Substituted 4-aryl-1,4-dihydro-1,6-naphthyridine amides and use thereof

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 4-aryl-1,4-dihydro-1,6-naphthyridine-3-carboxamides, method for production thereof, use thereof to produce a medicinal agent which inhibits MR activity.

EFFECT: improved method.

11 cl, 9 ex

 

The present application relates to new substituted 4-aryl-1,4-dihydro-1,6-naphthiridine-3-carboxamido, method of production thereof, their use for the treatment and/or prophylaxis of diseases and their use for the preparation of drugs for the treatment and/or prophylaxis of diseases, in particular cardiovascular diseases.

Aldosterone plays a key role in maintaining fluid and electrolyte homeostasis, because it ensures the retention of sodium and secretion of potassium in the epithelium of the distal nephron, which contributes to the persistence of extracellular volume and together with the regulation of blood pressure. In addition, aldosterone has a direct impact on the structure and function of the cardiovascular system, and the underlying action mechanisms are not fully elucidated [R.E.Booth, J.P.Johnson, J.D.Stockand, Adv. Physiol. Educ. 26(1), 8-20 (2002)].

Aldosterone is a steroid hormone that is produced in the adrenal cortex. Basically its products indirectly regulated depending on renal blood flow. Any reduction in renal blood flow causes the kidneys to the leaching of the enzyme renin into the bloodstream. It activates the formation of angiotensin II, which, on the one hand, has a narrowing effect on the arterial blood vessels, and, on the other hand, stimulates the formation and is of egostereo in the cortex of the adrenal gland. Thus, the kidney acts as a sensor of blood pressure and at the same time as indirect volume sensor in the blood circulation, and through the renin-angiotensin-aldosterone prevents a critical loss of volume, because on the one hand, increased blood pressure (angiotensin II), and, on the other hand, due to enhanced reabsorption of sodium and water in the kidney again balanced the state of filling of the vascular system (the action of aldosterone).

This regulation may be disrupted in a variety of ways. For example, chronic low blood flow to the kidney (for example, heart failure and the resulting delay the outflow of blood in the venous system) leads to chronic increased leaching of aldosterone. On the other hand, this leads to an increase in blood volume and, along with this increases cardiac weakness due to excessive volume of circulating blood to the heart. The result can be a stagnation of blood in the lungs with shortness of breath and the formation of edema in the extremities, ascites and pleural effusions; renal blood flow even more weakened. In addition, the increased action of aldosterone leads to a decrease in the concentration of potassium in the blood and extracellular fluid. In an already damaged heart muscle can occur failure critical minimum Majesty the us cardiac rhythm fatal. In this you should look for one of the main causes of sudden cardiac death, often coming in patients with heart failure.

Additionally, aldosterone is responsible for a number of processes of transformation of the heart muscle, usually observed in heart failure. Thus, giperaldosteronizm is a critical component in the pathogenesis and prognosis of heart failure, which may initially be caused by a variety of injuries, such as myocardial infarction, myocarditis, or hypertension. This assumption is confirmed by the fact that in numerous clinical studies in patients with chronic heart failure after acute myocardial infarction was significantly reduced total mortality by use of aldosterone antagonists [.Pitt, F.Zannad, W.J.Remme et al., N.Engl. J.Med. 341. 709-717 (1999); .Pitt, W.Remme, F.Zannad et al., N.Engl. J.Med. 348, 1309-1321 (2003)]. This is confirmed by, among other things, reduce the frequency of sudden cardiac death.

As a result of new research in a small part of patients suffering from essential hypertension, there are also so-called normokalemia option primary hyperaldosteronism [mostly in 11% of all hypertensives: L.Seller und M.Reincke, Der Aldosteron-Renin-Quotient bei sekundärer Hypertonie, Herz 28, 686-691 (2003)]. The best diagnostic method is Ohm at normokalemia hyperaldosteronism is the ratio of the aldosterone/renin relevant plasma concentrations, so that you can diagnose and, ultimately, to treat even the relative increase in concentration relative to the concentration of renin in the plasma. So giperaldosteronizm diagnosed in connection with essential hypertension, is the starting point for causal prophylaxis and for rational therapy.

Much rarer than the above forms of hyperaldosteronism, there are paintings of the disease at which a violation of either to be found in producing hormones of the adrenal cells, or their number or weight increases due to hyperplasia or proliferation. Adenoma or diffuse hyperplasia of the cortex of the adrenal gland is the most frequent cause of primary hyperaldosteronism, also called as the horse syndrome, the leading symptoms are hypertension and gipokaliemicakie alkalosis. While in the foreground in addition to surgical removal of unhealthy tissue is medical therapy aldosterone antagonists [N.A. Kühn und J. Schirmeister (Hrsg.), Innere Medizin, 4. Aufl., Springer Verlag, Berlin, 1982].

Another typical pattern of disease, followed by increasing concentrations of aldosterone in plasma, is cirrhosis of the liver in a far advanced stage. Here the reason for the increase in aldosterone lies mainly in a limited collapse of aldosterone from the liver. Volume is MNA overload of the heart, edema and hypokalemia are the typical consequences of that in clinical practice can be successfully facilitated aldosterone antagonists.

Actions of aldosterone are communicated through mineralocorticoid receptor localized in the target cells. Available until this time, aldosterone antagonists, like aldosterone, steroid underlying structure. The applicability of this kind of steroid antagonists is limited due to their interactions with receptors for other steroid hormones, which partially leads to side-effects such as gynecomastia and impotence, and to the interruption of treatment [..Zaman, S.Opahl, D.A.Calhoun, Nature Rev. Drug Disc. 1, 621-636 (2002)].

The use of effective, nesteroidnykh and selective to mineralocorticoid receptor antagonists makes it possible to bypass the profile of side effects and to achieve significant advantages in the treatment.

The present invention is to provide new compounds that can be used as selective to mineralocorticoid receptor antagonists for the treatment of diseases, in particular cardiovascular diseases.

In patents EP 0133530-AND, ER 0173933-AND, ER 0189898 and EP 0234516-reported 4-aryl-substituted 1,4-dihydro-1,6-naphthirydines-naphthyridinone with antagonistic effect of calcium for the treatment of diseases to wenonah vessels. About the pharmacological profile of these compounds is reported, inter alia, in the work of O. Werner et al., Naunyn-Schmiedeberg''s Arch. Pharmacol. 344(3), 337-344 (1991). In addition, in WO 02/10164 derivatives of 1,4-dihydro-1,6-naphthiridine intended as potassium channels openers for the treatment of various diseases and, above all, urology. Derivatives of 4-personil - and 4-chromenes-1,4-dihydropyridines as antagonists mineralocorticoid receptor described in WO 2005/087740 and WO 2007/009670. In WO 2006/066011 given 4-aryl-3-cyano-1,4-dihydropyridines-5-carboxylic acid esters and amides as partially dual modulators of steroid hormone receptors and calcium channel L-type, and in WO 2005/097118 described in connection with the structure of 4-aryl-1,4-dihydropyridines as receptor antagonists aldosterone.

The object of the present invention are compounds of General formula (I)

D is N or C-R4where

R4means hydrogen, fluorine, trifluoromethyl or (C1-C4)-alkyl,

Ar stands for a group of the formula

,or

where

* means the connection,

R5means hydrogen, fluorine, chlorine, cyano, nitro, trifluoromethyl or (C1-C4)-alkyl,

R6means hydrogen or fluorine,

R7means halogen, (C -C4)-alkyl, trifluoromethyl, (C1-C4)-alkoxy or triptoreline,

R8means cyano or nitro,

R9means hydrogen, halogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio or di-(C1-C4)-alkylamino, and an alkyl group in these residues (C1-C4)-alkyl, (C1-C4)-alkoxy and (C1-C4)-alkylthio may be substituted up to three times by fluorine,

or

phenyl which may be substituted with halogen, (C1-C4)-alkyl or trifluoromethyl,

R10means hydrogen, halogen or (C1-C4)-alkyl,

E. means CH, C-R7or N

and

n represents the number 0, 1 or 2,

moreover, if the substituent R7appears several times, its meanings can be identical or different,

R1is (C1-C4)-alkyl, which is up to three times can be replaced by fluorine,

R2is (C1-C6)-alkyl which may be substituted (C3-C7-cycloalkyl

or substituted up to three times by fluorine, or is a group of the formula-SO2-R11where

R11means (C1-C6)-alkyl, trifluoromethyl, (C3-C7-cycloalkyl, phenyl or 5 - or 6-membered heteroaryl having up to two heteroatoms from the series N, O and/or S,

moreover, the phenyl and heteroaryl, in its PTS who lived, may be once or twice, identically or differently substituted with halogen, cyano, nitro, (C1-C4)-alkyl, trifluoromethyl, (C1-C4)-alkoxy and/or triptoreline,

and

R3is hydrogen, fluorine, trifluoromethyl or (C1-C4)-alkyl,

and also their salts, solvate and solvate salts.

The compounds according to the invention are the compounds of formula (I) and their salts, solvate and solvate salts, the compounds of the following formulas covered by formula (I)and their salts, solvate and solvate salts, as well as the following as examples of execution of the compounds covered by formula (I), their salts, solvate, and a solvate of salt, even if for the following compounds covered by formula (I), we are not talking about their salts, solvate and solvate salts.

Compounds according to the invention, depending on their structure can be in stereoisomeric forms (enantiomers, diastereomers). Therefore, the present invention encompasses enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and/or diastereomers in a known manner can be isolated stereoisomeric homogeneous components.

If the compounds according to the invention may be in tautomeric forms, the present invention encompasses all tautomeric forms.

As salts within the framework on which the present invention the preferred physiologically harmless salts of the compounds according to the invention. Covered in salt, which are not suitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds according to the invention.

Physiologically harmless salts of the compounds according to the invention include salts of acids such as mineral acids, carboxylic and sulphonic acids, e.g. salts of hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonate, econsultancy, toluenesulfonic acid, benzosulfimide, naphthalenedisulfonate, acetic acid, triperoxonane acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, maleic and benzoic acids.

Physiologically harmless salts of the compounds according to the invention include salts of conventional bases such as, for example and preferably, alkali metal salts (e.g. sodium and potassium salts), salts of alkaline earth metals (e.g. calcium salts and magnesium), and ammonium salts, derived from ammonia or organic amines with 1 to 16 carbon atoms, as for example and preferably, ethylamine, diethylamine, triethylamine, ethyldiethanolamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, Ethylenediamine and N-methylpiperidin.

p> The solvate in the framework of the present invention are such forms of the compounds according to the invention, in which solid or liquid state, form a complex by coordination with solvent molecules. Hydrates are a special form of a solvate, in which coordination is carried out with water. The preferred solvate in the framework of the present invention are hydrates.

In addition, the present invention also includes prodrugs of the compounds according to the invention. The term "prodrug" means compounds which may themselves be biologically active or inactive, however, finding them in the body is converted into compounds according to the invention (for example, metabolicheskikh or hydrolytic processes).

In the framework of the present invention, the substituents have the following meanings, unless a different definition:

(C1-C6)-Alkyl and (C1-C4)-alkyl means in the framework of the invention the alkyl residue is branched or unbranched chain with 1-6 or 1-4 carbon atoms. Preferred alkyl residue with an unbranched or branched chain with 1 to 4 carbon atoms. For example, and can be mostly named the following residues: methyl, ethyl, n-propyl, isopropyl, n-butyl, ISO-butyl, sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl, ISO-ne is Teal, and n-hexyl.

(C3-C7-Cycloalkyl in the framework of the invention means a monocyclic saturated cycloalkyl group having 3-7 carbon atoms. Preferred cycloalkenyl balance with 3-6 carbon atoms. For example, and can be mostly named the following residues: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

(C1-C4)-Alkoxy in the framework of the invention means an alkoxy residue with an unbranched or branched chain with 1 to 4 carbon atoms. For example, and can be mostly named the following residues: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.

(C1-C4)-Alkylthio in the framework of the invention means the rest of alkylthio with unbranched or branched chain with 1 to 4 carbon atoms. For example, and can be mostly named the following residues: methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio and tert-butylthio.

Di-(C1-C4)-alkylamino means in the framework of the invention the amino with two identical or different alkyl substituents with unbranched or branched chain having 1-4 carbon atoms. For example, and can be mostly named the following residues: N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N,N-diisopropylamino, N-isopropyl-N-n-propylamino, N-n-butyl-N-mate the amino and N-tert-butyl-N-methylamino.

5 - or 6-membered heteroaryl means in the framework of the invention aromatic heterocycle (heteroaromatic compounds) with 5 or 6 ring atoms, which contains one or two ring heteroatoms, and linked via a ring carbon atom. For example, and can be mostly named the following residues: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolin, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl.

Halogen within the framework of the invention includes fluorine, chlorine, bromine and iodine. Preferred fluorine or chlorine.

If residues in the compounds according to the invention are substituted, they may be mono - or polyamidine, if there is no other definition. In the framework of the present invention, the rule that all appear repeatedly residues are independent one from the other values. Preferred is the replacement of one, two or three identical or different substituents. Especially preferably the substitution of one Deputy.

In the framework of the present invention preferred compounds of formula (I), in which

D means C-R4where

R4means hydrogen, methyl or trifluoromethyl,

Ar stands for a group of the formula

or,

where

* means the connection,

R5oz ACHAT hydrogen, fluorine, chlorine or cyano,

R8means cyano or nitro

and

R9means chlorine, bromine, (C1-C4)-alkyl, trifluoromethyl, (C1-C4)-alkoxy, triptoreline, (C1-C4)-alkylthio or triptoreline,

R1is methyl or trifluoromethyl,

R2is (C1-C4)-alkyl, trifluoromethyl or a group of the formula-SO2-R11in which

R11means (C1-C4)-alkyl or trifluoromethyl,

and

R3is hydrogen, methyl or trifluoromethyl,

and also their salts, solvate and solvate salts.

Especially preferred within the present invention are the compounds of formula (I), in which

D - C-R4where

R4means hydrogen or methyl,

Ar is a group of the formula

or,

or

in which

* means the connection

and

R9means ethyl, methoxy or triptoreline,

R1is methyl or trifluoromethyl,

R2is methyl, ethyl, n-propyl or isopropyl

and

R3is hydrogen or methyl,

and also their salts, solvate and solvate salts.

The most preferred compounds according to formula (I) with the following structures:

,

and

and the x salt the solvate and the solvate salts.

In this particularly preferred enantiomeric compounds with the following structures:

,,

,,

and

and also their salts, solvate and solvate salts.

These, in particular, determination of residues in existing or preferred combinations arbitrarily replaced by a residue other definitions combinations regardless combinations specified residues.

Especially preferred are combinations of two or more of the above preferred residues.

The next subject of invention is a method of obtaining compounds of formula (I) according to the invention, characterized in that the compound of formula (II)

,

in which Ar has the above meaning,

in an inert solvent, optionally in the presence of acid, a combination of acid/base and/or dehydrating reagent with the compound of the formula (III)

,

in which R1has the above value, and

T denotes allyl or 2-cyanoethyl,

converted to the compound of formula (IV)

,

in which Ar, T and R1 respectively have the above values,

then, this compound is condensed in an inert solvent with a compound of formula (V)

,

in which D and R3have the above meaning,

in the compound of formula (VI)

,

in which Ar, D, T, R1and R3respectively have the above values,

then the compounds of formula (VI) in an inert restoritive, if necessary, in the presence of a base with the compound of the formula (VII) or a salt trialkylamine formula (VIII)

in which

R12means (C1-C6)-alkyl which may be substituted (C3-C7-cycloalkyl or substituted up to three times by fluorine,

R12Ameans methyl or ethyl,

X means the original group, such as halogen, mesilate, toilet or triplet

and

Y-means not nucleophilic anion, such as, for example, tetrafluoroborate,

or in the presence of acid alkiliruyutza trialkylaluminium formula (IX)

,

in which R12Ahas the above value,

in the compounds of formula (X-A)

,

in which Ar, D, T, R1, R3and R12respectively have the above values,

or connection fo the formula (VI) in an inert solvent in the presence of a base with the compound of the formula (XI)

,

in which R11has the above value,

converted into compounds of the formula (X-B)

,

in which Ar, D, T, R1, R3and R11respectively have the above values,

after that, in compounds of formula (X) or (X-In) famous specialist way cleaved ether group T in the carboxylic acid of formula (XII)

,

in which Ar, D, R1, R2and R3respectively have the above values, then 1,1'-carbonyl diimidazol translated in imidazolidin formula (XIII)

,

in which Ar, D, R1, R2and R3respectively have the above values, and then these compounds in an inert solvent, optionally in the presence of a base is converted with ammonia amides of formula (I) and, if necessary, the compounds of formula (I) is known to the specialist methods are separated into their enantiomers and/or diastereomers, and/or by using appropriate solvents (i) and/or bases or acids (ii) are transformed into their solvate, salt and/or solvate salts.

The sequence of process (II)+(III)→(IV) and (IV)+(V)→(VI) may also be performed by one stage as a 3-component reaction (II)+(III)+(V)→(VI), without isolation of the intermediate stage (IV).

Stage of the process is (II)+(III)→(IV) and (IV)+(V)→(VI) or (II)+(III)+(V)→(VI) generally performed in an inert solvent in the temperature range from +20°C to the boiling point of the solvent at normal pressure.

As the inert solvent suitable for this, for example, alcohols like methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, kalogeropoulou as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane or 1,2-dichloroethane, or other solvents as acetonitrile, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, hexane, benzene, toluene, chlorobenzene, pyridine or glacial acetic acid. It is preferable to carry out the exchange reaction in dichloromethane, toluene, ethanol or isopropanol at reflux temperature and under normal pressure.

The above reaction can optionally be carried out in the presence of acid, a combination of acid/base and/or drying means, such as a molecular sieve. As suitable acids, for example acetic acid, triperoxonane acid, methanesulfonate or p-toluensulfonate; as grounds especially suitable piperidine or pyridine [regarding the synthesis of 1,4-dihydropyridines see also D.M. Stout, A.I.Meyers, Chem. Rev. 1982, 82, 223-243; H.Meier et al., Liebigs Ann. Chem. 1977, 1888; H.Meier et al., ibid. 1977, 1895; H. Meier et al., ibid. 1976, 1762; F.Bossert et al., Angew. Chem. 1981, 93, 755].

Inert solvents for process steps (VI)+(VII)→(X-A), (VI)+(VIII)→(X-a), and (VI)+(XI)→(X-B) are, for example, ethers like diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycolytically or di is telepistemology ether; hydrocarbons like benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions; kalogeropoulou as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, tetrachlorethane, trichloroethylene, chlorobenzene or chlorotoluene; or other solvents as N,N-dimethylformamide (DMF), dimethyl-sulfoxide (DMSO), N,N'-dimethylpropyleneurea (DMPC), N-methylpyrrolidone (NMP), pyridine or acetonitrile. It is also possible to use mixtures of the mentioned solvents. Preferably stage of the process (VI)+(VII)→(X-A) apply tetrahydrofuran or dimethylformamide, in stage (VI)+(VIII)→(X-A) is applied dichloromethane and in stage (VI)+(XI)→(X-C) - pyridine.

