Derivatives arylidene or arylalkyl-1-azacycloheptane, mixtures of their isomers or individual isomers or salts

 

(57) Abstract:

Usage: in the chemistry of heterocyclic compounds with inhibiting cholesterol biosynthesis activity. Disclosed are the compounds of formula I, where a is a simple link, unbranched or branched alkylene with 1-17 carbon atoms, albaniles with 2-4 carbon atoms, akinyan with 2-4 carbon atoms, W1and W2is a hydrogen atom or together form a carbon-carbon bond, X is carbonyl or sulfonyl, Y is oxygen atom or sulfur or the group >NR11, R1- R11defined in paragraph 1 of the formula of the invention, mixtures of their isomers or individual isomers or their salts. The proposed compounds may be useful in the treatment of hyperproliferative diseases of the skin and blood vessels, tumors, gallstone disease and mycosis. 3 C.p. f-crystals, 6 PL.

The invention relates to new chemical compounds with valuable properties, in particular to derive arylidene or arylalkyl-1-azacycloheptane General formula (I)

< / BR>
where a is a simple link, unbranched or branched alkylene with 1 to 17 carbon atoms, albaniles with 2 to 4 carbon atoms, akinyan with 2 to 4 carbon atoms,

W1and W2is a hydrogen atom or together form a plastics technology: turning & is UP> - R6is a hydrogen atom or 1, 2 or 3 of the radicals R1- R6which are identical or different, denote unbranched or branched alkyl with 1 to 4 carbon atoms, unsubstituted or substituted by hydroxyl, alkoxyl with 1 to 3 carbon atoms, alkylthiol with 1 to 3 carbon atoms, dialkylamino with 1 to 3 carbon atoms in each alkyl group, or phenyl, unsubstituted or substituted by a halogen atom or alkyl with 1 to 3 carbon atoms, and the remaining radicals R1- R6means a hydrogen atom, with 1, 2 or all three radicals R1, R3and R5can also mean phenyl, unsubstituted or substituted by alkyl with 1 to 3 carbon atoms or a halogen atom,

R7- the atom of hydrogen or halogen, alkyl with 1 to 3 carbon atoms, alkoxy with 1 to 3 carbon atoms,

R8and R9independently from each other mean a hydrogen atom or alkyl with 1 to 3 carbon atoms,

R10a hydrogen atom, cycloalkyl with 3 to 6 carbon atoms, phenyl, unsubstituted or substituted by a halogen atom, an unbranched or branched alkyl with 1 to 4 carbon atoms, trifluoromethyl, alkoxyl with 1 to 3 carbon atoms, a cyano, a nitro-group, alkylsulfonyl with 1 to 3 carbon atoms in the m atom of halogen and alkyl with 1 to 3 carbon atoms, naphthyl and tetrahydronaphthyl, unsubstituted or substituted by fluorine atom, pyridyl, thienyl, unsubstituted or substituted by a halogen atom or alkyl with 1 to 3 carbon atoms,

R11is a hydrogen atom or alkyl with 1 to 3 carbon atoms,

n is 0 or 1,

m is 1 or 2,

p is 0 or 1,

moreover, And does not mean a simple link, if X is sulfonyl and R10means a hydrogen atom,

mixtures of their isomers, or individual isomers or their salts.

Preferred are compounds of General formula (I), where a is a simple link, unbranched or branched alkylene with 1 to 17 carbon atoms, albaniles with 2 to 4 carbon atoms, akinyan with 2 to 4 carbon atoms, W1and W2is a hydrogen atom or together denote a carbon - carbon bond, X is carbonyl or sulfonyl, Y is oxygen atom or sulfur, or R1- R4is a hydrogen atom or 1 or 2 of the radicals R1- R4independent from each other and denote unbranched or branched alkyl with 1 to 4 carbon atoms, unsubstituted or substituted by hydroxyl, alkylthiol with 1 to 3 carbon atoms or dialkylamino with 1 to 3 carbon atoms in each alkyl group, or a phenyl, unsubstituted or substituted ar> which are identical or different, denote a hydrogen atom or methyl, R7- the atom of hydrogen or halogen, alkyl with 1 to 3 carbon atoms, alkoxy with 1 to 3 carbon atoms, R8is a hydrogen atom or alkyl with 1 to 3 carbon atoms, R9is a hydrogen atom, R10is a hydrogen atom, cycloalkyl with 3 to 6 carbon atoms, phenyl, unsubstituted or substituted by one or two halogen atoms, unbranched or branched alkyl with 1 to 4 carbon atoms, trifluoromethyl, methoxy group, cyano, a nitro-group, methylsulfonyl or phenyl, phenyl substituted by one or two triptoreline groups or halogen atom and stands, phenyl, substituted 3 - to 5 fluorine atoms, naphthyl, unsubstituted or substituted by fluorine atom, tetrahydronaphthyl, pyridyl, or thienyl, unsubstituted or substituted by a halogen atom, R11a hydrogen atom or alkyl with 1 to 3 carbon atoms, n is 0 or 1, m is 1 or 2, p is 0 or 1, and not a means of simple communication, if X is sulfonyl and R10means a hydrogen atom, their enantiomers, diastereomers or salts.

Especially preferred are compounds of the above General formula (I), where a is a simple link, unbranched or branched alkylene with 1 to 17 carbon atoms, alkene is less carbon - carbon bond, X is carbonyl or sulfonyl, Y is an oxygen atom or a group R1- R4is a hydrogen atom or 1 or 2 of the radicals R1- R4independent from each other and denote unbranched or branched alkyl with 1 to 4 carbon atoms, and the remaining radicals R1- R4means a hydrogen atom, R5and R6which are identical or different, denote a hydrogen atom or methyl, R7is a hydrogen atom or halogen, methyl or methoxy, R8is a hydrogen atom, methyl, R9is a hydrogen atom, R10a hydrogen atom, cycloalkyl with 3 to 6 carbon atoms, phenyl, unsubstituted or substituted by 1 to 2 halogen atoms, 5 fluorine atoms, alkyl with 1 to 3 carbon atoms, one or two triptoreline groups or halogen atom and alkyl with 1 to 3 carbon atoms, 1-naphthyl, unsubstituted or substituted in position 4 by a fluorine atom, 2-naphthyl, 1, 2, 3, 4-tetrahydro-2-naphthyl, pyridyl, 4-biphenyl, thienyl, unsubstituted or substituted by a halogen atom, R11is a hydrogen atom or methyl, n is 0 or 1, m is 1 or 2, p is 0 or 1, and not a means of simple communication, if X is sulfonyl and R10means a hydrogen atom, their enantiomers, diastereomers or their salts.

Particularly preferred compounds visiprise the low carbon bond, X is carbonyl, Y is an oxygen atom, R1- R6is a hydrogen atom, R7is a hydrogen atom or halogen, methyl, R8- R9is a hydrogen atom, R10is phenyl, substituted in position 4 by a fluorine atom, chlorine or bromine or trifluoromethyl, 4-chloro-3-were, 5-chloro-2-thienyl, cyclohexyl, n is 0 or 1, m is 1, p is 0 or 1, or their salts.

The proposed compounds are inhibitors of cholesterol biosynthesis, in particular inhibitors cyclase activity of 2,3-amoxicilina to lanstein, a key enzyme of the biosynthesis of cholesterol. Therefore, the proposed compounds suitable for the treatment and prevention of hyperlipidemia, hypercholesterolemia and atherosclerosis. Further potential applications of the proposed compounds are the treatment of hyperproliferative diseases of the skin and blood vessels, tumors, gallstone disease and mycosis.

The cyclase 2,3-amoxicilina to lanstein (international classification: EU 5.4.99.7) catalized key stage of the biosynthesis of cholesterol or ergosterol, namely the conversion of 2,3-amoxicilina to larosterna, the first connection with a steroid structure in the cascade biosynthesis. Compared with inhibitors of the previous stages of biosynthesis, as, for example, synthase 3-hydroxy-3-matingly is predominantly higher selectivity, because inhibition of these previous stages of the biosynthesis leads to a reduction in the number formed by the biosynthesis of avalonbay acid, and thus may have a negative impact on the biosynthesis dependent on avalonbay acid substances, such as dolichol, ubiquinone and isopentenyl-t-RNA (see J. Biol. Chemistry 265 p. 18075 - 18078, 1990).

Examples of inhibitors cyclase activity of 2,3-amoxicilina to larosterna are derivatives of diphenyl (see application EP N 0 464 465), derivatives of aminoalkylindole (see application EP N 0 410 359), as well as derivatives of piperidine (see J. Org. Chem. 57, pp. 2794 - 2803, 1992), who show antifugal action. In addition, the enzyme inhibited in mammalian cells the influence of decaline, isodecanol and derivatives indana (see international application WO 89/08450, J. Biol. Chemistry 254 p. 11258 - 11263, 1981, Biochem. Pharmacology 37, pp. 1955 - 1964, 1988 and application JP N 64003144), in addition, the influence of 2-Aza-2,3-dihydroequilin, 2,3-aminosilane (see Bioche. Pharmacology 34, pp. 2765 - 2777, 1985), squalene-epoxy-vinyl ester (see J. Chem. Soc. Perkin Trans. I, 1988, page 461) and 29-methylidene-2,3-occidentalia (see J. Amer. Chem. Soc. 113 p. 9673 - 9674, 1991).

Compounds of General formula (I) can be obtained via the following methods.

a) Compound of General formula (II),

< / BR>
where - to 10 carbon atoms,

subjected to interaction with the compound of General formula (III),

< / BR>
where n, Y and R1- R6have the above values.

The reaction should be carried out in an environment suitable solvent, such as, for example, an alcohol, like methanol, ethanol, or propanol, simple ether, such as diethyl ether, di-n-propyl ether, tetrahydrofuran or dioxane, dimethylformamide, dimethylsulfoxide or a mixture of these solvents, optionally in the presence of binding galoidovodorodov agent, such as, for example, tert.-amine, sodium carbonate or calcium, at a temperature of 0 - 100oC. Preferably the reaction is carried out in an environment of alcohol, such as methanol or ethanol, at a temperature of 20 - 80oC. it is Expedient to apply the compound of General formula (II) in the form of a salt, preferably the hydrochloride, the reaction is carried out in the presence of inorganic or organic bases, preferably tert. organic amine such as triethylamine or ethyldiethanolamine, or in excess of the compounds of General formula (III).

b) the Compound of General formula (IV)

< / BR>
where n, Y and R1- R6have the above values,

R13means alkyl with 1 to 10 atoms ug the/SUP> have the above values.

Thus obtain compounds of General formula I, in which n, m, p, A, X, Y, and R1- R10have the above values, and W1and W2together denote a carbon - carbon bond.

This reaction it is advisable to carry out in the environment of a suitable solvent, such as, for example, a simple ester, such as, diethyl ether, di-n-propyl ether, tetrahydrofuran and dioxane, hydrocarbons, such as benzene, toluene, n-hexane or cyclohexane, or a mixture of these solvents, preferably in a mixture of tetrahydrofuran and n-hexane or tetrahydrofuran and cyclohexane. In this connection the General formula IV is first subjected to interaction with a suitable base, such as, for example, n-utility, finality, sodium amide, sodium hydride or diisopropylamide lithium, at a temperature between -78oC and +20oC to obtain the corresponding phosphonate anion, which is then subjected to interaction with the compound of General formula V at a temperature between -78 and +100oC, preferably at temperatures between -15oC and +50oC.

If a compound of General formula IV contains a hydroxyl group, it is recommended before carrying out the but again be removed upon completion of the reaction. As reagent sililirovanie suitable, for example, trimethylchlorosilane. Removing the protective groups are, for example, by acid hydrolysis or by treatment with fluoride ions, for example, cesium fluoride or tetrabutylammonium fluoride.

C) compounds of General formula (VI)

< / BR>
where n, m, p, W1, W2, Y and R1- R9have the above values,

subjected to interaction with the compound of General formula (VII)

Z1- X - A - R10VII

where A, X and R10have the above values,

Z1means reactive delete the group, such as, for example, a halogen atom, preferably a chlorine atom, or imidazolidine group.

If Z1means a halogen atom, the reaction is carried out in a medium of a suitable inert solvent, such as diethyl ether, toluene, methylene chloride, preferably at temperatures between -50oC and +50oC in the presence of binding galoidovodorodov means, such as, for example, tertiary amines, sodium carbonate or calcium, with a compound of formula VI can be applied not only in free form or in the form of salts, from which place it is possible to free amine by the impact of imidazolidinyl residue, the reaction preferably takes place in an inert solvent, such as, for example, xylene or tetrahydrofuran, at temperatures from room temperature up to the boiling point of the reaction mixture.

