Xantina derivatives, their stereoisomers and the physiologically tolerated salts, pharmaceutical composition having reducing pathological hyperactivity eosinophilic granules activity
(57) Abstract:The invention relates to chemistry, medicine and pharmacology, new nitrogen-containing heterocyclic compounds possessing biological activity, and more particularly to a derivative of xanthine f-ly I, their stereoisomers and the physiologically tolerated salts, and pharmaceutical compositions having reducing pathological hyperactivity eosinophilic granules activity. The invention improves the activity of anti-asthma remedies. 2 S. and 3 C.p. f-crystals, 2 PL.The invention relates to new nitrogen-containing heterocyclic compounds possessing biological activity, and more particularly to a derivative of xanthine, their stereoisomers and the physiologically tolerated salts, and pharmaceutical compositions having reducing pathological hyperactivity eosinophilic granules activity.Known derivatives trialkylamine having biological activity, for example, reducing pathological hyperactivity eosinophilic granules activity (see application EP N 0544391, A1, a 61 K 31/52, 02.06.1993).The objective of the invention is the expansion of usertimer.activetime eosinophilic granulocytes activity.The problem is solved, we offer xanthine derivatives of General formula (I)
< / BR>where R1is methyl or ethyl,
R2is alkyl with 1-4 carbon atoms,
X is a hydrogen atom or a hydroxyl,
n is an integer from 1 to 5,
moreover, when R1is methyl, R2is methyl, X is a hydrogen atom, n represents the number 1, 2, 3, 5,
their stereoisomers and the physiologically tolerated salts.The first group preferred xanthine derivatives of General formula (I) include compounds in which R2means methyl or ethyl.The second group preferred xanthine derivatives of General formula (I) include compounds in which X means a hydrogen atom.The third group preferred xanthine derivatives of General formula (I) include compounds in which R1is methyl, R2is methyl or ethyl, X is hydrogen atom, n is an integer from 1 to 5.New xanthine derivatives of General formula (I) can be obtained by known methods.Chiefly so that the 3,7-disubstituted xanthine derivative of the formula (II),
< / BR>in which R2means an alkyl group containing from one to four carbon atoms, a Rameans legy residue or deleted recovery benzyl or diphenylmethyl group with unsubstituted or substituted phenyl rings, it is advisable in the presence of a basic condensing agent or its salt is subjected to interaction
a) with an alkylating agent of the formula (III)
< / BR>in which R1, X and n have the above values, a Z means a halogen, preferably chlorine, bromine or iodine, or a group of the ether sulfonic acid or ester of phosphoric acid,
to obtain 1,3,7-triple-substituted xanthine of the formula IV
< / BR>and R1, R2, Ra, X and n have videopreteen values or alternative for the case when X is hydrogen,
b) keto - compound of formula V,
H3C - CO - (CH2)n- Z (V)
in which n and Z have the above values,
to obtain 1,3,7 - triple-substituted xanthine of the formula VI
< / BR>then with methyl-or ethylethylenediamine (R1M), preferably in the form of methyl or utility (R1-Li) or the corresponding Grignard compounds (R1-MgHal) under conditions of reductive alkylation of the carbonyl group is transferred to 1,3,7-triple-substituted xanthine of the formula VII
< / BR>in which R1, R2and n have the above meanings, or an alternative for the case when X is hydrogen, a R1means methyl,
C) kotoroy n and Z have the above values,
to obtain 1,3,7-triple-substituted xanthine of the formula IX
< / BR>in which Ra, R2and n have the above values,
then two equivalents of methylethylenediamine, preferably CH3-Li or CH3-MgHal in a double reductive alkylation of the ester functions in turn 1,3,7-triple-substituted xanthine of the formula X
< / BR>in which R2, Raand n have the above values,