Process variant (VI)+(IX)→(X-A) is mainly performed with a significant excess ortogonalnogo ether in dimethylformamide or without the addition of another solvent; as a reaction catalyst is suitable, for example, inorganic acids such as sulfuric acid [see, for example, I.I. Barabanov et al., Russ. Chem. Bl 47(11), 2256-2261 (1998)].

As grounds for stage process (VI)+(VII)→(X-A) is suitable, in particular, carbonates of alkali and alkaline earth metals, such as lithium carbonate, sodium, potassium, calcium or cesium; hydrides of alkali metals as sodium hydride or potassium; amides as lithium, sodium or potassium bis(trimethylsilyl)amide or sitedisability; metalloorganic the e connection as utility or finality and fospassin-base, as, for example, P2-t-Bu or P4-t-Bu [the so-called "base of Slesinger", see R. Schwesinger, H. Schlemper, Angew. Chem. Int. Ed. Engl. 26, 1167 (1987); I. Pietzonka, D. Seebach, Chem. Ber. 124, 1837 (1991)]. Preferably using sodium hydride or fospassin-base P4-t-Bu.

As grounds for stage process (VI)+(XI)→(X-C) is suitable, in particular, carbonates of alkali and alkaline earth metals, such as lithium carbonate, sodium, potassium, calcium or cesium; hydrides of alkali metals as sodium hydride or potassium; ORGANOMETALLIC compounds as utility or finality, or organic amines as triethylamine, N-methylmorpholine, N-methylpiperidine, N,N-diisopropylethylamine, pyridine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,4-diazabicyclo[2.2.2]-octane (DABCO®). Preferably the use of pyridine, which simultaneously serves as the solvent.

Stage of the process (VI)+(VIII)→(X-A) vesalgasse in the General case without addition of base.

The exchange reaction (VI)+(VII)→(X-A), (VI)+(VIII)→(X-a), and (VI)+(XI)→(X-B) are carried out in General at temperatures from -20°C to +100°C, preferably at temperatures from 0°C to +60°C; process variant (VI)+(IX)→(X-A) is, as a rule, at temperatures from +100°C to +150°C. the Reaction may be carried out at normal, elevated or reduced pressure (e.g. from 0.5 d is 5 bar); in General operate at normal pressure.

Cleavage of allyl or 2-cyanoethylene ether stage of the process (X-A) or (X -)→(XII) is well-known methods in the literature. In the case of removal of 2-cyanoethylene ether is preferable to use an aqueous solution of alkali metal hydroxide, such as sodium hydroxide solution or potassium. The reaction is conducted in the General case, using miscible with water inert co-solvent, such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, in the temperature range from 0°C to +40°C. In the case of allyl ether cleavage is carried out using a Wilkinson catalyst [Tris(triphenylphosphine)rhodium(I)chloride] in a mixture of water, alcohol and acetic acid at a temperature from 50°C to +100°C [see, for example, Moseley, J.D., Tetrahedron Lett. 46, 3179-3181 (2005)].

As the inert solvent is suitable, for example, ethers, as simple diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycolytically or diethylethylenediamine ether; kalogeropoulou as dichloromethane, trichloromethane, 1,2-dichloroethane, trichloroethane, tetrachlorethane, chlorobenzene or chlorotoluene, or other solvents, such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N,N'-dimethylpropyleneurea (DMPC), N-methylpyrrolidone (NMH), acetone, acetonitrile or utilize is at. You can also use mixtures of the mentioned solvents. Preferably using tetrahydrofuran, dimethylformamide or ethyl acetate. Typically, the reaction is performed at a temperature from 0°C to +40°C.

For stage process (XIII)→(I) as the inert solvent used, for example, alcohols like methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol; ethers like diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycolytically or diethylethylenediamine ether, or other solvents, such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N,N'-dimethyl-propylenecarbonate (DMPC), N-methylpyrrolidone (NM), acetonitrile or even water. Can also be used in mixtures of these solvents. Preferably the use of tetrahydrofuran or dimethylformamide.

Sources of ammonia for these exchange reactions can be solutions of ammonia gas in one of the above-mentioned solvents, in particular water. The reaction mainly occurs in the presence of a tertiary amine as an auxiliary base, such as triethylamine, N-methylmorpholine, N-methylpiperidine, N,N-diisopropylethylamine or 4-N,N-dimethylaminopyridine. The exchange reaction takes place in General at temperatures from +20°C to +120°C, preferably at temperatures from +50°C up to +100°C./p>

The compounds of formula (II) are commercially available, known from the literature and can be obtained by analogy with the described in the literature (see the following scheme of reactions 1-7). Compounds of formula (III), (VII), (VIII), (IX) and (XI) are commercially available, known from the literature or can be obtained by analogy with the described in the literature methods.

The compounds of formula (V) described in the literature or can be obtained by analogy with the described in the literature methods [see, for example, .Searls, L.W.McLaughlin, Tetrahedron 55, 11985-11996 (1999); D. McNamara, P.D.Cook, J. Med. Chem. 30, 340-347 (1987); S.Nesnow, .Heidelberger, J.Heterocycl. Chem. 12,941-944 (1975); N.C.Hung, E.Bisagni, Synthesis 1984. 765-766; Z.Földi et al., Chem. Ber. 75(7), 755-763 (1942); G.W.Kenner et al., J. Chem. Soc., 388 (1943)].

If necessary, the separation of enantiomers and/or diastereomers can be already at an intermediate stage (VI), (X), (X) or (XII), which can then separately be subject to the following reactions of metabolism.

Obtaining the compounds according to the invention can be illustrated by the following synthesis schemes:

[a): allylbromide, potassium carbonate, cat. potassium iodide, acetone, reflux; (b): 230°C, 4 h; C): bis(benzonitrile)dichloropalladium(II), toluene, 120°C, 16 hours; (d): acetylchloride, sodium hydride, THF, 10-25°C, 16 hours; (e): 1. ozone, dichloromethane, -60°C, 30 minutes; 2. dimethyldisulfide].

[:n-utility, THF, 60°C, 3 hours; ): acetic anhydride, pyridine, reflux, 6 hours; (C): conc. H2SO4, HNO3, 0°C, 1 h; d): N-bromosuccinimide, AIBN, carbon tetrachloride, reflux; e): N-methylmorpholin-N-oxide, acetonitrile, reflux].

[:zinc(II)chloride-dihydrate, ethyl acetate, 70°C; b): 1. sodium nitrite, sulfuric acid, 0°C, 1.5 hours; 2. the copper cyanide(I), sodium cyanide, water/ethyl acetate, 0°C, 45 min; (C): N-bromosuccinimide, AIBN, tetrachloride hydrogen, reflux; (d): N-methylmorpholin-N-oxide, acetonitrile, reflux].

[:anhydride of triftoratsetata, pyridine, 0°C → room temp., 30 min; (b): acrylic acid tert-butyl ether, bis(triphenylphosphine)dichloropalladium(II), DMF, 120°C, 24 h; (C): cat. chetyrehokisi of osmia, cat. benzyltriethylammonium chloride, periodate sodium, THF/water, 20-25°C, 2 hours].

[a): n-utility, THF, -78°C, then N-formylmorpholine; (b): cyanide zinc, tetrakis(triphenylphosphine)palladium(0), DMF, microwave oven 250°C / 5 minutes].

[:N,N-dimethylformamide-dimethylacetal, DMF, 140-180°C; b): periodate sodium, THF/water].

[a): N-bromosuccinimide, ABBN, carbon tetrachloride, reflux; b): N-methylmorpholin-N-oxide, acetonitrile, 3Å molecular sieve].

[:cat. piperidine/acetic acid, dichloromethane, reflux, 24 h; b): from ropanol, reflux, 12-72 hours; (C): alkylacrylate or iodide, base, THF or DMF, room temp.; or triallylisocyanurate, dichloromethane, room temp.; or trialkylaluminium, Katsina acid, 100-130°C; or R11-SO2-Cl, pyridine, room temp.; d): T = 2-cyanoethyl: aqueous solution of NaOH, DME/water, room temp.; T=allyl: (PPh3)3RhCl, water/ethanol/acetic acid, 75°C; e): 1,1'-carbonyldiimidazole, ethyl ester acetic acid, room temp., 12 hours; (f): aqueous ammonia, DMF, 50-100°C, 0.5-12 hours].

Compounds according to the invention act as antagonists mineralcorticoid receptor and demonstrate not expected, a wide range of pharmacological actions. They are suitable for use as pharmaceuticals for the treatment and/or prevention of diseases in humans and animals.

Compounds according to the invention are suitable for the prophylaxis and/or treatment of various diseases and complications, particularly diseases caused either by increasing the concentration of aldosterone in the plasma, either by changing the ratio of the concentrations in plasma aldosterone and renin, or related to these changes in diseases. For example, you can call: idiopathic primary giperaldosteronizm, giperaldosteronizm when adrenal hyperplasia, adenoma and/or carcinoma of the adrenal gland, giperaldosteronizm in heart problems is technote, and (relative) giperaldosteronizm with essential hypertension.

In addition, the compounds according to the invention, due to their mechanism of action, suitable for the prevention of sudden cardiac death in patients at higher risk to die from a broken heart. In particular, this applies to patients suffering from, for example, one of the following diseases: primary and secondary hypertension; heart disease, acute high blood pressure, congestive heart failure, or without it; not curable hypertension; acute and chronic heart failure; coronary heart disease; stable and unstable angina; myocardial ischemia, myocardial infarction, dilated cardiomyopathy; congenital primary cardiomyopathy, such as Brugada syndrome, cardiomyopathy, caused by Chagas disease; shock, arteriosclerosis, atrial and ventricular arrhythmia, transitory and ischemic attacks, bleeding in the brain, inflammatory cardiovascular diseases, peripheral and cardiac vascular disorders of peripheral blood circulation, obliterating endarteritis, as intermittent claudication, asymptomatic left ventricular dysfunction, myocarditis, hypertrophic changes of heart, pulmonary hypertension, spasms of the coronary and peripheral Arte is s, thrombosis, thromboembolic disease, and vasculitis.

Further, the compounds according to the invention can be used for the prevention and/or treatment of the formation of edema, such as, for example, pulmonary edema, renal edema, or swelling caused by congestive heart failure, for the prevention and/or treatment of restenosis, for example, after thrombolytic therapy, percutaneous transluminal angioplasty (MOUTH) and coronary angioplasty (RTSA), heart transplant, and after shunting.

In addition, the compounds according to the invention is suitable for use as conservation potassium diuretic and disorders of electrolyte balance, such as hypercalcemia, hypernatremia or hypokalemia.

Compounds according to the invention is also suitable for the treatment of kidney diseases such as acute and chronic renal failure, kidney disease with hypertension, arteriosclerotic nephritis (chronic and interstitial), nephrosclerosis, chronic renal failure and cystic kidney disease, to prevent kidney damage that can be caused, for example, blockers in the immune response, as cyclosporine And for the transplantation of organs.

In addition, the compounds according to the invention can be used for the prevention and/or treatment of diabetes on the human Abete and diabetes-diseases as, for example, neuropathy and nephropathy.

Further, the compounds according to the invention can be used for the prevention and/or treatment of microalbuminuria, caused, for example, diabetes or hypertension, as well as for the prevention and/or treatment of proteinuria.

Compounds according to the invention is also suitable for the prophylaxis and/or treatment of diseases accompanied either by increasing the concentration of glucocorticoids in plasma or by a local increase in the concentration of glucocorticoids in the tissue (e.g., heart). For example, you can call: functional disorders of the adrenal glands, which lead to hyperproductive glucocorticoids (Cushing's syndrome), tumors of the adrenal cortex with the resulting overproduction of glucocorticoids and pituitary tumors that autonomously produces ACTH (adrenocorticotropic hormone) and this leads to adrenal hyperplasia, followed by Cushing disease.

In addition, the compounds according to the invention can be used for the prevention and/or treatment of obesity, metabolic syndrome and obstructive breathing during sleep.

Further, the compounds according to the invention can be used for the prevention and/or treatment of inflammatory diseases, caused for example by viruses, spirochaetes, fungi, bacteria or mycobacteria is, as well as inflammatory diseases of unknown etiology such as arthritis, systemic lupus erythematosus, peri - and polyarteritis, tinea corporis, scleroderma and sarcoidosis.

Further, the compounds according to the invention can be used for the treatment of Central nervous system diseases, like depression, the attacks of causeless fear and chronic pain, particularly migraine, as well as neurodegenerative diseases like Alzheimer's and Parkinson's disease.

Compounds according to the invention is also suitable for the prophylaxis and/or treatment of vascular lesions, for example, after such interventions, as percutaneous transluminal coronary angioplasty (RTSA), stent implantation, coronary angioscopy, occlusion or restenosis after bypass surgery and endothelial dysfunction, disease, Raynaud's disease, obliterative obliterans syndrome (Burger) and syndrome of ear noise.

The next subject of the present invention is the use of compounds according to the invention for the treatment and/or prevention of diseases, in particular the aforementioned diseases.

The next subject of the present invention is the use of compounds according to the invention for the preparation of drugs for the treatment and/or prevention of diseases, in particular the aforementioned diseases.

Mark is the missing subject of the present invention is a method of treatment and/or prevention of diseases, in particular the aforementioned diseases, using the current number of at least one of the compounds according to the invention.

Compounds according to the invention can be used alone or optionally in combination with other biologically active substances. The next subject of the present invention are drugs, containing at least one of the compounds according to the invention and one or more other biologically active substances, in particular for the treatment and/or prophylaxis of the abovementioned diseases. Suitable for combining the biologically active substances can be named, for example and preferably, the following:

- biologically active substances, lowering blood pressure, for example and preferably from the group of calcium antagonists, antagonists of angiotensin AII, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha blockers-receptorow and inhibitors of beta-receptors;

- diuretics, especially loop diuretics and thiazides and other diuretics;

- antithrombotic agents, for example and preferably from the group of platelet aggregation inhibitors, of anticoagulants or profibrinolytic substances;

- biologically active substances that alter fat metabolism, e.g. the measures and mainly from the group of agonists of the thyroid receptor, inhibitors of cholesterol synthesis, as, for example and preferably, inhibitors of the synthesis G-COA reductase or squalene, ACAT inhibitors, inhibitors SETR, MTP inhibitors, agonists of PPAR-alpha, PPAR-gamma and/or PPAR-Delta receptors, inhibitors of cholesterol absorption, lipase inhibitors, polymeric bile acid adsorbents, inhibitors of bile acid reabsorption and antagonists of lipoprotein(a);

organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide Mononitrate, isosorbide dinitrate treatment, molsidomine or SIN-1, and inhalational NO;

- positively acting inotropic compounds, as, for example, cardiac glycoside (digoxin), beta-adrenergic and dopaminergic agonists, as isoproterenol, adrenaline, noradrenaline, dopamine and dobutamine;

- compounds that inhibit the breakdown of cyclic guanosine monophosphate (cGMP) and/or cyclic adenosine monophosphate (camp), such as inhibitors fosfodiesterasa (PDE) 1, 2, 3, 4 and/or 5, in particular inhibitors of PDE-5 as sildenafil, vardenafil and tadalafil, as well as inhibitors of PDE-3, as amrinone, milrinone;

- natriuretic peptides, such as "trially natriuretic peptide" (ANP, anaritide), "natriuretic peptide In-or-type natriuretic patalganga brain (BNP, nesiritide), "natriuretic peptide C-type (CNP), as well as urodilatin;

- sensibilizatora calcium, as for example and preferably, " levosimendan";

- NO-independent but heme-dependent stimulators of guanylate cyclase, such as compounds described in particular in patents WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;

- NO - and heme-independent activators of guanylate cyclase, such as compounds described in particular in patents WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510;

inhibitors of human neutrophil elastase (CNA), as, for example, sivelestat or DX-890 (deltran);

connection, inhibiting transduction cascades of signals, as, for example, tyrosine kinase inhibitors, in particular sorafenib, imatinib, gefitinib and erlotinib; and/or

connections influencing the energy metabolism of the heart, as for example and preferably, etomoxir, dichloroacetate, ranolazine or Trimetazidine.

In a preferred form of execution of the invention compounds according to the invention are released in combination with any diuretic, as for example and preferably, furosemid, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, dichlorphenamide, methazolamide, glycerin, isosorbide, mannitol, amiloride or three is stern.

Under tools, lower blood pressure, refers mainly compounds from the group of calcium antagonists, antagonists of angiotensin AII, inhibitors of the enzyme ACE, endothelin antagonists, renin inhibitors, blockers, alpha-receptor blockers, beta-receptor, inhibitors of Rho-kinase, as well as diuretics.

In a preferred form of execution of the invention compounds according to the invention are used in combination with any calcium antagonist, such as, for example and preferably, nifedipine, amlodipine, verapamil or diltiazem.

In a preferred form of execution of the invention compounds according to the invention are used in combination with any antagonist of angiotensin AII, as for example and preferably, losartan, candesartan, valsartan, telmisartan or ambulanten.

In a preferred form of execution of the invention compounds according to the invention are used in combination with any ACE inhibitor, as for example and preferably, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinapril, perindopril or trancopal.

In a preferred form of execution of the invention compounds according to the invention are used in combination with any antagonist of endothelin, as for example and preferably, bosentan, darusentan, ambrisentan or sitaxsentan.

In a preferred form of execution of the invention compounds according to the invention are used in combination with any renin inhibitor, such as, for example and preferably, aliskiren, SPP-600, SPP-635, SPP-676, SPP-800 or SPP-1148.

In a preferred form of execution of the invention compounds according to the invention are used in combination with any inhibitor alpha receptors, as for example and preferably, prazosin.

In a preferred form of execution of the invention compounds according to the invention are used in combination with any blocker beta-receptors, as for example and preferably, propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazolol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, daprela, landiolol, nebivolol, epanolol or bucindolol.

In a preferred form of execution of the invention compounds according to the invention are used in combination with any inhibitor of Rho-kinase, as for example and preferably, fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or VA-1049.

Under antithrombotic controls include preimuschestvenno compounds from the group of platelet aggregation inhibitors, of anticoagulants or profibrinolytic the substantive is.

In a preferred form of execution of the invention compounds according to the invention are used in combination with any inhibitor of platelet aggregation, as for example and preferably, aspirin, clopidogrel, ticlopidine or dipyridamole.

In a preferred form of execution of the invention compounds according to the invention are used in combination with any inhibitor of thrombin, as for example and preferably, ximelagatran, melagatran, bivalirudin or therapy.

In a preferred form of execution of the invention compounds according to the invention are used in combination with any of the GPIIb/IIIa antagonist, such as, for example and preferably, tirofiban or abciximab.

In a preferred form of execution of the invention compounds according to the invention are used in combination with any inhibitor of factor XA, as for example and preferably, rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fedexcan, razaxaban, fondaparinux, edupreneurs, PMD-3112, YM-150, F-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

In a preferred form of execution of the invention compounds according to the invention are used in combination with heparin or a derivative of heparin with low molecular weight (LMW).

In a preferred form of execution of the invention compounds according to the invention primenews is in combination with any antagonist of vitamin K, as for example and preferably, coumarin.