If a compound of General formula VI contains hydroxyl group, the reaction can be conducted so as to apply two equivalent compounds of General formula VII and at the end of reaction formed from the hydroxyl group, ester group again omelet. Further, if necessary, saponification formed in this way, the ester group is preferably carried out by alkaline hydrolysis in aqueous solvent, such as, for example, water, a mixture of isopropanol and water, a mixture of tetrahydrofuran and water, a mixture of dioxane and water, for example, in the presence of an alkaline base, such as, for example, sodium hydroxide or potassium hydroxide, at temperatures of 0 - 100oC.

d) Hydrogenation of compounds of General formula I'

< / BR>
where n, m, p, X and R7- R8have the above values,

A' represents a simple bond or unbranched or branched alkylene with 1 to 17 carbon atoms,

W1'and W2'together denote a carbon - carbon bond,

Y' represents an oxygen atom except unbranched or branched alkyl with 1 to 4 carbon atoms, substituted alkylthiol,

R10have the above significance except tanila, unsubstituted or substituted by a halogen atom, a does not mean a simple link, if X is sulfonyl and R10- the hydrogen atom.

In the hydrogenation obtain compounds of General formula (I) in which n, m, p, X and R7- R8have the above values, A means of simple communication or unbranched or branched alkylene with 1 to 17 carbon atoms, W1and W2means a hydrogen atom, and Y represents an oxygen atom or group where R11have the above values, R1- R6have the above values except unbranched or branched alkyl with 1 to 4 carbon atoms, substituted alkylthiol, and R10have the above significance except tanila, unsubstituted or substituted by a halogen atom, and not a means of simple communication, if X is sulfonyl, and R10means a hydrogen atom.

The hydrogenation is carried out in a medium of a suitable solvent, such as, for example, an alcohol, e.g. methanol, ethanol or propanol, esters, such as ethyl acetate, a simple ether, for example diethyl, the mayor, as, for example, hydrogen in the presence of a hydrogenation catalyst, such as, for example, Raney Nickel, rhodium, palladium, palladium on charcoal, platinum, platinum on charcoal, at a hydrogen pressure from 0,2768 - at 13.84 kg/cm2preferably at 1,384 - 2,768 kg/cm2and temperatures 0 - 100oC, preferably at room temperature.

When the hydrogenation present in the radicals R1- R6and R10the halogen atom can be exchanged for a hydrogen atom.

d) Cyclization of compounds of General formula (VIII)

< / BR>
where n, m, p, A, X, W1, W2and R1- R10have the above values.

In the cyclization obtain compounds of General formula (I) in which n, m, p, A, X, W1, W2and R1- R10have the above meanings and Y represents an oxygen atom.

The cyclization is advisable to be implemented in the environment of a suitable solvent, such as, for example, diethyl ether, tetrahydrofuran, dioxane, dimethyl ether of diethylene glycol, methylene chloride, chloroform, benzene, toluene, n-hexane or a mixture of these solvents in the presence of a dehydrating agent such as, for example, a mixture of complex dialkylamide ester of azodicarboxylic acid, trifinio the>. The use of methyl-N-(triethylammonium)carbamate to obtain oxazoline described in Tetrahedron Letters 33, pp. 907 - 910, 1992. Further cyclization method described in Tetrahedron Letters 33, pp. 2807 - 2810, 1992.

Obtained by the above methods, the compound of General formula (I) can be cleaned and highlight well-known techniques, such as, for example, crystallization, distillation or chromatography. They can be translated by known techniques in kislotoupornye salts with inorganic or organic acids.

Depending on the values of R1- R6associated carbon atoms in the proposed compounds of General formula (I) may exist in optically active form. Therefore, this invention includes both the pure isomers and mixtures of various isomers.

The original connection.

The initial compounds of General formula II can be obtained by reacting compounds of General formula IX

< / BR>
where m, p, A, W1, W2X and R7- R10have the above values,

D means cyano, with an alcohol of formula R12OH, where R12means alkyl with 1 to 10 carbon atoms, in the presence of hydrogen chloride.

Compounds of General formula IX, where D oz the mules X

< / BR>
where R7and R8have the above values,

R13is alkyl with 1 to 10 carbon atoms,

D denotes cyano or alkoxycarbonyl,

with a ketone of the formula V

< / BR>
where m, p, A, X, R9and R10have the above values,

in the presence of a base, such as, for example, n-utility, finality, sodium amide, sodium hydride, diisopropylamide lithium, followed, if necessary, obtained by hydrogenation of olefinic double bonds.

An alternative method of preparing compounds of formula IX, where m, p, A, W1, W2X and R7- R10have the above values, and D means alkoxycarbonyl or cyano, is that an ester of phosphonic acid of the formula X, where R7, R8and R13have the above values, and D means alkoxycarbonyl or cyano, is subjected to the interaction with the ketone of formula XI

< / BR>
where m, p and R9have the above values.

Then remove the benzyl residue, for example, by reacting with 1-chloration ether Harborview acid, formed urethane split with methanol and the obtained compound is subjected to interaction with the compound of General formula VII

Z1- X - A - R

Olefinic double bond can then be subjected to hydrogenation.

Esters of phosphonic acid of the formula X can be obtained by the interaction of the halide of formula XII

< / BR>
where R7and R8have the above values,

D denotes cyano or alkoxycarbonyl,

Hal means a halogen atom, e.g. a chlorine atom or bromine, with trialkylphosphites formula (R13O)3P, where R13have the above meaning.

The preferred implementation of this reaction to produce compounds of formula X, where R8means alkyl, is that first obtained the compound of formula X, where R8means a hydrogen atom, which is then subjected to the interaction with the tool alkylation of formula R8- Z2where R8means of the above alkyl, and Z2a halogen atom, such as chlorine atom, bromine or iodine, or sulfonyloxy.

The initial compounds of General formulas III and XII are known in the literature or can be obtained by the known methods.

Ester phosphonic acids of General formula IV can be obtained by interaction of sayasane values

R13have the above significance, with a compound of General formula III.

Ester of phosphonic acid of the formula XIII can be obtained by reacting the compounds of formula X, where D denotes cyano, with an alcohol of formula R12OH, where R12has the abovementioned meaning in the presence of hydrogen chloride.

The compound of General formula V is produced by the interaction of the compounds of formula XIV

< / BR>
where m, p and R9have the above values,

with a compound of General formula VII.

The initial compounds of General formula VI can be obtained by interaction of ester phosphonic acids of General formula IV with a compound of General formula XV

< / BR>
where m, p and R9have the above values,

R14means triphenylmethyl or tert.-butyloxycarbonyl,

in the presence of a strong base, such as, for example, n-utility, finality, sodium amide, sodium hydride, diisopropylamide lithium, followed, if necessary, formed by the catalytic hydrogenation of olefinic double bond and removal of the specified residue R14by processing triperoxonane acid, and protective triphenylmethyl group can simultaneously be removed GID 0, m - 1, R8is a hydrogen atom, n, W1, W2, Y, R1- R7and R9have the above significance, is the fact that the compound of formula XVI

< / BR>
where R9has the above value,

subjected to interaction with the aldehyde of formula XVII

< / BR>
where R7has the above value,

while removing the N-acetylator remainder obtained when this compound is subjected to interaction with alcohol of formula R12OH, where R12have the above significance, in the presence of hydrogen chloride and the thus obtained intermediate product is subjected to cyclization in the result of interaction with the compound of the above formula III.

Then amide group restore, for example, lithium aluminum hydride, followed, if necessary, by hydrogenation of the olefinic double bond.

The initial compounds of General formula VIII can be obtained from compounds of General formula IX, where m, p, W1, W2, X, A, R7- R10have the above values, and D means alkoxycarbonyl by saponification of alkoxycarbonyl with subsequent interaction of the formed carboxylic acid first with N,N'-carbonyl diimidazol and then connected with the family.

As mentioned above, compounds of General formula I possess interesting biological properties. They are inhibitors of cholesterol biosynthesis, in particular inhibitors cyclase activity of 2,3-amoxicilina to larosterna. Due to its biological properties, they are particularly suitable for the treatment and prevention of hyperlipidemia, especially hypercholesterolemia, hyperlipoproteinemia and hypertriglyceridemia and which is the consequence of these changes diseases, such as, for example, coronary heart disease, cerebral ischemia, intermittent claudication, gangrene and other

Therefore, for the treatment of these diseases compounds of General formula I can be used either separately, for which they are applied in the form, which is a further object of the invention, pharmaceutical compositions, which may contain one or more conventional inert carriers and/or diluents, or in combination with other reducing cholesterol or lipid substances. This connection may be given preferably in the form of oral medication, when needed and in the form of rectal drug, for example, in the form of suppositories. Compounds of General formula I may be combined in the mines, holestipol and others, inhibiting the resorption of cholesterol compounds, such as, for example, sitosterol and neomycin affecting biosynthesis of cholesterol compounds, such as, for example, inhibitors of the reductase 3-hydroxy-3-methylglutaryl-coenzyme as lovastatin, simvastatin, pravastatin, and others, inhibitors epoxidase squalene, such as, for example, NB-598 and analog connections, the inhibitors synthesase squalene, such as, for example, representatives of the class isoprenoid-(povinelli)phosphonates, and squarestate.

Further known active substances, which can be combined proposed connection are representatives of the class of fibrates, such as clofibrate, bezafibrat, gemfibrozil, and others, nicotinic acid, its derivatives and analogs, such as, for example, acipimox and probucol.

In addition, compounds of General formula I are suitable for treating diseases that are associated with excessive cell proliferation. Cholesterol is an essential component of cells and therefore it must be available in sufficient quantity to ensure proliferation, i.e. the division of cells.

Inhibition of cell proliferation through inhibition of the biosynthesis of holes the Rila-coenzyme And, by lovastatin.

As examples of diseases associated with excessive cell proliferation, it should be called a tumour. In experiments on cell cultures and in vivo it has been shown that lowering cholesterol in serum or of inhibitors of the reductase 3-hydroxy-3-methylglutaryl-coenzyme And on the biosynthesis of cholesterol leads to reduced tumor growth (see Lancet 339, pp. 1154 - 1156, 1992). Therefore, as a result inhibiting the biosynthesis of cholesterol action proposed compounds of formula I can be applied in the case of neoplastic diseases. However, they can be used as the only active substance or as part of the implementation of known therapeutic methods.

As further examples of hyperproliferative diseases of the skin include, for example, psoriasis, basal cell cancer, squamous cell carcinoma, keratosis and disorders of keratinization. The term "psoriasis" refers to hyperproliferative-inflammatory disease of the skin, which changes the regulatory mechanism of the skin. In particular, there are lesions that are limited to primary and secondary changes of cell proliferation in the epidermis, inflammatory reactions of the skin and the auger in morfologicheskim relation is characterized by increased transformation of epidermal cells, thickened epidermis, deviating from the norm by keratinization and inflammatory cell infiltrates in the layer of the epidermis and infiltration polymorphically of cells in the epidermis, causing the growth cycle of basal cells. Additionally occur hyperkeratosis and parakeratosis cells. The term "keratosis", "basal cell cancer", "plascoenergy cancer and disorders of keratinization" refers to hyperproliferative diseases of the skin, which interrupted the regulation mechanism of proliferatio and differentiation of skin cells.

The compounds of formula I are active as of antagonistas hyperproliferative skin, i.e. as a means of impeding hyperproliferation human keratinocytes. Therefore, they can be used as a means to combat hyperproliferative skin diseases such as psoriasis, basal cell cancer, disorder of keratinization, and keratosis. Thus compounds of General formula I can be used alone or in combination with known active substances either orally or locally.

In addition, new connections can be used to combat hyperproliferative vascular diseases such as, for example, the author coronary balloon angioplasty or bypass surgery, and based on the proliferation of smooth muscle cells. As mentioned above, the proliferation of cells may be hampered by inhibitors of type mevinolin reductase 3-hydroxy-3-methylglutaryl-coenzyme a, such as, for example, lovastatin. Due to the inhibition of the biosynthesis of cholesterol compounds of General formula I are also suitable for the treatment and prophylaxis of these diseases. However, they are applied either separately or in combination with known active substances, such as, for example, used intravenous heparin. Oral same application is preferred.

