (m, 4H), 7.85 (s, 1H) h/mlnc

Example 28A.

Amide 5-amino-1-(2-pyridinyl)-1H-pyrazole-4-carboxylic acid.

Analogously to Example 15A of 2.3 g (12.4 mmol) of 5-amino-1-(2-pyridinyl)-1H-pyrazole-4-carbonitrile (Example 13A) in a mixture of 90 ml of ethanol and 23 ml of 30%hydrogen peroxide and 113 ml of 25%aqueous ammonia are 2.28 g (90% of theoretical) of the desired product after chromatography the silica gel (solvent dichloromethane with 0-10% methanol).

TPL=218°C.

MS (ESI pos): m/z=204 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ = 7.1 (breites d, 2H), 7.3 (dd, 1H), 7.5 (s, 2H), 7.85 (d, 1H), 7.95 (s, 1H), 8.0 (dd, 1H), 8.45 (d, 1H) h/mlnc

Example 29A.

Amide 5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carboxylic acid.

Analogously to Example 15A of 3.5 g (16.0 mmol, 98% purity) of 5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carbonitrile (Example 14A) in a mixture of 172 ml of ethanol and 34 ml of 30%hydrogen peroxide and 137 ml of 25%aqueous ammonia are 2,61 g (70% of theoretical) of the desired product after chromatography with silica gel (solvent dichloromethane with 0-10% methanol).

TPL=191°C.

MS (ESI pos): m/z=233 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 3.8 (s, 3H), 5.9 (s, 2H), 7.0 (breites s, 2H), 7.05-7.55 (m, 4H), 7.8 (s, 1H) h/mlnc

Example 30A.

5-amino-1-(2-ethoxyphenyl)-1H-pyrazole-4-carbonitrile.

Analogously to Example 1A from 4.0 g (of 21.2 mmol) of the hydrochloride of 2-ethoxypyrazine, 2.5 g (of 21.2 mmol) of dinitrile ethoxymethylenemalonic acid and 8.8 ml (63,6 mmol) of triethylamine obtain 2.9 g (59% of theoretical) of the desired product.

LC-MS (method 1): Rt=2,32 minutes

MS (ESI pos): m/z=229 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ = 1.25 (t, 3H), 4.08 (q, 2H), 6.37 (s, 2H), 7.04 (m, 1H), 7.25 (m, 2H), 7.45 (m, 1H), 7.71 (s, 1H) h/mlnc

Example 31A.

Amide 5-amino-1-(2-ethoxyphenyl)-1H-pyrazole-4-carboxylic acid.

Analogously to Example 15A of 2.5 g (10.9 mmol) of 5-amino-1-(2-ethoxyphenyl)-1H-pyrazole-4-carbonitrile (Example 30A) in a mixture of 20 ml ethanol, 10 ml of 30%hydrogen peroxide and 10 ml of 25%aqueous ammonia to obtain 2.2 g (84% of theoretical) of the desired product.

LC-MS (method 4): Rt=1,73 minutes

MS (ESI pos): m/z=247 (M+H)+.

Example 32A.

CIS-hexahydro-2H-cyclopent[b]furan-2-it.

32 ml of concentrated (96%) sulfuric acid is cooled to (-10)°C. Immediately thereafter slowly metered 5.0 g (to 39.6 mmol) 2-cyclopenten-1-yl-acetic acid and stirred the reaction mixture at the same temperature for 1 hour. Poured ice water to 100 ml and extracted with 100 ml diethyl ether. The organic phase is dried over sodium sulfate and carefully distilled off the solvent. Obtain 2.9 g of racemic mixture of the lactone with 70%purity (LC-MS), which is further used as a crude product.

MS (ESI pos):.m/z=127 (M+N)+.

Example 33A.

3 hydrazino-4-methylpyridin.

A solution of 4.0 g (37 mmol) of 3-amino-4-methylpyridine in 19 ml of 6N hydrochloric acid is mixed with 2.55 ml of a 2.5m aqueous solution of sodium nitrite while cooling in an ice bath and sodium chloride. The resulting solution of diazonium salts at a temperature of from -10°C. to -15°C. is slowly added dropwise to a solution of 21 g (111 mmol) of the chloride of the two is Alentova tin in 26 ml of hydrochloric acid. The solution is stored overnight in a refrigerator until completion of the reaction. Precipitated precipitated solid is sucked off, suspended in 26 ml of water, alkalinized with concentrated solution of sodium lye and filtered. The filtrate tenfold extracted, each time with 20 ml of dichloromethane, and the combined organic phases are dried over sodium sulfate and concentrated. After drying in high vacuum obtain 1.45 g (31% of theoretical) of the desired product as a colourless oil.

MS (ESI pos): m/z=124 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ = 2.05 (s, 3H), 4.05 (s, 2H), 6.4 (s, 1H), 6.9 (d, 1H), 7.75 (d, 1H), 8.3 (s, 1H) h/mlnc

Example 34A.

5-amino-1-(4-methylpyridin-3-yl)-1H-pyrazole-4-carbonitrile.

Analogously to Example 1A from 1.44 g (11.7 mmol) of 3-hydrazino-4-methylpyridine (Example 33A), 1.47 g (11.7 mmol) of dinitrile ethoxymethylenemalonic acid and 4.9 ml (35 mmol) of triethylamine gain of 1.75 g (75% of theoretical) of the desired product.

MS (ESI pos): m/z=200 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 2.1 (s, 3H), 6.7 (s, 2H), 7.45 (d, 1H), 7.8 (s, 1H), 8.4 (s, 1H), 8.55 (d, 1H) h/mlnc

Example 35A.

Amide 5-amino-1-(4-methylpyridin-3-yl)-1H-pyrazole-4-carboxylic acid.

Analogously to Example 15A out of 1.75 g (8,78 mmol) 5-amino-1-(4-methylpyridin-3-yl)-1H-pyrazole-4-carbonitrile (Example 34A) in a mixture of 105 ml of ethanol, and 9.2 ml of 30%hydrogen peroxide and 84 ml of 5%aqueous ammonia are of 1.75 g (91% of theoretical) of the desired product.

MS (ESI pos): m/z=218 (M+N)+.

1H-NMR (200 MHz, DMSO-d6): δ = 2.1 (s, 3H), 6.2 (s, 2H), 6.6-7.5 (2 breite s, 2H), 7.45 (d, 1H), 7.9 (s, 1H), 8.4 (s, 1H), 8.5 (d, 1H) h/mlnc

Examples of carrying out the invention

Example 1

6-Cyclopentylmethyl-1-(2,6-dimetilfenil)-1,5-dihydropyrazolo[3,4-d]-pyrimidine-4-one

0.1 g (0.43 mmol) of amide 5-amino-1-(2,6-dimetilfenil)-1H-pyrazole-4-carboxylic acid (Example 15A) was dissolved under argon in 6 ml of absolute ethanol and mixed with 0.24 g (1.7 mmol) of methyl ether checkpointissues acid and 0.17 g (4,34 mmol) of 60%sodium hydride (suspension in mineral oil). The reaction mixture is heated during the night with reflux. After cooling to room temperature, it is acidified with concentrated hydrochloric acid. Drop down in the precipitated sodium chloride is filtered off. The filtrate is concentrated in vacuum and the remaining residue purified preparative HPLC (YMC Gel ODS-AQ S-5/15 μm; eluent A: water, eluent b: acetonitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95%). Get 74 mg (53% of theoretical) of product as a colorless solid.

LC-MS (method 3): Rt=3,79 minutes

MS (electrospray ionization ESI pos): m/z=323 (M+N)+.

Example 2

6-Cyclopentylmethyl-1-(2,3-dimetilfenil)-1,5-dihydropyrazolo[3,4-d]-pyrimidine-4-one.

0.1 g (0.43 mmol) of amide 5-amino-1-(2,3-dimetilfenil)-1 is-pyrazole-4-carboxylic acid (Example 16A) is dissolved under argon in 6 ml of absolute ethanol and mixed with 0.24 g (1.7 mmol) of methyl ether cyclopentyloxy acid and 0.17 g (4,34 mmol) of 60%sodium hydride (suspension in mineral the oil). The reaction mixture is heated during the night with reflux. After cooling to room temperature, it is acidified with concentrated hydrochloric acid. Drop down in the sediment mixture of sodium chloride and the product is filtered and washed repeatedly with water and diethyl ether. After drying in high vacuum obtain 69 mg (49% of theoretical) of product as a colorless solid.

TX-MS (method 3): Rt=3,57 minutes

MS (ESI pos): m/z=323 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 1.17 (m, 2H), 1.48 (m, 2H), 1.59 (m, 4H), 1.87 (s, 3H), 2.19 (m, 1H), 2.33 (s, 3H), 2.54 (d, 2H), 7.16 (d, 1H), 7.25 (t, 1H), 7.36 (d, 1H), 8.21 (s, 1H), 12.12 (s, 1H) parts per million

Example 3

6-Cyclopentylmethyl-1-(4-were)-1,5-dihydropyrazolo[3,4-d]-pyrimidine-4-one

Analogously to Example 1 from 0.88 g (0.41 mmol) of amide 5-amino-1-(4-were)-1H-pyrazole-4-carboxylic acid (Example 17A), 0.26 g (1.8 mmol) of methyl ether cyclopentyloxy acid and 0.16 g (4.09 to mmol) of 60%sodium hydride get 97 mg (68% of theoretical) of the desired product as a colourless solid.

TX-MS (method 3): Rt=4.09 to minutes

MS (ESI pos): m/z=309 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 1.23 (m, 2H), 1.57 (m, 2H), 1.72 (m, 4H), 2.34 (m, 1H), 2.36 (s, 3H), 2.66 (d, 2H), 7.34 (d, 1H), 7.92 (d, 1H), 8.23 (s, 1H), 12.27 (s, 1H) parts per million

Example 4

6-Cyclopentylmethyl-1-(2,6-dichlorophenyl)-1,5-dihydropyrazolo[3,4-d]-Piri is one-4-one.