Under tools, altering fat metabolism, refers mainly compounds from the group of inhibitors SETR, agonists thyroid receptors, inhibitors of cholesterol synthesis, as inhibitors of HMG-CoA reductase inhibitor or synthesis of squalene, ACAT inhibitors, MTP inhibitors, agonists of PPAR-alpha, PPAR-gamma and/or PPAR-Delta receptors, inhibitors of cholesterol absorption, polymeric adsorbents, bile acid reabsorption inhibitors of bile acid, lipase inhibitors and antagonists of lipoprotein(a).

In a preferred form of execution of the invention compounds according to the invention are used in combination with any inhibitor SETR, as for example and preferably, torcetrapib (SR-529 414), JJT-705, BAY 60-5521, BAY 78-7499 or SETR vaccine (avant).

In a preferred form of execution of the invention compounds according to the invention are used in combination with any agonist thyroid receptors, as for example and preferably, D-thyroxine, 3,5,3'-thiiodothyronine (T3), CGS 23425 or axiotron (CGS 26214).

In a preferred form of execution of the invention compounds according to the invention are used in combination with any inhibitor of HMG-CoA reductase inhibitor from the class of statins, such as, for example and preferably, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosow is a statin, the tseriwastatina or pitavastatin.

In a preferred form of execution of the invention compounds according to the invention are used in combination with any inhibitor of the synthesis of squalene, as for example and preferably, BMS-188494 or SO-475.

In a preferred form of execution of the invention compounds according to the invention are used in combination with any ACAT inhibitor, such as, for example and preferably, avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.

In a preferred form of execution of the invention compounds according to the invention are used in combination with any MTP inhibitor, such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.

In a preferred form of execution of the invention compounds according to the invention are used in combination with any agonist of PPAR-gamma receptors, as for example and preferably, pioglitazone or rosiglitazone.

In a preferred form of execution of the invention compounds according to the invention are used in combination with any agonist of PPAR-Delta receptors, as for example and preferably, GW-501516 or BAY 68-5042.

In a preferred form of execution of the invention compounds according to the invention are used in combination with any inhibitor of cholesterol absorption, such as, for example and preferably, ezetimibe, tiqueside Il is plaquenil.

In a preferred form of execution of the invention compounds according to the invention are used in combination with any lipase inhibitor, such as, for example and preferably, orlistat.

In a preferred form of execution of the invention compounds according to the invention are used in combination with any polymeric bile acid adsorbent, such as, for example and preferably, cholestyramine, colestipol, kresolver, cholesta-gel or colestimide.

In a preferred form of execution of the invention compounds according to the invention are used in combination with any inhibitor reabsorption of bile acids, as for example and preferably, inhibitors ASBT (=IBAT), as AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

In a preferred form of execution of the invention compounds according to the invention are used in combination with any antagonist of lipoprotein (a), as for example and preferably, gemcabene calcium (CI-1027 or nicotinic acid.

As the subject of this invention are drugs that contain at least one compound according to the invention, usually together with one or more inert, non-toxic, acceptable pharmaceutical auxiliary substances, and their use for the aforementioned purposes.

Compounds according to the invention m is able to act systematically and/or locally. For this purpose they can be received in a suitable way, for example, orally, parenterally, pulmonale, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, through the ears or as implant or stent.

For these ways of accepting compounds according to the invention can be supplied in suitable forms.

For oral administration suitable existing applications, giving fast and/or in a modified form of the compounds according to the invention that the compounds according to the invention contain crystalline and/or amorphous and/or dissolved form, as for example, tablets (uncoated or coated, for example, resistant to gastric juice or dissolve with a delay or insoluble membranes that control the release of the compounds according to the invention), quickly disintegrating in the mouth tablets or wafers in the film, lyophilizate in the film, capsules (for example hard or soft gelatin capsules), pills, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral use may occur without stage suction (e.g., intravenous, intraarterial, intracardiac, intraspinal or intraluminally introduction) or activate the suction process (e.g., intramuscular, on the skin, intracutaneous, percutaneous or intraperitoneal administration). For parenteral admission as forms of acceptable drugs for injection and infusion in the form of solutions, suspensions, emulsions, or sterile lyophilized powder.

For other ways of accepting suitable, for example, pharmaceutical forms for inhalation (including powder inhalers, nebulizers), drops, solutions or sprays in the nose, taken on the tongue, under the tongue or transbukkalno tablets, wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, mash), fat-soluble suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), milk, pastes, foams, powders, implants or stents.

Preferred oral or parenteral intake, particularly oral and intravenous methods.

Compounds according to the invention can be translated in the form of application. It can be well-known manufacturer manner by mixing with inert, non-toxic acceptable in Farmaceutica auxiliary substances. Such excipients are, in particular, fillers (for example, microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycol), emulsifiers and dispersants or wetting is the means (for example, sodium dodecyl sulphate, polychiorinated), connecting means (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g. antioxidants like ascorbic acid), colorants (e.g. inorganic pigments such as iron oxide) and substances that improve the taste and smell of medicines.

In the General case of parenteral application to achieve the most effective results, it was useful to release medicine weight of 0.001-1 mg/kg, mainly of 0.01-0.5 mg/kg of body weight. For oral use dose is 0.01-100 mg/kg, mainly of 0.01-20 mg/kg and particularly preferably 0.1 to 10 mg/kg of body weight.

But in some cases, possible deviations from these quantities, namely the dosage may vary depending on body weight, route of administration, individual tolerance, Biologicheskie active substance, preparation method and time of reception intervals. Thus, in some cases it may be sufficient dose is less than the mentioned minimum amount, while in other cases must be exceeded mentioned upper limit. If the reception is more recommended to divide the medication into several doses for admission during the day.

The following application examples explain the invention. The invention is not limited to the example of the mi.

The above percentage the following tests and examples are mass percent, part - mass proportions, if no other value is specified. The ratio of solvents, thinners and data solution concentration of the two liquids, respectively, belong to the volume.

A. Examples

Abbreviations and abbreviation:
abs.absolute
AIBN2,2'-azobis-2-methylpropionitrile
cat.catalytic
CIchemical ionization (in MS)
dday (days)
DCthin-layer chromatography
DME1,2-dimethoxyethan
DMFdimethylformamide
DMSOthe sulfoxide
theory. prob. theory (yield)
itexcess enantiomers
EIionization by electron impact (MS)
entenantiomer / pure enantiomers from
eqequivalent (equivalent)
ESIthe spray ionization in the electric field (in MS)
GC-MSthe combination of gas chromatography with mass spectroscopy
wt.%mass percentage
hourhour (time)
HPLCliquid chromatography high pressure
high-performance liquid chromatography
conc.concentrated
LC-MSthe combination of the Jew is ostroy chromatography with mass spectroscopy
minminute (min)
MPLCliquid chromatography medium pressure
MSmass spectroscopy
NMRspectroscopy nuclear magnetic resonance
Phphenyl
Rfthe retention index (DC)
Rtthe retention time (in HPLC)
CTroom temperature
THFtetrahydrofuran
v/vthe ratio of volume to volume (solution)
waves.water, water solution

LC-MS and GC-MS methods:

Metol 1 (LC-MS):

Instrument type MS: Micromass ZQ; instrument type HPLC: Waters Alliance 2795; column: Phenomcnex Synergi 2 MK Hydro-RP Mercury 20 mm×4 mm; eluent A: 1 l water + 0.5 ml 50%formic acid, eluent B: 1 l Aceto is itril + 0.5 ml 50%formic acid; gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; flow: 0.0 min 1 ml/min → 2.5 min/3.0 min/4.5 min 2 ml/min; oven: 50°C; UV-indication: 210 nm.

Method 2 (LC-MS):

Instrument: Micromass Quattro LCZ with HPLC Agilent series 1100; column:

Phenomenex Synergi 2µ Hydro-RP Mercury 20 mm × 4 mm; eluent A: 1 l water + 0.5 ml 50%formic acid, eluent B: 1 l of acetonitrile + 0.5 ml 50%formic acid; gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A→4.5 min 5% A; flow: 0.0 min 1 ml/min → 2.5 min/3.0 min/4.5 min 2 ml/min; oven: 50°C.; UV-display: 208-400 nm.

Method 3 (LC-MS):

Instrument type MS: Micromass ZQ; instrument type HPLC: HP 1100 Series; UV DAD; column: Phenomenex Gemini 3 MK 30 mm × 3.00 mm; eluent A: 1 l water + 0.5 ml 50%formic acid, eluent B: 1 l of acetonitrile +0.5 ml 50%formic acid; gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; flow: 0.0 min 1 ml/min → 2.5 min/3.0 min/4.5 min 2 ml/min; oven: 50°C; UV-indication: 210 nm.

Method 4 (LC-MS):

Instrument: Micromass Platform LCZ with HPLC Agilent series 1100; column: Thermo Hypersil GOLD 3 MK 20 mm × 4 mm; eluent A: 1 l water +0.5 ml 50%formic acid, eluent B: 1 l of acetonitrile + 0.5 ml 50%formic acid; gradient: 0.0 min 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 5.5 min 10% A; oven: 50°C.; flow: 0.8 ml/min; UV-indication: 210 nm.

Method 5 (GC-MS):

Instrument: Micromass GCT, GC 6890; column: Restek RTX-35MS, 30 m × 250 μm × 0.25 μm; constant flow with helium: 0.88 ml/min; oven: 60°C.; inlet: 250°C.; gradient: 60°C (0.30 minutes in the hold), 50°C/min → 120°C, 16°C/min → 250°C, 30°C/min → 300°C (1.7 minutes to stand).

Metol 6 (LC-MS):

Instrument type MS: Waters ZQ; instrument type HPLC: Waters Alliance 2795; column: Phenomenex Onyx Monolithic C18, 100 mm × 3 mm; eluent A: 1 l water + 0.5 ml 50%formic acid, eluent B: 1 l of acetonitrile + 0.5 ml 50%formic acid; gradient: 0.0 min 90% A → 2 min 65% A → 4.5 min 5% A → 6 min 5% A; flow: 2 ml/min; oven: 40°C.; UV-indication: 210 nm.

Method 7 (LC-MS):

Instrument: Micromass Quattro LCZ with HPLC Agilent series 1100; column: Phenomenex Onyx Monolithic C18, 100 mm × 3 mm; eluent A: 1 l water + 0.5 ml 50%formic acid, eluent B: 1 l of acetonitrile + 0.5 ml 50%formic acid; gradient: 0.0 min 90% A → 2 min 65% A → 4.5 min 5% A → 6 min 5% A; flow: 2 ml/min; oven: 40°C.; UV-indication: 208-400 nm.

Method 8 (LC-MS):

Instrument type MS: Micromass ZQ; instrument type HPLC: Waters Alliance 2795; column: Phenomenex Synergi 2.5 MK MAX-RP 100A Mercury 20 mm × 4 mm; eluent A: 1 l water + 0.5 ml 50%formic acid, eluent B: 1 l of acetonitrile +0.5 ml 50%formic acid; gradient: 0.0 min 90% A → 0.1 min 90% A → 3.0 min 5% A → 4.0 min 5% A → 4.01 min 90% A; flow: 2 ml/min; oven: 50°C; UV-indication: 210 nm.

Method 9 (LC-MS):

Instrument: Micromass Quattro Premier with Waters UPLC Acquity; column: Thermo Hypersil GOLD 1.9 MK 50 mm × 1 mm; eluent A: 1 l water +0.5 ml 50%formic acid, eluent B: 1 l of acetonitrile + 0.5 ml 50%formic acid; gradient: 0.0 min 90% A → 0.1 min 90% A → 1.5 min 10% A → 2.2 min 10% A; flow: 0.33 ml/min; oven: 50°C; UV-display: 10 nm.

The source and intermediate connections:

Example 1A

1-[2-(Allyloxy)phenyl]alanon

542 g (3.9 mol) of 2-hydroxyacetophenone with 592 g (4.9 mol) of allylbromide, 1000 g (7.2 mol) of potassium carbonate and 13.2 g (79 mmol) of potassium iodide in 2.4 liters of acetone is slowly heated for 24 hours to reflux. After cooling to room temperature the mixture is filtered and the solvent removed in vacuum. The residue is dissolved in toluene and washed with 10%sodium hydroxide solution and water. After thickening is obtained 689 g (98% of theory. prob.) extracted in the connection header.

1H-NMR (300 MHz, CDCl3): δ=2.68 (s, 3H), 4.68 (dd, 2H), 5.89 (dd, 2H), 6.09 (m, 1H), 6.99 (dd, 2H), 7.44 (m, 1H), 7.71 (d, 1H).

Example 2A

1-(3-Allyl-2-hydroxyphenyl)alanon

160 g 0.9 mol) of 1-[2-(allyloxy)phenyl]ethanone mixed in a metal bath at 230-240°C for 4 hours. After cooling to room temperature the product is distilled in a film evaporator apparatus at 140°C and 0.4 bars. It turns out 155 g (97% of theory. prob.) extracted in the connection header.

1H-NMR (300 MHz, CDCl3): δ=2.68 (s, 3H), 3.44 (d, 2H), 5.09 (m, 2H), 6.01 (m, 1H), 6.85 (t, 1H), 7.38 (dd, 1H), 7.62 (dd, 1H), 12.61 (s, 1H).

Example 3A

1-{2-Hydroxy-3-[(1E)-prop-1-EN-1-yl]phenyl}alanon

40 g (227 mmol) of 1-(3-allyl-2-hydroxyphenyl)ethanone dissolved in 120 ml of toluene and mesivta with 2.17 g (5.6 mmol) of bis(benzonitrile)dichloropalladium(II). The reaction mixture during the night is heated to 120°C. After cooling to room temperature the mixture is filtered through diatomaceous earth and the solvent removed in vacuum. It turns out 20.9 g (95% of theory. prob.) extracted in the title compound, which is used in the next stage without additional purification.

LC-MS (method 1): Rt=2.36 min; [M+H]+=177

1H-NMR (300 MHz, CDCl3): δ=1.91 (dd, 3H), 2.63 (s, 3H), 6.32 (m, 1H), 6.73 (dd, 1H), 6.85 (t, 1H), 7.59 (m, 2H), 12.74 (s, 1H).

Example 4A

2-Methyl-8-[(1E)-prop-1-EN-1-yl]-4H-chromen-4-one

12.52 g (313.2 mmol) of 60%sodium hydride (suspension in mineral oil) in an argon atmosphere at 10°diluted With 300 ml of absolute THF. To a suspension drops slowly added 18.4 g (104.4 mmol) 1-{2-hydroxy-3-[(1E)-prop-1-EN-1-yl]phenyl}of ethanone. After 15 minutes added 9 g (114.9 mmol) acetylchloride. The reaction mixture is stirred over night at room temperature. The mixture is hydrolyzed with 300 ml of water and extracted several times using ethyl acetate. The organic phase after washing with saturated sodium chloride solution, dried over sodium sulfate. Then the solvent is removed in vacuum. The residue is diluted in 200 ml of methanol and, together with 50 ml of 20%hydrochloric acid for 30 minutes, heated to 80°C. then the solvent is removed in vacuum and the residue is diluted with whom I 400 ml of water. Several times extracted with dichloromethane. After drying the organic phase over magnesium sulfate the solvent is removed in vacuum and the residue is purified by column chromatography (solvent: dichloromethane/methanol 98:2). Obtained 10.5 g (50.2% of theory. prob.) output the title compound as a yellow oil.

LC-MS (method 2): Rt=2.07 min; [M+H]+=201

1H-NMR (300 MHz, CDCl3): δ=1.98 (dd, 3H), 2.43 (s, 3H), 6.18 (s, 1H), 6.40 (m, 1H), 6.85 (dd, 1H), 7.31 (t, 1H), 7.72 (dd, 1H), 8.05 (dd, 1H).

Example 5A

2-Methyl-4-oxo-4H-chromen-8-carbaldehyde

18.5 g (62.8 mmol) of 2-methyl-8-[(1E)-prop-1-EN-1-yl]-4H-chromen-4-she dissolved in 400 ml dichloromethane and cooled to -60°C. In the reaction mixture for 30 minutes is injected ozone. Then the reaction mixture is diluted with dimethyl sulfide. After heating to room temperature the solvent is removed in vacuum and the residue vspuchivaetsja with a small amount of methanol. After filtration, the remaining solid from diethyl ether precrystallization. Obtained 9.1 g (77.4% of theory. prob.) extracted in the connection header.

LC-MS (method 1): Rt=1.31 min; [M+H]+=189

1H-NMR (300 MHz, CDCl3): δ=2.48 (s, 3H), 6.27 (s, 1H), 7.51 (m, 1H), 8.21 (dd, 1H), 8.46 (dd, 1H), 10.67 (s, 1H).

Example 6A

4-Bromo-2-(triptoreline)benzaldehyd

20.00 g (54.51 mm is l) 4-bromo-2-(triptoreline)yogashala dissolved in 200 ml TTF and the solution is cooled to -78°C. Then drops added 26.16 ml (65.41 mmol) of a 2.5 M solution of n-utility in hexane. The mix get in for 30 minutes and then mix 14.43 g (125.37 mmol) N-formylmorpholine. Once fixed weight conversion (DC control), isopropanol at -78°C cleaved ions of the solvent. After heating to room temperature the mixture is diluted with water and extracted twice with dichloromethane. The combined organic phases are washed with a saturated solution of sodium chloride, dried sulfate Natia and the solvent Argonauts under reduced pressure. The residue is purified by column chromatography (silica gel, solvent: cyclohexane/ethyl ester acetic acid 5:1). It turns out 11.43 g (78% of theory. prob.) extracted in the connection header.

GC-MS (method 5): Rt=4.24 min; MS (EIpos): m/z=270 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=7.85-7.92 (m, 3H), 10.20 (s, 1H).

Example 7A

4-Formyl-3-(triptoreline)benzonitrile

10.63 g (39.51 mmol) 4-bromo-2-(triptoreline)benzaldehyde, 3.43 g (29.24 mmol) cyanide zinc and 1.37 g (1.19 mmol) of tetrakis(triphenylphosphine)palladium(0) are dissolved in 80 ml of dimethylformamide. Then the reaction mixture in several portions converted by the microwaves in the single-mode regime (Emrys Optimizer, 5 minutes at 220°C). United precipitation is diluted with water and twice ek is traceroute with toluene. The combined organic phases are washed with a saturated solution of sodium chloride, dried with sodium sulfate, then the solvent is removed in a rotary evaporator apparatus. The residue is purified by column chromatography (silica gel, solvent: cyclohexane/ethyl ester acetic acid 10:1). Get 3.32 g (78% of theory. prob.) extracted in the title compound with a purity of 80% (according to LC-MS).

MS (EIpos): m/z=215 [M]+

1H-NMR (300 MHz, DMSO-d6): δ=7.85-7.91 (m, 3H), 10.20 (s, 1H).

Example 8A

4-Cyano-2-methoxyphenyl-triftorbyenzola

To a solution of 20 g (134 mmol) of 4-hydroxy-3-methoxybenzonitrile in pyridine (80 ml) slowly messing with 24 ml (141 mmol) of triftoratsetata anhydride, and the reaction temperature is maintained using an ice bath to below 25°C. Then the suspension is stirred for 1 hour at room temperature. Added ice water (400 ml) and stirring the suspension continues until it reaches room temperature. Then filtered, the solid is dissolved in ethyl acetate and the solution washed with a saturated solution of sodium chloride. The organic phase is dried over magnesium sulfate and condensed. It turns out 37.13 g (92% of theory. prob.) extracted in the title compound in the form of a solid white color.