Furthermore, the new compounds of General formula I can be used for the prevention and treatment associated with gallstones disease. The formation of gallstones is called to the fact that the concentration of cholesterol in bile exceeds the maximum solubility of cholesterol in bile fluid, resulting in cholesterol precipitates as gallstones. Reduces the content of lipids tool of the class of fibrates leads to increased secretion of neutral steroids via the bile and increases the tendency to form gallstones.

In contrast, inhibitors of cholesterol biosynthesis, such as, for example, lo is to reduce the concentration of cholesterol in bile and thereby reduce the so-called lithogenic index, representing the criterion of the probability of gallstone formation. This is indicated in the Gut 31, pp. 348 - 350, 1990, and Z. Gastroenterol. 29, pages 242 - 245, 1991.

In addition, Gastroenterology 102, No. 4, part 2, And 319, 1992, described the activity of lovastatin in the destruction of gallstones, especially in combination with ursodeoxycholic acid. Therefore, due to the mechanism of action of compounds of General formula I are also important for the prevention and treatment associated with gallstones disease. However, they can be used either separately, or in combination with known therapies, such as, for example, the use of ursodeoxycholic acid and canadaline shock waves, preferably in the form of oral medication.

Compounds of General formula I are also suitable for the treatment of infections caused by pathogenic fungi, such as, for example, Gandida albicans, Aspergillus niger, Trichophyton mentagrophytes, Penicillium sp., Cladosporium sp. etc. As mentioned above, the final product of the biosynthesis of sterols in the body of fungi is not cholesterol and ergosterol, which is essential for the integrity and function of cell membranes. Therefore, the inhibition of the biosynthesis of ergosterol leads to impaired growth and possibly to umers the oral, or locally. However, they can be applied, either separately or in combination with known fungicidal active substances, especially with such active substances that affect other stages of the biosynthesis of the Sterol, such as an inhibitor of epoxidase squalene, terbinafine, naftifine, or azole-type inhibitors of lanosterol-14-demethylase, such as ketoconazole and fluconazole.

Further, the compounds of General formula I can be used in poultry. Already described the reduction of cholesterol in eggs due to give the chickens-laying hens inhibitor reductase 3-hydroxy-3-methylglutaryl-coenzyme a, lovastatin (FASEB Journal, 4, A 533, Abstracts 1543, 1990). Getting poor cholesterol eggs is of interest, because the load of the body cholesterol caused by eggs with low cholesterol can be reduced without changing eating habits. Due to the inhibition of the biosynthesis of cholesterol compounds of General formula I can be used in poultry to obtain poor cholesterol eggs. When this connection is preferably used as an additive to feed.

The proposed pharmaceutical composition contains an active substance in terapeutiche the compounds of General formula I was determined by the following methods.

I. Determination of inhibition introduction14C-acetate in steroids besieged by digitonin.

Method

After three days of cultivation cells human hepatoma (HEP-G2) was stimulated in free cholesterol environment for 16 hours. The compounds (dissolved in dimethyl sulfoxide to a final concentration of 0.1%) was added during this phase of stimulation. Then added 200 µmol/l14C-acetate, and then further incubated in a thermostat at 37oC for a further two hours. After cell isolation, saponification of esters of sterols and extraction of sterols was deposited using digitonin. Built-in process digeronimo sterols 14C-acetate was determined by scintillation.

The inhibitory effect was investigated at concentrations of the investigated substances, equal to 10-7mol/l and 10-8mol/L. In this experience we investigated the following connections:

A = 1-(4-chlorobenzoyl)-4-[4-(2-oxazoline-2-yl)-benzylidene]piperidine,

B = 1-(4-chlorobenzoyl)-4-[4-(4,5-dihydro-6H-oxazin-2-yl)-benzylidene] piperidine,

In = 4-[4-(2-oxazoline-2-yl)-benzylidene] -1-(4-trifluoromethyl-benzoyl)piperidine,

G = 1-(4-chloro-3-methylbenzoyl)-4-[4-(2-oxazoline-2-yl)-benzylidene]piperidine,

D = 1-(4-piperidin,

W = 1-cyclohexanecarbonyl-4-[4-(2-oxazoline-2-yl)benzylidene]-piperidine,

C = 4-[4-(2-oxazoline-2-yl)-benzyl]-1-(4-trifluoromethyl-benzoyl)piperidine,

And = 1-(4-chlorobenzoyl)-4-[4-(2-oxazoline-2-yl)-benzyl]piperidine,

K = 1-(4-chlorobenzoyl)-3-[4-(2-oxazoline-2-yl)-benzylidene]-pyrrolidin,

L = 1-(4-chlorobenzoyl)-4-[2-fluoro-4-(2-oxazoline-2-yl)-benzylidene]piperidine,

M = 1-(4-chlorobenzoyl)-4-[3-methyl-4-(2-oxazoline-2-yl)-benzylidene]piperidine,

N = 1-(4-chlorobenzenesulfonyl)-4-[4-(2-oxazoline-2-yl)benzylidene]piperidine,

O = 1-(4-chlorobenzenesulfonyl)-4-[4-(2-imidazolin-2-yl)benzylidene]piperidine,

P = 1-(4-chlorobenzoyl)-4-[4-(2-thiazolin-2-yl)benzyl]piperidine,

P = 1-(4-chlorobenzoyl)-4-[4-(S-5-methyl-2-oxazoline-2-yl)-benzylidene]piperidine,

C = 1-(4-chlorobenzoyl)-4-[4-(R-4-methyl-2-oxazoline-2-yl)-benzylidene]piperidine,

T = 1-(4-chlorobenzoyl)-4-[4-(5-phenyl-2-oxazoline-2-yl)benzylidene]piperidine,

Y = 1-(4-chlorobenzoyl)-4-[4-(5-diethylaminomethyl-2-oxazoline-2-yl)benzylidene]piperidine,

F = 1-(4-chlorobenzoyl)-4-[4-(4-oxymethyl-2-oxazoline-2-yl)benzylidene] piperidine,

X = 4-[4-(S-4-benzyl-2-oxazoline-2-yl)benzylidene] -1-(4-chlorobenzoyl)piperidine,

C = 1-(4-chlorobenzoyl)-4-[4-(2-oxazoline-2-yl)--methyl-benzylidene]piperidine,

H = 1-(5-chloro-2-thienoyl)-4-(2-oxazoline-2-yl)bin-2-yl)benzylidene]-1-(pentafluorobenzoyl)-piperidine,

S = 1-benzoyl-4-[4-(2-oxazoline-2-yl)benzylidene]piperidine,

Yu = 1-(4-tert.-butylbenzoyl)-4-[4-(2-oxazoline-2-yl)benzylidene]piperidine,

I = 1-(4-methoxybenzoyl)-4-[4-(2-oxazoline-2-yl)benzylidene]-piperidine,

AA = 1-(4-bromobenzoyl)-[4-(2-oxazoline-2-yl)benzylidene]-piperidine,

AB = 1-(4-nitrobenzoyl)-4-[4-(2-oxazoline-2-yl)benzylidene]-piperidine,

AB = 1-(4-chlorophenylacetyl)-4-[4-(2-oxazoline-2-yl)benzylidene]piperidine,

AG = 1-(1-afterburner)-4-[4-(2-oxazoline-2-yl)benzylidene]piperidine.

The percentage inhibition installing fragment14C-acetate, achieved the above compounds are summarized in table 1.

As mentioned above, the literature already described cyclase inhibitors of 2,3-amoxicilina to larosterna, which, however, differ significantly in structure from the proposed compounds of General formula I. Similar in structure to compounds of General formula I compounds described in the application EP N 0 468 457 Al. The compound of example 1 of this European application was investigated by the technique described above. It is established that it is active only at concentrations of 10-5and 10-6mol/L. In this case, the percentage inhibition of the known compounds is 41% and 13%, respectively. Sledovatel the distribution activity in vivo in rats after oral villas.

Inhibition of cyclase activity of 2,3-amoxicilina to larosterna leads to increased levels of 2,3-amoxicilina in plasma and liver. Therefore, the number of obrazovavshegosya 2,3-epoxysilane is a direct measure of the activity on the animal. The determination was carried out according to the following method.

Rats-males breed Wistar weight of 160 - 190 g by means of a gastric probe was applicious investigational compound in suspension in a 1.5% aqueous methylcellulose. After 5 hours after application of the blood was taken retroorbital from the venous plexus. Obtaining plasma was carried out according to the method of Bligh and Dyer (see Canad. J. Biochem. Physiol. 37, page 912, 1959). The obtained plasma was purified on a column, and then analyzed using liquid chromatography under pressure. Resulting peaks were identified using standard substances and determining their number. The internal standard was used for checking the reproducibility of the results obtained. The compounds were used at concentrations of 0.1 and 1.0 mg/kg of the compounds and the results of the experiment the concentration of 2,3-amoxicilina in µg/ml in the plasma of rats are summarized in table 2.

Control animals measurable level 2,3-amoxicilina larosterna still not been studied in terms of their ability to inhibit the biosynthesis of cholesterol on the animal.

III. The content of lipids in normolipidemic hamsters.

Hamsters-the males were given free from cholesterol food for 13 days. Feed was mixed with an investigational compound in concentrations of from 0.01 to 0.10%. At the end of the experiment was determined by the total cholesterol content of the fractions of lipids high density, and the content of fractions of lipids low and very low density, for which we used the standard methods. As a comparison served as the control group, which has not been investigated compound. This experience was investigated reduces the content of lipids the effect of the above compound A. the results of the experiment are summarized in table 3.

IV. The definition of lithogenic index normolipemic the hamster.

Lithogenic index is a measure of the tendency to the formation of gallstones and it is defined as the quotient of the maximum equilibrium solubility of cholesterol at a given concentration of bile acids and phospholipids and the actual content of cholesterol in mol. %. It was determined by the method of brown and small, are described in J. Clin. Investig. 61, pages 998 - 1026, 1978). The more lithogenic index, the higher the probability of formation of gallstones. Definition lithog the Rina food for 20 days. This investigational compound was added to the feed at concentrations of 0.01 - 0.1%. At the end of the experience in the serum was determined by the total cholesterol content of the fractions of lipids high density and content of the fractions of lipids low and very low density, and the amount of bile acids, cholesterol and phospholipids in the bile, for which we used the standard methods. This experience has investigated the above-described connection N A. was measured% decrease lithogenic index compared with the control. The results of the experiment are summarized in table 4.

V. Inhibition of cell proliferation

Normal epidermal keratinocytes were grown in standard culture medium in the wet, containing 5% carbon dioxide atmosphere under sterile conditions. Cells of the third passage were inoculated at a density of 12,000/ml After 24 hours the medium was given an investigational compound and the cell number was determined after a further 48 hours. The results of the experiment are defined in comparison with the control, and they are specified as% decrease in the number of cells.

This experience was determined by inhibiting the proliferation of the above-mentioned compounds N A in comparison with the known active substances the ptx2">

The results of the experiment are summarized in table 5.

Definition fungistatic action.

Fungistatic activity was determined using the method of serial dilution. As nutrient broth served Saburo. For the implementation of inoculation was used in about 104- 105colony-forming units/ml Inoculation was carried out with 36oC for 2 to 4 days. It was determined the minimum concentration of inhibition (ICB), i.e. the lowest concentration, which prevents visible growth, as well as the lowest concentration at which there was slow growth of the organism compared to control. This experience has investigated the above connection N and the experimental Results are summarized in table 6.

In therapeutic doses of the compounds N And And are non-toxic. So, for example, the compounds N And H and showed no toxic action on mice after oral application in a dose of 100 mg/kg, once a day for 4 days.

For pharmaceutical applications, the compound of General formula I are known techniques to be processed in the usual pharmaceutical preparations for oral, rectal and local villas.

Preparation for ora who are suppositories. A daily dose of 1 to 1200 mg in the case of patient body weight 60 kg, preferably, however, a daily dose of 5 to 100 mg in the case of patient body weight of 60 kg, the Daily dose is preferably divided into 1 to 3 single doses.

When the local application of the compounds of General formula I may be given in the form of preparations, which contain about 1 to 1000 mg, in particular 10 to 300 mg of active substance per day. The daily dose is preferably divided into 1 to 3 single doses.

Local drugs include gel, cream, lotion, mazes, powders, aerosols and other standard drugs for the application of drugs to the skin. The number of the active substance is 1 to 50 mg/g of the preparation, preferably 5 to 20 mg/g product. In addition to application to the skin of the local drugs can also be used for processing of the mucous membranes, which are available for local treatment. For example, the local drugs can be applied on the mucous membrane of the mouth, lower colon and on other mucous membranes.