Analogously to Example 2 from 0.1 g (0,37 mmol) of amide 5-amino-1-(2,6-dichlorophenyl)-1H-pyrazole-4-carboxylic acid (Example 18A), 0.2 g (1.4 mmol) of methyl ether cyclopentyloxy acid and 0.14 g (3.6 mmol) of 60%sodium hydride obtain 61 mg (45% of theoretical) of the desired product as a colourless solid.

TX-MS (method 3): Rt=to 3.73 min

MS (ESI pos): m/z=363 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 1.15 (m, 2H), 1.49 (m, 2H), 1.60 (m, 4H), 2.21 (m, 1H), 2.57 (d, 2H), 7.60 (m, 2H), 7.69 (m, 1H), 8.41 (s, 1H), 12.51 (s, 1H) parts per million

Example 5

6-Cyclopentylmethyl-1-(2,5-dichlorophenyl)-1,5-dihydropyrazolo[3,4-d]-pyrimidine-4-one

Analogously to Example 1 from 0.1 g (0,37 mmol) of amide 5-amino-1-(2,5-dichlorophenyl)-1H-pyrazole-4-carboxylic acid (Example 19A), 0.2 g (1.4 mmol) of methyl ether cyclopentyloxy acid and 0.14 g (3.6 mmol) of 60%sodium hydride obtain 32 mg (23% of theoretical) of the desired product as a colourless solid.

TX-MS (method 3): Rt=4,0 minutes

MS (ESI pos): m/z=363 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 1.15 (m, 2H), 1.49 (m, 2H), 1.60 (m, 4H), 2.22 (m, 1H), 2.55 (d, 2H), 7.16 (d, 1H), 7.31 (m, 1H), 7.32 (m, 2H), 8.23 (s, 1H), 12.39 (s, 1H) parts per million

Example 6

1-(2-AMINOPHENYL)-6-cyclopentylmethyl-1,5-dihydropyrazolo[3,4-d]-pyrimidine-4-one

Analogously to Example 1 from 0.1 g (0.46 mmol) of amide 5-AMI is about-1-(2-AMINOPHENYL)-1H-pyrazole-4-carboxylic acid (Example 21A), 0,19 g (1.4 mmol) of methyl ether cyclopentyloxy acid and 0.18 g (4.6 mmol) of 60%sodium hydride obtain 61 mg (42% of theoretical) of the desired product as a colourless solid.

TX-MS (method 4): Rt=3,9 minutes

MS (ESI pos): m/z=310 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 1.17 (m, 2H), 1.45 (m, 2H), 1.56 (m, 4H), 2.19 (m, 1H), 2.52 (d, 2H), 6.12 (s, 2H), 6.64 (m, 1H), 6.90 (m, 1H), 7.05 (m, 2H), 8.25 (s, 1H), 12.47 (s, 1H) parts per million

Example 7

6-Cyclopentylmethyl-1-(3-forfinal)-1,5-dihydropyrazolo[3,4-d]-pyrimidine-4-one

Analogously to Example 1 from 0.1 g (0.45 mmol) of amide 5-amino-1-(3-forfinal)-1H-pyrazole-4-carboxylic acid (Example 22A), 0.26 g (1.8 mmol) of methyl ether cyclopentyloxy acid and 0.18 g (4.5 mmol) of 60%sodium hydride obtain 82 mg (58% of theoretical) of the desired product as a colourless solid.

TX-MS (method 3): Rt=3,74 minutes

MS (ESI pos): m/z=313 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 1.12 (m, 2H), 1.58 (m, 2H), 1.75 (m, 4H), 2.34 (m, 1H), 2.69 (d, 2H), 7.23 (m, 1H), 7.63 (m, 1H), 8.00 (m, 2H), 8.31 (s, 1H), 12.37 (s, 1H) parts per million

Example 8

6-(2-Cyclopenten-1-yl-methyl)-1-(2-ethylphenyl)-1,5-dihydro-4H-pyrazolo-[3,4-d]pyrimidine-4-one

Analogously to Example 1 from 0.15 g (of 0.65 mmol) of amide 5-amino-1-(2-ethylphenyl)-1H-pyrazole-4-carboxylic acid (Example 24A), 0.27 g (1,95 mmol) methyl ester 2-cyclopenten-1-yl-acetic acid and 13 g (3.2 mmol) of 60%sodium hydride get 64 mg (31% of theoretical) of the desired product as a colourless solid.

TPL=146°C.

MS (ESI pos): m/z=321 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 0.95 (t, 3H), 1.45 (m, 1H), 1.95 (m, 1H), 2.1-2.75 (m, 6N), 3.0 (m, 1H), 5.5-5.8 (m, 2H), 7.25-7.5 (m, 4H), 8.2 (s, 1H), 12.2 (s, 1H) parts per million

Example 9

6-(2-Cyclopenten-1-yl-methyl)-1-(2-were)-1,5-dihydro-4H-pyrazolo-[3,4-d]pyrimidine-4-one.

Analogously to Example 1 from 0.12 g (0,56 mmol) of amide 5-amino-1-(2-were)-1H-pyrazole-4-carboxylic acid (Example 23A), 0.24 g (1.7 mmol) of methyl ester of 2-cyclopenten-1-yl-acetic acid and 0.11 g (2.8 mmol) of 60%sodium hydride obtain 44 mg (26% of theoretical) of the desired product as a colourless solid.

TPL=179°C.

MS (ESI pos): m/z=307 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 1.45 (m, 1H), 1.95 (m, 1H), 2.1 (s, 3H), 2.1-2.75 (m, 4H), 3.05 (m, 1H), 5.5-5.8 (m, 2H), 7.3-7.5 (m, 4H), 8.25 (s, 1H), 12.2 (s, 1H) parts per million

Example 10

6-Cyclohexylmethyl-1-(2-were)-1,5-dihydro-4H-pyrazolo[3,4-d]-pyrimidine-4-one

Analogously to Example 1 from 0.15 g (of 0.68 mmol) of amide 5-amino-1-(2-were)-1H-pyrazole-4-carboxylic acid (Example 23A), 0.35 g (2.04 mmol) of ethyl ether cyclohexyloxy acid and 0,136 g (3.4 mmol) of 60%sodium hydride obtain 65 mg (29% of theoretical) of the desired product as a colourless solid.

TPL=169°C.

MS (ESI pos): m/z=323 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 0.9-1.3(m, 5H), 1.5-1.9 (m, 6H), 2.1 (s, 3H), 2.45 (d, 2H), 7.3-7.5 (m, 4H), 8.2 (s, 1H), 12.2 (s, 1H) parts per million

Example 11

6-Cyclopentylmethyl-1-(2-were)-1,5-dihydro-4H-pyrazolo[3,4-d]-pyrimidine-4-one

Analogously to Example 1 from 0.1 g (0.46 mmol) of amide 5-amino-1-(2-were)-1H-pyrazole-4-carboxylic acid (Example 23A), 0,237 g (92% purity, of 1.39 mmol) of ethyl ether cyclopentyloxy acid and 0,093 g (2.32 mmol) of 60%sodium hydride obtain 43 mg (30% of theoretical) of the desired product as a colourless solid.

TPL=181°C.

MS (ESI pos): m/z=309 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 1.1-1.55 (m, 8H), 2.1 (s, 3H), 2.2 (m, 1H), 2.55 (d, 2H), 7.3-7.5 (m, 4H), 8.2 (s, 1H), 12.15 (s, 1H) parts per million

Example 12

6-Cyclopentylmethyl-1-(2-ethoxyphenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]-pyrimidine-4-one

Analogously to Example 1 from 0.1 g (0.41 mmol) of amide 5-amino-1-(2-ethoxyphenyl)-1H-pyrazole-4-carboxylic acid (Example 31A), 0,231 g (1.6 mmol) of ethyl ether cyclopentyloxy acid and rate £ 0.162 g (4.1 mmol) of 60%sodium hydride obtain 73 mg (52% of theoretical) of the desired product as a colourless solid.

TX-MS (method 3): Rt=3,5 minutes

MS (ESI pos): m/z=339 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 1.10 (t, 3H), 1.22 (m, 2H), 1.45 (m, 2H), 1.59 (m, 4H), 1.96 (m, 1H), 2.54 (d, 2H), 4.02 (q, 2H), 7.08 (m, 1H), 7.23 (m, 1H), 7.37 (m, 1H), 7.48 (m, 1H), 8.16 (s, 1H), 12.06 (s, 1H) parts per million

Example 13

6-Cyclopentylmethyl-1-(2-hydroxyphenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]-pyrimidine-4-one

0.2 g (0.59 mmol) of 6-cyclopentylmethyl-1-(2-ethoxyphenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (Example 12) is mixed with 4 ml of 1M solution tribromide boron in dichloromethane and stirred the reaction mixture at room temperature for 1 hour. After hydrolysis with water is extracted with dichloromethane. The product was then purified by preparative HPLC (YMC Gel ODS-AQ S-5/15 μm; eluent A: water, eluent b: acetonitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95%). Get 0.167 g (91% of theoretical) of the desired product as a colourless solid.