LC-MS (method 3): Rt=2.54 is in; MS (EIpos): m/z=282 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=3.97 (s, 3H), 7.60 (dd, 1H), 7.71 (d, 1H), 7.92 (d, 1H).

Example 9A

tert-Butyl(2E)-3-(4-cyano-2-methoxyphenyl)acrylate

To a degassed solution of 37.13 g (132 mmol) of 4-cyano-2-methoxyphenyl-triftoratsetata, 35 ml (245 mmol) of tert-butyl acrylate and 90 ml (645 mmol) of triethylamine in dimethylformamide (250 ml) are added 4 g (5.7 mmol) chloride bis(triphenylphosphine)palladium(II). The solution is stirred for 24 hours at 100°C. in a protective gas atmosphere. Then added ice water (1000 ml) and the suspension extracted with ethyl acetate (3 times 100 ml). The organic phase is washed with a saturated solution of sodium chloride, dried over magnesium sulfate and condensed. The residue is purified column chromatography (silica gel, solvent: cyclohexane/ethyl ester acetic acid 10:1). It turns out 24.6 g (72% of theory. prob.) extracted in the title compound in the form of a solid white color.

LC-MS (method 1): Rt=2.59 min; MS (EIpos): m/z=260 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=1.48 (s, 9H), 3.93 (s, 3H), 6.65 (d, 1H), 7.42 (d, 1H), 7.58 (s, 1H), 7.74 (d, 1H), 7.89 (d, 1H).

Example 10A

4-Formyl-3-methoxybenzonitrile

To intensively mixed solution of 48 g (185 mmol) of tert-butyl(2E)-3-(4-cyano-2-methoxyphenyl)acrylate, 207 mg (0.81 mmol) of chetyrehokisi OS the Oia and 1.4 g (6.14 mmol) of the chloride of benzyltriethylammonium in 750 ml of water/TF (2:1) portions are added 79 g (370 mmol) of metaperiodate sodium, moreover, the reaction temperature is maintained below 30°C. the Solution is stirred for another 1 hour at room temperature. Added water (2000 ml), after which the mixture is filtered. The remaining solid is dissolved in ethyl acetate and the solution washed with a saturated solution of sodium chloride. The organic phase is dried over magnesium sulfate and condensed. The residue is mixed with petroleum ether. It turns out 21.18 g (71% of theory. prob.) extracted in the title compound in the form of a solid white color.

LC-MS (method 3): Rt=1.87 min; MS (EIpos): m/z=162 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=3.98 (s, 3H), 7.53 (d, 1H), 7.80 (s, 1H), 7.81 (d, 1H), 10.37 (s, 1H).

Example 11A

4-Formyl-3-hydroxybenzonitrile

To a solution of 8 g (49.64 mmol) of 4-formyl-3-methoxybenzonitrile in 80 ml of anhydrous dichloromethane in an argon atmosphere at -78°messing With 100 ml of tribromide boron in dichloromethane (1 M, 100 mmol). The reaction mixture was stirred at room temperature until complete conversion of the product (about 5 days). Then the reaction solution is neutralized at 0°C with saturated solution of sodium bicarbonate. The phases are separated, and the organic phase is washed with a saturated solution of sodium chloride, dried over magnesium sulfate and condensed. The residue is purified by column chromatography on forces is the Kagel (solvent: cyclohexane/ethyl acetate 3:1). Obtained 4.5 g (61% of theory. prob.) extracted in the title compound in a solid yellow color.

LC-MS (method 1): Rt=1.38 min; [M-H]-=146

1H-NMR (300 MHz, CDCl3): δ=7.38 (d, 1H), 7.38 (s, 1H), 7.77 (d, 1H), 10.33 (s, 1H), 11.38 (s, 1H).

Example 12A

5-Cyano-2-formylphenyl-triftorbyenzola

To a solution of 2 g (13.59 mmol) of 4-formyl-3-hydroxybenzonitrile and 2.5 ml (14.27 mmol) of N,N-diisopropylethylamine in 37 ml of anhydrous dichloromethane in an argon atmosphere at 0°C drops are added 2.4 ml (14.27 mmol) of anhydride of triftoratsetata. The reaction mixture was stirred 1 hour at room temperature, then diluted with dichloromethane (70 ml) and sequentially washed with 1 M hydrochloric acid, a saturated solution of hydrogencarbonate sodium and saturated solution of sodium chloride. The organic solution is dried over magnesium sulfate and condensed. The residue is purified by column chromatography on silica gel (solvent: cyclohexane/ethyl acetate 7:1). It turns out 2.36 g (62% of theory. prob.) extracted in the title compound in the form of a solid white color.

LC-MS (method 3):Rt=2.34 min; [M+H]+=280

1H-NMR (300 MHz, CDCl3): δ=8.27 (m, 2H), 8.33 (s, 1H), 10.13 (s, 1H).

Example 13A

4-Formyl-3-vinylbenzoate

To a solution of 1 g (3.58 mmol) 5-is IANA-2-formylphenyl-triftoratsetata and 1.15 ml (3.94 mmol) of tri-n-butylaniline in 6 ml of anhydrous and degassed DMF (dimethylformamide) in an argon atmosphere is added 125 mg (0.18 mmol) chloride bis(triphenylphosphine)palladium(II). Then the reaction mixture was stirred for 90 minutes at 80°C. then added 100 ml of 10%aqueous solution of potassium fluoride and the mixture is stirred for 1 hour at room temperature. The suspension is extracted three times with ethyl acetate (20 ml) and purified organic phases are successively washed with a saturated solution of hydrogencarbonate sodium and saturated solution of sodium chloride. The organic solution is dried over magnesium sulfate and condensed. The residue (0.6 g) used without additional purification in the next stage.

GC-MS (method 5):Rt=5.02 min; [M]+=157

1H-NMR (300 MHz, CDCl3): δ=5.62 (d, 1H), 6.05 (d, 1H), 7.58 (dd, 1H), 7.95 (d, 1H), 8.00 (d, 1H), 8.24 (s, 1H), 10.32 (s, 1H).

Example 14A

3-Ethyl-4-formylbenzoate

A solution of 1.3 g (8.27 mmol) of 4-formyl-3-vinylbenzoate in 35 ml of ethanol is mixed with 880 mg of 10%palladium on coal and within 2 hours intensively stirred in hydrogen atmosphere. The suspension is filtered through a layer of silica gel, the precipitate is washed with ethanol and the filtrate is condensed. The precipitate (890 mg) is used in the next stage without additional purification.

1H-NMR (300 MHz, CDCl3,): δ=1.2 (t, 1H), 3.07 (q, 2H), 7.88 (d, 1H), 7.90 (s, 1H), 7.97 (d, 1H), 10.32 (s, 1H).

Example 15A

Methyl 4-cyano-2-perbenzoate

13.20 g (79.9 mmol) 4-cyano-2-fermenting acid rest rauda in 300 ml of acetone. Then added 22.10 g (159.9 mmol) of potassium carbonate and 9.08 ml (95.9 mmol) of dimethylsulfate. The mixture is stirred for 20 hours at reflux temperature. After that the reaction mixture is diluted with 300 ml of water and the acetone is removed by rotary evaporation apparatus. Several times extracted with dichloromethane. The combined organic phases are washed with a saturated solution of sodium chloride and dried over sodium sulfate. Then the solvent is removed in vacuum. The remaining solid is used further without additional purification. It turns out 16.1 g (84% of theory. prob.) output the title compound as a colourless solid.

GC-MS (method 5): Rt=6.23 min; [M]+(EIpos): m/z=179

1H-NMR (300 MHz, DMSO-d6): δ=3.90 (s, 3H), 7.83 (dd, 1H), 8.01-8.08 (m, 2H).

Example 16A

3-Fluoro-4-(hydroxymethyl)benzonitrile

16.10 g (89.9 mmol) of methyl 4-cyano-2-perbenzoate dissolved in 150 ml of methanol. Then portions is added 3.40 g (89.9 mmol) of sodium borohydride. After completion of the exchange reaction (DC control) pH is brought diluted hydrochloric acid to 3 and the mixture is extracted several times with dichloromethane. The combined organic phases are washed with a saturated solution of sodium chloride and dried with magnesium sulfate. Then the solvent adalee is camping in a vacuum, and the residue is purified by column chromatography (silica gel, solvent: cyclohexane/ethyl acetate 15:1→3:7). It turns out 3.70 g (27.2% of theory. prob.) extracted in the connection header.

GC-MS (method 5): Rt=6.51 min; [M]+(EIpos): m/z=151

1H-NMR (300 MHz, DMSO-d6): δ=4.61 (s, 2H), 5.53 (s, 1H), 7.61-7.74 (m, 2H), 7.79 (dd, 1H).

Example 17A

3-Fluoro-4-formylbenzoate

1.00 g (6.62 mmol) of 3-fluoro-4-(hydroxymethyl)benzonitrile dissolved in 50 ml dichloromethane and mixed with 9.20 g (105.9 mmol) oxide manganese(IV). The mixture was stirred over night at room temperature and then filtered through a layer of diatomaceous earth. The solvent Argonauts under reduced pressure, and the residue is purified by column chromatography (silica gel, solvent: dichloromethane). Obtained 120 mg (12.1% of theory. prob.) extracted in the connection header.

GC-MS (method 5): Rt=5.11 min; [M]+(EIpos): m/z=149

1H-NMR (300 MHz, DMSO-d6): δ=7.89 (d, 1H), 8.00 (t, 1H), 8.11 (d, 1H), 10.24 (d, 1H).

Example 18A

3-Chloro-4-formylbenzoate

25.0 g (164.91 mmol) 3-chloro-4-methylbenzonitrile dissolved in 150 ml of dimethylformamide and mixed with 25.55 g (214.39 mmol) of N,N-dimethylformamide-dimethylacetal. A mixture of the way first 20 hours at 140°C, and then 4 hours at an oil bath temperature of 180°C. the Volatile components of the Department who are on a rotary evaporation apparatus, and the remaining precipitate immediately undergo exchange reactions.

Thus obtained crude 3-chloro-4-[2-(dimethylamino)vinyl]benzonitrile introduced in 500 ml THF/water (1:1) and mixed with 77.6 g (362.9 mmol) periodate sodium. The mixture mixes 18 hours at room temperature and then precipitated precipitate is separated by filtration. The filtrate is diluted with a saturated solution of sodium hydrogencarbonate and extracted three times with ethyl acetate. The combined organic phases are dried with sodium sulfate and the solvent is removed in a rotary evaporator apparatus. The original product is purified by column chromatography (silica gel, solvent: cyclohexane/ethyl acetate 7:3). Obtained 3.0 g (15% of theory. prob.) extracted in the connection header.

GC-MS (method 5): Rt=6.64 min; [M]+(EIpos): m/z=165

1H-NMR (300 MHz, DMSO-d6): δ=7.97-8.03 (m, 2H), 8.27 (s, 1H), 10.34 (d, 1H).

Example 19A

4-Formyl-1-naphthonitrile

2.50 g (14.95 mmol) of 4-methyl-1-naphthonitrile dissolved in 40 ml of carbon tetrachloride and mixed with 3.19 g (17.94 mmol) of N-bromosuccinimide and 245 mg (1.50 mmol) of 2,2'-azobis-2-methylpropionitrile. Mix in the way during the night when the temperature of reflux. After cooling the product is filtered. Obtained 2.75 g (74.7% of theory. prob.) 4-(methyl bromide)-1-naphthonitrile 90%purity, which is used in the future is without further purification.

2.75 g (11.17 mmol) thus obtained bromide are dissolved in 60 ml of acetonitrile and mixed with 2 g of molecular sieves (3Å). Then added 1.44 g (12.29 mmol) N-methylmorpholine-N-oxide and the mixture is stirred over night at room temperature. The deposition is filtered through silica gel and the filtrate is condensed. The residue is purified via Biotage cartridge (40 M) (eluent: isohexane/ethyl acetate 3:1). Fractions of purified product, the solvent is removed in a rotary evaporation apparatus, and then the precipitate is mixed with diethyl ether, and observed the crystallization process. The product is washed with a small amount of diethyl ether and dried in high vacuum. It turns out 254 mg (12.6% of theory. prob.) extracted in the connection header.

LC-MS (method 3): Rt=2.27 min; [M+H]+(EIpos): m/z=182

1H-NMR (300 MHz, CDCl3): δ=7.79-7.87 (m, 2H), 8.05 (d, 1H), 8.09 (d, 1H), 8.37 (m, 1H), 9.27 (m, 1H), 10.51 (s, 1H).

Example 20A

2-Cyanoethyl 4-(4-cyano-2-methoxyphenyl)-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthiridine-3-carboxylate

14.63 g (90.81 mmol) of the compound from example 10A, 10.00 g (90.81 mmol) of 4-aminopyridine-2(1H)-she [Searls, T., McLaugMin, L.W., Tetrahedron 55. 11985-11996 (1999)] and 15.65 g (90.81 mmol) 2-cyanoethyl-3-oxobutanoate [Yamamoto, T., et al., Bioorg. Med. Chem. Lett. 16, 798-802 (2006)] are dissolved in 300 ml of isopropanol and the mixture mixes 3 days in an atmosphere of argon at a temperature of reflux the and. Then the mixture thickens and then purified by column chromatography (silica gel; solvent: first, ethyl ester acetic acid, then dichloromethane/methanol 10:1). The obtained fractions of the product are concentrated and absorbed in a small amount of ethyl ester of acetic acid. The precipitated product filtered and dried overnight in vacuum at 40°C. Receive 10.11 g (27% of theory. prob.) extracted in the connection header.

LC-MS (method 6): Rt=1.83 min; MS (EIpos): m/z=391 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=2.27 (s, 3H), 2.79 (m, 2H), 3.75 (s, 3H), 3.96-4.14 (m, 2H), 5.19 (s, 1H), 5.87 (d, 1H), 7.10 (d, 1H), 7.23 (dd, 1H), 7.30-7.35 (m, 2H), 9.30 (s, 1H), 10.83 (s, 1H).

Example 21A

2-Cyanoethyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1,4-dihydro-1,6-naftopidil-3-carboxylate

10.00 g (25.62 mmol) of the compound from example 20A into suspension in 250 ml teeterboro ether orthomorphisms acid and the suspension is heated to 130°C. Then the reaction mixture every hour for 8 hours added 15 drops of concentrated sulfuric acid. The mixture was stirred overnight at the same temperature. After cooling, the excess orthoepy is removed in a rotary evaporator apparatus and the original product is purified by column chromatography (silica gel; solvent: cyclohexane/ethyl ether uksu the Noah acid 1:1). Receive 7.20 g (65% of theory. prob.) extracted in the connection header.

LC-MS (method 6):Rt=2.82 min; MS (EIpos): m/z=419 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=1.12 (t, 3H), 2.33 (s, 3H), 2.77 (m, 2H), 3.78 (s, 3H), 3.99-4.13 (m, 4H), 5.37 (s, 1H), 6.48 (d, 1H), 7.25 (dd, 1H), 7.29-7.35 (m, 2H), 7.73 (d, 1H), 9.53 (s, 1H).

Example 22A

4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthiridine-3-carboxylic acid

7.20 g (17.21 mmol) of the compound from example 21A dissolved in 200 ml of 1,2-dimethoxyethane and water (3:1 ratio of volume), diluted 34.42 ml (34.42 mmol) of 1 N sodium hydroxide solution and the mixture is way over night at room temperature. Then the deposition is diluted with 100 ml of diethyl ether and 100 ml of water, the organic phase is separated, and the aqueous phase is acidified 1 N hydrochloric acid to pH 4-5. The resulting suspension is prohibited from 1 hour and the precipitated precipitate is separated by filtration. The precipitate is washed with water and a small amount of diethyl ether. After drying in vacuum at 40°C obtain 3.57 g (57% of theory. prob.) extracted in the connection header.

LC-MS (method 7): Rt=2.32 min; MS (EIpos): m/z=366 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=1.12 (t, 3H), 2.28 (s, 3H), 3.74 (s, 3H), 4.07 (m, 2H), 5.33 (s, 1H), 6.44 (d, 1H), 7.23-7.29 (m, 2H), 7.32 (s, 1H), 7.70 (d, 1H), 9.25 (s, 1H), 11.34 (s, 1H).

Example 23A

4-[5-Ethoxy-3-(1H-imidazol-1-ylcarbonyl)-2-methyl-1,4-dihydro-1,6-naphthiridine-4-yl]-3-methoxybenzonitrile

1.20 g (3.28 mmol) of the compound from example 22A are introduced into 25 ml of ethyl ether acetic acid, diluted 0.666 g (4.11 mmol) of 1,1'-carbonyldiimidazole and mixed overnight at room temperature. The reaction mixture was concentrated in a rotary evaporator apparatus and thus obtained the original product is used for further reactions without purification.

MS (EIpos): m/z=416 [M+H]+.

Example 24A

2-Cyanoethyl 2-(4-cyano-2-methoxybenzylidene)-3-oxobutanoate

3.00 g (18.62 mmol) of the compound from example 10A, 3.18 g (20.48 mmol) 2-cyanoethyl-3-oxobutanoate acetic acid [Yamamoto, T., et al., Bioorg. Med. Chem. Lett. 16. 798-802 (2006)], 213 μl (3.72 mmol) of acetic acid and 368 μl (3.72 mmol) of piperidine are dissolved in 50 ml of anhydrous dichloromethane and during the night in a tangle at reflux in a water separator. Thereafter, the volatile components are separated in a rotary evaporation apparatus, and the residue is purified by column chromatography (silica gel; solvent: gradient cyclohexane/ethyl ester acetic acid 7:3→1:1). It turns out 2.77 g (48% of theory. prob.) extracted in the title compounds as a mixture of E/Z-isomers.

LC-MS (method 7): Rt=2.89 and 3.00 min; MS (EIpos): m/z=299 [M+H]+.

Example 25A

2-Cyanoethyl 4-(4-cyano-2-methoxyphenyl)-2,7-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthiridine-3-carboxylate

1.49 g (5.00 mmol) of the compound from example 24A are introduced into 30 ml of 2-propanol, mixed with 620 mg (5.00 mmol) of 4-amino-6-methylpyridin-2(1H)-she [Bisagni, E., Hung, N.C., Synthesis, 765-766 (1984)] and mixed overnight at reflux temperature. After cooling, the precipitate filtered, washed with diethyl ether and dried in high vacuum. Obtain 1.53 g (76% of theory. prob.) extracted in the connection header.

LC-MS (method 3): Rt=1.73 min; MS (EIpos): m/z=405 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=2.05 (s, 3H), 2.26 (s, 3H), 2.78 (m, 2H), 3.74 (s, 3H), 3.96-4.13 (m, 2H), 5.14 (s, 1H), 5.64 (d, 1H), 7.23 (dd, 1H), 7.28-7.33 (m, 2H), 9.22 (s, 1H), at 10.82 (s, 1H).