In poultry compounds of General formula I can be used to obtain poor cholesterol eggs as a Supplement to a suitable feed. In the stern COA can be added as such to food. So, for example, intended for chickens hens feed in addition to the active substance and, optionally, a standard mixture of vitamins and minerals has, for example, corn, soy flour, meat meal and soybean oil. Such feed mixed with at least one of the compounds of General formula I as active substance in a concentration of 0.01 to 1%, preferably same 0,05 - 0,5%.

The following examples serve to explain the invention. The values of Rfwas determined using the records of the firm of E. Mepk, ,Darmstadt, DE. Used plates on the basis of aluminum oxide brand F-254 and silicagel 60 F-254.

Obtaining parent compounds

An example of a

Complex diethyl ether 4-cyano-benzylphosphonic acid

98 g of 4-(methyl bromide)-benzonitrile and 300 ml of triethylphosphite heated to a temperature of 140oC prior to the reaction. Then heated under reflux for two hours at a bath temperature of 150 - 160oC, the resulting ethylbromide distilled is heated for a further hour at 150oC and then vacuum distilled triethylphosphite. The residue is mixed with 250 ml of cyclohexane in an ice bath, the resulting crystals are sucked off and tx2">

In the same way get:

a) diethyl ether Complex 3-cyano-benzylphosphonic acid from 3-(methyl bromide)-benzonitrile and triethylphosphite. A colorless oil.

b) Complex diethyl ether 4-methoxycarbonyl-3-methyl-benzylphosphonic acid from 4-methoxycarbonyl-3-methylbenzylamine and triethylphosphite. A colorless oil.

in Complex diethyl ether 2-fluoro-4-methoxycarbonyl-benzylphosphonic acid from 2-fluoro-4-methoxycarbonyl-benzylbromide (obtained from complex methyl ester 3-fluoro-4-methyl-benzoic acid and bromine in the environment of carbon tetrachloride in the presence of benzoyl peroxide upon irradiation with a tungsten lamp (power: 1000 watts) and triethylphosphite. A colorless oil.

d) Complex diethyl ether, 2-bromo-4-methoxycarbonyl-benzylphosphonic acid from 2-bromo-4-methoxycarbonylbenzyl (obtained from complex methyl ester 3-bromo-4-methylbenzoic acid and bromine in the environment of carbon tetrachloride in the presence of benzoyl peroxide upon irradiation with a tungsten lamp (power: 1000 watts) and triethylphosphite. A colorless oil.

d) Complex diethyl ether 2-methoxy-4-methoxycarbonyl-benzylphosphonic acid 2-methoxy-4-methyl-benzylbromide (received and risotti benzoyl peroxide upon irradiation with a tungsten lamp (power: 1000 watts) and triethylphosphite. A colorless oil.

Example B

Complex diethyl ether 1-(4-cyanophenyl)-ethylphosphonic acid

To a solution of 7.5 g of a complex of diethyl ether 4-cyano-benzylphosphonic acid in 60 ml of tetrahydrofuran, with stirring, was added dropwise at -50oC to 18.7 ml of a 1.6 M solution of n-utility in n-hexane, and then stirred at -40oC for 25 minutes and then at -40oC was added dropwise 4.7 g of methyliodide in 20 ml of tetrahydrofuran. After stirring overnight at room temperature, evaporated, the residue is mixed with a complex ethyl ester acetic acid, washed with water, the organic phase is dried and evaporated. After purification by column chromatography on silica gel using as eluent a mixture of simple petroleum ether and 2-propanol in a volume ratio of 6 : 1-2 : 1 obtain 5.7 g of the target compound as a colorless oil.

The value of Rf: of 0.52 (silica gel, eluent: a mixture of simple petroleum ether and 2-propanol in a volume ratio of 3 : 1).

The example IN

N-(4-chlorobenzoyl)-4-piperidone

To a suspension of 80.6 g of powder hydrate of the hydrochloride of 4-piperidone in 100 l of tetrahydrofuran, stirring consistently add to 87.5 g of 4-chlorobenzylchloride and ogee within 45 minutes. Then the organic phase is separated, the aqueous phase is extracted twice with complex ethyl ester acetic acid, the combined organic phases, dried and evaporated. The residue is dissolved in ethyl ether complex of acetic acid and mixed with petroleum ether. Get to 88.6 g of target compound with a melting point of 61 - 63oC.

In the same way get:

a) N-(4-chlorobenzenesulfonyl)-4-piperidone of the hydrate of the hydrochloride of 4-piperidone and 4-chlorobenzenesulfonamide. Melting point: 158 - 160oC.

b) N-(4-methylbenzoyl)-4-piperidone of 4-methylbenzylamine and hydrate hydrochloride 4-piperidone. Colorless resin.

C) N-(4-dihydrolinalool)-4-piperidone of the acid chloride of 4-dihydrocortisol acid and a hydrate of the hydrochloride of 4-piperidone. Colorless crystals.

g) N-(4-chlorocinnamoyl)-4-piperidone of the acid chloride of 4-harkrisnowo acid and a hydrate of the hydrochloride of 4-piperidone. Colorless resin.

d) N-hexanoyl-4-piperidone of the acid chloride hexacarbonyl acid and a hydrate of the hydrochloride of 4-piperidone. Colorless resin.

e) N-pivaloyl-4-piperidone from pivaloyloxy and hydrate hydrochloride 4-piperidone. Colorless crystals.

W) N-cyclohexanecarbonyl the crystals.

Example g of 1-(4-chlorobenzoyl)-4-(4-cyano-benzylidene)piperidine

To a solution of Diisopropylamine lithium obtained from 3,34 g Diisopropylamine in 20 ml of tetrahydrofuran and 19 ml of a 1.6 M solution of n-utility in n-hexane, was added dropwise 7.6 g complex diethyl ether 4-cyano-benzylphosphonic acid in 50 ml of tetrahydrofuran at a temperature of 50oC. After 20 minutes stirring at this temperature was added dropwise a solution 7,13 g of N-(4-chlorobenzoyl)-4-piperidone. The reaction mixture is allowed to warm to room temperature over a further 2 hours the mixture is poured on ice and extracted with complex ethyl ester of acetic acid. The organic phase is dried and evaporated. After recrystallization of the complex ethyl ester acetic acid obtain 7.6 g of target compound with a melting point of 134 - 135,5oC.

In the same way get:

a) 1-(4-chlorobenzoyl)-4-(3-cyano-benzylidene)piperidine from diethyl ether complex 3-cyano-benzylphosphonic acid and N-(4-chlorobenzoyl)-4-piperidone. Colorless foam.

b) 1-(4-chlorobenzenesulfonyl)-4-(4-cyano-benzylidene)piperidine complex diethyl ether 4-cyano-benzylphosphonic acid and N-(4-chlorobenzenesulfonyl)-4-piperidone. Melting point: 129 - 130oC.

the new acid and N-(4-chlorobenzoyl)-4-piperidone. Melting point: 134oC.

g) 1-benzyl-3-(4-cyano-benzylidene)piperidine complex diethyl ether 4-cyano-benzylphosphonic acid and N-benzyl-3-piperidone. Melting point: 113oC.

d) 1-(4-chlorobenzoyl-4-(4-methoxycarbonyl-3-methyl-benzylidene)piperidin of complex diethyl ether 4-methoxycarbonyl-3-methyl-benzylphosphonic acid and N-(4-chlorobenzoyl)-4-piperidone. Melting point: 142 - 144oC.

e) 1-(4-chlorobenzoyl-4-(2-fluoro-4-methoxycarbonyl-benzylidene)piperidine complex diethyl ether 2-fluoro-4-methoxycarbonyl-benzylphosphonic acid and N-(4-chlorobenzoyl)-4-piperidone. Melting point: 110 - 112oC.

g) 4-(2-bromo-4-methoxycarbonyl-benzylidene)-1-(4-chloro-benzoyl)piperidine complex diethyl ether, 2-bromo-4-methoxycarbonyl-benzylphosphonic acid and N-(4-chlorobenzoyl)-4-piperidone. Melting point: 140 - 142oC.

C) 1-(4-chlorobenzoyl)-4-(2-methoxy-4-methoxycarbonyl-benzylidene)piperidine complex diethyl ether 2-methoxy-4-methoxycarbonyl-benzylphosphonic acid and N-(4-chlorobenzoyl)-4-piperidone. A colorless oil.

Example D 1-(4-chlorobenzene)-3-(4-cyano-benzylidene)piperidine

To 2.9 g of 1-benzyl-3-(4-cyanobenzylidene)-piperidine in 20 ml of Gloria at a temperature of 0oC, after which the reaction mixture is stirred at a temperature of 0oC for 30 minutes. After 20 minutes at room temperature, evaporated, the residue is mixed with 20 ml of methanol and heated under reflux for 30 minutes. The reaction solution is evaporated, the residue is stirred with 100 ml of complex ethyl ester of acetic acid and sucked off. Gain of 1.9 g of the hydrochloride of 3-(4-cyanobenzylidene)piperidine as a colorless powder, which, together with 2.1 triethylamine are dissolved in 15 ml of methylene chloride, and then at room temperature was added dropwise a 1.75 g of 4-chlorobenzylchloride in 5 ml of methylene chloride. After 30 minutes at room temperature add 100 ml of methylene chloride, twice shaken with water, dried over anhydrous magnesium sulfate, evaporated and purified by column chromatography on silica gel using as eluent a complex ethyl ester of acetic acid. Obtain 1.8 g of the target compound in the form of colourless crystals with a melting point > 210oC.

Example E

1-(4-chlorobenzoyl)-4-(4-cyano-benzyl)piperidine

of 8.4 g of 1-(4-chlorobenzoyl)-4-(4-cyano-benzylidene)piperidine is subjected to hydrogenation in the environment 400 ml of toluene in the presence of 2 g of the further 1 g of palladium catalyst further hydronaut for 2.5 hours, then add 1 g of palladium catalyst and then hydronaut within one hour. Obtain 7.9 g (93.3% of theory) of the target compound as colorless powder with a melting point of 137 - 139oC.

Example G

Hydrochloride of 1-(4-chlorobenzoyl)-4-(4-ethoxymethyl-benzylidene)piperidine

To a suspension of 10.8 g of 1-(4-chlorobenzoyl)-4-(4-cyanobenzylidene)of piperidine in 70 ml of anhydrous ethanol is injected 40,7 hydrogen chloride while cooling with ice. After 16 hours stirring at room temperature the solvent is distilled at a bath temperature of 30oC, the residue is again dissolved in 35 ml of ethanol, and then evaporated. The residue is mixed with a complex ethyl ester of acetic acid. Gain of 13.2 g of the target compound as a colorless powder.

In the same way get:

a) Hydrochloride of 1-(4-chlorobenzoyl)-4-(3-methoxymethyl-benzylidene)piperidine from 1-(4-chlorobenzoyl)-4-(3-cyanobenzylidene)of piperidine and methanol. Colorless resin.

b) Hydrochloride of 1-(4-chlorobenzenesulfonyl)-4-(4-methoxymethyl-benzyliden)-piperidine from 1-(4-chlorobenzenesulfonyl)-4-(4-cyanobenzylidene)of piperidine and methanol. Colorless resin.

b) Hydrochloride of 1-(4-chlorobenzoyl)-4-(4-ethoxymethyl--m is A.

g) of the Hydrochloride of 1-(4-chlorobenzoyl)-3-(4-ethoxymethyl-benzylidene)piperidine from 1-(4-chlorobenzoyl)-3-(4-cyanobenzylidene)of piperidine and ethanol. Colorless crystals.

d) Hydrochloride 1-(4-chlorobenzoyl)-4-(4-ethoxymethyl-benzyl)piperidine from 1-(4-chlorobenzoyl)-4-(4-cyanobenzyl)of piperidine and ethanol. Melting point: 236oC.

Example C

Hydrochloride complex of diethyl ether 4-ethoxymethyl-benzylphosphonic acid

5.6 g of a complex of diethyl ether 4-cyanobenzeneboronic acid and 24 g of hydrogen chloride in 35 ml of anhydrous ethanol was stirred at room temperature for 17 hours. Then the reaction solution is evaporated and the residue is twice evaporated to dryness after prior addition of ethanol. Get colorless crystals, which can then be turned without pre-treatment.

Example

Complex diethyl ether 3-(2-oxazoline-2-yl)benzylphosphonate acid

The product of example And dissolved in 50 ml of ethanol. After adding 1.8 g ethanolamine and 4.1 g of triethylamine, the reaction solution is heated under reflux for two hours, then evaporated at 50oC and the residue is dissolved in 100 ml of complex ethyl ester acetic SUP>oC.