TX-MS (method 4): Rt=2,54 minutes

MS (ESI pos): m/z=311 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ = 1.17 (m, 2H), 1.42 (m, 6H), 2.19 (m, 1H), 2.54 (d, 2H), 6.93 (m, 1H), 7.04 (m, 1H), 7.32 (m, 1H), 8.18 (s, 1H), 9.92 (s, 1H), 12.12 (s, 1H) parts per million

Example 14

6-(2-Cyclopenten-1-yl-methyl)-1-[2-(trifluoromethyl)phenyl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

Analogously to Example 1 from 0.15 g (0,56 mmol) of amide 5-amino-1-[2-(trifluoromethyl)phenyl]-1H-pyrazole-4-carboxylic acid (Example 25A), 0,233 g (1,67 mmol) methyl ester 2-cyclopenten-1-yl-acetic acid and 0,111 g (2,78 mmol) of 60%sodium hydride obtain 57 mg (29% of theoretical) of the desired product as a colourless solid.

TPL=153°C.

The with (ESI pos): m/z=361 (M+N) +.

1H-NMR (300 MHz, DMSO-d6): δ = 1.45 (m, 1H), 1.9 (m, 1H), 2.1-2.4 (m, 2H), 2.45-2.7 (m, 2H), 3.0 (m, 1H), 5.5-5.8 (m, 2H), 7.6 (d, 1H), 7.75-8.0 (m, 3H), 8.25 (s, 1H), 12.2 (s, 1H) parts per million

Example 15

6-(2-Cyclopenten-1-yl-methyl)-1-(2-forfinal)-1,5-dihydro-4H-pyrazolo-[3,4-d]pyrimidine-4-one

Analogously to Example 1 from 0.15 g (0.66 mmol) of amide 5-amino-1-(2-forfinal)-1H-pyrazole-4-carboxylic acid (Example 26A), 0,279 g (1,99 mmol) methyl ester 2-cyclopenten-1-yl-acetic acid and of 0.133 g (2,78 mmol) of 60%sodium hydride obtain 77 mg (37% of theoretical) of the desired product as a colourless solid.

TPL=163°C.

MS (ESI pos): m/z=311 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 1.5 (m, 1H), 1.95 (m, 1H), 2.1-2.45 (m, 2H), 2.45-2.7 (m, 2H), 3.0 (m, 1H), 5.6-5.8 (m, 2H), 7.3-7.7 (m, 4H), 8.3 (s, 1H), 12.3 (s, 1H) parts per million

Example 16

6-(2-Cyclopenten-1-yl-methyl)-1-(2-chlorophenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

Analogously to Example 1 from 0.15 g (0,63 mmol) of amide 5-amino-1-(2-chlorophenyl)-1H-pyrazole-4-carboxylic acid (Example 27A), 0,266 g (1,90 mmol) methyl ester 2-cyclopenten-1-yl-acetic acid and to 0.127 g (3,17 mmol) of 60%sodium hydride receive 50 mg (24% of theoretical) of the desired product as a colourless solid.

TPL=150°C.

MS (ESI pos): m/z=327 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 1.5 (m, 1H), 1.95 (m, 1H), 2.1-2.4 (m, 2H), 2.5-27 (m, 2H), 3.05 (m, 1H), 5.6-5.8 (m, 2H), 7.5-7.8 (m, 4H), 8.25 (s, 1H), 12.2 (s, 1H) parts per million

Example 17

6-(2-Cyclopenten-1-yl-methyl)-1-(2-pyridinyl)-1,5-dihydro-4H-pyrazolo-[3,4-d]pyrimidine-4-one

Analogously to Example 1 from 0.15 g (0,74 mmol) of amide 5-amino-1-(2-pyridinyl)-1H-pyrazole-4-carboxylic acid (Example 28A), 0.31 g (2.21 mmol) of methyl ester of 2-cyclopenten-1-yl-acetic acid and 0,147 g (3,69 mmol) of 60%sodium hydride obtain 76 mg (35% of theoretical) of the desired product as a colourless solid.

TPL=239°C.

MS (ESI pos): m/z=294 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 1.55 (m, 1H), 2.0 (m, 1H), 2.15-2.45 (m, 2H), 2.55-2.75 (m, 2H), 3.15 (m, 1H), 5.65-5.8 (m, 2H), 7.5 (dd, 1H), 8.0 (d, 1H), 8.05 (m, 1H), 8.3 (s, 1H), 8.6 (d, 1H), 12.3 (s, 1H) parts per million

Example 18

6-(2-Cyclopenten-1-yl-methyl)-1-(2-methoxyphenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one.

Analogously to Example 1 from 0.15 g (of 0.65 mmol) of amide 5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carboxylic acid (Example 29A), 0,272 g (1.94 mmol) of methyl ester of 2-cyclopenten-1-yl-acetic acid and 0,129 g (3,23 mmol) of 60%sodium hydride obtain 82 mg (39% of theoretical) of the desired product as a colourless solid.

TPL=182°C.

MS (ESI pos): m/z=323 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 1.5 (m, 1H), 1.95 (m, 1H), 2.1-2.45 (m, 2H), 2.45-2.75 (m, 2H), 3.05 (m, 1H), 3.0 (s, 3H), 5.6-5.8 (m, 2H), 7.0-7.55 (m, 4H), 8.2 (s, 1H), 12.15 (s, 1H)parts per million

The compounds listed in the following Table 2 as Examples 19-31 embodiment of the invention, as well as the appropriate starting compound, receive by analogy with the above examples.

Table 2
Approx No.The structural formulaOutput [% of theory.]MC: m/z [M+H]Rt[min]TX-MS method
1914.13644.053
2029.83373.973
2126.13374.523
2248.53634.39/td> 3

Approx No.The structural formulaOutput [% of theory.]MC: m/z [M+H]Rt[min]TC-MS method
2314.63984.203
2478.73253.883
2528.43644.703
2648.93294.303
2760.13253.793

Approx No.The structural formulaOutput [% of theory.]MC: m/z [M+H]Rt[min]TC-MS method
2810.53403.611
297.93244.004
3048.83394.104
3138.83433.071

Example 32

6-[(4-Methylcyclohexyl)methyl]-1-(2-were)-1,5-dihydropyrazolo-[3,4-d]pyrimidine-4-one

150 mg (0.69 mmol) of 5-amino-1-(2-were)-1H-pyrazole-4-carboxamide (Example 23A) and 130 mg (0,mol) 2-(4-methylcyclohexyl)acetic acid mixed with 3 ml trimethylsilyl ester of polyphosphoric acid and stirred for 3 hours at 130°C. In the hot reaction mixture was added to 20 ml of water and then extracted with dichloromethane (2×20 ml). The combined organic phases are washed with water (20 ml), saturated solution of sodium chloride (20 ml) and dried over sodium sulfate. The solvent is distilled off under reduced pressure, and the crude product purified by preparative HPLC (YMC Gel ODS-AQ S-5/15 μm; eluent A: water, eluent b: acetonitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95%). Obtain 182 mg (78% of theoretical) of the desired product.

TC-MS (method 3): Rt=4.09 to minutes

MS (ESI pos): m/z=337 (M+N)+.

1H-NMR (200 MHz, DMSO-d6): δ = 0.68-0.90 (5H), 0.99-1.61 (8H), 1.98-2.07 (4H), 2.16 (d, 1H), 7.19 (d, 1H), 7.28-7.51 (m, 3H), 8.26 (s, 1H), 10.27 (s, 1H) parts per million

Example 33

6-{[(1,2-CIS)-2-hydroxycyclopent]methyl}-1-(2-were)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (racemate)

200 mg (0,93 mmol) of amide 5-amino-1-(2-were)-1H-pyrazole-4-carboxylic acid (Example 23A) and 525 mg of CIS-hexahydro-2H-cyclopent[b]-furan-2-it (about 70%, Example 32A) is dissolved under argon in 10 ml of absolute ethanol and mixed with 315 mg (4.6 mmol) of sodium methylate. The reaction mixture is heated to reflux over night. After cooling to room temperature by hydrolyzing 25 ml of water and then extracted with ethyl ether acetic acid (2×25 ml). The combined organic phases are dried over su is hatom sodium and the solvent is distilled off under reduced pressure. The crude product is purified by preparative HPLC (YMC Gel ODS-AQ S-5/15 μm; eluent: water; eluent b: acetonitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95%). Receive 90 mg (30% of theoretical) of the desired product.

MS (ESI pos): m/z=325 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ = 1.28-1.74 (7H), 2.07 (s, 3H), 2.55 (dd, 1H), 2.80 (dd, 1H), 3.97 (m, 1H), 4.43 (d, 1H), 7.36 (m, 2H), 7.43 (m, 2H), 8.22 (s, 1H), 12.07 (s, 1H) parts per million

Example 34

6-{[(1,2-TRANS)-2-hydroxycyclohexyl]methyl}-1-(2-were)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

200 mg (0,93 mmol) of amide 5-amino-1-(2-were)-1H-pyrazole-4-carboxylic acid (Example 23A) and 583 mg (4,16 mmol) rat-hexahydro-1-benzofuran-2(3H)-it (a mixture of CIS-and TRANS-diastereomers, receive, see, for example, K.F.Podraza et al., J. Heterocycl. Chem. 1987, 24, 293-295) is dissolved under argon in 10 ml of absolute ethanol and mixed with 315 mg (4.6 mmol) of sodium methylate. The reaction mixture is heated to reflux over night. After cooling to room temperature by hydrolyzing 25 ml of water and then extracted with ethyl ether acetic acid (2×25 ml). The combined organic phases are dried over sodium sulfate and the solvent is distilled off under reduced pressure. The crude product is purified by preparative HPLC (YMC Gel ODS-AQ S-5/15 μm; eluent A: water, eluent b: acetonitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95%). Obtain 68 mg (21% of t is eroticheskoe) of the desired product.

