Derivatives of 4h-piran, a mixture of their isomers, individual isomers and their salts

 

(57) Abstract:

Describes new derivatives of 4H-Piran General formula (I) in which a represents cycloalkyl with 3-6 carbon atoms or aryl with 6-10 carbon atoms, which may be the same or different substituted up to three times the nitro-group, a hydroxy-group, aryl with 6-10 carbon atoms, halogen, trifluoromethyl or alkyl straight or branched chain, alkoxycarbonyl, alkylthio or alkoxygroup, containing in each case up to 6 carbon atoms, or a group of the formula-O-CO-R5where R5means alkyl straight or branched chain containing up to 6 carbon atoms, R1and R2are the same or different and mean hydrogen, amino or alkyl straight or branched-chain alkoxy - or alkylamino, containing in each case up to 8 carbon atoms, R3and R4mean alkyl straight or branched chain containing up to 6 carbon atoms, a mixture of their isomers, individual isomers and their salts, and except 3,5-dietoksikarbonil-2,6-dimethyl-4-phenyl-4H-Piran. The compounds of formula (I) are modulators with selectivity towards Kalnyshevsky and sensitive charismaticism potassium Kahn who applies to the new oxygen-containing cyclic compounds with valuable biological properties, in particular derived 4H-Piran, having the properties of modulators with selectivity towards Kalnyshevsky and sensitive charismaticism potassium channels.

Known derivatives of 4H-Piran, having the properties of modulators with selectivity to calcium-dependent and sensitive to charismaticism potassium channels (see application EP N 0088276, class C 07 D 211/90, published. 14.08.1983 year).

The objective of the invention is the expansion of the Arsenal derivatives of 4H-Piran, having the properties of modulators with selectivity to calcium-dependent and sensitive to charismaticism potassium channels.

The problem is solved proposed derivatives of 4H-Piran General formula (I)

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in which

A means cycloalkyl with 3-6 carbon atoms or aryl with 6-10 carbon atoms, which may be the same or different substituted up to three times the nitro-group, a hydroxy-group, aryl with 6-10 carbon atoms, halogen, trifluoromethyl or alkyl straight or branched chain, alkoxycarbonyl, alkylthio or alkoxygroup, containing in each case up to 6 carbon atoms, or a group of the formula-O-CO-R5where R5means alkyl with straight or times and represent hydrogen, the amino group or alkyl straight or branched-chain alkoxy - or alkylamino, containing in each case up to 8 carbon atoms,

R3and R4mean alkyl straight or branched chain containing up to 6 carbon atoms,

the mixture of their isomers, individual isomers and their salts.

In the framework of the invention preferred are physiologically acceptable salt. Physiologically acceptable salts are usually salts of the proposed compounds with inorganic or organic acids. Preferred are salts with inorganic acids, such as hydrochloric acid, Hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic acids or sulphonic acids, such as acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid or methansulfonate, econsultation, vinylsulfonate, toluensulfonate or naphthalenedisulfonate.

The proposed connection can be a direct or inverse form (enantiomers) or not to be (diastereoisomer). The invention relates to stereoisomer, separated by known methods to separate stereoisomeric components.

Preferred are compounds of General formula (I), in which

A means cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or denotes phenyl, naphthyl, which may be the same or different substituted up to three times the nitrogroup, fluorine, chlorine, bromine, iodine, phenyl, naphthyl, trifluoromethyl, hydroxy-group, or alkyl straight or branched chain, alkoxycarbonyl, alkylthio or alkoxygroup, containing in each case up to 4 carbon atoms, or a group of the formula-O-CO-R5where R5means alkyl straight or branched chain containing up to 4 carbon atoms,

R1and R2are the same or different and mean hydrogen, amino or alkyl straight or branched-chain alkoxy - or alkylamino, containing in each case up to 6 carbon atoms,

R3and R4mean alkyl straight or branched chain containing up to 4 carbon atoms,

the mixture of their isomers, individual isomers and their salts.

Especially preferred are compounds of General formula (I), in which

A means cyclopropyl, cyclohexyl by Jordan, chlorine, bromine, iodine, phenyl, naphthyl, hydroxy-group, a trifluoromethyl or alkyl straight or branched chain, alkoxycarbonyl, alkylthio or alkoxygroup, containing in each case up to 4 carbon atoms, or a group of the formula-O-CO-R5where R5means alkyl straight or branched chain containing up to 4 carbon atoms,

R1and R2are the same or different and mean hydrogen, amino or alkyl straight or branched-chain alkoxy - or alkylamino, containing in each case up to 4 carbon atoms,

R3and R4mean alkyl straight or branched chain containing up to 4 carbon atoms,

the mixture of their isomers, individual isomers and their salts.