Example 26A

2-Cyanoethyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,7-dimethyl-1,4-dihydro-1,6-naphthiridine-3-carboxylate

1.52 g (3.76 mmol) of the compound from example 25A turns into suspension in 40 ml teeterboro ether orthomorphisms acid and the suspension is heated to 130°C. thereafter, to the reaction mixture every tea within 8 hours is added 10 drops of concentrated sulfuric acid. The mixture is then stirred overnight at the same temperature. After cooling, the excess orthoepy is removed in a rotary evaporator apparatus, and the original product is purified by column chromatography (silica gel; solvent: cyclohexane/ethyl ester acetic acid 1:1). Fraction of the product are combined,the solvent is removed, and to the precipitate is added a small amount of methanol. Product crystallization filtered. After drying in high vacuum obtain 1.09 g (67% of theory. prob.) extracted in the connection header.

LC-MS (method 3): Rt=2.23 min; MS (EIpos): m/z=433 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=1.11 (t, 3H), 2.20 (s, 3H), 2.32 (s, 3H), 2.76 (m, 2H), 3.78 (s, 3H), 3.97-4.12 (m, 4H), 5.32 (s, 1H), 6.30 (s, 1H), 7.24 (d, 1H), 7.27-7.32 (m, 2H), 9.43 (s, 1H).

Example 27A

4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,7-dimethyl-1,4-dihydro-1,6-naphthiridine-3-carboxylic acid

642 mg (2.52 mmol) of the compound from example 26A dissolved in 40 ml of a mixture of 1,2-dimethoxyethane and water (3:1 ratio of volume), diluted 5.04 ml (5.04 mmol) of 1 N sodium hydroxide and mixed overnight at room temperature. After that, the residue is diluted with 30 ml of diethyl ether and 30 ml of water, the organic phase is separated, and the aqueous phase is acidified 1 N hydrochloric acid to pH 4-5. The resultant slurry mixes for 1 hour, and the precipitated solid is separated by filtration. The precipitate is washed with water and a small amount of diethyl ether. After drying in vacuum at 40°C receive 642 mg (67% of theory. prob.) extracted in the connection header.

LC-MS (method 3): Rt=1.87 min; MS (EIpos): m/z=380 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=1.11 (t, 3H), 2.19 (s, 3H), 2.28 (s, 3H), 3.74 (s, 3H), 4.05 (m, 2H), 5.28 (s, 1H), 6.27 (s, 1H), 7.20-7.28 (m, 2H), 7.31 (, 1H), 9.17 (s, 1H), 11.31 (s, 1H).

Example 28A

2-Cyanoethyl 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthiridine-3-carboxylate

2.69 g (9.00 mmol) of the compound from example 24A introduced into 45 ml of 2-propanol, mixed with 1.17 g (9.00 mmol) of 4-amino-5-methylpyridin-2(1H)-she [Bisagni, E., Hung, N.C., Synthesis, 765-766 (1984)] and in a tangle over night at a temperature of reflux. After cooling, the precipitate filtered, washed with diethyl ether and dried in high vacuum. Obtain 2.22 g (61% of theory. prob.) extracted in the connection header.

LC-MS (method 3):Rt=1.75 min; MS (EIpos): m/z=405 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=2.03 (s, 3H), 2.35 (s, 3H), 2.80 (m, 2H), 3.74 (s, 3H), 4.04 (m, 1H), 4.11 (m, 1H), 5.20 (s, 1H), 6.95 (s, 1H), 7.23 (dd, 1H), 7.28-7.33 (m, 2H), 8.18 (s, 1H), 10.76 (s, 1H).

Example 29A

2-Cyanoethyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthiridine-3-carboxylate

2.22 g (5.44 mmol) of the compound from example 28A into suspension in 100 ml teeterboro ether orthomorphisms acid and the suspension is heated to 130°C. thereafter, to the reaction mixture for 8 hours every hour is added 10 drops of concentrated sulfuric acid. The mixture is then prohibited from overnight at the same temperature. After cooling, the excess orthoepy is removed in a rotary evaporator apparatus and the source productised by column chromatography (silica gel; solvent: first dichloromethane, then isohexane ethyl ester acetic acid 1:1). Fraction of the product are combined, the solvent removed and the residue crystallized from a mixture of ethyl ester of acetic acid and diethyl ether. The precipitate is filtered and dried in high vacuum. Obtain 1.80 g (77% of theory. prob.) extracted in the connection header.

LC-MS (method 6): Rt=3.02 min; MS (EIpos): m/z=433 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=1.11 (t, 3H), 2.16 (s, 3H), 2.42 (s, 3H), 2.78 (m, 2H), 3.77 (s, 3H), 4.01-4.13 (m, 4H), 5.37 (s, 1H), 7.25 (d, 1H), 7.28-7.33 (m, 2H), 7.60 (s, 1H), 8.35 (s, 1H).

Example 30A

4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthiridine-3-carboxylic acid

1.75 g (4.05 mmol) of the compound from example 29A dissolved in 60 ml of a mixture of 1,2-dimethoxyethane and water (2:1 ratio of volume), diluted 8.09 ml (8.09 mmol) of 1 N sodium hydroxide and one hour mixes at room temperature. Then the initial mixture is mixed with 30 ml of diethyl ether and the aqueous phase is acidified 6 N hydrochloric acid. The resulting precipitate filtered and washed with water and a small amount of diethyl ether. After drying at 40°C in a vacuum drying Cabinet obtain 1.47 g (96% of theory. prob.) extracted in the connection header.

LC-MS (method 7): Rt=2.50 min; MS (EIpos): m/z=380 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=1.14(t, 3H), 2.14 (s, 3H), 2.37 (s, 3H), 3.73 (s, 3H), 4.04 (m, 2H), 5.33 (s, 1H), 7.26 (m, 2H), 7.32 (s, 1H), 7.57 (s, 1H), 8.16 (s, 1H), 11.43 (br. s, 1H).

Example 31A

2-Cyanoethyl 2-methyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-5-oxo-1,4,5,6-tetrahydro-1,6-naphthiridine-3-carboxylate

3.00 g (15.94 mmol) of the compound from example 5A, 1.75 g (15.94 mmol) of 4-aminopyridine-2(1H)-she [Searls, T., McLaughlin, L.W., Tetrahedron 55, 11985-11996 (1999)] and 2.47 g (15.94 mmol) 2-cyanoethyl-3-oxobutanoate [Yamamoto, T., et al., Bioorg. Med. Chem. Lett. 16. 798-802 (2006)] are dissolved in 60 ml of ethanol and a tangle during the night in an argon atmosphere at a temperature of reflux. After that precipitated precipitated product is filtered, washed with ethanol and diethyl ether and dried in high vacuum. Obtain 2.30 g (35% of theory. prob.) output the title compound as beige crystals.

LC-MS (method 7): Rt=1.59 min; MS (EIpos): m/z=418 [M+H]+.

Example 32A

2-Cyanoethyl 5-ethoxy-2-methyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-1,4-dihydro-1,6-naphthiridine-3-carboxylate

2.20 g (5.27 mmol) of the compound from example 31A into suspension in 80 ml teeterboro ether orthomorphisms acid and heated to 130°C. thereafter, to the reaction mixture for 8 hours every hour is added 5 drops of concentrated sulfuric acid. The mixture is then prohibited from overnight at the same temperature. After cooling, the excess ortho the IDF is removed in a rotary evaporator apparatus and the original product is purified by column chromatography (silica gel; solvent: first dichloromethane, then ethyl ester acetic acid, at the end of the ethyl ester of acetic acid/methanol 20:1). Fraction of the product concentrated to a volume of about 5 ml of Precipitated precipitated product filtered and washed with ethyl ether, acetic acid and diethyl ether, dried in high vacuum. Obtain 282 mg (12% of theory. prob.) output the title compound as brown crystals.

LC-MS (method 3):Rt=1.96 min; MS (EIpos): m/z=446 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=1.01 (t, 3H), 2.38 (s, 6H), 2.74 (m, 2H), 3.96-4.13 (m, 4H), 5.54 (s, 1H), 6.19 (s, 1H), 6.53 (d, 1H), 7.31 (t, 1H), 7.67 (dd, 1H), 7.76 (d, 1H), 7.80 (dd, 1H), 9.69 (s, 1H).

Example 33A

5-Ethoxy-2-methyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-1,4-dihydro-1,6-naphthiridine-3-carboxylic acid

270 mg (0.61 mmol) of the compound from example 32A dissolved in 15 ml of a mixture of 1,2-dimethoxyethane and water (2:1 volume ratio), mixed with 1.21 ml (1.21 mmol) of 1 N sodium hydroxide solution and get 1 hour at room temperature. After that the reaction mixture is diluted with 30 ml of diethyl ether. The aqueous phase is separated and acidified 1 N hydrochloric acid. The precipitation is filtered and washed with water and a small amount of diethyl ether. After drying at 40°C in vacuum obtain 167 mg (70% of theory. prob.) extracted in the connection header.

LC-MS (method 7):Rt=2.01 min; MS (EIpos): m/z=393 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=1.02 (t, 3H), 2.33 (s, 3H), 2.35 (s, 3H), 3.97 (m, 1H), 4.08 (m, 1H), 5.52 (s, 1H), 6.18 (s, 1H), 6.50 (d, 1H), 7.31 (t, 1H), 7.60 (dd, 1H), 7.74 (d, 1H), 7.79 (dd, 1H), 9.42 (s, 1H), 11.45 (br. s, 1H).

Example 34A

2-Cyanoethyl 4-[4-bromo-2-(triptoreline)phenyl]-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthiridine-3-carboxylate

10.00 g (31.17 mmol) of the compound from example 6A and 6.41 g (31.17 mmol) 2-cyanoethyl-3-oxobutanoate [Yamamoto, T., et al., Bioorg. Med. Chem. Lett. 16, 798-802 (2006)] are introduced into 100 ml of 2-propanol, mixed with 4.09 g (37.17 mmol) of 4-aminopyridine-2(1H)-she [Searls, T., McLaughlin, L.W., Tetrahedron 55, 11985-11996 (1999)] and the mixture mixes three days at the temperature of reflux. After cooling, the solvent is removed under reduced pressure and the raw product is purified by column chromatography (silica gel; solvent: dichloromethane/methanol 10:1). Get 7.38 g (36% of theory. prob.) extracted in the connection header.

LC-MS (method 6): Rt=2.84 min; MS (EIpos): m/z=499 [M+H]+.

Example 35A

2-Cyanoethyl 4-[4-bromo-2-(triptoreline)phenyl]-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthiridine-3-carboxylate

7.30 g (13.19 mmol) of the compound from example 34A into suspension in 150 ml teeterboro ether orthomorphisms acid and heated to 130°C. thereafter, to the reaction mixture for 7 hours every hour added 15 drops of concentrated the sulfuric acid. The mixture is then prohibited from overnight at the same temperature. After cooling, the excess orthoepy is removed in a rotary evaporator apparatus and the original product is purified by column chromatography (silica gel; solvent: cyclohexane/ethyl ester acetic acid 1:1). Get 4.59 g (64% of theory. prob.) extracted in the connection header.

LC-MS (method 3): Rt=2.74 min; MS (EIpos): m/z=527 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=1.17 (t, 3H), 2.33 (s, 3H), 2.81 (m, 2H), 3.99-4.21 (m, 4H), 5.29 (s, 1H), 6.50 (d, 1H), 7.31 (t, 1H), 7.37 (d, 1H), 7.44 (dd, 1H), 7.78 (d, 1H), 9.63 (s, 1H).

Example 36A

2-Cyanoethyl-4-[4-cyano-2-(triptoreline)phenyl]-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthiridine-3-carboxylate

4.59 g (8.72 mmol) of the compound from example 35A, 758 mg (6.45 mmol) of cyanide of zinc and 504 mg (0.436 mmol) of tetrakis(triphenylphosphine)palladium(0) are dissolved in 40 ml of dimethylformamide and then divided into three mixtures are heated by microwaves in a single-mode mode (Emrys Optimizer) for 5 min to 220°C. Separate the mixture again combined and the solvent removed in a rotary evaporator apparatus. The original product is absorbed ethyl ester, acetic acid and filtered through diatomaceous earth. The organic phase is washed with water (2 times) and a saturated solution of sodium chloride. After removal of the solvent the original product is purified through a column of chromatogr is Sofia (silica gel; solvent: cyclohexane/ethyl ester acetic acid 7:3→1:1). Obtain 1.40 g (31% of theory. prob.) extracted in the connection header.

LC-MS (method 3): Rt=2.48 min; MS (EIpos): m/z=473 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=1.10 (t, 3H), 2.34 (s, 3H), 2.80 (m, 2H), 4.00-4.21 (m, 4H), 5.36 (s, 1H), 6.51 (d, 1H), 7.60 (d, 1H), 7.66-7.74 (2H), 7.79 (d, 1H), 9.70 (s, 1H).

Example 37A

4-[4-Cyano-2-(triptoreline)phenyl]-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthiridine-3-carboxylic acid

1400 mg (2.96 mmol) of the compound from example 36A dissolved in a mixture of 35 ml of 1,2-dimethoxyethane and water (2.5:1 ratio of volume), diluted 5.93 ml (5.93 mmol) of 1 N sodium hydroxide solution and the mixture mixes 2 hours at room temperature. Then the reaction mixture is mixed with 50 ml of diethyl ether and 50 ml of water. The aqueous phase is separated and acidified 1 N hydrochloric acid to pH 4-5. The resulting suspension stirred for 1 hour. The precipitation is filtered and washed with water and a small amount of diethyl ether. After drying in vacuo get 850 mg (68% of theory. prob.) extracted in the connection header.

LC-MS (method 3): Rt=2.19 min; MS (EIpos): m/z=420 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=1.11 (t, 3H), 2.31 (s, 3H), 4.06 (m, 1H), 4.13 (m, 1H), 5.37 (s, 1H), 6.49 (d, 1H), 7.51 (d, 1H), 7.65-7.72 (m, 2H), 7.76 (d, 1H), 9.42 (s, 1H), 11.62 (s, 1H).

Example 38A

4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2-(trifluoromethyl)-1,4-dihydr is -1,6-naphthiridine-3-carboxylic acid

Displayed in the title compound can be obtained on the basis of stoichiometric amounts of 4-formyl-3-methoxybenzonitrile (example 10A), 4-aminopyridine-2(1H)-she [Searls, T., McLaughlin, L.W., Tetrahedron 55, 11985-11996 (1999)] and allyl 4,4,4-Cryptor-3-oxobutanoate [Moseley, J.D., Tetrahedron Lett. 46. 3179-3181 (2005)]. In this first overnight at the temperature of reflux is the synthesis of dihydropyridines in ethanol without additives. The resulting first intermediate product allyl 4-(4-cyano-2-methoxyphenyl)-2-hydroxy-5-oxo-2-(trifluoromethyl)-1,2,3,4,5,6-hexahydro-1,6-naphthiridine-3-carboxylate can then be dehydration acetic acid, as described in the literature [see Moseley, J.D., Tetrahedron Lett. 46, 3179-3181 (2005)]. Then by analogy with the synthesis of example 29A is obtained allyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-(trifluoromethyl)-1,4-dihydro-1,6-naphthiridine-3-carboxylate by the exchange reaction with triethyl-orthoformate. Final cleavage of the allyl ether by Wilkinson catalyst [Tris(triphenylphosphine)rhodium(1) chloride] in acetic acid gives compound, displayed in the header [see Moseley, J.D., Tetrahedron Lett. 46, 3179-3181 (2005)].

LC-MS (method 7): Rt=2.98 min; MS (EIpos): m/z=420 [M+H+]

1H-NMR (300 MHz, DMSO-d6): δ=1.09 (t, 3H), 3.77 (s, 3H), 3.98-4.16 (m, 2H), 5.37 (s, 1H), 6.73 (d, 1H), 7.19 (d, 1H), 7.34 (dd, 1H), 7.42 (d, 1H), 7.78 (d, 1H), 9.62 (s, 1H).

Example 39A

2-Cyanoethyl 2,8-dimethyl-4-(2-methyl-4-oxo-4H-is Romain-8-yl)-5-oxo-1,4,5,6-tetrahydro-1,6-naphthiridine-3-carboxylate

1.50 g (7.97 mmol) of the compound from example 5A, 1.86 g (9.57 mmol) of 2-cyanoethyl-3-oxobutanoate [Yamamoto, T., et al., Bioorg. Med. Chem. Lett. 16, 798-802 (2006)], 91 μl (1.59 mmol) of acetic acid and 158 μl (1.59 mmol) of piperidine are dissolved in 30 ml of anhydrous dichloromethane and get in the water separator during the night under conditions of reflux. After that, the mixture is washed with water, the organic phase is dried with magnesium sulfate and the volatile components are removed in a rotary evaporator apparatus. 2.91 g (approximately 7.33 mmol) thus obtained raw product 2-cyanoethyl-(2Z)-2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylidene]-3-oxobutanoate diluted 0.990 g (9.00 mmol) of 4-amino-5-methylpyridin-2(1H)-she [Bisagni, E., Hung, N.C., Synthesis, 765-766 (1984)], connected with 40 ml of 2-propanol and the mixture is comfortable during the night when the temperature of the reflux. After cooling, the precipitated precipitate is filtered and washed with a small amount of diethyl ether.

After drying in high vacuum is obtained 1.20 g (38% of theory. prob.) extracted in the connection header.

LC-MS (method 8): Rt=1.00 min; MS (EIpos): m/z=432 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=2.06 (s, 3H), 2.34 (s, 3H), 2.44 (s, 3H), 2.77 (m, 2H), 3.98-4.14 (m, 2H), 5.76 (s, 1H), 6.15 (s, 1H), 6.98 (s, 1H), 7.28 (t, 1H), 7.71 (dd, 1H), 7.78 (dd, 1H), 8.29 (s, 1H), 10.78 (br. s, 1H).

Example 40A

2-Cyanoethyl 5-ethoxy-2,8-dimethyl-4-(2-methyl-4-oxo-4-chroman-8-yl)-1,4-dihydro-1,6-naphthiridine-3-carboxylate

1.20 g (2.78 mmol) of the compound from example 39A and 9.25 ml (55.6 mmol) of diethyl ether orthomorphisms acid are introduced into 30 ml of dry dimethylformamide, the mixture is heated to 130°C. and diluted with 5 drops of concentrated sulfuric acid. After 2 hours, HPLC-control shows complete conversion of the components. After cooling, the volatile components are removed in a rotary evaporator apparatus and the original product is purified by liquid chromatography, medium pressure (Biotage cartridge 40 M, eluent: isohexane/ ethyl acetate 1:2). Get 640 mg (50% of theory. prob.) extracted in the connection header.

LC-MS (method 9): Rt=0.99 min; MS (EIpos): m/z=460 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=1.01 (t, 3H), 2.19 (s, 3H), 2.38 (s, 3H), 2.48 (s,

3H), 2.75 (m, 2H), 3.93-4.14 (m, 4H), 5.55 (s, 1H), 6.18 (s, 1H), 7.30 (t, 1H), 7.63 (s, 1H), 7.67 (dd, 1H), 7.79 (dd, 1H), 8.49 (s, 1H).