Example 4-[4-(2-oxazoline-2-yl)benzylidene]-1-cetilpiridini

To 2,97 g complex diethyl ester 4-(2-oxazoline-2-yl)benzylphosphonate acid was added dropwise at 6.25 ml of a 1.5 M solution of n-utility in hexane at a temperature of -60oC, and then stirred for 20 minutes and added dropwise 3.4 g of N-trityl-4-piperidone (obtained from the hydrochloride hydrate of 4-piperidone and Fritillaria) in 20 ml of tetrahydrofuran. Stir at a temperature of -60oC for 25 minutes. Then the reaction solution is allowed to warm to room temperature and at this temperature, stirred for 1.5 hours. Then the reaction solution vmeshivat 150 ml ice water, extracted three times difficult ethyl ester acetic acid, taken in an amount of 150 ml, the organic phase is dried and evaporated. The residue is purified by column chromatography on silica gel using as eluent a mixture of petroleum ether and complex ethyl ester of acetic acid in a volume ratio of 1 : 1. Obtain 1.7 g of the target compound with a melting point of 110 - 115oC.

Similarly, get:

a) 4[4-(2-oxazoline-2-yl)benzylidene] -1-trityl-hexahydroazepin of complex diethyl ester 4-(2-oxazoline-2-yl)benzyl escueta foam. The value of Rf: to 0.40 (silica gel; eluent: a mixture of petroleum ether and complex ethyl ester of acetic acid in a volume ratio 1 : 1).

b) 1-tert.-butyloxycarbonyl-4-[4-(2-oxazoline-2-yl)benzylidene]-piperidine complex diethyl ester 4-(2-oxazoline-2-yl)benzylphosphonate acid and N-tert. -butyloxycarbonyl-4-piperidone (obtained from the hydrochloride hydrate of 4-piperidone and complex di-tert.-butyl ether pyrogallol acid). Melting point: 74oC.

Example L

1-tert.-butyloxycarbonyl-4-[4-(2-oxazoline-2-yl)benzyl]piperidine

2.4 g (7 mmol) of 1-tert. -butyloxycarbonyl-4-[4-(2-oxazoline-2-yl)benzylidene] piperidine, dissolved in 70 ml of anhydrous ethanol and 20 ml of complex ethyl ester acetic acid, is subjected to hydrogenation at room temperature and hydrogen pressure 3,5155 kg/cm2within 20 minutes in the presence of 2.5 g of 10% palladium on coal. The catalyst is sucked off, the filtrate evaporated and the residue is subjected to further transformation without purification.

Example M

4-[4-(2-oxazoline-2-yl)benzylidene]piperidine

1.0 g of 4-[4-(2-oxazoline-2-yl)benzylidene]-1-cetilpiridini in 20 ml of methylene chloride is slowly mixed with 2 ml triperoxonane CMEs poured into 150 ml ice water and the pH of the medium also adjusted to 11.5 using 6 N. sodium lye. After 10 minutes of stirring extracted twice with simple diethyl ether, taken in an amount of 150 ml, the combined organic phases are washed, dried and evaporated. The residue is purified by column chromatography on aluminium oxide using as elution solvent a mixture of methylene chloride and methanol in a volume ratio of 40 : 1. Obtain 340 mg of the target compound with a melting point of 126oC.

In the same way get:

a) 4[4-(2-oxazoline-2-yl)benzylidene]hexahydroazepin 4[4-(2-oxazoline-2-yl)benzylidene] -1-trityl-hexahydroazepin and triperoxonane acid. Melting point: sintering, since the temperature 46oC.

b) 4-[4-(2-oxazoline-2-yl)benzyl] piperidine from 1-tert.-butyloxycarbonyl-4-[4-(2-oxazoline)-2-yl)-benzyl] -piperidine and triperoxonane acid. Melting point: 110oC.

Example N

3-[4-(2-oxazoline-2-yl)benzylidene]pyrrolidin

To the suspension are 5.36 g of sodium hydride (55% in oil) in 50 ml of tetrahydrofuran was added dropwise a solution of 5.0 g of N-acetyl-2-pyrrolidone and 5.1 g of 4-cyanobenzaldehyde in 50 ml of tetrahydrofuran at a temperature of 5 to 10oC, and then stirred at a temperature of 0oC for one hour. Excess sodium hydride glacial acetic acid. The residue is sucked off, dissolved in a mixture of methylene chloride and methanol, dried and concentrated. Obtain 1.4 g of 3-(4-cyanobenzylidene)-2-pyrrolidone as a colorless powder with a melting point of 260oC.

of 1.36 g of the specified product are suspended in 30 ml of methanol. Under ice cooling injected approximately 10 g of hydrogen chloride, stirred at room temperature for 20 hours and the reaction mixture is allowed to stand at room temperature for two days. After thickening, the residue is mixed with 40 ml of ethanol, add to 0.68 g of ethanolamine and 1.52 g of triethylamine, the mixture is heated under reflux for two hours and concentrated. The residue is stirred with a mixture of water and complex ethyl ester acetic acid, the residue is sucked off and dried.

Get 1.5 g of 3-[4-(2-oxazoline-2-yl)benzylidene]-2-pyrrolidone with a melting point of 258 - 262oC.

To 0,49 g of the product specified in 10 ml of tetrahydrofuran added 152 mg of lithium aluminum hydride, and then stirred at room temperature for two hours. After adding 0.3 ml of water was stirred at room temperature for 30 minutes and the rest suck. The target connection receive in the form of a solution, which is then transformed without PR is n] piperidine

9.0 g of 1-(4-chlorobenzoyl)-4-[2-fluoro-4-methoxycarbonyl-benzylidene]piperidine in 150 ml of methanol is mixed with a solution of 4.0 g 84% sodium hydroxide in 100 ml of water, then stirred at room temperature overnight. The methanol is evaporated, the residue is mixed with water when cooled and acidified with diluted hydrochloric acid. The residue is sucked off, washed with water and dried in vacuum. Obtain 8.6 g (95% of theory) of 4-(4-carboxy-2-fluoro-benzylidene)-1-(4-chlorobenzoyl)piperidine with a melting point of 170 - 173oC.

2.0 g of the specified product and 0.88 g of N,N'-carbonyldiimidazole in 50 ml kisslola heated to a temperature of 60oC for one hour, then add 0.32 g ethanolamine and stirred for three hours at a bath temperature of 160oC. After evaporation of the solvent the residue is mixed with water, extracted three times with methylene chloride, the organic extract is dried and evaporated. The residue is purified by column chromatography on silica gel using as eluent a mixture of complex ethyl ester of acetic acid and methanol in a volume ratio of 10 : 0.5 to. Obtain 0.4 g of the target compound as a colorless oil. The value of Rf: of 0.25 (silica gel; a complex mixture of ethyl ether acetic kolloksilinovy)-3-methyl-benzylidene] piperidine from 1-(4-chlorobenzoyl)-4-(4-methoxycarbonyl-3-methyl-benzylidene)of piperidine and ethanolamine. A colorless oil. The value of Rf: 0,2 (eluent: a mixture of complex ethyl ester acetic acid, petroleum ether and methanol in a volume ratio of 10 : 5 : 1).

Saponification source of ester is carried out at boiling.

b) 4-[2-bromo-4-(2-acetylaminobenzoic)benzylidene]-1-(4-chlorobenzoyl)-piperidine from 4-(2-bromo-4-methoxycarbonyl-benzylidene)-1-(4-chlorbenzoyl)of piperidine and ethanolamine. Melting point: 90 - 92oC.

C) 1-(4-chlorobenzoyl)-4-[4-(2-acetylaminobenzoic)-2-methoxy-benzylidene] piperidine from 4-(2-methoxy-4-methoxycarbonyl-benzylidene)-1-(4-chlorbenzoyl)of piperidine and ethanolamine. A colorless oil.

Get the targeted products

Example 1

1-(4-chlorobenzoyl)-4-[4-(2-oxazoline-2-yl)benzylidene]piperidine

of 13.2 g (0,0315 mol) of the hydrochloride of 1-(4-chlorobenzoyl)-4-(4-ethoxymethyleneamino)piperidine suspended in 59 ml of anhydrous ethanol. After addition of 2.64 g (0,042 mol) of ethanolamine and 6.5 g (0,063 mol) of triethylamine is heated under reflux for 90 minutes. After cooling in an ice bath is sucked off and washed with ethanol. Obtain 10.4 g (88,6% of theory) of the target compound with a melting point of 181 - 183oC. Range1H-NMR (200 MHz, CDCl3); the signals at h/mill is unity gain by interacting with efitnessnow acid in ethanol medium during cooling. Hydrochloride specal at 69 - 71oC and hardens again when 80 - 81oC with evolution of gas.

In the same way get: a) 1-(4-chlorobenzenesulfonyl)-4-[4-(2-oxazoline-2-yl)benzylidene] piperidine from 1-(4-chlorobenzenesulfonyl)-4-(4-methoxymethyl-benzyliden)piperidine as hydrochloride and ethanolamine. Melting point: 191,5 - 192.5 kgoC.

b) 1-(chlorobenzoyl)-4-[4-(4,5-dihydro-6N-oxazin-2-yl)-benzylidene]piperidine of the hydrochloride of 1-(4-chlorobenzoyl)-4-[4-(4-ethoxymethyl)-benzylidene]piperidine and 3-aminopropanol. Melting point: 159 - 160oC.

C) 1-(4-chlorobenzoyl)-4-[4-(4,4-dimethyl-2-oxazoline-2-yl)-benzylidene]piperidine of the hydrochloride of 1-(4-chlorobenzoyl)-4-(4-ethoxymethyl-benzylidene)piperidine and 2-amino-2-methylpropanol. Melting point: 145 - 146oC.

g) 1-(4-chlorobenzoyl)-4-[4-(2-thiazolin-2-yl)benzylidene] piperidine of the hydrochloride of 1-(4-chlorobenzoyl)-4-(4-ethoxymethyl-benzyliden)of piperidine and group probably facilitates. Melting point: 162 - 163oC.

d) 1-(4-chlorobenzoyl)-4-[4-(R-5-methyl-2-oxazoline-2-yl)-benzylidene] piperidine of the hydrochloride of 1-(4-chlorobenzoyl)-4-(4-ethoxymethyl-benzyliden)of piperidine and R-1-amino-2-propanol. Melting point: 104 - 106oC.

e) 1-(4-chlorobenzoyl)-4-[4-(S-5-methyl-2-oxazoline-2-yl)-b is-2-propanol. Melting point: 107 - 108oC.

W) 1-(4-chlorobenzoyl)-4-[3-(-oxazoline-2-yl)benzylidene] piperidine of the hydrochloride of 1-(4-chlorobenzoyl)-4-(3-methoxymethyl-benzyliden)of piperidine and ethanolamine. Melting point: 90 - 92oC.

C) 1-(4-chlorobenzoyl)-4-[4-(5,5-dimethyl-2-oxazoline-2-yl)-benzylidene] piperidine of the hydrochloride of 1-(4-chlorobenzoyl)-4-(4-ethoxymethyl-benzylidene)piperidine and 2-hydroxy-2-methylpropylamine. Melting point: 145 - 156oC.

s) 1-(4-chlorobenzenesulfonyl)-4-[4-(2-imidazolin-2-yl)benzylidene]piperidine of the hydrochloride of 1-(4-chlorobenzenesulfonyl)-4-(4-methoxymethyl-benzyliden)of piperidine and Ethylenediamine. Melting point: 222 - 224oC.