MS (ESI pos): m/z=339 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ = 0.97 (m, 2H), 1.15 (m, 2H), 2.51 (d, 2H), 1.64 (m, 2H), 1.81 (m, 1H), 2.07 (s, 3H), 2.26 (dd, 1H), 2.99-3.10 (2H), 4.61 (d, 1H), 7.37 (m, 2H), 7.44 (m, 2H), 8.23 (s, 1H), 12.11 (s, 1H) parts per million

Example 35

6-(2-Methylbutyl)-1-(2-were)-1,5-dihydro-4H-pyrazolo[3,4-d]-pyrimidine-4-one (racemate).

Analogously to Example 1 from 0.8 g (3.7 mmol) of amide 5-amino-1-(2-were)-1H-pyrazole-4-carboxylic acid (Example 23A), 2,72 g (98% purity, 18.5 mmol) of ethyl ester of 3-methylvaleramide acid and 0,740 g (24 mmol) of 60%sodium hydride receive 784 mg (71% of theoretical) of the desired product.

TPL=132°C.

MC (ESI pos): m/z=297 (M+H)+.

1H-NMR (300 MHz, DMSO-d6): δ = 0.8 (m, 6H), 1.1-1.4 (m, 2H), 1.9 (m, 1H), 2.1 (s, 3H), 2.4 (dd, 1H), 2.55 (dd, 1H), 7.3-7.5 (m, 4H), 8.2 (s, 1H), 12.2 (s, 1H) parts per million

Example 35-1

6-(2-Methylbutyl)-1-(2-were)-1,5-dihydro-4H-pyrazolo[3,4-d]-pyrimidine-4-one (enantiomer I).

The racemate from Example 35 (380 mg) is separated into the enantiomers by HPLC on chiral stationary phase (based on the chiral selector poly(N-methacryloyl-L-leucine-L-methylamide), the principle of obtaining and using see European patent application EP-A-379917; column 380 mm × 100 mm, flow 100 ml/min, temperature 24°C, solvent: isohexane/ethyl acetate 20:80) Example 35-1 is under these conditions quickly eluting the enantiomer of I (Rt=min 15,2).

TPL =122°C.

Example 35-2

6-(2-Methylbutyl)-1-(2-were)-1,5-dihydro-4H-pyrazolo[3,4-d]-pyrimidine-4-one (enantiomer II).

The racemate from example 35 (380 mg) is separated into the enantiomers by HPLC on chiral stationary phase [based on the chiral selector poly(N-methacryloyl-L-leucine-L-methylamide), the principle of obtaining and using see European patent application EP-A-379 917; column 380 mm × 100 mm, flow 100 ml/min, temperature 24°C, solvent: isohexane/ethyl acetate 20:80] Example 35-2 is under these conditions slowly eluting the enantiomer II (Rt=18,1 min).

TPL=122°C.

Example 36

1-(2-Were)-6-(3,3,3-Cryptor-2-methylpropyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (racemate).

Analogously to Example 1 from 0.2 g (0,92 mmol) of amide 5-amino-1-(2-were)-1H-pyrazole-4-carboxylic acid (Example 23A), 0,852 g (to 4.62 mmol) of ethyl ester of 3-methyl-4,4,4-cryptomelane acid and 0,129 g (3,24 mmol) of 60%sodium hydride obtain 216 mg (69% of theoretical) of the desired product as a colourless solid.

TPL=160°C.

MS (ESI pos): m/z=337 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ = 1.1 (d, 3H), 2.1 (s, 3H), 2.7 (dd, 1H), 2.85-3.0 (m, 2H), 7.3-7.5 (m, 4H), 8.3 (s, 1H), 12.4 (s, 1H) parts per million

Example 36-1

1-(2-Were)-6-(3,3,3-Cryptor-2-methylpropyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (enantiomer I)

The racemate of PR is a measure 36 (180 mg) is separated into the enantiomers by HPLC on chiral stationary phase (column Chiralpak AD, 250 mm × 20 mm, flow 20 ml/min, temperature 24°C, solvent: isohexane/isopropanol 92:8). Under these conditions, the Example 36-1 is a fast eluting enantiomer I (Rt=10,37 min).

TPL=154°C.

Example 36-2

1-(2-Were)-6-(3,3,3-Cryptor-2-methylpropyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (enantiomer II).

The racemate from Example 36 (180 mg) is separated into the enantiomers by HPLC on chiral stationary phase (column Chiraipak AD, 250 mm × 20 mm, flow 20 ml/min, temperature 24°C, solvent: isohexane/isopropanol 92:8). Under these conditions, the Example 36-2 is a slow eluting enantiomer II (Rt=11,73 min).

TPL=153°C.

Example 37

1-(2-Chlorophenyl)-6-(3,3,3-Cryptor-2-methylpropyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (racemate).

Analogously to Example 1 from 0.3 g (1,27 mmol) of amide 5-amino-1-(2-chlorophenyl)-1H-pyrazole-4-carboxylic acid (Example 27A), 1,17 g (6,34 mmol) of ethyl ester of 3-methyl-4,4,4-cryptomelane acid and 0,254 g (6,34 mmol) of 60%sodium hydride receive 321 mg (69% of theoretical) of the desired product as a colourless solid.

TPL=166°C.

MS (ESI pos): m/z=357 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ = 1.1 (d, 3H), 2.7 (dd, 1H), 2.85-3.0 (m, 2H), 7.5-7.8 (m, 4H), 8.3 (s, 1H), 12.4 (s, 1H) parts per million

Example 37-1

1-(2-Chlorophenyl)-6-(3,3,3-Cryptor-2-methylpropyl)-1,5-dihydro-4H-is irazola[3,4-d]pyrimidine-4-one (enantiomer 1).

The racemate from Example 37 (240 mg) is separated into the enantiomers by HPLC on chiral stationary phase (column Chiralpak AD, 250 mm × 20 mm, flow 20 ml/min, temperature 24°C, solvent: isohexane/isopropanol 92:8). Under these conditions, the Example 37-1 is a fast eluting enantiomer I (Rt=11,92 min).

TPL=220°C.

Example 37-2

1-(2-Chlorophenyl)-6-(3,3,3-Cryptor-2-methylpropyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (enantiomer II).

The racemate from Example 37 (240 mg) is separated into the enantiomers by HPLC on chiral stationary phase (column Chiralpak AD, 250 mm × 20 mm, flow 20 ml/min, temperature 24°C, solvent: isohexane/isopropanol 92:8). Under these conditions, the Example 37-2 is a slow eluting enantiomer II (Rt=12,67 min).

TPL=218°C.

Example 38

6-Cyclopentylmethyl-1-(4-methylpyridin-3-yl)-1,5-dihydro-4H-pyrazolo-[3,4-d]pyrimidine-4-one

Analogously to Example 1 from 0.1 g (0.45 mmol) of amide 5-amino-1-(4-methylpyridin-3-yl)-1H-pyrazole-4-carboxylic acid (Example 35A), 0,353 g (of 2.26 mmol) of ethyl ether cyclopentyloxy acid and 0.09 g (of 2.26 mmol) of 60%sodium hydride obtain 102 mg (73% of theoretical) of the desired product as a colourless solid.

TPL=206°C.

MS (ESI pos): m/z=310 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ = 1.1-1.8 (m, 8H), 2.2 (s, 3H), 2.22 (m, 1H), 2.6 (d, 2H),7.5 (d, 1H), 8.3 (s, 1H), 8.6 (m, 2H), 12.3 (s, 1H) parts per million

Example 39

6-(2-Methylbutyl)-1-(4-methylpyridin-3-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]-pyrimidine-4-one (racemate)

Analogously to Example 1 from 0.2 g (0,92 mmol) of amide 5-amino-1-(4-methylpyridin-3-yl)-1H-pyrazole-4-carboxylic acid (Example 35A), 0,677 g (4.6 mmol) of ethyl ester of 3-methylvaleramide acid and 0,184 g (4.6 mmol) of 60%sodium hydride obtain 186 mg (68% of theoretical) of the desired product as a colourless solid.

TPL=149°C.

MS (ESI pos): m/z=298 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ = 0.8 (m, 6N), 1.1-1.4 (m, 2H), 1.9 (m, 1H), 2.2 (s, 3H), 2.4 (dd, 1H), 2.6 (dd, 1H), 7.5 (d, 1H), 8.3 (s, 1H), 8.6 (m, 2H), 12.25 (s, 1 H) parts per million

Example 39-1

6-(2-Methylbutyl)-1-(4-methylpyridin-3-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]-pyrimidine-4-one (enantiomer I).

The racemate from Example 39 (160 mg) is separated into the enantiomers by HPLC on chiral stationary phase (based on the chiral selector poly(N-methacryloyl-L-leucine-L-methylamide), the principle of obtaining and using see European patent application EP-A-379917; column 380 mm × 75 mm, a flow of 100 ml/min, temperature 24°C, solvent: isohexane/ethyl acetate 30:70) Example 39-1 is under these conditions quickly eluting the enantiomer I).

TPL=149°C.

Rt=7,25 min (chiral selector poly(N-methacryloyl-L-leucine-L-methylamide), 250 mm × 4.6 mm column; on the OK 1 ml/min; temperature 24°C, the solvent is ethyl acetate).

Example 39-2

6-(2-Methylbutyl)-1-(4-methylpyridin-3-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]-pyrimidine-4-one (enantiomer II).

The racemate from Example 39 (160 mg) is separated into the enantiomers by

HPLC on chiral stationary phase [based on the chiral selector poly(N-methacryloyl-L-leucine-L-methylamide), the principle of obtaining and using see European patent application EP-A-379 917; column 380 mm × 75 mm, a flow of 100 ml/min, temperature 24°C, solvent: isohexane/ethyl acetate 30:70] Example 39-2 is under these conditions slowly eluting the enantiomer II.

TPL=148°C.

Rt=8,0 min (chiral selector poly(N-methacryloyl-L-leucine-L-methylamide, 250 mm × 4.6 mm column; flow 1 ml/min; temperature 24°C, the solvent is ethyl acetate).