Compounds of General formula (I) can be obtained in such a way that

[A] Aldehydes of General formula (II)

A-CHO (II)

in which

A has the abovementioned meaning,

and compounds of General formula (III)

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in which

R6covers in each case, the above values of R1and R2and

R7covers the above values of R3and R4,

or

[B] Radenovi compounds of General formula (IV)

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in c˘te>/BR>< / BR>
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in which

R1and R4have the above values and

D together with CO-group forms electron-activated acceptor residue, and D means, for example, hydrogen, trifluoromethyl, phenyl or alkyl with 1-4 carbon atoms, predominantly means methyl,

subject interaction in an inert solvent in the presence of auxiliary substances and/or in the presence of dehydrating means, and upon receipt of the compounds of General formula (I) in which R1/R2mean amino - and/or alkylamino based on esters, are first obtained in the saponification corresponding acid, which under the action of, for example, thionyl chloride was transferred to a carboxylic acid anhydrides, which are then subjected to reaction with ammonia or alkylamines followed.

The above method can be illustrated by the following scheme:

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The solvent can be used all inert organic solvents which do not change under the reaction conditions. These include primarily ethers, such as diethyl ether, dioxane, tetrahydrofuran, dimethoxyethane or diglyme, ethyl acetate, or acetonitrile, or amides, such as hexalite carbon, or aromatic hydrocarbons as benzene or toluene, or pyridine, or carboxylic acids, as acetic acid or triperoxonane acid. It is also possible to use mixtures of the mentioned solvents. Preferred is glacial acetic acid.

As the dehydrating means suitable anhydrides and acid chlorides of the acids, such as acetic anhydride, acetyl chloride, phosphorus oxychloride, thionyl chloride, sulfurylchloride, or molecular sieves. Preferred is acetic anhydride. The water formed in the reaction can also be removed azeotrope.

If in the reaction using the enol acetates, does not require dehydrating agent.

As auxiliary substances are suitable, for example, titanium tetrachloride, tin tetrachloride, apirat boron TRIFLUORIDE, zinc acetate, perchlorate, lithium or zinc chloride. Preferred is zinc chloride.

Excipients are added in quantities of from 0.1 mole to 5 moles, preferably 1 mole to 2 moles, each time counting on 1 mol entering the reaction of compounds of General formulas (II) and (IV).

The process is conducted usually at temperatures from 0 to 150oC, pre is decayed or reduced pressure (for example, from 0.5 to 3 bar). Usually operate at normal pressure.

Compounds of General formula (II), (III), (IlIa), (IIIB) and (IV) are available by themselves or they can be obtained by conventional methods.

Enantiomerically form receive, for example, by separation of diastereomeric mixtures of compounds of General formula (I) in which R1means optically active residue of ester, by conventional methods, followed either by direct transesterification, or the initial receipt of chiral carboxylic acids that form when the esterification enantiomerically connection.

Division of diastereoisomers usually carried out either in fractional crystallization, chromatography column, or by distributing the Krag. Whatever the best way, the decision is made for each individual case, it is sometimes advisable to use a combination of a number of ways. Particularly suitable separation by crystallization or distribution by Craig, or a combination of both.

Enantiomerically connection is also obtained by chromatography of racemic esters on chiral phases.

As mentioned above, the proposed modulator compounds are the channels), in particular the Central nervous system.

On the basis of their pharmacological properties of the proposed connection can be used to obtain drugs, in particular drugs for the treatment of diseases that cause degeneration of the Central nervous system, such diseases include the emergence of dementia, dementia caused by multiple hemorrhages, primary degenerative dementia, predtechenskii and senile dementia in Alzheimer's disease, HIV dementia and other forms of dementia. In addition, they may be suitable for the treatment of Parkinson's disease or progressive muscular atrophy, and multiple sclerosis.

Further, the proposed compounds suitable for the treatment of brain disorders in old age, organic brain psychosyndrome and memory disorders associated with aging.