and finally by removal of the group R from the intermediate compounds of formula IV, VII or X get xanthine of the formula I according to the invention.Used here as starting compounds 3,7 - disubstituted xantina formula II and alkylating means of formulae III, V and VIII for the most part known or can be easily obtained well-known literature methods. Thus, the tertiary alcohols of the formula III can be, for example, obtained by ORGANOMETALLIC synthesis, which steric not employed kaleidostone formula Hal-(CH2)n-CO-CH2X convert so-called reaction-build using reductive alkylation of the carbonyl group by alkylhalogenide R1-M, in which M stands for metal, mainly about cility connections R1-Li in normal conditions. A similar transformation of kaleidostone formula Hal-(CH2)n-CO-R1methylacrylamide or methyllithium also leads to compounds of the formula III in which X represents hydrogen. A convenient approach to compounds of formula III in which R1represents methyl, and X is a hydrogen atom, gives the reaction alilovic esters-halogenoalkanes acids (Hal-(CH2)n-COO-alkyl) with two equivalents of methylethylenediamine, and ether reacts through the ketone followed by the formation of the tertiary alcohol by introduction of two methyl residues. Similarly esters-hydroxycarbonic acid with an unprotected or protected hydroxyl group, such as tetrahydropyran-2-silt or methoxymethyl esters or, if necessary, in the form of a lactone as a cyclic ether complex, the action of methylethylenediamine can be converted into diols, of which by selective esterification of the primary hydroxyl function halides or anhydrides, sulfonic acid or phosphoric acid can be obtained active alkylating means of the formula III.The reaction of interaction disubstituted xanthine derivatives Faure is Yu reagents solvent or dispersing agent. As such, first of all, suitable dipolar, aprotic solvents, such as formamide, dimethylformamide, dimethylacetamide, N-organic, tetramethylrhodamine, hexamethylphosphoramide, dimethylsulfoxide, acetone or butanone; can also be used alcohols such as methanol, ethylene glycol and its mono - or dialkyl ethers containing from one to four carbon atoms in the alkyl group, ethanol, propanol, isopropanol, and various butanol; hydrocarbons, such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane or chloroform; pyridine, as well as mixtures of the mentioned solvents with water.Alkylation reaction, it is expedient to carry out in the presence of an alkaline condensing agent tools. For this approach, for example, hydroxides, carbonates, hydrides, alkaline alcoholate or alkaline earth metals and organic bases, such as trialkylamine, triethyl - or tributylamine, Quaternary hydroxide ammonium or phosphonium and crosslinked resin fixed if necessary substituted groups ammonium or phosphonium. However, xanthine derivatives can be used directly in the form of a separately derived salts, such as sole, the th. In addition, disubstituted compounds xanthine can be conveniently alkilirovanii as in the presence of the above-mentioned inorganic condensing means, and means in the form of their salts with alkali or alkaline earth metals with the help of so-called transfer catalysts phase, for example tertiary amines, Quaternary ammonium or fofanah salts or crown ethers, preferably in a two-phase system under the conditions of catalysis of the transfer phase. Suitable often the trademarks transfer catalysts phase are, in particular, salt tetraalkyl-(containing from one to four carbon atoms in the alkyl group) and methyltrioctylammonium and phosphonium, methyl-, myristyl-, phenyl - and benzyl-trialkyl-(containing from one to four carbon atoms in the alkyl group), cetyltrimethylammonium, and alkyl containing from one to twelve carbon atoms) and benzyltriphenylphosphonium salt, and, as a rule, those compounds that have larger and more symmetrically built cation, are more effective. In General, in the above-described methods, the process is conducted at the reaction temperature between 0oC and boiling point is used in each case, the reaction medium, preferably davlenie, moreover, the reaction time may range from less than one hour to several hours.In the interaction of xantina VI and IX, which in position 1 functional group, with the ORGANOMETALLIC compound, the process occurs in the same way as when receiving used as alkylating funds tertiary alcohols according to formula III. Thus, reductive alkylation of ketones VI or esters IX can be carried out, for example, alkiline-alternati-alcolici-, alkilani, alkylzinc, alkylidene-, alkylamino and alkilirovannami. Also applicable recommended recently alkylsilane and alkylsilanes connection. Since, however, alkylhalogenide sodium and potassium due to their high reactivity prone to adverse reactions, and similar compounds of zinc and cadmium is relatively inert, is usually preferred compounds alkylate and alkaline (Grignard compounds).Strongly nucleophilic ORGANOMETALLIC compounds are very sensitive to hydrolysis and oxidation. Their use requires work in an anhydrous environment, if necessary - in a protective gas atmosphere. Conventional solvents or