Example 40

1-(2-Chlorophenyl)-6-(2-methylpropyl)-1,5-dihydro-4H-pyrazolo[3,4-d]-pyrimidine-4-one

Analogously to Example 1 from 0.1 g (0.42 mmol) of amide 5-amino-1-(2-chlorophenyl)-1H-pyrazole-4-carboxylic acid (Example 27A), 0,344 g (2,96 mmol) of ethyl ester of 3-methylmalonic acid and 0,059 g (1.48 mmol) of 60%sodium hydride obtain 57 mg (45% of theoretical) of the desired product as a colourless solid.

TPL=204°C.

MS (ESI pos): m/z=303 (M+N)+.

1H-NMR (200 MHz, DMSO-d6): δ = 0.9 (d, 6N), 2.05 (m, 1H), 2.45 (d, 2H), 7.5-7.8 (m, 4H), 8.3 (s, 1H), 12.3 (s, 1H) cha the TEI in million

Example 41

6-(2-Ethylbutyl)-1-(4-methylpyridin-3-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]-pyrimidine-4-one

Analogously to Example 1 from 0.08 g (0,37 mmol) of amide 5-amino-1-(4-methylpyridin-3-yl)-1H-pyrazole-4-carboxylic acid (Example 35A), 0,303 g (of 1.84 mmol) of ethyl ester of 3-atillasoy acid and 0,074 g (of 1.84 mmol) of 60%sodium hydride obtain 56 mg (49% of theoretical) of the desired product as a colourless solid.

TPL=143°C.

MC (ESI pos): m/z=312 (M+H)+.

1H-NMR (200 MHz, DMSO-d6): δ = 0.8 (t, 6H), 1.3 (m, 4H), 1.8 (m, 1H), 2.2 (s, 3H), 2.5 (d, 2H), 7.5 (d, 1H), 8.3 (s, 1H), 8.6 (m, 2H), 12.3 (s, 1H) parts per million

Example 42

6-Cyclopentylmethyl-1-(4-methyl-1-oxidability-3-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one.

A solution of 40 mg (0.13 mmol) of 6-cyclopentylmethyl-1-(4-methylpyridin-3-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-it (Example 38) in 2 ml of dichloromethane is mixed at room temperature with 48 mg (70% purity, of € 0.195 mmol) m-chlorbenzoyl acid and stirred over night. Then stirred at 40°C for 1.5 hours to complete interaction under control (DC) response. To process mixed with a saturated solution of sodium bicarbonate and the mixture extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate and concentrated. The crude product is purified group is a rotary preparative HPLC. Obtain 32 mg (76% of theoretical) of the desired product as a colourless solid.

MS (ESI pos): m/z=310 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ = 1.1-1.8 (m, 8H), 2.2 (s, 3H), 2.22 (m, 1H), 2.6 (d, 2H), 7.5 (d, 1H), 8.3 (s, 1H), 8.6 (m, 2H), 12.3 (s, 1H) parts per million

Example 43

6-Cyclohexylmethyl-1-(4-methylpyridin-3-yl)-1,5-dihydro-4H-pyrazolo-[3,4-d]pyrimidine-4-one.

Analogously to Example 1 from 0.08 g (0,37 mmol) of amide 5-amino-1-(4-methylpyridin-3-yl)-1H-pyrazole-4-carboxylic acid (Example 35A), 0.32 g (of 1.84 mmol) of ethyl ether cyclohexyloxy acid and 0,074 g (of 1.84 mmol) of 60%sodium hydride obtain 68 mg (73% of theoretical) of the desired product as a colourless solid.

TPL=206°C.

MS (ESI pos): m/z=324 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ = 0.8-1.3 (m, 6N), 1.5-1.9 (m, 5H), 2.2 (s, 3H), 2.5 (d, 2H), 7.5 (d, 1H), 8.3 (s, 1H), 8.6 (m, 2H), 12.25 (s, 1H) parts per million

Compounds according to the invention can be converted into pharmaceutical compositions as follows.

Tablets

Brief description

100 mg of the compounds according to the invention, 50 mg of lactose (monohydrate), 50 mg of maize starch (native), 10 mg polyvinylpyrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

The weight of the tablets 212 mg, a diameter of 8 mm, the radius of curvature of 12 mm

Manufacturing

The mixture of compounds according to the invention, lactose and starch granularit 5 th solution (m/m) polyvinylpyrolidone (PVP) in water. After drying, the granulate is mixed with magnesium stearate for 5 minutes. This mixture is pressed through a conventional tablet press with a pressing force of 15 kN.

Suspension for oral administration

Brief description

1000 mg of the compounds according to the invention, 1000 mg of ethanol (96%), 400 mg Rhodigel® (Xanthan gum company FMC, Pennsylvania, USA) and 99 g of water.

A single dose of 100 mg of the compounds according to the invention corresponds to 10 ml of oral suspension.

Getting

Xanthan gum (Rhodigel) is suspended in ethanol, the compound according to the invention is introduced into the suspension. With stirring, add water. Stirred for about 6 hours until the swelling xanthan gum.

Solution for oral administration

Brief description

500 mg of the compounds according to the invention, 2.5 g of Polysorbate and 97 g of polyethylene glycol 400. A single dose of 100 mg of the compounds according to the invention corresponds to 20 g of oral solution.

Cooking

The connection according to the invention is suspended under stirring in a mixture of polyethylene glycol and Polysorbate. The mixing process continued until complete dissolution of the compounds according to the invention.

Intravenous (i.v.) solution

The connection according to the invention are used in concentrations below the solubility at saturation in a physiologically acceptable solvent (e.g., isotonic saline, 5% rest the d-glucose and/or a 30% solution of polyethylene glycol 400 (PEG 400). The solution is sterile filtered and filled them sterile and pyrogen-free containers for injection.

Solution for intravenous injection

The composition of

1 mg of the compounds according to the invention, 15 g of polyethylene glycol 400 and 250 g of water for injection.

Cooking

The connection according to the invention are dissolved together with polyethylene glycol 400 in water under stirring. The solution is sterile filtered (pore size 0.22 μm) and in sterile conditions fill them sterilized by heating the flask for infusion (infusion flask), which is pressurized infusion tubes and caps on the boards.

1. The compounds of formula:

in which R1means alkyl with 1-8 carbon atoms or cycloalkyl with 5-6 carbon atoms, which may optionally have up to three substituents selected, independently from each other, from the group: alkyl with 1-6 carbon atoms, hydroxy, halogen and trifluoromethyl, and the alkyl with 1-6 carbon atoms optionally can be replaced by a 1-3 substituents, independently from each other selected from the group of halogen and trifluoromethyl, R2means phenyl or aromatic mono - or bicyclic heteroaryl with 5 to 10 atoms in the ring and up to 5 heteroatoms from the series: sulfur, oxygen and/or nitrogen and the phenyl is substituted by 1-3 substituents, and heteroaryl if necessary, may be samewe is 1-3 substituents, selected in each case independently of one another, from the group: alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, trifluoromethyl, triptoreline, amino, hydroxy and halogen,
and their pharmaceutically acceptable salts.

2. Compounds according to claim 1, in which
R1means alkyl with 1-8 carbon atoms or cycloalkyl with 5-6 carbon atoms, which may optionally have up to three substituents selected, independently from each other, from the group: alkyl with 1-6 carbon atoms and hydroxy, and the alkyl with 1-6 carbon atoms optionally can be substituted with halogen,
R2means phenyl or an aromatic 5 to 6 membered heteroaryl containing up to 4 heteroatoms from the series: sulfur, oxygen and/or nitrogen and the phenyl is substituted by 1-3 substituents, and heteroaryl may optionally be substituted by 1-3 substituents selected in each case independently of one another, from the group: alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, trifluoromethyl, amino, hydroxy and halogen, as well as their pharmaceutically acceptable salts.

3. Compounds according to claim 1, in which
R1means alkyl with 1-5 carbon atoms or cycloalkyl with 5-6 carbon atoms, which may have up to three substituents selected, independently from each other, from the group: alkyl with 1-4 carbon atoms and hydroxy, and the alkyl with 1-4 carbon atoms which ri can be replaced by substituents, selected from the group of fluorine, chlorine, bromine,
R2means phenyl, pyrimidyl, N-oxidability or pyridyl, and phenyl is substituted by 1-3 substituents, and pyrimidyl, N-oxidability and pyridyl may optionally be substituted by 1-3 substituents selected in each case independently of one another, from the group: alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, trifluoromethyl, amino, hydroxy, fluorine, chlorine and bromine,
and their pharmaceutically acceptable salts.

4. Compounds according to claim 1, in which R1has the meaning indicated in claims 1 to 3, and
R2means phenyl, N-oxidability or pyridyl, and phenyl is substituted by 1-3 substituents, pyridyl and N-oxidability may optionally be substituted by 1-3 substituents selected in each case independently of one another, from the group: methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, ethoxy, fluorine and chlorine,
and their pharmaceutically acceptable salts.

5. Compounds according to claim 1, in which
R1means alkyl with 1-5 carbon atoms or cycloalkyl with 5-6 carbon atoms, which may have up to three substituents selected, independently from each other, from the group: alkyl with 1-4 carbon atoms and hydroxy, and
R2means phenyl, N-oxidability or pyridyl, and phenyl is substituted by 1-3 substituents, pyridyl and N-oxidability if necessary, which may be substituted by 1-3 substituents, selected, in each case independently of one another, from the group: methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, ethoxy, fluorine and chlorine, as well as their pharmaceutically acceptable salts.