They can be used for prevention and treatment and to eliminate the effects of cerebral circulatory disorders such as cerebral ischemia, stroke, craniocerebral trauma and subarachnoid hemorrhage.

The proposed compounds are useful for the treatment of depression and psychosis, for example, sizefree pulse and related health problems, such as manic syndrome, alcoholism, abuse of drugs, addiction or pathological relationship with food. Other applications include the treatment of migraines, sleep disorders and neuropathies. In addition, they are suitable as pain relievers. In addition, can be used to treat disorders of the immune system, in particular, proliferation of T-lymphocytes, to impact on the smooth musculature, in particular, uterus, bladder and bronchial tract, so they are suitable for the treatment of related diseases, such as asthma and urinary incontinence, and treatment of high blood pressure, arrhythmia, angina, diabetes, sickle cell anemia, cancer, restenosis, chronic pulmonary diseases, accompanied obstructive syndrome, and edema.

The proposed connection can be an active ingredient of pharmaceutical compositions, which may be in the form of any standard of drug.

The active substance of the formula (I) are in this composition in a preferred concentration of from 0.1 to 99.5 wt.%, in particular, from 0.5 to 95,0% wt. of the total mixture.

Along with the active substance of the formula (I), pharmaceutical composition and and other pharmaceutical active substances.

The pharmaceutical composition may be obtained by known methods.

In General, to achieve the desired result has been very effective use of one or more active substances of the formula (I) in total amounts from about 0.01 to 100 mg/kg, preferably in an amount of about 1 to 50 mg/kg of body weight every 24 hours, in each case in the form of several individual doses.

In each case it may be useful deviation from these quantities, depending on the type and weight of the object of treatment, the individual tolerability of the drugs on the type and severity of the disease, method of preparation and application, and also the frequency of drug administration.

The biological activity of the proposed compounds has been demonstrated by inhibition allocation of rubidium from glioma cells C6-BU1.

This experience was carried out in accordance with the method described Tas et al. (Neurosci. Lett. 94, 279-284, (1988)), with minor changes. This used the glioma C6-BU1 rats. Detection was performed using atomic absorption spectroscopy.

This experience was determined by the concentration of the compounds of examples 3, 32, 44, 46, and 47 Ámol, obespechiva Ámol.

The proposed compounds belong to the category of low-toxic substances.

The following examples illustrate how to obtain the invention concerns compounds of formula (I).

Example 1

Dimethyl 4-(4-chlorophenyl)-2,6-diethyl-4H-Piran-3,5 - dicarboxylic acid

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to 7.0 g (0.05 mol) of 4-chlorobenzaldehyde, 15.6 g (0.12 moles) of methyl ether 3-oxovalerate acid and 6.8 g (0.05 mole) of anhydrous zinc chloride are dissolved with stirring in a mixture of 9.3 g of glacial acetic acid and 10.4 g of acetic anhydride and then aged 5 weeks at room temperature (20 - 25oC). The homogeneous solution was poured into 100 g of ice and extracted with dichloromethane. Dichloromethane extracts are washed successively with water, saturated sodium bicarbonate solution and water. After drying dichloromethane phase with anhydrous sodium sulfate filtered, the filtrate evaporated in vacuum and the residue (20,3 g) chromatographic on 600 g of silica gel in toluene/ethyl acetate (10:1). Obtain 2.7 g of a homogeneous colorless oil, which remove any traces of solvent by distillation on a rotary evaporator (200oC/0.01 mbar).

The value of Rf(toluene/ethyl acetate=10:1):0,52

C19H21ClO5(and 364.8): Calculated C: 62OOCH3and C5-COOCH3), 2,84, and 2,74 dddd, manifests itself in the form of a signal of 12 lines (4, C2-CH2- and C6-CH2and 1,90 m D. t (6, C2-CH2-CH3and C6-CH2-CH3).

Example 2

3,5-Diacetyl-4-(4-chlorophenyl)-2,6-dimethyl-4H-Piran

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to 7.0 g (0.05 mol) of 4-chlorobenzaldehyde, 12.0 g (0.12 moles) pentane-2,4-dione and 6.8 g (0.05 mole) of anhydrous zinc chloride is kept in a mixture of 8.9 ml of glacial acetic acid and 9.6 ml of acetic anhydride at room temperature for three weeks. The resulting product was poured on ice and extracted with dichloromethane. The organic extracts are successively washed with saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and filtered. After evaporation in vacuo obtain 13.3 g of oil.