K) 1-(4-chlorobenzenesulfonyl)-4-[4-(N-methyl-2-imidazolin-2-yl)benzylidene] piperidine of the hydrochloride of 1-(4-chlorobenzenesulfonyl)-4-(4-methoxymethyl-benzylidene)piperidine and N-methylethylenediamine. Colorless foam. The value of Rf: 0,24 (aluminium oxide; complex ethyl ester of acetic acid).

l) 1-(4-chlorobenzoyl)-4-[4-(S-4-methyl-2-oxazoline-2-yl)-benzylidene] piperidine of the hydrochloride of 1-(4-chlorobenzoyl)-4-(4-ethoxymethyl-benzyliden)of piperidine and L-alaninol. Melting point: 143oC.

m) 1-(4-chlorobenzoyl)-4-[4-(R-4-methyl-2-oxazoline-2-yl)benzylidene]Pieper isoC.

n) 1-(4-chlorobenzoyl)-4-[4-(5-phenyl-2-oxazoline-2-yl)benzylidene]piperidine of the hydrochloride of 1-(4-chlorobenzoyl)-4-(4-ethoxymethyl-benzylidene)piperidine and 2-amino-1-phenylethanol. Melting point: 147oC.

o) 1-(4-chlorobenzoyl)-4-[4-(5-diethylaminomethyl-2-oxazoline-2-yl)benzylidene] piperidine of the hydrochloride of 1-(4-chlorobenzoyl)-4-(4-ethoxymethyl-benzylidene)piperidine and 1-amino-3-diethylamino-2-propanol. Melting point: 91oC.

p) 1-(4-chlorobenzoyl)-4-[4-(4-oxymethyl-2-oxazoline-2-yl)-benzylidene] piperidine of the hydrochloride of 1-(4-chlorobenzoyl)-4-(4-ethoxymethyl-benzyliden)of piperidine and DL-serinol. Melting point: 137oC.

R) 1-(4-chlorobenzoyl)-4-[4-(2-oxazoline-2-yl)--methyl-benzylidene]piperidine of the hydrochloride of 1-(4-chlorobenzoyl)-4-(4-ethoxymethyl--methyl-benzylidene)of piperidine and ethanolamine. Melting point: 192oC.

C) 1-(4-chlorobenzoyl)-4-[4-(R-4-phenyl-2-oxazoline-2-yl)-benzylidene] piperidine from 1-(4-chlorobenzoyl)-4-(4-ethoxymethyl-benzyliden)of piperidine and R-2-amino-2-phenylethanol. Melting point: 130oC.

t) 4-[4-(R-4-benzyl-2-oxazoline-2-yl)benzylidene] -1-(4-chlorobenzoyl)piperidine from 1-(4-chlorobenzoyl)-4-(4-ethoxymethyl-benzyliden)of piperidine and R-2-amino-3-phenyl-1-propanol. Point plale the oil)-4-(4-ethoxymethyl-benzyliden)of piperidine and S-2-amino-3-phenyl-1-propanol. Melting point: 142 - 143oC.

f) 1-(4-chlorobenzoyl)-4-[4-(4-((4-chlorbenzyl))-2-oxazoline-2-yl)benzylidene] piperidine from 1-(4-chlorobenzoyl)-4-(4-ethoxymethyl-benzylidene)piperidine and 4-chlorophenylalanine. Melting point: 127oC.

x) 1-(4-chlorobenzoyl)-4-[4-(4-((2-methylthioethyl))-2-oxazoline-2-yl)benzylidene] piperidine from 1-(4-chlorobenzoyl)-4-(4-ethoxymethyl-benzyliden)of piperidine and L-methioninol. Melting point: 95 - 96oC.

C) 1-(4-chlorobenzoyl)-4-[4-(4-((1-methyl-S-propyl))-2-oxazoline-2-yl)benzylidene] piperidine from 1-(4-chlorobenzoyl)-4-(4-ethoxymethyl-benzyliden)of piperidine and S-isoleucinol. Melting point: 101oC.

h) 1-(4-chlorobenzoyl)-4-[4-(2-imidazolin-2-yl)benzyl]piperidine from hydrochloride of 1-(4-chlorobenzoyl)-4-(4-ethoxymethyl-benzyl)piperidine and Ethylenediamine. Melting point: 155 - 157oC.

W) 1-(4-chlorobenzoyl)-4-[4-(S-4-methyl-2-oxazoline-2-yl)-benzyl]piperidine from hydrochloride of 1-(4-chlorobenzoyl)-4-(4-ethoxymethyl-benzyl)piperidine and L-alaninol. Melting point: 92 - 95oC.

y) 1-(4-chlorobenzoyl)-4-[4-(N-methyl-2-imidazolin-2-yl)-benzyl] piperidine from hydrochloride of 1-(4-chlorobenzoyl)-4-(4-ethoxymethyl-benzyl)piperidine and N-methylethylenediamine. Melting point: 163 - 167oC.

s) 1-(4-what SIL)of piperidine and S-1-amino-2-propanol. Melting point: 98 - 100oC.

h) 1-(4-chlorobenzoyl)-4-[4-(R-5-methyl-2-oxazoline-2-yl)-benzyl]piperidine from hydrochloride of 1-(4-chlorobenzoyl)-4-(4-ethoxymethyl-benzyl)piperidine and R-1-amino-2-propanol. Melting point: 99 - 101oC.

I) 1-(4-chlorobenzoyl)-4-[4-(2-thiazolin-2-yl)benzyl] piperidine from hydrochloride of 1-(4-chlorobenzoyl)-4-(4-ethoxymethyl-benzyl)piperidine and group probably facilitates. Melting point: 106 - 108oC.

AA) 1-(4-chlorobenzoyl)-4-[4-(4,5-dihydro-6N-oxazin-2-yl)benzyl]piperidine from hydrochloride of 1-(4-chlorobenzoyl)-4-(4-ethoxymethyl-benzyl)piperidine and 3-aminopropanol. Melting point: 106 - 108oC.

AB) 1-(4-chlorobenzoyl)-3-[4-(2-oxazoline-2-yl)benzylidene] -piperidine of the hydrochloride of 1-(4-chlorobenzoyl)-3-(4-ethoxymethyl-benzyliden)of piperidine and ethanolamine. Melting point: 151oC.

Example 2

1-(4-chlorobenzoyl)-4-[4-(2-oxazoline-2-yl)benzylidene]piperidine

To 6 g (0.02 mol) diethyl ether complex of 4-(2-oxazoline-2-yl)benzylphosphonate acid in 80 ml of tetrahydrofuran was added dropwise 12.5 ml (0,021 mol) of 1.6 m solution of n-utility in n-hexane at a temperature of -50oC. the Dark red solution was stirred at a temperature of -55oC for 25 minutes, then added dropwise 4.7 g (0.02 mol) of N-(4-harbou mixture vmeshivat in 30 ml of water, the residue is sucked off after a further 20 minutes and recrystallized from ethanol. Obtain 3.2 g (42% of theory) of the desired product, identical with the product of example 1.

In the same way get:

a) 1-(4-methylbenzoyl)-4-[4-(2-oxazoline-2-yl)benzylidene] piperidine complex diethyl ester 4-(2-oxazoline-2-yl)benzylphosphonate acid and N-(4-methylbenzoyl)-4-piperidone. Melting point: 169 - 171oC.

b) 1-(dehydrolinalool)-4-[4-(2-oxazoline-2-yl)benzylidene] piperidine complex diethyl ester 4-(2-oxazoline-2-yl)benzylphosphonate acid and N-dihydroindol-4-piperidone. Melting point: 98 - 100oC.

C) 1-(4-chlorocinnamoyl)-4-[4-(2-oxazoline-2-yl)-benzylidene]piperidine complex diethyl ester 4-(2-oxazoline-2-yl)benzylphosphonate acid and N-(4-chlorocinnamoyl)-4-piperidone. The value of Rf: 0,86 (aluminium oxide; complex ethyl ester of acetic acid).

g) 1-hexanoyl-4-[4-(2-oxazoline-2-yl)benzylidene] piperidine complex diethyl ester 4-(2-oxazoline-2-yl)benzylphosphonate acid and N-hexanoyl-4-piperidone. Melting point: 98 - 100oC.

d) 4-[4-(2-oxazoline-2-yl)benzylidene-1-Jaloliddin of complex diethyl ester 4-(2-oxazoline-2-yl)pencilfish[4-(2-oxazoline-2-yl)-benzylidene]piperidine complex diethyl ester 4-(2-oxazoline-2-yl)benzylphosphonate acid and N-cyclohexanecarbonyl-4-piperidone. Melting point: 163 - 164oC.

Example 3

4-[4-(2-oxazoline-2-yl)benzylidene]-1-(4-trifloromethyl)piperidine

120 mg (0.5 mmol) 4-[4-(2-oxazoline-2-yl)benzylidene]piperidine and 75 mg (0.75 mmol) of triethylamine in 3 ml of complex ethyl ester of acetic acid and 2 ml of methylene chloride cooled to a temperature (-5) - (-10)oC and add the 104.3 mg (0.5 mmol) 4-triftormetilfullerenov. Stir at room temperature for 90 minutes, diluted with complex ethyl ester acetic acid, successively washed with water, 2 N. sodium lye and saturated common salt solution, dried and evaporated. Obtain 115 mg (56% of theory) of the target compound with a melting point of 142oC.

Range1H-NMR (200 MHz, CDCL3); the signals at h/mill.: 2.3 - 2.7 (m, 4H), 3.3 - 3.5 (m, 2H), 3.7 - 3.9 (m, 2H), 4.05 (t, 3H), 4.4 (t, 3H), 6.4 (s, 1H), 7.2 (d, 2H), 7.55 (d, 2H), 7.7 (d, 2H), 7.9 (d, 2H).

In the same way get:

a) 4-[4-(2-oxazoline-2-yl)benzylidene] -1-steroiddependent of 4-[4-(2-oxazoline-2-yl)benzylidene] piperidine and acid chloride stearic acid. Melting point: 72oC.

b) 1-cyclopropanecarbonyl-4-[4-(2-oxazoline-2-yl)benzylidene]-piperidine from 4-[4-(2-oxazoline-2-yl)benzylidene] piperidine and acid chloride CEC is Il)benzylidene]piperidine from 4-[4-(2-oxazoline-2-yl)benzylidene] piperidine and 4-chloro-3-methylbenzonitrile. Melting point: 145oC.

g) 1-(3,4-dichlorophenylethyl)-4-[4-(2-oxazoline-2-yl)benzylidene]piperidine from 4-[4-(2-oxazoline-2-yl)benzylidene] piperidine and acid chloride 3,4-dichlorophenylamino acid. Melting point: 132oC.

d) 1-(4-perbenzoic)-4-[4-(2-oxazoline-2-yl)benzylidene] -piperidine from 4-[4-(2-oxazoline-2-yl)benzylidene]piperidine and acid chloride of 4-fermenting acid. Melting point: 146oC.

e) 1-(5-chloro-2-thienoyl)-4-[4-(2-oxazoline-2-yl)benzylidene)-piperidine from 4-[4-(2-oxazoline-2-yl)benzylidene] piperidine and acid chloride of 5-fortifikatsionnoy acid. Melting point: 145oC.

W) 1-(2-naphthylacetyl)-4-[4-(2-oxazoline-2-yl)benzylidene)-piperidine from 4-[4-(2-oxazoline-2-yl)benzylidene] piperidine and acid chloride of 2-naftiluksusnoi acid. Melting point: 133oC.

C) 1-(4-chlorobenzoyl)-4-[4-(2-oxazoline-2-yl)benzylidene]hexahydroazepin of 4-[4-(2-oxazoline-2-yl)benzylidene] hexahydroazepin and 4-chlorobenzylchloride. Viscous oil. The value of Rf: 0,42 (aluminium oxide; a mixture of simple petroleum ether and complex ethyl ester of acetic acid in a volume ratio 1 : 1).

s) 1-(4-chlorobenzoyl)-4-[4-(2-oxazoline-2-yl)benzyl] piperidine from 4-[4-(2-oxazoline-2-yl)gasoline is in-2-yl)benzylidene] piperidine from 4-[4-(2-oxazoline-2-yl)benzylidene]piperidine and acid chloride of 1-naphthaleneboronic acid. Melting point: 146 - 149oC.

l) 1-(3,4-differentail)-4-[4-(2-oxazoline-2-yl)benzylidene]piperidine from 4-[4-(2-oxazoline-2-yl)benzylidene] piperidine and 3,4-differentiald. Melting point: 133 - 135oC.

m) 1-(3,5-bis-trifloromethyl)-4-[4-(2-oxazoline-2-yl)-benzylidene] piperidine from 4-[4-(2-oxazoline-2-yl)benzylidene]piperidine and 3,5-bis-triftormetilfullerenov. Melting point: 137oC.

n) 1-(4-cyanobenzoyl)-4-[4-(2-oxazoline-2-yl)-benzylidene] piperidine from 4-[4-(2-oxazoline-2-yl)benzylidene] piperidine and 4-cyanobenzaldehyde. Melting point: 166oC.

o) 1-(2-afterburner)-4-[4-(2-oxazoline-2-yl)-benzylidene]-piperidine from 4-[4-(2-oxazoline-2-yl)benzylidene]piperidine and acid chloride of 2-naphthaleneboronic acid. Melting point: 167oC.

p) 4-[4-(2-oxazoline-2-yl)benzylidene]-1-(2-trifloromethyl)piperidine from 4-[4-(2-oxazoline-2-yl)benzylidene] piperidine and 2-triftormetilfullerenov. Melting point: 128oC.