6. Compounds according to any one of claims 1 to 5, in which
R1means alkyl with 1-5 carbon atoms or cycloalkyl with 5-6 carbon atoms, which may have up to three substituents selected, independently from each other, from the group: alkyl with 1-4 carbon atoms and hydroxy, and
R2means phenyl, N-oxidability or pyridyl, and phenyl is substituted by the Deputy, and pyridyl and N-oxidability optionally can be substituted by the Deputy, is selected, in each case independently of one another, from the group: methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, ethoxy, fluorine and chlorine,
and their pharmaceutically acceptable salts.

7. Compounds according to one of claims 1 to 6, having the properties of phosphodiesterase inhibitor PDE9A for the treatment and/or prevention of diseases mediated by the action of PDE9A.

8. Method of preparing compounds according to claim 1, characterized in that compounds of the formula (II)

subjected to interaction with the compound of the formula:

in which R1has specified in claim 1 value, and
R5means methyl or ethyl,
in an inert solvent in the presence of a base, and I is th the cyclization of the compounds of formula (I),
and the compounds of formula (I), if necessary, with bases or acids are converted into their pharmaceutically acceptable salts.

9. Drug, possessing properties of phosphodiesterase inhibitor PDE9A, containing at least one of the compounds according to one of claims 1 to 6 in an effective amount and at least one pharmaceutically acceptable, essentially nontoxic carrier or excipient.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine-condensed derivatives of formula , where n is selected from 0, 1, 2, 3 and 4, Z1 is selected from N, C(O) and CR3, where R3 represents hydrogen, Z2 is selected from N and CR4, where R4 is selected from hydrogen and halogen, where the bond between Z1 and Z2 is selected from a single bond and a double bond, R1 is selected from C1-C4alkyl and C1-C4alkoxy, R2 is selected from NR5C(O)R6, C(O)NR5R6 and NR5R6, where R5 represents hydrogen, and R6 is selected from hydrogen, C1-C4alkyl and phenyl, where phenyl as R6 is optionally substituted with 1-2 radicals independently selected from a group comprising halogen(C1-C4)alkyl, heteroaryl(C0-C4)alkyl and heterocycloalkyl(C0-C4)alkyl, where any heteroaryl or heterocycloalkyl substitute R6 can be optionally substituted with a substitute independently selected from C1-C4alkyl and heterocycloalkyl, where the said heteroaryl and heterocyclyl represent a saturated or unsaturated 5-6-member ring containing 1 or 2 N atoms as a heteroatom, and to their pharmaceutically acceptable salts, hydrates, solvates and isomers. The invention also relates to a pharmaceutical composition base on a formula I compound and to use of formula I compound for preparing a medicinal agent which can be used for treating diseases or disorders associated with anomalous or disrupted kinase activity, primarily diseases or disorders related to anomalous activation of kinase Ab1, Bcr-Ab1, BMX, BTK, CHK2, c-RAF, CSK, c-SRC, Fes, FGFR3, Flt3, IKKα, IKKβ, JNK2α2, Lck, Met, MKK4, MKK6, MCST2, NEK2, p70S6K, PDGFRβ, PKA, PKBα, PKD2, Rsk1, SAPK2α, SAPK2β, SAPK3, SGK, Tie2 and TrkB.

EFFECT: novel compounds have useful biological properties.

7 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula : in which R1 represents a hydrogen atom or alkyl optionally substituted with (1) aralkyloxy group, (2) aroyl, (3) isoquinolinyl or (4) aryl, optionally substituted with an alkoxy group; the solid line and the dashed line between A1 and A2 represent a double bond (A1=A2) or a single bond (A1-A2); A1 is a group of formula C(R4), and A2 is a nitrogen atom when the solid line and the dashed line between A1 and A2 represents a double bond (A1=A2); A1 is a group of formula C=O, and A2 is a group of formula N(R5) when the solid line or the dashed line between A1 and A2 represent a single bond (A1-A2); R2 represents alkyl optionally substituted with a cyano group, aryl optionally substituted with an alkoxy group, aralkyl optionally substituted with a halogen atom, a cyano group, an alkoxy group, an alkyl or carbamoyl or alkynyl; R3 represents a hydrogen atom, a halogen atom, cyano, formyl, carboxyl, alkyl optionally substituted with (1) amino group optionally substituted with alkyl, or (2) alkoxy group, aryl optionally substituted with an alkoxy group, tetrazolyl, alkylcarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, where heteroaryl is a 4-6-member monocyclic radical containing 1-2 heteroatoms selected from a nitrogen atom or oxygen atom, alkoxycarbonyl, carbamoyl optionally substituted with alkyl, cycloalkyl or cycloalkylalkyl, hydroxyl, alkoxy group or a group of formula: -Rd-C(O)O-Re, where Rd represents a single bond, and Re represents a group of formula: -CH(R4a)OC(O)R4b, where R4a represents alkyl or R4b represents cycloalkyloxy or aryloxy; R represents a hydrogen atom, hydroxyl, cyano, alkyl, carbamoyl, carboxyl, aryloxy optionally substituted with an alkoxy group or carbamoyl, alkylsulfonyl, alkylcarbonyl or alkoxycarbonyl; R5 represents a hydrogen atom or alkyl; -Y represents a group of formula (A) given below: in which m1 equals 2, and R6 is absent, or to pharmaceutically acceptable salts of the said compounds. The invention also relates to compounds of formula (VI), to pharmaceutical compositions, to a dipeptidyl peptidase IV inhibitor, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds with dipeptidyl peptidase IV inhibition properties.

20 cl, 76 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: described are novel compounds with general formula , their stereoisomers and pharmaceutically acceptable salts or solvates, where the dashed line can represent a double bond (together with the present single bond); R represents phenyl or benzodioxolyl, each of which can be substituted; R1, R3 and R4 independently represent hydrogen or C1-C6alkyl; R5 represents C1-C6alkyl; R7 represents hydrogen; R12 represents R3 or -C(O)R2, where R2 represents C1-C4 alkyl; D and G represent -CH2 - or -CH- when they are bonded to each other by a double bond; m equals 1; a pharmaceutical composition containing said compounds, and use of the novel compounds in treating conditions mediated by corticotropin-releasing factor (CRF).

EFFECT: increased effectiveness of compounds.

11 cl, 13 ex, 11 tbl

FIELD: medicine.

SUBSTANCE: there are described new compounds of general formula

where Xa represents 2 to 4 condensed cycloalkyl, aryl, heterocyclic rings containing 1 to 2 heteroatoms, chosen of N and O, and heteroaryl rings containing 1 to 4 heteroatoms, chosen of N, O or S where said rings can be additionally substituted. (Radical values R1-R4, R1, Y and n are specified in the patent claim), specific representatives of said compounds and a pharmaceutical composition containing them.

EFFECT: new compounds are effective in stimulation of endogenous development or release of growth hormone and can be used in treating obesity, osteoporosis and for increasing muscle bulk and muscle strength.

17 cl, 339 ex, 10 tbl

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of pyrazolo[1,5-a]pyrimidine with general formula 1 (values of radicals are given in the formula of invention), a pharmaceutical composition containing said derivatives and use of the novel compounds for preparing a medicinal agent for treating one or more diseases associated with cyclin-dependant kinalse CDK2.

EFFECT: novel compounds have useful biological properties.

36 cl, 87 tbl, 607 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of benzene sulphonamide of formula (I), tautomeric and stereoisomeric forms and physiologically acceptable salts thereof: where X is O, S; R1 is H, halogen; R2 is H, halogen; halogen; R3 is NO2, CN; R4 is: ,

where R71 is H; R72 is H; Z1 is -[CH2]P-, where p = 2.

EFFECT: compounds have antagonistic activity towards CCR3, which enables for their use in making medicinal agents.

13 cl, 1 tbl, 3 ex

FIELD: pharmacology.

SUBSTANCE: present invention relates to antagonists of serotonin 5-HT5 receptors with general formula 1 and their pharmaceutically acceptable salts and/or hydrates, particularly to substituted 3-sulphonyl-[1,2,3]triazolo[1,5-a]quinazolines and 3-sulphonyl-thieno[2,3-e][1,2,3]triazolo [1,5-a]pyrimidines, as active compounds for pharmaceutical compositions and medicinal agents, and methods of producing said compounds. In general formula 1 , Ar is a phenyl which is unsubstituted or substituted with halogen or at least one lower alkyl; R1 is a hydrogen atom or optionally substituted amine group, or optionally substituted 5-6 member azaheterocyclyl, bonded by a nitrogen atom to a carbon atom of a triazolopyrimidine ring with 1-2 heteroatoms selected from nitrogen, oxygen or sulphur, and optionally annulated with a benzene ring; where the substitutes are selected from hydrogen, optionally substituted C1-C5alkyl, optionally substituted C3-C8cycloalkyl, alkoxy group, acyl, saturated or unsaturated optionally annulated 5-7 member heterocyclyl, where heteroatoms are selected from nitrogen, oxygen or sulphur, optionally substituted phenyl; R2 and R3 together with carbon atoms to which they are bonded form an optionally substituted benzene or thiophene ring, where substitutes are selected from C1-C5alkyl or halogen atom.

EFFECT: invention also relates to pharmaceutical compositions and medicinal agents, a method of treating or preventing development of CNS diseases mediated by action of serotonin 5-HT5 receptors, for example Alzheimer's disease.