Technical product obtained from the same two parties, is subjected to rapid chromatography on silica gel in colorealimentare (increasing gradient) obtain 9.6 g of a mixture of 2-acetyl-4-(4-chlorophenyl)-butene-2-she and 3,5-diacetyl-4-(4 - chlorophenyl)-2,6-dimethyl-4H-Piran. After repeated chromatography on 700 g of silica gel in toluene or toluene/ethyl acetate =20:1 to obtain 4.1 g of a homogeneous product.

So pl.: 86-88oC (major) (from dichloromethane/petroleum is chileno, C: 67,00%; H: 5,62%

Found, C: 66,9%; H: 5,77%

1H-NMR (deuterochloroform): m (4, arene. protons), 4,88 (1, C4-H), 2,32 (6, C3-COCH3and C5-COCH3and of 2.21 M. D. (C2-CH3and C6-CH3).

Example 3

Dimethyl 4-(4-chlorophenyl)-2,6-dimethyl-4H-paradisebeach acid

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a) To a mixture of 9.6 ml of acetic anhydride and 6.8 g (0.05 mole) of anhydrous zinc chloride are added at 25oC under stirring of 13.9 g (0.12 moles) of methyl ester of acetoacetic acid and 7.0 g (0.05 mol) of 4-chlorobenzaldehyde. With increasing temperature (up to approximately 60oC) receive light yellow solution, which is three times heated for 8 hours 60 - 65oC. For further processing, the reaction mixture was poured into 200 ml ice water and extracted with dichloromethane. The organic layer is washed successively with water, saturated sodium bicarbonate solution and again with water, dried over anhydrous sodium sulfate, filtered and evaporated in vacuum. The residue (18,8 g) chromatographic on silica gel (1650 g) in toluene/ethyl acetate = 25:1 and gain of 9.8 g (58%) of pure Piran, and 1.2 g of a mixture containing equal parts of Piran and the methyl ester of 2-acetyl-3-(4-chlorophenyl)-acrylic acid. Crystallization of the main fraction from petroleum ether/diethyl ether of directiy of 17.4 g (of 0.11 mol) of methyl ester of 3-ecotoxicological acid, to 6.8 g of zinc chloride and 7 g (0.05 mol) of 4-chlorobenzaldehyde. After water treatment obtain 14.9 g of a technical product, which, after separation on silica gel yields of 10.5 g of pure Piran.

The value of Rf(toluene/ethyl acetate = 10:1): 0,41

C17H17ClO5(336,8): Calculated C: 60,63%; H: 5,09%

Found, C: 60,6%; H: 5,20%

1H-NMR (deuterochloroform): m (4, arene. protons), 4,74 (1, C4-H), 3,64, with (6, C3-COOCH3and C5-COOCH3and 2,36 M. D. (6, C2-CH3and C6-CH3).

Example 4

4-(4-Chlorophenyl)-2,6-dimethyl-3-etoxycarbonyl-5-methoxycarbonyl-4H-Piran

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A mixture of 9.5 g (0,04 mole) of methyl ester of 2-acetyl-3-(4-chlorophenyl)-acrylic acid, 5.7 g (0,044 mole) of ethyl ester of acetoacetic acid, 5.4 g (0,04 mole) of anhydrous zinc chloride and 7.5 ml of acetic anhydride is stirred three times for 8 hours at 60-65oC. To the mixture was added 4 ml of glacial acetic acid and again stirred three times for 8 hours at 60-65oC. After treatment, similar to that described above, a technical product (15.9 g) chromatographic at 2000 g of silica gel in toluene. Gain of 5.3 g (30%) of crystalline Piran.

So pl.: 67-69oC (from petroleum ether).

The value of Rf(toluene/ethyl acetate=10:1):0,53

1H-NMR (IS and C6-CH3) and 1.20 m D. t (3, C3-COOCH2-CH3).

Example 5

Methyl ester of 5-acetyl-2,6-dimethyl-4-(4-chloro-3 - triptoreline)-4H-Piran-3-carboxylic acid

< / BR>
10 g (32,6 mmole) of methyl ester of 2-acetyl-3-(4-chloro-3 - triptoreline)-acrylic acid and 10 g (97.8 mmol) of 2,4 - pentanedione mixed with 8.4 g of zinc chloride in 20 ml of acetic anhydride for 3 hours at 60oC. After water treatment and chromatography to give 2.83 g of compound indicated in the title.