Example 41 A

5-Ethoxy-2,8-dimethyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-1,4-dihydro-1,6-naphthiridine-3-carboxylic acid

640 mg (1. organisations from example 40A dissolved in a mixture of 30 ml of 1,2-dimethoxyethane and water (2:1 ratio of volume), diluted 2.76 ml (2.76 mmol) of 1 N sodium hydroxide solution and get 30 minutes at room temperature. Then the reaction mixture is diluted with 20 ml diethyl ether. The aqueous phase is separated, acidified 1 N hydrochloric acid to pH 4-5 and three times extragere is by using the ethyl ester of acetic acid. The organic phases are combined and dried with magnesium sulfate. Volatile components is distilled over in a rotary evaporation apparatus. After drying in vacuo get 335 mg (56% of theory. prob.) extracted in the title compound with a purity of 94% (LC-MS).

LC-MS (method 8): Rt=1.21 min; MS (EIpos): m/z=407 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=1.01 (t, 3H), 2.18 (s, 3H), 2.35 (s, 3H), 2.42 (s, 3H), 3.90-4.10 (m, 2H), 5.54 (s, 1H), 6.18 (s, 1H), 7.31 (t, 1H), 7.58 (dd, 1H), 7.60 (s, 1H), 7.78 (dd, 1H), 8.25 (s, 1H), 11.52 (br. s, 1H).

Application examples:

Example 1

4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthiridine-3-carboxamide

100 mg (about 0.24 mmol) of the compound from example 23A are introduced into 3 ml of dimethylformamide. Then mixed with 2.94 mg (0.024 mmol) of 4-N,N-dimethylaminopyridine and 340 μl of ammonia (28 wt.%-cent solution in water, 2.41 mmol) and the mixture is aged for 3 hours at 100°C. After cooling, the original product is purified directly by preparative liquid chromatography high pressure (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80 → 95:5). Obtained 32 mg (37% of theory. prob.) extracted in the connection header.

LC-MS (method 3): Rt=1.57 min; MS (EIpos): m/z=365 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=1.07 (t, 3H), 2.13 (s, 3H), 3.83 (s, 3H), 4.04 (m, 2H), 5.36 (s, 1H), 6.42 (d, 1H), 6.66 (br. s, 2H), 7.18 (d, 1H), 7.29 (dd, 1H), 7.38 (d, 1H), 7.67 (d, 1H), 8.80 (s, 1H).

Example 2

4-(4-Cyano-2-methoxyphenyl)-5-etox the -2,7-dimethyl-1,4-dihydro-1,6-naphthiridine-3-carboxamide

640 mg (1.69 mmol) of the compound from example 27A are introduced into 30 ml of ethyl ether, acetic acid, mixed with 342 mg (2.11 mmol) of 1,1'-carbonyldiimidazole, then the mixture is way over night at room temperature. The control thin-layer chromatography (silica gel; solvent: cyclohexane/ethyl ester acetic acid 1:1 dichloromethane/methanol 9:1) shows complete conversion of the components. Volatile components is distilled over in a rotary evaporation apparatus, and the residue is soaked in 20 ml of dimethylformamide. Then added 2.36 ml of ammonia (28 wt.%-cent solution in water, 16.87 mmol) and the reaction mixture is aged for 8 hours at 50°C. the Solvent Argonauts under reduced pressure, and the residue is purified by preparative liquid chromatography high pressure (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). Get 368 mg (58% of theory. prob.) extracted in the connection header.

LC-MS (method 7): Rt=1.91 min; MS (EIpos): m/z=379 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=1.05 (t, 3H), 2.13 (s, 3H), 2.19 (s, 3H), 3.84 (s, 3H), 4.02 (q, 2H), 5.32 (s, 1H), 6.25 (s, 1H), 6.62 (br. s, 2H), 7.16 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 8.71 (s, 1H).

Example 3

ent-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,7-dimethyl-1,4-dihydro-1,6-naphthiridine-3-carboxamide [(-)-enantiomer and (+)-enantiomer]

Racemic compound of the example 2 can be divided in preparative scale using HPLC in chiral phase on its enantiomers [column: Chiralpak IA, 250 mm × 20 mm; eluent: tert-butyl ether/methanol 85:15 ratio (volume); flow: 15 ml/min; temperature: 30°C.; UV-indication: 220 nm].

(-)-enantiomer:

HPLC: Rt=5.28 min, it>98% [column: Chiratpak IA, 250 mm × 4.6 mm; eluent: tert-butyl ether/methanol 80:20 (ratio of volumes); flow: 1 ml/min; temperature: 25°C; UV-indication: 220 nm];

the value of specific rotation (chloroform, 589 nm, 19.8°C, with a=0.50500 g/100 ml): - 239.3°.

X-ray analysis on single crystal makes this enantiomer S-configuration at C*-atom.

(+)-enantiomer:

HPLC: Rt=4.50 min, it>99% [column: Chiralpak IA, 250 mm × 4.6 mm; eluent: tert-butyl ether/methanol 80:20 (ratio of volumes); flow: 1 ml/min; temperature: 25°C; UV-indication: 220 nm];

the value of specific rotation (chloroform, 589 nm, 20°C, with a=0.51000 g/100 ml):+222.7°.

Example 4

4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthiridine-3-carboxamide

1.46 g (3.84 mmol) of the compound from example 30A is introduced into 50 ml of ethyl ether, acetic acid, mixed with 777 mg (4.79 mmol) of 1,1'-carbonyldiimidazole and the mixture is stirred over night at room temperature. DC-control (silica gel; solvent: ethyl ester of acetic acid) shows complete conversion of the components. Volatile components is distilled over in a rotary evaporation apparatus, and the residue of propitia the tsya 20 ml of dimethylformamide. Then added 10.74 ml of ammonia (28 wt.%-cent solution in water, 76.8 mmol) and the reaction mixture is maintained for 30 minutes at 100°C. the Solvent Argonauts under reduced pressure, and the residue is purified by means of preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). After concentration of fractions of the product residue is dissolved in 40 ml of a mixture of dichloromethane and methanol (1:1 ratio of volume) and diluted with 100 ml ethyl ester of acetic acid. The solvent is concentrated to a volume of about 20 ml, and the product crystallizes. The precipitate is filtered and washed with a small amount of diethyl ether. After drying at 40°C in a vacuum drying Cabinet obtain 1.40 g (96% of theory. prob.) extracted in the connection header.

LC-MS (method 3): Rt=1.64 min; MS (EIpos): m/z=379 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H), 5.37 (s, 1H), 6.60-6.84 (m, 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H).

Example 5

ENT-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthiridine-3-carboxamide [(-)-enantiomer and (+)-enantiomer]

Racemic compound from example 4 can be divided in preparative scale using HPLC in chiral phase on its enantiomers [column: 680 mm × 40 mm; phase silica gel, based on the chiral selector is Oli(N-methacryloyl-D-leucine-Dicyclopentadiene; eluent: ethyl ester of acetic acid; temperature: 24°C.; flow: 80 ml/min; UV-indication: 260 nm].

(-)-enantiomer:

HPLC: Rt=2.48 min, ee=99.6% [column: 250 mm × 4.6 mm; phase silica gel, based on the chiral selector poly(N-methacryloyl-D-leucine-Dicyclopentadiene; eluent: ethyl ester of acetic acid; temperature: 24°C.; flow: 2 ml/min; UV-indication: 260 nm];

the value of specific rotation (chloroform, 589 nm, 19.7°C, c=0.38600 g/100 ml): - 148.8°.

X-ray analysis on single crystal makes this enantiomer S-configuration at C*-atom.

(+)-enantiomer:

HPLC: Rt=4.04 min, ee=99.3% [column: 250 mm × 4.6 mm; phase silica gel, based on the chiral selector poly(N-methacryloyl-D-leucine-Dicyclopentadiene; eluent: ethyl ester of acetic acid; temperature: 24°C.; flow: 2 ml/min; UV-indication: 260 nm];

the value of specific rotation (chloroform, 589 nm, 19.8°C, with a=0.36300 g/100 ml): +153.0°.

Example 6

5-Ethoxy-2-methyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-1,4-dihydro-1,6-naphthiridine-3-carboxamide

155 mg (0.395 mmol) of the compound from example 31A are introduced in 10 ml of THF, mixed with 80.1 mg (0.494 mmol) of 1,1'-carbonyldiimidazole and the mixture is way over night at room temperature. DC-control (silica gel; solvent: ethyl ester of acetic acid or dichloromethane/methanol 9:1) shows complete one accepts Amenia components. Volatile components is distilled over in a rotary evaporation apparatus, and the residue is impregnated with 3 ml of dimethylformamide. Then added 553 mg of ammonia (28 wt.%-cent solution in water, 3.95 mmol) and the reaction mixture is aged for 10 minutes at 100°C. the Solvent Argonauts under reduced pressure, and the residue is purified by means of preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). Receive 30 mg (19% of theory. prob.) extracted in the connection header.

LC-MS (method 6): Rt=1.17 min; MS (EIpos): m/z=392 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=0.96 (t, 3H), 2.09 (s, 3H), 2.36 (s, 3H), 3.94 (m, 1H), 4.03 (m, 1H), 5.59 (s, 1H), 6.19 (s, 1H), 6.42 (d, 1H), 6.66 (br. s, 1H), 7.00 (br. s, 1H), 7.31 (t, 1H), 7.53 (dd, 1H), 7.68 (d, 1H), 7.79 (dd, 1H), 8.83 (s, 1H).

Example 7

4-[4-Cyano-2-(triptoreline)phenyl]-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthiridine-3-carboxamide

200 mg (0.477 mmol) of the compound from example 37A are introduced into 5 ml of ethyl ether, acetic acid, mixed with 96.7 mg (0.596 mmol) of 1,1'-chronicdisease and then the mixture was stirred over night at room temperature (DC-control: lack of transformation). After this is added 1 ml of dimethylformamide and the mixture hinder one night at room temperature (DC-control: complete metamorphosis). Volatile components is distilled over in a rotary evaporation apparatus, and the residue is moistened with 4 ml digitiform the foreign Ministry. Then added 663 μl of ammonia (28 wt.%-cent solution in water, 4.77 mmol) and the reaction mixture is maintained in a closed vessel at 100°C during the night. After cooling, the solvent is removed under reduced pressure, and the residue is purified by means of preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). Obtain 140 mg (70% of theory. prob.) extracted in the connection header.

LC-MS (method 6): Rt=2.26 min; MS (EIpos): m/z=419 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=1.04 (t, 3H), 2.04 (s, 3H), 4.06 (m, 2H), 5.42 (s, 1H), 6.41 (d, 1H), 6.80 (br. s, 1H), 6.97 (br. s, 1H), 7.45 (d, 1H), 7.68-7.74 (m, 3H), 8.82 (d, 1H).

Example 8

4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2-(trifluoromethyl)-1,4-dihydro-1,6-naphthiridine-3-carboxamide

180 mg (0.429 mmol) of the compound from example 38A are introduced into 5 ml of ethyl ether, acetic acid, mixed with 87.0 mg (0.537 mmol) of 1,1'-carbonyldiimidazole and then two hours in a tangle at room temperature. DC-control is set to full transformation. Volatile components is distilled over in a rotary evaporation apparatus, and the residue is moistened with 4 ml of dimethylformamide. Then added 597 μl of ammonia (28 wt.%-cent solution in water, 4.29 mmol) and the reaction mixture for three hours is maintained in a closed vessel at 100°C. After cooling, the solvent is removed under reduced pressure, and the residue is purified by preparation the tive HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). Receive 10 mg (5% of theory. prob.) extracted in the connection header.

LC-MS (method 3): Rt=1.85 min; MS (EIpos): m/z=419 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=1.03 (t, 3H), 3.79 (s, 3H), 3.96-4.11 (m, 2H), 5.37 (s, 1H), 6.62 (d, 1H), 7.08-7.14 (m, 2H), 7.32 (dd, 1H), 7.37-7.46 (m, 2H), 7.73 (d, 1H), 9.18 (s, 1H).

Example 9

5-Ethoxy-2,8-dimethyl-4-(2-methyl-4-oxo-4-chroman-8-yl)-1,4-dihydro-1,6-naphthiridine-3-carboxamide

335.0 mg (0.824 mmol) of the compound from example 41A are introduced into 10 ml of ethyl ether, acetic acid and mixed with 167.1 mg (0.537 mmol) of 1,1'-carbonyldiimidazole. Then the suspension is stirred over night at room temperature. Because there is no clear formation of the solution, add 2 ml of dimethylformamide and the mixture is stirred Yeshe two hours at room temperature. After that, the DC-control is set to full transformation components. Volatile components is distilled over in a rotary evaporation apparatus, and the residue is moistened with 4 ml of dimethylformamide. Then added 2.293 ml of ammonia (28 wt.%-cent solution in water, 16.5 mmol) and 10.1 mg of 4-N,N-dimethylaminopyridine. The reaction mixture is aged for thirty minutes in a closed vessel at 100°C. After cooling, the solvent is removed under reduced pressure, and the residue is purified by means of preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). Coat the AI product gathering, the precipitate is impregnated with a small amount of dichloromethane and diluted with diisopropyl ether to turbidity. Settling solid matter stands out and dried in vacuum. Obtain 207 mg (59% of theory. prob.) extracted in the connection header.

LC-MS (method 9): Rt=0.67 min; MS (EIpos): m/z=406 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=0.94 (t, 3H), 2.13 (s, 3H), 2.14 (s, 3H), 2.34 (s, 3H), 3.90 (m, 1H), 4.00 (m, 1H), 5.58 (s, 1H), 6.18 (s, 1H), 6.70 (br. s, 1H), 7.06 (br. s, 1H), 7.30 (t, 1H), 7.50 (dd, 1H), 7.56 (s, 1H), 7.71 (s, 1H), 7.78 (dd, 1H).

C. Evaluation of pharmacological efficacy

Abbreviations:
DMEMThe Dulbecco's Modified Eagle
DNADeoxyribonucleic acid
FCSThe rest calf serum
HEPES4-(2-Hydroxyethyl)-1-piperazine-econsultation
PCRPolymerase chain reaction
TrisTris-(hydroxymethyl)-methylamine

The predominant pharmacological properties of the compounds according to the invention can be shown by the following tests:

1. Cellular and is a test in vitro to determine the inhibitory MRI activity and MP-selectivity compared with other steroid hormone receptors

Identification of antagonists of human mineralocorticoid receptor (Mr) and quantitative expression of the effectiveness of these compounds is carried out by using recombinant cell lines. The cell is initially derived from the ovarian epithelial cells of the hamster (Chinese Hamster Ovary, Cho K1, ATCC: American Type Culture Collection, VA 20108, USA).

In this cell line is used chimeric system Cho cell line K1 in which the ligand-binding domains of human steroid hormone receptors combined with DNA-binding domains of the transcription factor of yeast GAL4. So produced GAL4 chimeras of steroid hormone receptors are moved in Cho cells with reporter structure and consistently copied.

Cloning:

To generate GAL4 chimeras of the steroid hormone receptor is cloned CAL4-DNA-binding domain (amino acids 1-147) of the vector pFC2-dbd (firm Stratagene) PCR-enhanced ligand-binding domains mineralocorticoid receptor (Mr, amino acids 734-985), receptor glucocorticoid (GR, amino acids 443-777), progesterone receptor (PR, amino acids 680-933) and androgen receptor (AR, amino acids 667-919) in the vector pIRES2 (firm Ctontech). Reporter structure, which contains five copies of the GAL4 binding places, upstream promoter before timedancing, leads to expression of luciferase fireflies(Photinus pyralis) after activation and adhesion GAL4 chimeras receptor steroid hormones relevant specific agonist aldosterone (Mr), dexamethasone (GR), progesterone (PR) and dihydrotestosterone (AR).

The test is run:

Cell Mr, GR, PR and AR on the day before testing are placed in the medium (Optimem, 2,5% FGS, 2 mm glutamine, 10 mm HEFES) microtitre with 96 (or 384 or 1536) holes and kept in a cell incubator (humidity 96%, the volume ratio of CO25%, 37°C). On the day of the test subject substance is entered in the above-described medium and added to cells. After 10-30 minutes after adding the investigated substances added specific agonists of steroid hormone receptors. After an incubation period of 5-6 hours using the camcorder measured luciferase activity. The measured relative light units give sigmoidal curve stimulation. The calculation of the IC50-values by using the computer program GraphPad PRISM (version 3.02).

In table a shows the IC50values (Mr) is presented in example connections:

Table a
Example No.Mr IC50[nm]
135
423
5 [(-)-enantiomer] 16

2. Test in vitro to determine the possible activation of the binding of calcium channel L-type

Slices of cerebral cortex of rats Wistar serve as source material for radioactive testing of the binding, which is described in detail in the literature as the standard test method [Ehlert, F.J., Roeske, W.R., E. Itoga, Yamamura, H.I., Life Sci. 30, 2191-2202 (1982); Gould, R.J., Murphy, K.M.M., Snyder, S.H., Proc. Natl. Acad. Sci. U.S. 79, 3656-3660] and is used by commercial providers (e.g., MDS Pharma Services) within the framework of contractual research. In this test the binding of a series of dilutions of the studied compounds in dimethyl sulfoxide kept typically for 90 minutes at 25°C in 50 mm buffer solution of Tris HCl, pH 7,7, slice and tritium labeled ligands nitrendipine (0.1 nm) and specific binding of the studied compounds determined by the quantitative assessment is specifically superseded by the radioactively labeled ligand. The values of the IC50obtained using nonlinear regression analysis.

In this test the binding of calcium channels, L-type for classical calcium antagonists type dihydropyridines, such as, for example, nitrendipin, is determined by the value of the IC50equal to 0.3 nm, while for the studied examples described herein the compounds according to the invention obtained values IC50pain is 1 μm, that at least shows reduced 3000 times the affinity for calcium channel L-type. Connection with such little residual affinity binding of calcium channel L-type does not demonstrate in vivo expressed no hemodynamic effects, mediated through calcium channel L-type.

3. Test in vivo for evidence of cardiovascular effects: studies of diuresis in conscious rats in metabolic cages

Rats Wistar (body weight 250-350 g) are kept with free access to food (altromin) and drinking water. 72 hours prior to the test animals instead of normal food receive food with low content of salt, only 0.02% of sodium chloride, (ssniff R/M-H, 10 mm from 0.02% Na, S0602-E081 the firm. ssniff Spezialdiäten GmbH, D-59494 Soest). During the test animals at 24 hours and placed in metabolic cages specially adapted for rats in this weight category (firm Tecniplast Deutschland GmbH, D-82383 Hohenpeiβenberg) with free access to food low in salt and drinking water. By the beginning of the test animals through the gastric tube into the stomach enter the test substance with a volume of 0.5 ml/kg body weight with a suitable solvent. Control animals received only the solvent. The control and test substances are executed in parallel in the same day. The control group and groups receiving a dose of a substance, the state is t, accordingly, from 3-6 animals. During the test animals allocated urine is collected in a receiver at the bottom of the cell. For each animal is determined by the volume of urine per unit of time and the concentration selected in urine sodium and potassium ions using standard methods flame photometry. The measured values are used to calculate the sodium/potassium as a measure of validity of the analyte. The measurement intervals are usually up to 8 hours after the start of the test (day interval) and the time period from 8 to 24 hours after the start of the test (night interval). When the daily range urine is collected with an interval of two hours. In order to obtain a sufficient amount of urine, the animals to the beginning of the test and subsequently at intervals of two hours through the gastric tube is inserted a certain amount of water.