20 cl, 6 dwg, 4 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrazolpyrimidine derivatives of formula (I) where p is 0 or 1; R1 and R2 can independently represent H, halogen, lower alkyl, lower alkoxy, possibly substituted with one or more halogens or CF3; R3 is lower alkyl, hydroxy-lower alkyl or NRaRb; Ra and Rb are independently selected from a group consisting of H; cycloalkyl containing 3-6 carbon atoms; phenyl; lower alkyl possibly substituted with one or more hydroxy, fluorine, C3-6cycloalkyl, phenyl, pyridyl or NRcRd, where Rc and Rd are independently selected from H or lower alkyl; or where Ra and Rb together with the nitrogen atoms to which they are bonded can form a 5- or 6-member hetero-ring, possibly additionally containing 1 or 2 heteroatoms selected from O or N, and possibly substituted with lower alkyl or hydroxy-lower alkyl; R4 is H, Cl, lower alkoxy, cycloalkyl, containing 3-6 carbon atoms, or straight lower alkyl which is possibly substituted with one or more F; R5 is H; halogen or lower alkyl; as well as to their pharmaceutically acceptable salts.

EFFECT: invention also relates to pharmaceutical compositions based on these compounds and their use in preparing medicine for treating or preventing acute and/or chronic neurological disorders in which activation of mGluR2 is involved.

19 cl, 179 ex

FIELD: pharmacology.

SUBSTANCE: invention refers to new 2-alkylamino-3-arylsulphonylcycloalkano[e]pyrazolo[1,5-a]pyrimidines of general formula 1 and 2-alkylamino-3-arylsulphonylcycloalkano[d]pyrazolo[1,5-a]pyrimidines of general formula 2 with properties of serotonin 5-NT6 receptor antagonists, to pharmaceutical compositions containing specified compounds as a principle, medical products and method of treatment and the prevention of CNS diseases. In general formulae 1 and 2, R1 represents hydrogen atom or C1-C3 alkyl; R2 represent C1-C3 alkyl; R3 represent hydrogen atom, one or two optionally substituted identical halogen atoms, C1-C3 alkyl or hydroxyl optionally substituted with C1-C3alkyl; n represents an integer 1, 2 or 3. The invention also relates to the method for making the compounds of general formula 1 or 2 by interaction of 3-amino-4-arylsulphonyl-2H-pyrazoles of general formula 3 with relevant β-dicarbonyl compounds of general formula 4 or their derivatives of general formula 5. 3, 4, 5, where: R1, R2, R3 and n have said values.

EFFECT: new 2-alkylamino-3-arylsulphonyl-cycloalkano[e or c1]pyrazolo[1,5]pyrimidines - serotonin 5-NT6 receptor antagonists, methods of making and applying thereof.

12 cl, 1 dwg, 4 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: invention is related to 4-((2)-4'-hydroxybutene-2'-yl)-2-R-6-phenyl-1,2,4-triazolo[5,1-c][1,2,4]triazine-7-ons of common formula (1) ,

where R=H, CH3,SCH3 have antiviral action against herpesvirus of simple type 1 (HSV-1).

EFFECT: new derivatives have useful biological properties.

1 tbl

FIELD: medicine.

SUBSTANCE: for prevention and treatment of diseases of cardiovascular and/or nervous system, arterial hypertension claimed is original composition of ethylmethylhydroxypyridine succinate, succinic acid and ethylenediaminetetraacetic acid disodium salt in form of solution for injections, which additionally contains pyridoxin or its pharmaceutically acceptable salt and povidon.

EFFECT: high stability, convenience in application and high therapeutic efficiency in prevention and treatment of diseases of cardiovascular and nervous system and arterial hypertension.

14 cl, 5 ex

FIELD: medicine.

SUBSTANCE: invention relates to compounds of general formula (I) and their pharmaceutically acceptable salts and pharmaceutically acceptable asters, possessing activity with respect to LXRα and/or LXRβ receptors. Compounds can be applied for treatment and prevention of diseases mediated by LXRα and/or LXRβ receptors, namely: increased level of lipids and cholesterol level, atherosclerotic diseases, diabetes, metabolic syndrome, dyslipidermia, sepsis, inflammatory diseases, pancreatitis, liver cholestasis/fibrosis, and diseases which include inflammatory component, such as Alzheimer's disease and reduced/improvable cognitive function. In general formula n represents integer number from 0 to 3; R1 is independently selected from group consisting of halogen, -CN, -NO2, -SO2Me, lower alkyl, -OR11, pyperidinyl and -N(R11)(R11), where R11 is independently selected from lower alkyl and H, X1, X2, X3 and X4 are independently selected from nitrogen and carbon, on condition that, not more than two of X1, X2, X3 and X4 can simultaneously represent nitrogen, and in case when two of X1, X2, X3 and X4 represent nitrogen, n represents 0,1 or 2; k represents integer number 0 or 1; R2 represents H; R3 represents H, lower alkyl or halogen; R4 represents aryl, heteroaryl, lower alkylaryl or lower alkylheteroaryl, each of which is optionally substituted with substituents in amount from one to five, which are independently selected from group consisting of halogen, lower alkyl, -OR41, lower alkinyl and NR42R43, where R41 represents lower alkyl, R42 and R43 independently on each other represent hydrogen or lower alkyl, or NR42R43 represents pyrrolidinyl, or R4 represents lower alkyl; R5 is selected from group, heteroaryl, consisting of and , said aryl and heteroaryl being optionally substituted in one or more positions with one or more substituents, independently selected from group consisting of H, halogen, lower alkyl and (CH2)VR53, where R51 is selected from group consisting of H, lower alkyl, lower alkenyl and lower alkylaryl, said lower alkylaryl is optionally substituted in one or more positions with one or more lower alkyl, -CN, halogen, group -COOR54 and group -CH2OR54, where R54 represents lower alkyl or H; R52 represents lower alkyl or -H; R53 represents H, lower alkyl, C3-C6-cycloalkyl, -COOR55, -N(R55)(R56), -CH2OH, -CN, CF3, -CONH2 or -CH2OR55, where R55 is independently selected from group consisting of lower alkyl, -H, -C(O)aryl or -C(O)-lower alkyl, and R56 is selected from group consisting of H, lower alkyl, -C(O)CF3, -C(O)aryl, -C(O)-lower alkyl and lower alkylaryl, and where said aryl and lower alkylaryl are optionally substituted in one or more positions with one or more lower alkyl, halogen, group COOR57 and group -CH2OR57, where R57 represents lower alkyl or -H, or R55 and R56 together with atom to which they are bound, form ring system; or R53 represents aryl, which can be optionally substituted with benzyloxy, carboxy, lower alkoxycarbonyl, hydroxy-(lower alkyl), halogen, carbamoyl, (lower alkyl)carbamoyl, di-(lower alkyl)carbamoyl, m represents integer number from 0 to 2; v represents integer number from 0 to 4; where term "lower alkyl" separately or in combination with other groups refers to branched or linear monovalent alkyl radical, containing from one to six carbon atoms, where term "aryl" separately or in combination with other groups refers to phenyl or naphthyl, and where term "hetyeroaryl" refers to aromatic 5- or 6-member ring, which can include 1-3 heteroatoms selected from nitrogen, oxygen and/or sulphur, and which can be condensed with phenyl group.

EFFECT: increase of compound application efficiency.

38 cl, 5 dwg, 137 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula or to any isomer thereof, or mixture of isomers thereof, or pharmaceutically acceptable salt thereof, where R1 represents hydrogen or alkyl; R2 and R3 together form -(CH2)2-, and R2' and R3' represent hydrogen, m equals 1; n equals 1; X represents -O-; and Q represents chroman-2-on-7-yl, which is possibly substituted with one or more substitutes independently selected from a group consisting of halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, nitro, alkoxy, cycloalkoxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl and alkynyl. The invention also relates to a pharmaceutical composition, as well as to use of chemical compound in any of paragraphs 1-4.

EFFECT: obtaining novel biologically active compounds having monoamine neuromediator reuptake inhibitory activity.

8 cl, 10 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to an acid addition dopenzil salt [(±)-2-[(1-benzyl-4-piperidinyl)mathyl]-5,6-dimehoxy-1-indanone] of general formula (II), where X stands for a radical of fumaric acid prepared by reaction of dopenzil base and fumaric acid in ethanol or 2-propanol as a solvent, separation of dopenzil salt produced thereby and optionally washings with an organic solvent. The invention also concerns a pharmaceutical composition, the method of preparing the pharmaceutical compositions, application of acid addition dopenzil salt, and also the method for prevention or treatment of the diseases.

EFFECT: preparation of new acid addition dopenzil salt which is applicable for prevention or treatment of the diseases associated with acetylcholine lack in brain, Alzheimer's disease or senile psychosis.

8 cl, 12 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a morpholine type cinnamide derivative with general formula I or its pharmacologically acceptable salt, where (a) R1, R2 , R3 and R4 are identical or different and each represents a hydrogen atom or C1-6alkyl group; X1 represents a C1-6alkylene group, where the C1-6alkylene group can be substituted with 1-3 hydroxyl groups or C1-6alkyl groups, or a C3-8cycloalkyl group formed by two C1-6alkyl groups all bonded to the same carbon atom of the C1-6alkylene group; Xa represents a methoxy group or a fluorine atom; Xb represents an oxygen atom or a methylene group, under the condition that Xb represents only an oxygen atom when Xa represents a methoxy group; and Ar1 is an aryl group, pyridinyl group which can be substituted with 1-3 substitutes selected from A1 group of substitutes; (b) Ar1-X1- represents a C5-7cycloalkyl group condensed with a benzene ring, where one methylene group in the C5-7cycloalkyl group can be substituted with an oxygen atom, the C5-7cycloalkyl group can be substituted with 1-3 hydroxyl groups and/or C1-6alkyl groups, and R1, R2, R3, R4, Xa and Xb assume values given in (a); (d) Ar1-X1- and R4 together with the nitrogen atom bonded to the Ar1-X1- group and the carbon atom bonded to the R4 group form a 5-7-member nitrogen-containing heterocyclic group which is substituted with an aryl group or a pyridinyl group, where one methylene group in the 5-7-member nitrogen-containing heterocyclic group can be substituted with an oxygen atom, and the aryl or pyridinyl group can be substituted with 1-3 substitutes selected from A1 group of substitutes, Xb is an oxygen atom, and R1, R2, R3 and Xa assume values given in (a) and (b); group A1 of substitutes: (1) halogen atom. The invention also relates to a pharmaceutical composition containing a formula I compound, which is useful in treating Alzheimer's disease, senile dementia, Down syndrome or amyloidosis.