So pl.: 96oC (petroleum ether)

NMR (deuterochloroform): 2,20 (s, 3H), of 2.36 (s, 6H), of 3.69 (s, 3H), 4,82 (s, 1H), of 7.48 (m, 2H), 7,51 (s, 1H).

C18H18O4F3Cl (388,77): Calculated: C: 55,61%; H: 4,15%; O: 16,46%

Found: C: 55,55%; H: 4.17 percent; A: 16,32%

Additionally, the product from example 5 is obtained as a by-product of synthesis of the compound from example 32.

The above examples 1-5, the compounds presented in tables 1 and 2.

Example 41

Amide 5-acetyl-4-(4-chloro-3-triptoreline)-2,6-dimethyl-4H - Piran-3-carboxylic acid

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Stage a)

1.01 g (to 2.57 mmole) of the compound from example 5 are dissolved in 10 ml of tetrahydrofuran and added 10 ml of methyl alcohol and 10 ml of 1 N. sodium hydroxide, paramashiva and ethyl ether. Bring the pH of the aqueous phase to 5 and the formed precipitate is sucked off and washed. Get 432 mg (45% of theory) of colorless powder, which requires treatment before being subjected to further transformations.

Stage b)

1 g of the acid obtained above is dissolved in 10 ml chloride tiomila and boil for 1.5 hours Then chloride thionyl distilled off and the residue is mixed with 50 ml of tetrahydrofuran.

Added dropwise while cooling 10 ml of 25% ammonia solution and stirred for 30 min at room temperature. Then concentrated and the residue distributed between ethyl acetate and water. After extraction (ethyl acetate), dried over magnesium sulfate and concentrate.

Technical product is purified by chromatography on silica gel (petroleum ether/acetic acid gradient). Get 319 mg (31%) of light brown powder.

So pl.: 129oC

Rf=0,65

NMR (deuterochloroform 200 MHz): to 2.18 (s, 3H); 2,24 (s, 3H); to 2.35 (s, 3H); 4,82 (s, 1H); 5,10-of 5.40 (m, user., 2H) and 7,31-7,52 M. D. (m, 3H).

Examples 42 and 43

4-(4-Chlorophenyl)-2,6-dimethyl-3-methoxycarbonyl-5-(N - methylamino)-4H-Piran and di-N-methylamide-4-(4-chlorophenyl)-2,6-dimethyl - 4H-Piran-3,5-dicarboxylic acid

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To a suspension of 1.35 g (20 mmol) of methyl chloride is aluminum (5 M in n-hexane). The temperature is allowed to rise to 25oC, stirred for another 1-2 hours until gas evolution stops and get a clear solution (1M solution reagent).

In the thus obtained solution reagent (20 mmol) was added dropwise 2.0 g (6 mmol) of the dimethyl ester of 4-(4-chlorophenyl)- 2,6-dimethyl-4H-Piran-3,5-dicarboxylic acid in 60 ml of absolute toluene in an argon atmosphere at 25oC. After a 12-hour heating at 80oC (control reaction using chromatography in thin layer) the mixture is cooled to 25oC and carefully acidified with 5% hydrochloric acid. The organic phase is separated and the aqueous extracted three times with ethyl acetate. The combined organic phases are washed with water until neutral, dried over sodium sulfate, filtered and concentrated in vacuo. Technical product (1.5 g) share on silica gel in toluene/ethyl acetate/methanol (gradient) and obtain 0.1 g of the raw product, 0.7 g of mono-N-methylamide, and 0.7 g of bis-N-methylamide.

4-(4-Chlorophenyl)-2,6-dimethyl-3-methoxycarbonyl-5-(N - methylamino)-4H-Piran (example 42)

So pl.: 163-165oC (major) (from dichloromethane/petroleum ether), the value of

Rf:0,18 (toluene/ethyl acetate 3:1).