4. Model DOC/salt

The introduction of desoxycorticosterone (DOC) in combination with a diet with a high content of salt and unilateral nephrectomy causes rats hypertonicity, which is characterized by relatively low levels of renin. This endocrine hypertension (DOCK is a direct prestage of aldosterone) results depending on the selected concentration of the DOCK to hypertrophy of the heart and subsequent damage to end organs such as the kidneys, which characterized the proteinuria and glomerulosclerosis. This model with rats allows you to explore the test substance in the presence of antihypertrophic and protecting target organs of action.

Male rats Sprague Dawtey (SD) at the age of 8 weeks (body weight between 250 and 350 grams) are uninephrectomy. For this purpose, rats anestesiologica of 1.5-2%isoflurane in a mixture of 66% N2O and 33% O2and the kidney is removed through a lateral incision. Control animals are so-called fictitious operated individuals whose kidney is not removed.

SD rats that were exposed to uninephrectomy get 1% sodium chloride in drinking water and once a week they done subcutaneous injection desoxycorticosterone (dissolved in sesame oil; firm Sigma) between the blades (high dose: 100 mg/kg / week s.c.; normal dose of 30 mg/kg / week s.c.). The day before the test animals are randomly divided into groups, usually of 10 animals. During the entire test animals receive food and drinking water (ad libitum). Substance is given once daily during 4-8 weeks as an additive to feed or by forced feeding. The control group includes those animals that are kept in the same conditions, but only get either the solvent or feed without analyte.

The action of the investigated substances is determined by measuring heme is dynamic parameters [blood pressure, heart rate, inotropy (dp/dt), relaxation time (Tau), the maximum pressure of the left ventricle, the pressure at the end of the diastole of the left ventricle (LGCDG)], determine the weight of the heart, kidneys and lungs, discharge measurement of protein, as well as by measuring the gene expression of biomarkers (e.g., ANP, Atrial Natriuretic Peptide, BNP, Brain Natriuretic Peptide) by RT/TaqMan-PCR after RNA extraction from cardiac tissue. Statistical evaluation is carried out by testing the student distribution (t-distribution) after pre-checking of deviations in uniformity.

5. Test in vivo for evidence antimineralocorticoid steps on anesthetized dogs

Dogs male or female (Mongrels, Marshall BioResources, USA) weighing 20 to 30 kg is given anesthesia (30 mg/kg intravenously, Narcoren®, Merial, Germany). While the chloride alcuronium (3 mg/animal intravenously, Alloferin®, ICN Pharmaceuticals, Germany) is designed for more myorelaxation. Dogs inhabitauts and introduces a mixture of oxygen and ambient air (40/60 vol.%, approximately 5-6 liters per minute). Ventilation is carried out by the apparatus for artificial respiration company Draeger (Sulla 808) and is controlled by the analyzer CO2(company Engström). Anesthesia is maintained constant infusion pentobarbital (50 µg/kg/min) or izoflurana (1-2 vol.%). Analyti the om serves as fentanyl (10 mcg/kg/hour).

The primary goal of the experience is the study of the influence of the tested compounds acting against mineralocorticoid receptors on the retention of sodium induced by aldosterone. When apply by analogy to a published method [..Ramjoe, U.M.Bucher, J.Richter, and M. De Gasparo, Anti-mineralocorticoid activity of three novel aldosterone antagonists in the conscious dog and in man, in: Diuretics II: Chemistry, Pharmacology, and Clinical Applications, J.B.Puschett und A.Greenberg (Ed.), Elsevier Science Publishing Co., Inc., 1987]. A constant infusion of aldosterone after 3 hours leads to a decrease of the ratio of sodium and potassium in the urine (determination of sodium and potassium by flame photometer). With continued infusion of aldosterone is entered the test substance intravenously, intraduodenal or orally. The positive control is spironolactone, which depending on the dose increases the ratio of sodium and potassium in the urine.

To provide ongoing hemodynamic and to account for the functional parameters of the cardiovascular system is controlled hemodynamics dogs, and it is processed as follows:

- enter the catheter into the bladder to measure urine flow and its composition;

- attach ECG wires to the extremities for ECG measurement;

- input soft tube Fluidmedic PE 300, filled with saline, in A.femoralis, which is connected to the pressure sensor (firm Braun Mclsungen, Germany) for the measurement system is tematicheskoe blood pressure;

- enter the catheter type Millar (type 350 PC, Millar Instruments, Houston, USA) through the left atrium or through the shutter built into the atrium (A.carotis) for measuring hemodynamics of the heart;

- enter the catheter Swan-Ganz (CCOmbo 7.5F, Edwards, Irvine, USA) via the jugular vein (V.jugularis) in the pulmonary artery (A.pulmonalis) for measurement of cardiac output, oxygen saturation, pressure in pulmonary artery pressure and Central Vienna;

- attach the ultrasonic probe fluxmeter (Transsonic Systems, Ithaka, USA) to A.descendens for measuring flow through the aorta;

- attach the ultrasonic probe fluxmeter (Transsonic Systems, Ithaka, USA) to the left coronary artery of the heart (A.coronaria) to measure coronary flow;

- enter Branly in the brain (V.cephalicae) for infusion of pentobarbital, replacement of fluid and blood sampling (determination of the level of the substance in plasma or other clinical blood);

- enter Branly in the saphenous vein of the thigh (V.saphenae) for infusion of fentanyl, aldosterone and for the introduction of substances. The primary signals, if necessary, amplified (amplifier Gould, Gould Instrument Systems, Valley View, United States and monitor Edwards Vigilance, Edwards, Irvine, USA) and then stored in the system Ponemah (DataSciences Inc., Minneapolis, USA). Signals continuously during the entire time of the test is recorded, processed in digital format and are averaged over 30 seconds.

6. The model of chronic INF is rcta myocardial awake rats

Male rats Wistar (body weight 280-300 g, Harlan-Winkelmann) are entered in anesthesia 5%soporano in cells for anaesthesia, inhabitauts, connected to the pump for inhalation (ugo basile 7025 rodent, 50 cycles/min, 7 ml) and injected 2%isofluran/N2O/O2. Body temperature is maintained heated mats at the level of 37-38°C. as analgetika subcutaneously injected temgesic (0.05 mg/kg). The chest is opened on the side between the third and fourth rib and exposed heart. Coronary artery left ventricle of the heart (LAD) using occlusive thread (Prolene 1 metric 5-0 Ethicon1H) is placed below its start (lower left atrium) and Perevoznaya. The onset of myocardial infarction is controlled by the measurement of ECG (Cardioline, Remco, Italy). The chest is closed again and the muscular layer of stitched thread Ethibond excel 1 metric 5/0 6951H, and the upper layer of the skin thread Ethibond excel 3/0 N. Operating seam humidified aerosol adhesive (for example, Nebacetin®N Sprühverband, biologically active substance: semicircular) and anesthesia is terminated.

One week after occlusion of the LAD estimates the size of infarction by echocardiography (Sequoia 512, Acuson). Animals are randomly divided into treatment group and allocated control group not receiving treatment for substance. As an additional control group is "simulators", which was t is like surgery, but was not completed blockage of LAD.

The treatment substance is made within 8 weeks of forced feeding or addition of a substance in food or drinking water. Animals are weighed weekly, and every 14 days is determined by the consumption of water and feed.

After 8 weeks of treatment the animals again given anesthesia (2% isoflurane/N2O/air) and a catheter (Millar SPR-320 2F) through the carotid artery (A. carotis) in the left ventricle. Recorded and measured heart rate, pressure in the left ventricle (DLG), pressure at end diastole left ventricular (DCDLR), contractility (dp/dt) and rate of relaxation (τ) using the Powerlab system (AD Instruments, ADI-PWLB-4SP) and software Chart-5 (SN 425-0586). Then a sample of blood to determine the level of substance in plasma and plasma biomarker, and kills bacteria that cause animals. Heart (the ventricles of the heart, the left ventricle with a septum, right ventricle), liver, lungs and kidney are extracted and weighted.

7. The model rats prone to kick in spontaneous pressure increase

The introduction of salt from the so-called prone to kick in spontaneous increase of pressure in rats (SU-SCAP) paradoxically in a few days results in this model to the termination physiological suppression of renin release and angiotensin induced salt is. Thus, hypertension in SU-SCAP-animals is characterized by relatively high levels of renin. The result of developing hypertension are clearly expressed by the human target organs heart and kidneys, which among other things is characterized by proteinuria and glomerulosclerosis, and General vascular changes. So, first of all due to violations of cerebral circulation in the subsequent course of the disease may develop apoplexy ("heart beats"), which leads to high mortality are not covered by the treatment of animals. In this model, rats can be investigated the effect of a test substance for lowering blood pressure and protecting target organs.

Male SU-SCAP-rats aged 10 weeks (body weight from 190 to 220 g) on the day before the test randomly divided into groups with the same number of animals, usually 10-12 rats. Throughout the test animals optionally salted drinking water (2% NaCl) and food. Substances are entered daily for 6-8 weeks forced feeding or by additives to food (Ssniff, Germany). In the control group animals are kept in the same conditions, but only get either the solvent or feed without the test substance. The study of mortality experience ends when you die approximately 50% of the animal is x from the control group. The action of the test substances is monitored by measuring the systolic blood pressure (through the cuff on the tail) and excretion of protein in the urine. After death is determined by the weight of the heart, kidneys and lungs, as well as the histological pathology of the heart, kidneys and brain semi-quantitative assessment of histological changes. Various biomarkers (e.g., ANP, Atrial Natriuretic Peptide, BNP, Brain Natriuretic Peptide, KIM-1, kidney induced molecule 1, Osteopontin-1) are determined using RT/TaqMan-PCR for the isolation of RNA from heart and kidney tissue or serum or plasma. Statistical evaluation is carried out by testing the student distribution (t-distribution) after pre-checking of deviations in uniformity

C. application Examples of pharmaceutical compositions

Compounds according to the invention can be converted into pharmaceutical preparations as follows:

Tablets:

Composition:

100 mg of the compounds according to the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (natural), 10 mg polyvinylpyrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate. Weight pills 212 mg, a diameter of 8 mm, the radius of convexity 12 mm

Preparation:

The mixture of compounds according to the invention, lactose and starch together with a 5%solution of PVP in water (mass) is converted into granules. After drying, the granulate 5 minutes p is remeshed with stearate. This mixture is pressed standard pressure for tabletting (format tablet see above). Estimated value of the effort of pressing is 15 kN.

Suspension for oral administration:

Composition:

1000 mg of the compounds according to the invention, 1000 mg of ethanol (96%), 400 mg of Redigera®(xanthan gum company. FMC, Pennsylvania, USA) and 99 g of water. A dose of 100 mg of the compounds according to the invention correspond to the 10 ml oral suspension.

Preparation:

Redigel converted to ethanol, the suspension is added to it the connection according to the invention. While stirring the water is added. The mixture constantly getting about 6 hours before the final swelling Rodies.

Solution for oral administration:

Composition:

500 mg of the compounds according to the invention, 2.5 g of Polysorbate and 97 g of papeteries 400. A dose of 100 mg of the compounds according to the invention correspond to 20 g of oral solution.

Preparation:

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

Solution for intravenous infusion:

The connection according to the invention in the concentration, the smaller the solubility of up to saturation, dissolved in a physiologically favourable R is the target (for example, isotonic saline, glucose solution 5% and/or a solution of PEG 400 30%). The solution is filtered under sterile conditions and filled into sterile and pyrogen-free vials for injection.

1. The compound of formula (I)

in which
D means C-R4where
R4means hydrogen or (C1-C4)-alkyl,
Ar stands for a group of the formula
or
where
* means the connection,
R5means hydrogen,
R6means hydrogen,
R8means cyano,
R9means (C1-C4)-alkoxy which can be substituted up to three times by fluorine,
R10means hydrogen,
R1means (C1-C4)-alkyl, which is up to three times can be replaced by fluorine,
R2means (C1-C6)-alkyl,
R3means hydrogen or (C1-C4)-alkyl,
and their pharmaceutically acceptable salts.

2. The compound of formula (I) according to claim 1, in which
D means C-R4where
R4means hydrogen or methyl,
Ar stands for a group of the formula
or
where
* means the connection,
R5means hydrogen,
R8means cyano and
R9means (C1-C4)-alkoxy or triptoreline,
R1Osnach the em methyl or trifluoromethyl,
R2means (C1-C4)-alkyl, and
R3means hydrogen or methyl,
and their pharmaceutically acceptable salts.

3. The compound of formula (I) according to claim 1, in which
D means C-R4where
R4means hydrogen or methyl,
Ar stands for a group of the formula
or
where
* means the connection and
R9means methoxy or triptoreline,
R1means methyl or trifluoromethyl,
R2means methyl, ethyl, n-propyl or isopropyl and
R3means hydrogen or methyl,
and their pharmaceutically acceptable salts.

4. The compound according to claim 1, having one of the following structures

and

and their pharmaceutically acceptable salts.

5. The connection according to one of claims 1 to 4, with one of the following structures


and
and their pharmaceutically acceptable salts.

6. The method of obtaining compounds of formula (I), as defined according to claims 1-5,
characterized in that the compound of formula (II)

in which Ar has the meaning indicated in claims 1 to 5,
in an inert R is storytale with the compound of the formula (III)

in which R1has the meaning specified in claims 1 to 5, and
T denotes allyl or 2-cyanoethyl,
turn in the compound of formula (IV)

in which Ar, T and R1respectively have the above values, which is then in an inert solvent with a compound of formula (V)

in which D and R3have the meanings indicated in claims 1 to 5, condense in the compound of formula (VI)

in which Ar, D, T, R1and R3respectively have the above values,
then the compounds of formula (VI) in an inert solvent with a compound of formula (VII) or a salt trialkylamine formula (VIII)

in which
R12means (C1-C6)-alkyl which may be substituted (C3-C7-cycloalkyl or substituted up to three times by fluorine,
R12Ameans methyl or ethyl,
X represents a leaving group such as halogen, mesilate, toilet or
triplet, and
Y-means dinucleophiles anion, such as tetrafluoroborate, or in the presence of acid with trialkylaluminium formula (IX)

in which R12Ahas the above value, alkylate in the compounds of formula (X-A)

in which Ar, D, T, R1, R3and R12respectively have the above values,
or the compounds of formula (VI) in an inert solvent in the presence of a base transform for the compound of formula (XI)

in which R11is specified according to claim 1 or 2, the value in the compound of the formula (X-C)

in which Ar, D, T, R1, R3and R11respectively have the above values,
after that, in compounds of formula (X) or (X-B) difficult ester group T break down on the carboxylic acid of formula (XII)

in which Ar, D, R1, R2and R3respectively have the meanings indicated in claims 1 to 5,
then 1,1'-carbonyl diimidazol transferred to imidazolidin formula (XIII)

in which Ar, D, R1, R2and R3respectively have the above values,
and then imidazole in an inert solvent transform ammonia into amides of formula (I) with subsequent separation of the final product in free form as a salt or in the form of enantiomers and/or diastereomers.

7. The method according to claim 6, characterized in that the exchange reaction of compounds of formula (II) with the compound of the formula (III) is conducted in the presence of acid, combinations of acids and bases and/or dehydrating reagent.

8. The method according to the .6, characterized in that the exchange reaction of compounds of formula (VI) with the compound of the formula (VII) is carried out in the presence of a base.

9. The method according to one of p-8, characterized in that the exchange reaction of compounds of formula (XIII) with ammonia is carried out in the presence of an auxiliary base.

10. The use of the compounds of formula (I), as defined according to one of claims 1 to 5, for the manufacture of drugs that inhibits SXR activity.

11. Pharmaceutical composition having selective properties to mineralocorticoid receptor antagonists containing the compound of formula (I)as defined according to one of claims 1 to 5, in combination with an inert, non-toxic, pharmaceutically acceptable auxiliary substance.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) where values of substituents are given in description, possessing inhibiting activity with respect to cathepsin K as well as to pharmaceutical compositions for treating diseases, associated with cysteine protease activity and to methods of inhibiting cathepsin K in mammals, requiring such treatment by introduction of efficient amount of compound to mammal.

EFFECT: claimed is application of formula (I) compound or its pharmaceutically acceptable salt in manufacturing medication for application in cathepsin K inhibition in a warm-blooded animal.

10 cl, 45 ex, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to derivatives of antibiotics, which represent compounds of formula (I) and their pharmaceutically acceptable salts, where U, V, W, X, R1, R2, R3, R4, R5, R6, A, B, D, E, G, m and n are determined in description. Invention also relates to pharmaceutical composition, containing said compounds and their application for obtaining medication for prevention or treatment of bacterial infections.

EFFECT: obtaining useful antimicrobial agents, efficient against various pathogens of people and animals.

23 cl, 1 tbl, 186 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazopyridine compounds of formula (I) and pharmaceutically acceptable salts thereof, which inhibit kinase activity, selected from IGF-1R, IR, EGFR and Erb2 and have cell proliferation inhibitor properties. In formula (I) halogeno denotes a halogen; X1 is H or halogen, R1 is H, halogen or halogen-C1-C4alkyl; R2 is H or O-C1-C4alkyl; each R3 is identical or different and is independently selected from H, halogen, C1-C4alkyl, halogen-C1-C4alkyl and O-C1-C4alkyl; one of R4 and R5 is selected from H, halogen, C1-C4alkyl and O-C1-C4alkyl; and the other is a group selected from: (i), (ii) and (iii) where:(1) each R7 is H; a equals 0, 1, 2 or 3; R8 is selected from NH2, N(H)C1-C4alkyl, N(C1-C4alkyl)2 and a group of formula (iv): (iv), where: ring D is a 5-6-member saturated N-heterocycle, possibly containing 1 or 2 additional heteroatoms selected from N and O. Other values of radicals are given in the claim.

EFFECT: compounds can be used in treating different types of cancer.

4 tbl, 250 ex

Chemical compounds // 2469034

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes compounds of formula (I) wherein: R1 means C1-6alkyl or C3-6cycloalkyl; wherein R1 may be optionally carbon-substituted by one or more R6; R2 means hydrogen; R3 and R4 are carbon substitutes, and each is independently specified in carboxy, carbamoyl, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, N-(C1-6alkoxy)carbamoyl, phenyl-R9 - or heterocyclyl-R10-; wherein R3 and R4 may be independently carbon-substituted by one or more R11; and wherein provided said heterocyclyl contains -NH - residue, then nitrogen may be optionally substituted by a group specified in R12; m has the value of 0, 1 or 2; wherein the values R3 may be equal or different; p has the value of 0, 1 or 2; wherein the values R4 may be equal or different; the ring A means nitrogen-containing 5- or 6-member heterocyclic group; wherein drawn nitrogen represents = N- and is found in an ortho-position to R1R2NC(O)NH group in formula (I); the ring B means phenyl or heterocyclyl; wherein provided said heterocyclyl contains -NH- residue, then nitrogen may be optionally substituted by a group specified in R14; R5 is specified in hydroxy, C1-6alkoxy or -N(R15)(R16); R6 and R11 are carbon substitutes and each is independently specified in halo, C1-6alkyl or C1-6alkoxy; R15 and R16 are independently specified in hydrogen, C1-6alkyl, C1-6alkoxy, cyclopropyl or cyclopentyl; R12 and R14 mean C1-6alkyl; wherein R14 may be optionally carbon specified by one or more R23; R9 and R10 mean a direct link; and R23 means halo or methoxy; wherein said heterocyclyl means pyridine, imidazole, triazole, thiazole, benzothiazole, imodazolepyridine, dihydroquinoline or thiadiazole, or its pharmaceutically acceptable salt; provided said compound represents other than ethyl ester of 5-[2-[[(ethylamino)carbonyl]amino]pyridin-4-yl]-4-methyl-4H-1,2,4-triazole-3-carboxylic acid or their pharmaceutically acceptable salts. There are also described pharmaceutical compositions on the basis of said compounds, a method for bacterial DNA-hydrase and/or bacterial topoisomerase IV inhibition in a homoiothermal animal, as well as a method of treating an infection in a homoiothermal animal.