R) 1-(3,4-dichlorobenzoyl)-4-[4-(2-oxazoline-2-yl)benzylidene]-piperidine from 4-[4-(2-oxazoline-2-yl)benzylidene] piperidine and 3,4-dichlorobenzotrifluoride. Melting point: 159oC.

C) 1-(4-fluoro-1-afterburner)-4-[4-(2-oxazoline-2-yl)-benzylidene] piperidine: first, when 132oC, then after a temporary hardening at 157oC.

t) 4-[4-(2-oxazoline-2-yl)benzylidene]-1-(pentafluorobenzoyl)-piperidine from 4-[4-(2-oxazoline-2-yl)benzylidene] piperidine and pentafluorobenzylbromide. Melting point: 212oC.

y) 1-benzoyl-4-[4-(2-oxazoline-2-yl)benzylidene]piperidine from 4-[4-(2-oxazoline-2-yl)benzylidene]piperidine and benzoyl chloride. Melting point: 136oC.

t) 1-(4-methylsulfonylbenzoyl)-4-[4-(2-oxazoline-2-yl)benzylidene] piperidine from 4-[4-(2-oxazoline-2-yl)benzylidene] piperidine and 4-methylsulfonylbenzoyl. Melting point: 191oC.

x) 1-(4-tert.-butylbenzoyl)-4-[4-(2-oxazoline-2-yl)benzylidene]piperidine from 4-[4-(2-oxazoline-2-yl)benzylidene] piperidine and 4-tert.-butylbenzylamine. Melting point: 193oC.

C) 4-[4-(2-oxazoline-2-yl)benzylidene]-1-(3-trifloromethyl)piperidine from 4-[4-(2-oxazoline-2-yl)benzylidene] piperidine and 3-triftormetilfullerenov. Melting point: 99oC.

h) 1-(3-chlorobenzoyl)-4-[4-(2-oxazoline-2-yl)benzylidene]piperidine from 4-[4-(2-oxazoline-2-yl)benzylidene] piperidine and 3-chlorobenzylchloride. Melting point: 116oC.

W) 1-(4-methoxybenzoyl)-4-[4-(2-oxazoline-2-yl)benzylidene] piperidine from 4-[4-(2-oxazoline-2 and the Il)-4-[4-(2-oxazoline-2-yl)benzylidene]-piperidine from 4-[4-(2-oxazoline-2-yl)benzylidene] piperidine and 2.5-differentiald. Melting point: 137oC.

s) 1-(4-bromobenzoyl-4-[4-(2-oxazoline-2-yl)benzylidene]-piperidine from 4-[4-(2-oxazoline-2-yl)benzylidene] piperidine and 4-bromobenzonitrile. Melting point: 199oC.

e) 4-[4-(2-oxazoline-2-yl)benzylidene] -1-(1,2,3,4-tetrahydro-2-afterburner)piperidine from 4-[4-(2-oxazoline-2-yl)benzylidene] piperidine and acid chloride 1,2,3,4-tetrahydro-2-naphthaleneboronic acid. Melting point: 151oC.

h) 1-(4-nitrobenzoyl)-4-[4-(2-oxazoline-2-yl)benzylidene] -piperidine from 4-[4-(2-oxazoline-2-yl)benzylidene] piperidine and 4-nitrobenzylamine. Melting point: 192oC.

I) 1-(4-chlorophenylacetyl)-4-[4-(2-oxazoline-2-yl)benzylidene]piperidine from 4-[4-(2-oxazoline-2-yl)benzylidene] piperidine and 4-chlorophenylacetyl. Melting point: 107oC.

AA) 1-benzoyl-4-[4-(2-oxazoline-2-yl)benzyl] piperidine from 4-[4-(2-oxazoline-2-yl)benzyl]piperidine and benzoyl chloride. Melting point: 78 - 80oC.

AB) 1-(2-chlorobenzoyl)-4-[4-(2-oxazoline-2-yl)benzyl]piperidine from 4-[4-(2-oxazoline-2-yl)benzyl]piperidine and 2-chlorobenzylchloride. Melting point: 105 - 108oC.

AB) 1-(3-chlorobenzoyl)-4-[4-(2-oxazoline-2-yl)benzyl]piperidine from 4-[4-(2-oxazoline-2-yl)benzyl] piperidine and 3-chlorobenzoyl olango ether in a volume ratio of 10 : 2).

AG) 1-(4-perbenzoic)-4-[4-(2-oxazoline-2-yl)benzyl]piperidine from 4-[4-(2-oxazoline-2-yl)benzyl]piperidine and 4-tormentilla. Melting point: 111 - 113oC.

ad) 1-(4-tert.-butylbenzoyl)-4-[4-(2-oxazoline-2-yl)benzyl]piperidine from 4-[4-(2-oxazoline-2-yl)benzyl] piperidine and 4-tert. -butylbenzylamine. The resin. The value of Rf: (silica gel; complex ethyl ester of acetic acid).

AE) 1-(4-biphenylcarboxylic)-4-[4-(2-oxazoline-2-yl)benzyl] piperidine from 4-[4-(2-oxazoline-2-yl)benzyl] piperidine and 4-biphenylcarboxylic. Melting point: 158 - 160oC.

AJ) 1-(2-afterburner)-4-[4-(2-oxazoline-2-yl)benzyl]piperidine from 4-[4-(2-oxazoline-2-yl)benzyl] piperidine and acid chloride of 2-naphthaleneboronic acid. Melting point: 100 - 105oC.

AZ) 1-(1-afterburner)-4-[4-(2-oxazoline-2-yl)benzyl]piperidine from 4-[4-(2-oxazoline-2-yl)benzyl] piperidine and acid chloride of 1-naphthaleneboronic acid. Melting point: 70 - 73oC.

AI) 1-(4-chlorophenylsulfonyl)-4-[4-(2-oxazoline-2-yl)benzyl] piperidine from 4-[4-(2-oxazoline-2-yl)benzyl] piperidine and 4-chlorophenylsulfonyl. Melting point: 155 - 157oC.

AK) 1-(4-methylbenzoyl)-4-[4-(2-oxazoline-2-yl)benzyl] piperidine from 4-[4-(2-oxazoline-2-yl)benzyl] plin-2-yl)benzyl] piperidine from 4-[4-(2-oxazoline-2-yl)benzyl] piperidine and 4-cyanobenzaldehyde. Melting point: 148 - 150oC.

s) 4-[4-(2-oxazoline-2-yl)benzyl]-1-(4-pyridyl)piperidine from 4-[4-(2-oxazoline-2-yl)benzyl] piperidine and acid chloride of isonicotinic acid. Melting point: 148 - 150oC.

EN) 1-(4-chlorobenzoyl)-3-[4-(2-oxazoline-2-yl)benzylidene] -pyrrolidin of 3-[4-(2-oxazoline-2-yl)benzylidene] pyrrolidine and 4-chlorobenzylchloride. The value of Rf: of 0.36 (silica gel; a mixture of methylene chloride and methanol in a volume ratio 24 : 1).

Example 4

4-[4-(2-oxazoline-2-yl)benzylidene]-1-(4-pentanoyl)piperidine

356 mg (2.2 mmol) of N,N'-carbonyldiimidazole in 3 ml of tetrahydrofuran is mixed with 200 mg (2 mmol) 4-petinsurance acid in 2 ml of tetrahydrofuran at room temperature. Stir at a temperature of 40oC for one hour, then add 363 mg (1.5 mmol) 4-[4-(2-oxazoline-2-yl)benzylidene] piperidine and stirred at a temperature of 40oC for two hours. Then the reaction solution is concentrated and the residue purified column chromatography on silica gel using as eluent a complex ethyl ester of acetic acid. Obtain 320 mg (66% of theory) of the desired product with a melting point of 118oC. Range1H-NMR (200 MHz, CDCl3); the signals at h/mill.: 2,0 (s, casolin-2-yl)benzylidene]-1-(4-phenyl-3-butenyl)piperidine from 4-[4-(2-oxazoline-2-yl)benzylidene] piperidine, 4-phenyl-3-butterboom acid and N,N'-carbonyldiimidazole. Melting point: 139oC.

Example 5

4-[4-(2-oxazoline-2-yl)benzyl]-1-(4-trifloromethyl)-piperidine

441 mg (1 mmol) 4-[4-(2-oxazoline-2-yl)benzylidene]-1-(4-trifloromethyl)piperidine is subjected to hydrogenation in the environment 10 ml of anhydrous ethanol and 2.5 ml complex ethyl ester of acetic acid in the presence of 0.5 g of 10% palladium on coal at room temperature and a hydrogen pressure of 3.1 kg/cm2within 30 minutes. Then sucked off from the catalyst, the filtrate is evaporated at a bath temperature of 50oC under reduced pressure and the residue purified column chromatography on silica gel using as eluent a complex ethyl ester of acetic acid. Receive 200 mg (48% of theory) of the desired product with a melting point of 115oC. Range1H-NMR (200 MHz, CDCl3); the signals at h/mill.: 1,0 - 1,4 (m, 2H), 1,6 - 1,9 (m, 3H), and 2.6 (d, 2H), of 2.7 - 3.1 (m, 2H), 3,6 (m, 1H), of 4.05 (t, 2H), 4,4 (t, 2H), 4,7 (m, 1H), 7,15 (d, 2H), 7.5 (d, 2H), 7,65 (d, 2H), a 7.85 (d, 2H).

In the same way get:

a) 1-(4-chlorobenzoyl)-4-[4-(R-4-methyl-2-oxazoline-2-yl)-benzyl]piperidine from 1-(4-chlorobenzoyl)-4-[4-(R-4-methyl-2-oxazoline-2-yl)-benzylidene] -piperidine. Colorless resin. The value of Rf: 0,37 (silicagel of 1-(4-chlorobenzoyl)-4-[4-(2-oxazoline-2-yl)benzylidene] piperidine. Melting point: 136 - 138oC.

C) 1-(4-chlorobenzoyl)-3-[4-(2-oxazoline-2-yl)benzyl] piperidine from 1-(4-chlorobenzoyl)-3-[4-(2-oxazoline-2-yl)benzylidene]piperidine. Colorless resin. The value of Rf: 0.5 (silica gel; complex ethyl ester of acetic acid).

Example 6

1-(4-chlorobenzoyl)-4-[2-fluoro-4-(2-oxazoline-2-yl)benzylidene]-piperidine

0.4 g (0.95 mmol) of 1-(4-chlorobenzoyl)-4-[2-fluoro-4-(2-acetylaminobenzoic)-benzylidene] piperidine in 20 ml of tetrahydrofuran portions mixed with 0.3 g (1.1 mmol) of methyl-N-(triethylammonium)-carbamate by boiling for 45 minutes. Boil for two hours, then evaporated, the residue is mixed with water, three times extracted with methylene chloride, dried over anhydrous sodium sulfate, evaporated and the residue purified column chromatography on silica gel using as eluent a mixture of complex ethyl ester of acetic acid and petroleum ether in a volume ratio of 10 : 4. Get 0,105 g (26% of theory) of the desired product with a melting point of 158 - 160oC. Range1H-NMR (200 MHz, DMSO-d6); the signals at h/mill.: 2,4 (m, 4H), 3,4 - 3,7 (m, 4H), of 3.95 (t, 2H), 4,4 (t, 2H), 6.35mm (s, 1H), and 7.3 to 7.7 (m, 7H).

In the same way get:

a) 1-(4-chlorobenzoyl)-4-[3-methyl-4-(Dean and methyl-N-(triethylammonium)-carbamate. Melting point: 88 - 90oC.

b) 4-[2-bromo-4-(2-oxazoline-2-yl)benzylidene]-1-(4-chlorobenzoyl)piperidine from 4-[2-bromo-4-(2-acetylaminobenzoic)benzylidene] -1-(4-chlorobenzoyl)-piperidine and methyl-N-(triethylammonium)-carbamate. Melting point: 185 - 187oC.

C) 1-[4-chlorobenzoyl)-4-[2-methoxy-4-(2-oxazoline-2-yl)benzylidene] piperidine from 1-(4-chlorobenzoyl)-4-[4-(2-acetylaminobenzoic)-2-methoxy-benzylidene] piperidine and methyl-N-(triethylammonium)-carbamate. Melting point: 150 - 152oC.