C17H18ClNO4(335,8): In the (s, 3H), 4,55 (s, 1H), 5,20 (user. s, 1H) and 7,20-7,30 M. D. (m, 4H),

Di-N-methylamide 4-(4-chlorophenyl)-2,6-dimethyl-4H-Piran-3,5 - dicarboxylic acid (example 43)

So pl.: 256-259oC (major) (from ethyl acetate), the value of Rf(ethyl acetate): 0,13

C17H19ClN2O3(334,8): Calculated: C 60,9%; H 5,70%; N 8,66%

Found: C 60,99%; H 5,72%; N, 8.37% PER

NMR (deuterochloroform): to 2.13 (s, 6H), 2,70 (d, 6H), 4,50 (s, 1H), and 5.30 (user. s, 2H), 7,20-7,35 M. D. (m, 4H).

By analogy with the above examples 41-43 the compounds obtained according to examples listed in table 3.

1. Derivatives of 4H-Piran General formula I

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in which A denotes cycloalkyl 3 to 6 carbon atoms or aryl with 6 to 10 carbon atoms, which may be the same or different substituted up to three times the nitro-group, a hydroxy-group, aryl with 6 to 10 carbon atoms, halogen, trifluoromethyl or alkyl straight or branched chain, alkoxycarbonyl, alkylthio or alkoxygroup, containing in each case up to 6 carbon atoms, or a group of the formula-O-CO-R5where R5means alkyl straight or branched chain containing up to 6 carbon atoms,

R1and R2are the same or different and mean hydrogen, amino or alkyl with straight or the 3 and R4mean alkyl straight or branched chain containing up to 6 carbon atoms;

mixtures of their isomers, individual isomers and their salts, and except 3,5-dietoksikarbonil-2,6-dimethyl-4-phenyl-4H-Piran.

2. Derivatives of 4H-Piran General formula I under item 1, in which A means cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or denotes phenyl, naphthyl, which may be the same or different substituted up to three times the nitrogroup, fluorine, chlorine, bromine, iodine, phenyl, naphthyl, trifluoromethyl, hydroxy-group, or alkyl straight or branched chain, alkoxycarbonyl, alkylthio-, or alkoxygroup, containing in each case up to 4 carbon atoms, or a group of the formula-O-CO-R5means alkyl straight or branched chain containing up to 4 carbon atoms, R1and R2are the same or different and mean hydrogen, amino or alkyl straight or branched-chain alkoxy - or alkylamino, containing in each case up to 6 carbon atoms, R3and R4mean alkyl straight or branched chain containing up to 4 carbon atoms, a mixture of their isomers, individual isomers and their salts, and except 3,5-dietoksikarbonil-2,6-is sawdust, cyclohexyl or means naphthyl or phenyl, which may be the same or different substituted up to three times the nitrogroup, fluorine, chlorine, bromine, iodine, phenyl, naphthyl, hydroxy-group, a trifluoromethyl or alkyl straight or branched chain, alkoxycarbonyl, alkylthio or alkoxygroup, containing in each case up to 4 carbon atoms, or a group of the formula-O-CO-R5where R5means alkyl straight or branched chain containing up to 4 carbon atoms, R1and R2are the same or different and mean hydrogen, amino or alkyl straight or branched-chain alkoxy - or alkylamino, containing in each case up to 4 carbon atoms, R3and R4mean alkyl straight or branched chain containing up to 4 carbon atoms, a mixture of their isomers, individual isomers and their salts, and except 3,5-dietoksikarbonil-2,6-dimethyl-4-phenyl-4H-Piran.

 

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12 cl, 8 dwg, 6 tbl, 1 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to medicinal agents, namely, to a novel medicinal agent possessing hypolipidemic effect and representing molecular complex of simvastatin with β-glycyrrhizic acid in the mole ratio simvastatin : β-glycyrrhizic acid= 1:(1-4). Proposed complex possess higher effectiveness in lower doses that results to reducing toxicity in treatment.

EFFECT: improved and valuable medicinal properties of agent.

3 dwg, 5 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 means hydrogen atom or lower alkyl; R2 means substituted or unsubstituted thiazolinyl or oxazolinyl residue; each R5 and R6 means independently hydrogen atom or protective group; X means oxygen (O), sulfur atom (S) or -NR7 wherein in each case R7 means hydrogen atom or lower alkyl; RB means in each case independently hydrogen atom, (C1-C6)-alkyl, -CY3, -CHY2 or -CH2Y wherein Y means F, Br, Cl or J. Also, invention relates to a pharmaceutical composition containing compounds of the formula (I) and possessing cytotoxic activity, and using this compound in treatment of malignant tumor with multiple drug resistance.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

44 cl, 77 dwg, 13 ex

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