EFFECT: there are prepared and described new compounds showing antibacterial activity.

24 cl, 165 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to fluorinated compounds of formula , where: D, G and L are independently selected from a group consisting of: CH, C and N, and J and M are independently selected from a group consisting of C and N, under the condition that one of J and M denotes C and the other denotes N, wherein at least two of D, G, M, J and L denote N; X denotes CH2; Y is absent; Z denotes NR1R2; R1 and R2 are independently selected from a group consisting of: hydrogen, C1-C10 alkyl, aryl and heteroaryl, which is associated with aromatic radicals having 6 ring atoms, where 1-2 of these ring atoms are N; each of which can be substituted with one or more halogen atoms; or R1 and R2, together with nitrogen to which they are bonded, form a heterocyclic ring having 5 ring members; R3 is selected from a group consisting of: halogen, C1-C10 alkyl; E denotes aryl which can be substituted with one or more fluoro-substitutes or one or more of the following substitutes: C1-C6 alkyl, QC1-C10 alkyl, QC2-C10 alkenyl, each of which can be substituted with one or more fluoro-substitutes, and where Q denotes O; m denotes a number from 1 to 2; under the condition that: R3 is a fluoro-substitute, or group E includes a fluoro-substitute, or group Z includes a fluoro-substitute, with the condition that E does not denote 4-fluorophenyl or a compound of formula , where D, G and L are independently selected from a group consisting of: CH, C and N, and J and M are independently selected from a group consisting of C and N, under the condition that one of J and M denotes C and the other denotes N, wherein at least two of D, G, M, J and L denote N; X denotes CH2; Y is absent; Z denotes NR1R2; R1 and R2 are independently selected from a group consisting of: hydrogen, C1-C10 alkyl, aryl and heteroaryl, which is associated with aromatic radicals having 6 ring atoms, where 1-2 of these ring atoms are N; each of which can be substituted with one or more of the following substitutes: chlorine, bromine, iodine; or R1 and R2, together with nitrogen to which they are bonded, form a heterocyclic ring having 5 ring members; R3 is selected from a group consisting of: chlorine, bromine, iodine, C1-C10 alkyl; E denotes aryl which can be substituted with one or more chlorine, bromine or iodine atoms, and/or one or more of the following substitutes: C1-C6 alkyl, QC1-C10 alkyl, QC2-C10 alkenyl, each of which can be substituted with one or more substitutes selected from chlorine, bromine, iodine or hydroxy, where Q denotes O, wherein when E denotes phenyl, E does not contain, as a substitute, iodine which is directly bonded to it at position 4; m denotes a number from 1 to 2; wherein at least one of Z, E and R3 includes iodine; under the condition that E does not denote 4-iodophenyl and under the condition that said compound is not a compound of formula (Ia), defined in the following table:

The invention also relates to a pharmaceutical composition based on the compound of formula (I) or (Ia), a diagnosis method, a method of treating said disorders, based on use of the compound of formula (I) or (Ia), and use of the compound of formula (I) or (Ia).

EFFECT: obtaining novel compounds useful in treating disorders in mammals, characterised by anomalous density of peripheral benzodiazepine receptors.

24 cl, 13 dwg, 9 tbl, 23 ex

FIELD: chemistry.

SUBSTANCE: compounds, which have formula I , in which A, B, R1, R1a, R2, R3, R4, R5 R6, R7 and R8 have values given in description and are inhibitors of receptor tyrosinkinases, useful in treatment of diseases, mediated by class 3 and class 5 receptor tyrosinkinases. It has been also discovered that specific compounds of the claimed invention are Pim-1 inhibitors. Also claimed is method of obtaining formula I compound.

EFFECT: increase of compound efficiency.

27 cl, 51 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of [1,8]naphthyridine, described by formula I(a), where Z represents -NR41-; A represents phenyl; each R10, R17, R31, R33, R35 and R41 in each case is independently selected from group, consisting of hydrogen, C1-C6alkyl, C1-C6haligenalkyl, phenyl, C3-C6cycloalkyl, -Ls-O-Rs, -Ls-C(O)Rs, -Ls-C(O)ORs and LE-Q-LE-(morpholine); X is selected from group, consisting of bond, -Ls-O-, -Ls-S- and -Ls-C(O)N(Rs)-; R22 is selected from group, consisting of halogen, C1-C6alkyl, phenyl, and phenyl C1-C2alkyl, and, optionally, is substituted with one R26, where R26 in each case is independently selected from group, consisting of halogen, hydroxy, nitro, C1-C6alkyl, -Ls-OSO2Rs; Y is selected from group, consisting of bond, -Ls-O-, -Ls-S(O)-, -Ls-C(O)N(R15) - and -Ls-S-, where R15 represents hydrogen; R50 represents -L1-A1, where A1 is selected from group, consisting of C1-C6alkyl and phenyl and L1 is selected from group, consisting of bond and C1-4alkylene, where A1 is optionally substituted with from one to three R30, and R30 in each case is independently selected from group, consisting of halogen, hydroxy, amino, azido, C1-C6alkyl, -Ls-O-Rs, -Ls-C(O)ORs, -LS-N(RSRS), -Ls-C(=NRs)RS', -Ls-C(O)N(RsRsO, -Ls-N(Rs)C(O)Rs', -LE-Q-LE'- (phenyl or naphthyl) and -LE-Q-LE'-(M5-M6heterocyclyl, which represents pyridine, pyrazine, pyrrolodine, furan, thiophene, piperidine); Ls in each case is independently selected from group, consisting of bond and C1-4alkylene; each RS and Rs' in each case is independently selected from group, consisting of hydrogen, C1-C6alkyl, C3-6alkenyl, C1-6alkoxy, C1-6alkoxyC1-C6alkyl and C1-6alkoxycarbonylC1-C6alkyl; each LE and LE' in each case is independently selected from group, consisting of bond, C1-4alkylene, -C1-4alkylene-NC(O)-C1-4alkylene-; Q in each case is independently selected from group, consisting of bond, -O-, -N(Rs)C(O)-, -C(O)N(Rs)- and -O-SO2-; each R17 and R30 in each case is optionally independently substituted with from one to three substituent(s), selected from group, consisting of halogen and hydroxy; and each heterocyclyl group in -LE-Q-LE'-(M5-M6heterocyclyl) in each case is optionally independently substituted with at least one or two substituents, selected from group, consisting of hydrogen, hydroxy, C1-C6alkyl, C1-6alkoxy, C1-6alkoxycarbonyl, phenyloxy and phenylC1-6alkoxycarbonyl, or to their pharmaceutically acceptable salts. Invention also relates to compounds of formula II(a), pharmaceutical composition based on claimed compounds, application of claimed compounds, method of inhibition of HCV virus replication, method of treating HCV infection.

EFFECT: obtained are novel derivatives, useful in treatment of HCV infection.

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of dihydroquinone and dihydronaphthyridinone of formula (I) or to its pharmaceutically acceptable salts, in which X represents group CR11 or N; Y represents group -C(O)R3, oxazolyl or isoxazolyl; Z represents phenyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydropyranyl, pyridinyl, pyrimidinyl or pyrazolyl, and is substituted with groups R1 and R2; R1 and R2 each independently represents H, halogen, CN group, C1-6alkyl or group -Y1-Y2-Y3-R8, or R1 and R2 together form group -O(CH2)nO-, where n represents 1 or 2; Y1 represents group -O-, -C(O)-, -C(O)O-, -C(O)NR9-, -NR9C(O), -S-, -SO2- or bond; Y2 represents heterocycloalkylene, C1-6alkylene or bond, where heterocycloalkylene stands for cycloalkylene group, in which one, two carbon atoms are substituted with heteroatoms O or N, where heterocycloalkylene group also contains, at least, two carbon atoms and cycloalkylene represents ; Y3 represents group -O-, -C(O)-, -C(O)O-, -C(O)NR9-, -NR9C(O)-, -SO2- or bond; R8 represents H, C1-6alkyl, C1-6alkoxy, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, or group -NR9R10, where R8, different from H, is optionally substituted with C1-6alkyl, halogen, group -CF3 or group -OH; R9 and R10 each independently represents H or C1-6alkyl; R3 represents OH, C1-6alkyl, C1-6alkoxy, (C1-6alkoxy)-C1-6alkoxy; R4 represents C1-6alkyl, phenyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclohexyl, tetrahydropyranyl or tetrahydrothiophene 1,1 -dioxide, and is optionally substituted with C1-6alkyl, hydroxyl group, C1-6alkoxy, halogen, nitro group, amino group, cyano group or halo-lower alkyl; R5 and R6 each independently represents H, halogen, C1-6alkyl, group -CF3, C1-6alkoxy; R7 represents H; R11 represents H. Invention also re4lates to pharmaceutical composition based on formula (I) compound.

EFFECT: obtained are novel dihydroquinone and dihydronaphthyridinone derivatives, useful for treatment of disease mediated by JNK kinase.

9 cl, 4 tbl, 38 ex

FIELD: medicine.

SUBSTANCE: invention refers to an agent for activation of lipoprotein lipase containing a benzene derivative of general formula (1) which is used for preventing and treating hyperlipidemia and obesity. The invention also refers to the benzene derivatives of general formula (1a).

EFFECT: composition improvement.

8 cl, 6 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of general formula 1:

wherein Q, X1, X2, Y, Z, R1, R2, R3, R3', R4, R4', R5, R6, R6' have the values specified in the description.

EFFECT: compounds are the IAP inhibitors which can be used as therapeutic agents for malignant diseases.

13 cl, 20 ex

FIELD: chemistry; pharmaceutics.

SUBSTANCE: present invention relates to 6-substituted isoquinoline and isoquinolinone derivatives of formula or stereoisomer and/or tautomer forms thereof, and/or pharmaceutically acceptable salts thereof, where R1 is H or OH; R2 is R', (C7-C8)alkyl, (C1-C6)alkylene-R', (C2-C6)alkenyl; or R2 is (C1-C6)alkyl, under the condition that in said alkyl residue, at least one hydrogen is substituted with OH or OCH3; or R2 is (C1-C6)alkylene, bonded with cycloalkylamine, where (C1-C4)alkylene forms a second bond with another carbon atom of the cycloalkylamine ring and, together with carbon atoms of the cycloalkyalmine, forms a second 5-8-member ring; R3, R5 and R8 denote H; R4 is H, (C1-C6)alkyl or (C1-C6)alkylene-R'; R6 and R6' independently denote H, (C1-C8)alkyl, (C1-C6)alkylene-R' or C(O)O-(C1-C6)alkyl; R7 is H, halogen or (C1-C6)alkyl; n equals 1; m equals 3 or 5; r equals 0 or 1 and L is O(CH2)p, where p=0; where R' is (C3-C8)cycloalkyl, (C6)aryl; where in residues R2-R8 (C6)aryl is unsubstituted or substituted with one or more suitable groups independently selected from halogen, (C1-C6)alkyl, O-(C1-C6)alkyl, where the alkyl group can be substituted with 1-3 halogen atoms. The invention also relates to use of the compound of formula (I) and a medicinal agent based on the compound of formula (I).

EFFECT: obtaining novel 6-substituted isoquinoline and isoquinolinone derivatives suitable for treating and/or preventing diseases associated with Rho-kinase and/or Rho-kinase-mediated myosin light chain phosphatase phosphorylation.

36 cl, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, more specifically to a new 3-(2,2,2-trimethylhydrazinium)propionate derivative, 3-(2,2,2-trimethylhydrazinium)potassium propionate 5-bromnicotinate (CH3)3N+HCH2CH2COOKRCOO- wherein .

EFFECT: preparing the compound showing high endothelioprotective activity.

1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, more specifically to a new chemical compound, a 3-(2,2,2-trimethylhydrazinium)propionate derivative, namely 3-(2,2,2-trimethylhydrazinium)potassium propionate 5-nicotinate hydroxide showing endothelioprotective activity.

EFFECT: preparing the compound which can find application in medicine in the integrated treatment for endothelial dysfunction correction in cardiovascular diseases.

1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: crystalline form of aliskiren hemifumarate is characterized by the picture of X-ray diffraction in powder demonstrating the following main peaks, given at degrees 2 Teta+/- 0.3 degree: 3.8, 6.5, 7.7, 8.0, 15.6 and 17.4. said form is obtained from solution with weight ratio (weight/weight) acetonyl : ethanol, being in the interval from 90:10 to 75:25 (for instance, 80:20) at suitable temperature in the interval from 15 to 40°C, for instance, by cooling from 37°C to 35°C and especially after dimming - by further cooling to 20°C, ensuring aliskiren hemifumarate crystallisation, filtered and dried under vacuum, for instance, at 10 mbar and 40°C. Crystalline form of aliskiren hemifumarate is applied for obtaining pharmaceutical composition, suitable for treating disease in warm-blooded animal, modulated by rennin inhibition.

EFFECT: stable aliskiren form, with long storage term, purity, improved parameters of fluidity.

10 cl, 16 tbl, 12 dwg, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition by invention possesses antagonistic activity with respect to angiotensin II. Pharmaceutical composition contains 30-80 wt % of inrbesartan or its pharmaceutically acceptable salt as active ingredient and more than 10 wt % of loosening agent in terms of complete composition weight. Pharmaceutical composition does not contain silicon-containing antiadhesive. Pharmaceutical composition of irbesartan is made in form of tablet with film coating. Also described is method of irbesartan tablet manufacturing.

EFFECT: irbesartan tablet possesses dissolution profile at which 80 wt % or more of irbesartan dissolve not later than after 30 min.

25 cl, 1 dwg, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a pharmaceutical composition for treating cardiovascular diseases which contains a therapeutically effective amount of metoprolol succinate as an active substance, and excipients - a combination of hypromellose type 2910 and hypromellose type 2208 taken in the relation of 1:(0.18-472.5), a filler, a glidant, a lubricant. Said pharmaceutical composition is presented in the form of a coated tablet.

EFFECT: said composition is characterised by modified release of the active substance; it is storage-stable and has high mechanical strength.

4 cl, 2 tbl, 12 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely pulmonology, and concerns treating chronic obstructive pulmonary disease accompanied by bronchiectasia. That is ensured by the endotracheal introduction of berodual 2 ml, 0.25% novocaine 5 ml, 1% diphenylhydramine 1 ml, and 1% dioxidine 15 ml; the procedure is performed for 15-20 min; the therapeutic course makes 10-15 daily instillations.

EFFECT: endotracheal introduction of such complex of the therapeutic preparations provides the effective treatment with no side effects, particularly antibiotic-induced bronchial spasm.

2 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine. Group of inventions involves the use of lisuride or terguride or their enantiomers, or their salts or hydrates for treating and preventing pulmonary arterial hypertension, endogenic or exogenic induced glomerular sclerosis, as well as secondary Reynaud's syndrome; the use of lisuride or terguride or their enantiomers, or their salts or hydrates for treating and preventing said diseases; a pharmaceutical composition for treating and preventing said diseases containing a compound specified in a group consisting of lisuride, terguride, their enantiomers, as well as their salts or hydrates, together with a pharmaceutically compatible carriers, excipients and/or solvents.

EFFECT: group of inventions provides higher therapeutic and preventive effectiveness.

6 cl, 10 ex, 3 dwg

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to cardiology and deals with increase of antihypertensive therapy efficiency and reduction of left ventricle hypertrophy in patients with arterial hypertension of 2-nd degree with high risk of development of cardio-vascular complications (risk 3). For this purpose antihypertensive therapy is performed taking into account prevailing temperament or prevailing part of vegetative nervous system, as well as personality anxiety. With account of said factors elaborated are versions of complex therapy, namely: a) beta-adrenoreceptor antagonist (BAA) and diuretic in average day dose in combination with anxiolytic in minimal day dose; b) BAA and diuteric in minimal day dose; c) ACE inhibitor and diuretic in average day dose in combination with antidepressant in minimal day dose; d) ACE inhibitor and diuretic in minimal day dose and antidepressant in minimal day dose.

EFFECT: method ensures efficient treatment of arterial hyopertension and prevention of acute disorders in blood circulation system due to differentiated administration of drug therapy taking into account psychoemotional background in said group of patients.

5 ex, 23 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel polyfunctional fullerene C60 amino acid derivatives of formula (1) , wherein R is H, mono- or dinitroxyC1-6alkyl, maleinimide; N-Z denotes a α, β, γ, ω-amino acid fragment of general formula where m=2-5 and M is a nitroxyC1-6alkyl group, a C1-6alkyl group or an alkali metal salt, having biological activity, as well as methods for production thereof and a method for covalent bonding of fullerene derivatives with SH-containing proteins. The invention also relates to the use of nitroxyalkyl-N-(fullerenyl)amino acids as nitrogen monoxide donors and to use of nitroxyalkyl-N-(fullerenyl)amino acids as quick-acting vasodilatators for antihypertensive therapy. The invention also relates to a method of inhibiting a metastasis process and a method of enhancing antileukemic activity of cyclophosphamide. Disclosed nitroxyalkyl-N-fullerenyl amino acid derivatives have an effect on coronary, contractile and pumping ability of the isolated heart of Vistar rats and are quick-acting vasodilatators which reduce arterial pressure and heart rate and cause relaxation of coronary vessel with less depressive effect on myocardial function compared to nitroglycerine.

EFFECT: disclosed compounds considerably intensify antileukemic activity of cyclophosphamide, increase chemosensitising activity when combined with cyclophosphamide.

9 cl, 8 ex, 3 tbl, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine derivatives of general formula (I-a), having the capacity to simulate axonal growth coupled with the capacity to stimulate angiogenesis and can be used in treating spinal chord damage, damage to the central nervous system as a result of head injuries, ischaemic stroke, ischemic heart disease, peripheral arterial occlusive disease, vascular dementia, cerebrovascular dementia or senile dementia. In the compound of formula (I-a): R0 is a group where R3 and R4 denote a hydrogen atom; R1 is a methyl group; R2 is a methyl group; R5 is a hydrogen atom; R6 is a hydrogen atom; R7 is a methyl group; E is an oxygen atom; is a benzyl group, a cyclohexyl methyl group, an isobutyl group, a cyclohexane carbonyl group, an acetyl group, a phenylsulphonyl group, a cyclohexyl group, a piperidine-1-carbonyl group, a methylbenzyl group, a phenyl group, a fluorobenzyl group, a methoxybenzyl group or a trifluorobenzyl group; or a pharmaceutically acceptable salt thereof.

EFFECT: high efficiency of using the compounds.

4 cl, 16 dwg, 27 tbl, 148 ex

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