1. Derivatives arylidene or arylalkyl-1-azacycloheptane General formula I

< / BR>
where a is a simple link, unbranched or branched alkylene with 1 to 17 carbon atoms, albaniles with 2 to 4 carbon atoms, akinyan with 2 to 4 carbon atoms;

W1and W2is a hydrogen atom or together form a carbon-carbon bond;

X is carbonyl or sulfonyl;

Y is an oxygen atom or sulfur or a group

R1- R6is a hydrogen atom, or 1, 2 or 3 of the radicals R1- R6which are identical or different, denote unbranched or branched alkyl with 1 to 4 carbon atoms, unsubstituted or substituted by hydroxyl, alkoxyl with 1 to 3 carbon atoms, alkylthiol 1 - 3 aconym or substituted by a halogen atom or alkyl with 1 to 3 carbon atoms, and the remaining radicals R1- R6means a hydrogen atom, with 1, 2 or all three radicals R1, R3and R5can also mean phenyl, unsubstituted or substituted by alkyl with 1 to 3 carbon atoms or a halogen atom;

R7- the atom of hydrogen or halogen, alkyl with 1 to 3 carbon atoms, alkoxy with 1 to 3 carbon atoms;

R8and R9independently from each other mean a hydrogen atom or alkyl with 1 to 3 carbon atoms;

R10is a hydrogen atom, cycloalkyl with 3 to 6 carbon atoms, phenyl, unsubstituted or substituted by a halogen atom, an unbranched or branched alkyl with 1 to 4 carbon atoms, trifluoromethyl, alkoxyl with 1 to 3 carbon atoms, a cyano, a nitro-group, alkylsulfonyl with 1 to 3 carbon atoms in the alkyl part, or phenyl, phenyl substituted by two triptoreline groups, 2 to 5 halogen atoms or one atom of halogen and alkyl with 1 to 3 carbon atoms, naphthyl and tetrahydronaphthyl, unsubstituted or substituted by fluorine atom, pyridyl, thienyl, unsubstituted or substituted by a halogen atom or alkyl with 1-3 carbon atoms;

R11is a hydrogen atom or alkyl with 1 to 3 carbon atoms;

n is 0 or 1;

m is 1 or 2;

p is 0 or 1,

the x isomers, or individual isomers, or their salts.

2. Derivatives arylidene or arylalkyl-1-azacycloheptane General formula I on p. 1, where a is a simple link, unbranched or branched alkylene with 1 to 17 carbon atoms, albaniles with 2 to 4 carbon atoms, akinyan with 2 to 4 carbon atoms, W1and W2is a hydrogen atom or together denote a carbon - carbon bond, X is carbonyl or sulfonyl, Y is oxygen atom or sulfur, or R1- R4is a hydrogen atom or 1 or 2 of the radicals R1- R4independent from each other and denote unbranched or branched alkyl with 1 to 4 carbon atoms, unsubstituted or substituted by hydroxyl, alkylthiol with 1 to 3 carbon atoms or dialkylamino with 1 to 3 carbon atoms in each alkyl group, or a phenyl, unsubstituted or substituted by a halogen atom, or phenyl, and the other of the radicals R1- R4means a hydrogen atom, R5and R6which are identical or different, denote a hydrogen atom or methyl, R7- the atom of hydrogen or halogen, alkyl with 1 to 3 carbon atoms, alkoxy with 1 to 3 carbon atoms, R8is a hydrogen atom or alkyl with 1 to 3 carbon atoms, R9is a hydrogen atom, R10is a hydrogen atom, cycloalkyl with 3 - 6 Atitlan by alkyl with 1 to 4 carbon atoms, trifluoromethyl, methoxy group, cyano, a nitro-group, methylsulfonyl or phenyl, phenyl substituted by one or two triptoreline groups or halogen atom and stands, phenyl, substituted 3 - to 5 fluorine atoms, naphthyl, unsubstituted or substituted by fluorine atom, tetrahydronaphthyl, pyridyl or thienyl, unsubstituted or substituted by a halogen atom, R11is a hydrogen atom or alkyl with 1 to 3 carbon atoms, n is 0 or 1, m is 1 or 2, p is 0 or 1, and not a means of simple communication, if X means sulfonyl and R10means a hydrogen atom, their enantiomers, diastereomers or salts.

3. Derivatives arylidene or arylalkyl-1-azacycloheptane General formula I on p. 1, where a is a simple link, unbranched or branched alkylene with 1 to 17 carbon atoms, albaniles with 2 to 4 carbon atoms, W1and W2is a hydrogen atom or together denote a carbon-carbon bond, X is carbonyl or sulfonyl, Y is an oxygen atom or a group R1- R4is a hydrogen atom or 1 or 2 of the radicals R1- R4independent from each other and denote unbranched or branched alkyl with 1 to 4 carbon atoms, and the remaining radicals R1- R4means a hydrogen atom, R5and R6kotamaki, R8is a hydrogen atom, methyl, R9is a hydrogen atom, R10is a hydrogen atom, cycloalkyl with 3 to 6 carbon atoms, phenyl, unsubstituted or substituted by 1 to 2 halogen atoms, 5 fluorine atoms, alkyl with 1 to 3 carbon atoms, one or two triptoreline groups or halogen atom and alkyl with 1 to 3 carbon atoms, 1-naphthyl, unsubstituted or substituted in position 4 by a fluorine atom, 2-naphthyl, 1,2,3,4-tetrahydro-2-naphthyl, pyridyl, 4-biphenyl, thienyl, unsubstituted or substituted by a halogen atom, R11is a hydrogen atom or methyl, n is 0 or 1, m is 1 or 2, p is 0 or 1, and not a means of simple communication, if X means sulfonyl, and R10means a hydrogen atom, their enantiomers, diastereomers or their salts.

4. Derivatives arylidene or arylalkyl-1-azacycloheptane General formula I on p. 1, where a is a simple link, W1and W2is a hydrogen atom or together denote a carbon - carbon bond, X is carbonyl, Y is an oxygen atom, R1- R6is a hydrogen atom, R7is a hydrogen atom or halogen, methyl, R8and R9is a hydrogen atom, R10is phenyl, substituted in position 4 by a fluorine atom, chlorine or bromine or trifluoromethyl, 4-chloro-3-were,5-chloro-2-thienyl, cyclohexyl, n is 0 or 1, m is 1, p is 0 or 1, or their salts.

the volumes of carbon albaniles with 2 to 4 carbon atoms, akinyan with 2 to 4 carbon atoms, W1and W2together form a carbon-carbon bond, X is carbonyl or sulfonyl, Y is oxygen atom or sulfur, or R1- R6is a hydrogen atom or a 1,2 or 3 of the radicals R1- R6which are identical or different, denote unbranched or branched alkyl with 1 to 4 carbon atoms, unsubstituted or substituted by hydroxyl, alkoxyl with 1 to 3 carbon atoms, alkylthiol with 1 to 3 carbon atoms, dialkylamino with 1 to 3 carbon atoms in each alkyl group, or phenyl, unsubstituted or substituted by a halogen atom or alkyl with 1 to 3 carbon atoms, and the remaining radicals R1- R6means a hydrogen atom, with 1, 2 or all three radicals R1, R3and R5can also mean phenyl, unsubstituted or substituted by alkyl with 1 to 3 carbon atoms or a halogen atom, R7is a hydrogen atom, alkyl with 1 to 3 carbon atoms, alkoxy with 1 to 3 carbon atoms, R8and R9independently from each other mean a hydrogen atom or alkyl with 1 to 3 carbon atoms, R10is a hydrogen atom, cycloalkyl with 3 to 6 carbon atoms, phenyl, unsubstituted or substituted by one or two atoms by Holodomor halogen and alkyl with 1 to 3 carbon atoms, naphthyl and tetrahydronaphthyl, thienyl, unsubstituted or substituted by a halogen atom or alkyl with 1 to 3 carbon atoms, R11is a hydrogen atom or alkyl with 1 to 3 carbon atoms, n is 0 or 1, m is 1 or 2, p is 0 or 1, And does not mean a simple link, if X means sulfonyl and R10means a hydrogen atom;

10.02.93 when W1and W2is a hydrogen atom;

21.10.93 when R7a halogen atom, R10is phenyl, unsubstituted or substituted by alkoxyl with 1 to 3 carbon atoms, a cyano, a nitro-group, alkylsulfonyl with 1 to 3 carbon atoms in the alkyl part, or phenyl, phenyl substituted by two triptoreline groups or 3 to 5 halogen atoms, naphthyl and tetrahydronaphthyl, unsubstituted or substituted by fluorine atom, a pyridyl.

 

Same patents:

The invention relates to new derivatives aminoquinolone

The invention relates to the derivatives of indole, methods and intermediates for their receipt containing their pharmaceutical compositions and to their medical use

The invention relates to new preparations of thiazolidinediones of the formula I, where A denotes a carbocyclic ring with 5 or 6 carbon atoms or a heterocyclic aromatic 5-or 6-membered ring containing an S atom or N; B is-CH=CH-; W represents O; X represents O; Y represents N; R represents pyridyl, thienyl or phenyl, in case you need one - or disubstituted C1-C3-alkyl, CF3, Cl or bromine; R1represents C1-C6-alkyl;n represents 2, and their tautomers, enantiomers, diastereomers or physiologically acceptable salts and medicinal product on the basis of their

The invention relates to 2,3-dihydro-1,4-benzodioxin-5-yl-piperazinyl derivative of the formula I, where R1denotes halogen, lower alkyl or alkoxyl, or cyano; m = 1 or 2, n = 0 or 1, And - Allenova chain with 2 to 6 carbon atoms which may be substituted by one or two lower alkyl groups or one phenyl group; B is methylene, ethylene, carbonyl, sulfinil, sulfonyl or sulfur, or their salts with 5-HTIA-antagonistic activity

The invention relates to a derivative of thiazolidinedione formula

,

where X is unsubstituted or substituted indayla, indolenine, asiandaily, asiandaily, imidazopyridine or imidazopyridine group; Y is an oxygen atom or a sulfur atom; Z-2,4-dioxothiazolidine-5-ylidenemethyl, 2,4-dioxothiazolidine-5-ylmethylene, 2,4-dioxoimidazolidin-5-ylmethylene, 3,5-dioxoimidazolidin-2-ylmethylene or N-gidroksilaminopurina group; R is a hydrogen atom, an alkyl group, alkoxygroup, halogen atom, hydroxy-group, a nitrogroup, kalkilya group or unsubstituted or substituted amino group; and m is an integer from 1 to 5

The invention relates to branched amino-thiazole, methods for their preparation and the pharmaceutical compositions

The invention relates to new preparations of thiazolidinediones of the formula I, where A denotes a carbocyclic ring with 5 or 6 carbon atoms or a heterocyclic aromatic 5-or 6-membered ring containing an S atom or N; B is-CH=CH-; W represents O; X represents O; Y represents N; R represents pyridyl, thienyl or phenyl, in case you need one - or disubstituted C1-C3-alkyl, CF3, Cl or bromine; R1represents C1-C6-alkyl;n represents 2, and their tautomers, enantiomers, diastereomers or physiologically acceptable salts and medicinal product on the basis of their

The invention relates to heterocyclic compounds having excellent pharmacological properties, and to intermediate compounds used for the synthesis of these compounds

The invention relates to a neuroprotective (anti-ischemic and excited by blocking amino acid receptor) analogues 5-(1-hydroxy-2-piperidinophenyl)-2-(1H, 3H)-indole-defined formula (I), (II) and (III) below; their pharmaceutically acceptable salts; method of using these compounds in the treatment of stroke, traumatic brain injury or degenerative diseases of the CNS (Central nervous system), such as disease Alzheimer, senile dementia Alzheimers.com type, Huntington's disease and Parkinson's disease; and some of their intermediates

The invention relates to cyclic urethane compounds and their pharmaceutical compositions suitable for the treatment of humans and other mammals with cardiac arrhythmia and cardiac fibrillation

The invention relates to the derivatives of indole, methods and intermediates for their receipt containing their pharmaceutical compositions and to their medical use

The invention relates to new Amida 4 - oxoazetidin-2-sulphonic acids and their salts, to a process of obtaining

The invention relates to a method for 3-{ 2-[4-(6-toranzo[d]isoxazol-3-yl) piperidine-1-yl] ethyl} -2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a] pyrimidine-4-it (I) interaction of 3-(2-amino-ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidine-4-it (II) isoxazol derivative of the formula (III)where Y and Z represent the deleted group, such as halogen or alkyl - or arylsulfonate, in the presence of a suitable solvent and base
Up!