EFFECT: obtaining novel morpholine type cinnamide derivatives with inhibitory effect on amyloid-β production.

17 cl, 9 tbl, 113 ex

FIELD: medicine.

SUBSTANCE: invention concerns chemical-pharmaceutical industry, more specifically to a pharmaceutical composition expressing nootropic activity and cholinomimetic action. There is offered original pharmaceutical composition containing choline alphoscerate as an active ingredient in therapeutically effective amount and pharmaceutically acceptable carriers, differing that as pharmaceutically acceptable carriers it contains macrogol (polyethylene glycol 400) and povidone (Plasdone or collidone). There is also offered method for making thereof that enables making a high-yield end product. The pharmaceutical composition produced by the declared method exhibits minimum by-effects, improved bioavailability and prolonged storage stability.

EFFECT: invention can be used for treatment or prevention of CNS diseases and consequences of craniocereberal injuries.

11 cl, 1 tbl

FIELD: medicine.

SUBSTANCE: there is described thiomorpholine compound presented by formula (I) wherein the ring A represents benzene ring; the ring B represents benzene ring; R1 represents hydrogen atom, R2 represents C1-6-alkyl group; R3a and R3b are identical or different, each representing hydrogen atom or C1-6-alkyl group, and n represents an integer equal to 2, or its pharmaceutically acceptable salt. There is also described method for making the compound of formula (1), a pharmaceutical composition and application of the compound of formula (1) for making a medical product used for treatment and prevention of the disease chosen from inflammation, allergic diseases, pain, migraine, neuralgia, itch, cough, central nervous system diseases, alimentary organ diseases, nausea, vomiting and urological disorders.

EFFECT: compounds exhibits affinity to neurokinine-1 receptor.

6 cl, 4 tbl, 16 ex

Gsk-3 inhibitors // 2379300

FIELD: medicine.

SUBSTANCE: invention concerns GSK-3 inhibitors of general formula (I), method for making thereof and based pharmaceutical compositions which can be used in medicine: formula I, where R1 means an organic group containing at least 8 atoms, chosen of C or O, including aromatic ring of phenyl, naphthyl or methylene dioxypjenyl, which is not bound directly with N through -C(O)- or oxygen; Ra, Rb, Rz, R3, R4, R5 and R6 represent hydrogen.

EFFECT: production of new biologically active compounds for treatment of GSK-3 mediated diseases.

28 cl, 13 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: novel isoquinoline derivatives are described by general formula I, where q equals zero; p equals zero or one; Ra is -COOH or WR8; under the condition that, if Ra is -COOH, then p equals zero, and if Ra is -WR8, then p equals one; W is selected from an oxygen atom and -NR9-, where R9 is selected from a group consisting of a hydrogen atom, acyl and alkyl; and R8 is selected from a group consisting of a hydrogen atom and alkyl; R1 is selected from a group consisting of a hydrogen atom, alkyl, alkyl substituted with one group selected from alkoxy and dialkylamino, a halogen atom, heteroaryl containing up to six carbon atoms, one of which is nitrogen, aminoacyl, aryl, aryl substituted with alkyl, and -XR6, where X is an oxygen atom, -S(O)n- or -NR7, where n equals zero, one or two, R6 is selected from a group consisting of alkyl, aryl, aryl substituted with one group selected from a halogen atom, alkoxy, alkylcarbonylamino and alkylsulfonamide, heteroaryl, containing up to six carbon atoms, one of which is nitrogen, and R7 is a hydrogen atom or aryl; R2 and R3 are independently selected from a group consisting of a hydrogen atom, amino, amino substituted with alkoxy-substituted phenylsulfonyl, alkyl, alkyl substituted with up to three times by a halogen atom, aryl, halogen atom -NR6C(O)NR6R6, and -XR6, where X is an oxygen atom or -S(O)n-, where n equals zero, one or two, each of the substitutes R6 is independently selected from a group consisting of hydrogen, alkyl, alkyl substituted with aryl, aryl , aryl substituted with one or two groups selected from a halogen atom, alkyl, alkyl substituted with up to three times by a halogen, alkoxy, alkoxy substituted with up to three times by a halogen, aryloxy substituted with a halogen, nitro, alkylsulfonamide, arylsulfonamide and alkyl-substituted arylsulfonamide, cycloalkyl, heteroaryl, containing up to six carbon atoms, one of which is nitrogen, under the condition that if X is -SO2-, R6 cannot be a hydrogen atom; or R2 and R3 together with carbon atoms to which they are bonded, are bonded with formation of an aryl group; R4 and R5 are independently selected from a hydrogen atom or aryl; R is selected from a group which includes a hydrogen atom, deuterium and methyl; R' is selected from a group consisting of a hydrogen atom, deuterium, alkyl or alkyl substituted with one group selected from hydroxyl, amino, carboxyl, aryl, aryl substituted with one hydroxyl and heteroaryl, containing up to five carbon atoms, two of which can be nitrogen; on the other hand, R and R' and the carbon atom to which they are bonded can be bonded with formation of cycloalkyl; R" is formed from a hydrogen atom and alkyl, or R" together with R' and the nitrogen atom to which they are bonded can be bonded with formation of a heterocyclic group containing up to six carbon atoms, one of which is nitrogen; R'" is selected from a group consisting of hydroxyl, alkoxy, alkoxy substituted with aryl, acyloxy, aryl, -S(O)n-R10, where R10 is hydrogen, and n is zero; or its pharmaceutically acceptable salts, esters or amides; under the condition that restrictive conditions given in paragraph 1 of the formula of invention are met. The invention also relates to specific produced and described compounds, a pharmaceutical composition based on compounds with general formula I, a method of treating, preventing and pretreatment using said pharmaceutical composition, a method of inhibiting activity of hydrolase enzyme, based on taking an effective amount of a formula I compound, a composition for preventing and pretreatment, based on formula I compound and erythropoietin.

EFFECT: new isoquinoline derivatives have useful biological properties.

53 cl, 4 tbl, 253 ex

FIELD: medicine.

SUBSTANCE: claimed invention relates to chemical-pharmaceutical industry and concerns pharmaceutical composition for prevention and treatment of diseases and disease states connected with metabolic pathways of cycloxygenase-2 (CG-2) and 5-lipooxygenase (5-LO), which contains mixture of extract obtained from Scutellariae and enriched with flavonoids with free B-ring, which include baicalein, and extract obtained from Acacia and enriched with flavans, which include catechine and epicatechine. Claimed invention also relates to method of body weight loss and control over glucose level in blood. Methods by claimed invention include introduction to person, who needs it, of efficient amount of composition by claimed invention together with pharmaceutically acceptable carrier. Claimed invention mainly relates to prevention and treatment of diseases and states connected with metabolic pathways of cycloxygenase-2 (CG-2) and 5-lipooxygenase (5-LO), including, but not confining to it, stopping discomfort and pain in joints, induced by such states as osteoarthritis, rheumatoid arthritis and other injuries caused by overload.

EFFECT: composition possesses high efficiency.

35 cl, 22 ex, 15 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula : in which R1 represents a hydrogen atom or alkyl optionally substituted with (1) aralkyloxy group, (2) aroyl, (3) isoquinolinyl or (4) aryl, optionally substituted with an alkoxy group; the solid line and the dashed line between A1 and A2 represent a double bond (A1=A2) or a single bond (A1-A2); A1 is a group of formula C(R4), and A2 is a nitrogen atom when the solid line and the dashed line between A1 and A2 represents a double bond (A1=A2); A1 is a group of formula C=O, and A2 is a group of formula N(R5) when the solid line or the dashed line between A1 and A2 represent a single bond (A1-A2); R2 represents alkyl optionally substituted with a cyano group, aryl optionally substituted with an alkoxy group, aralkyl optionally substituted with a halogen atom, a cyano group, an alkoxy group, an alkyl or carbamoyl or alkynyl; R3 represents a hydrogen atom, a halogen atom, cyano, formyl, carboxyl, alkyl optionally substituted with (1) amino group optionally substituted with alkyl, or (2) alkoxy group, aryl optionally substituted with an alkoxy group, tetrazolyl, alkylcarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, where heteroaryl is a 4-6-member monocyclic radical containing 1-2 heteroatoms selected from a nitrogen atom or oxygen atom, alkoxycarbonyl, carbamoyl optionally substituted with alkyl, cycloalkyl or cycloalkylalkyl, hydroxyl, alkoxy group or a group of formula: -Rd-C(O)O-Re, where Rd represents a single bond, and Re represents a group of formula: -CH(R4a)OC(O)R4b, where R4a represents alkyl or R4b represents cycloalkyloxy or aryloxy; R represents a hydrogen atom, hydroxyl, cyano, alkyl, carbamoyl, carboxyl, aryloxy optionally substituted with an alkoxy group or carbamoyl, alkylsulfonyl, alkylcarbonyl or alkoxycarbonyl; R5 represents a hydrogen atom or alkyl; -Y represents a group of formula (A) given below: in which m1 equals 2, and R6 is absent, or to pharmaceutically acceptable salts of the said compounds. The invention also relates to compounds of formula (VI), to pharmaceutical compositions, to a dipeptidyl peptidase IV inhibitor, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds with dipeptidyl peptidase IV inhibition properties.

20 cl, 76 ex, 1 tbl

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