dispersing agents are the first and foremost about ethers with one or more ether oxygen atoms, for example diethyl, DIPROPYLENE, debutalbum or vitaminum esters, 1,2-dimethoxyethane, tetrahydrofuran, dioxane, tetrahydropyran, furan and anisole and aliphatic or aromatic hydrocarbons, such as petroleum ether, cyclohexane, benzene, toluene, xylene, diethylbenzene, tetrahydronaphthalen; can also be successfully used tertiary amines such as triethylamine, or dipolar aprotic solvents of the type hexamethylphosphoramide, as well as mixtures of the mentioned solvents. In the interaction of carbonyl compounds VI or IX with Grignard compounds of the formula R1-MgHal you to successfully carry out the process so that the ORGANOMETALLIC compound is placed in a simple ether and added to it dropwise ketone or ester in the form of a solution in dichloromethane or 1,2-dichloroethane. Often suitable additive magnesium bromide, which because of its participation in kompleksoobrazovaniem cyclic transition state could increase the nucleophilicity of ORGANOMETALLIC compounds.Join ketone or ether complex to ORGANOMETALLIC coupling occurs, as a rule, at temperatures between -20oC and 100oC, preferably between 0omenaut in slight excess. Then substitution usually ends with a short reflux, which usually happens enough period of time from several minutes to several hours. Decomposition of the resulting alcoholate carried out preferably in an aqueous solution of ammonium chloride or dilute acetic acid.Removing tsepliaeva group, R1of the compounds of formulae IV, VII and X in the formation of xantina formula I according to the invention is carried out in standard conditions, which were primarily developed in the framework of the technology of protective groups in the synthesis of alkaloids and peptides and, therefore, can be largely known in advance.Then, if necessary, preferably reductive, cleaved replacement phenyl ring of the benzyl or diphenylmethylene group. Along with chemical recovery method, in particular, benzyl compounds with sodium in liquid ammonia, mainly carry out eliminirovali both Uralkalij groups by catalytic hydrogenolysis using a catalyst of a noble metal, and often substitute for molecular hydrogen is ammonium formate as don is avinou acid or ammonia; aprotic solvent such as dimethylformamide or especially glacial acetic acid, but may also be used mixtures thereof with water. Suitable hydrogenation catalysts are primarily of palladium black and palladium on charcoal or barium sulphate, while other noble metals such as platinum, rhodium and ruthenium due to the competing reactions of hydrogenation of the ring often predispose to adverse reactions and therefore are used only in extreme cases. In practice, the hydrogenolysis is carried out at temperatures between 20oC and 100oC at atmospheric pressure or preferably at slightly elevated pressures of up to about 10 bar, and, as a rule, required for the reaction time from several minutes to several hours.1,3,7-triple-substituted xantina formula IV, VII and X, containing as Raalkoxymethyl group, represent 0,N-acetals and as a consequence easy to split under normal conditions of acid hydrolysis. Preferred residues are, for example, a methoxy group, ethoxypropan, propoxylate and butoxymethyl group. The reaction is mainly carried out by heating in dilute mineral acids, such as zooporno or a lower alcohol as an agent of the dissolution. Sometimes also used perchloro acid or organic acids such as trichloroacetic, formic and acetic acid, in combination with catalytic amounts of mineral acids. Cleavage of the ether group can be in principle carried out by using Lewis acids such as zinc bromide and tetrachloride titanium, in anhydrous medium, preferably in dichloromethane or chloroform. By splitting the solution of mineral acid, the reaction temperature should be selected so as to avoid any appreciable dehydration located in position 1 of the tertiary hydroxyalkyl group; therefore, it should not normally exceed 60oC.The compounds of formula I deprotonated in position 7 and therefore with the substances of the main character form a salt and a solvate. They are pharmaceutically acceptable salts of alkali and alkaline earth metals and salts and solvate with organic bases, for example, Ethylenediamine, or basic amino acids: lysine, ornithine and arginine. Thus, the invention also concerns a pharmacologically-tolerated salt and/or solvate 1,3-dialkylamino according to the formula (I).Tertiary 1-(hydroxyalkylated hydrogen, a R1means ethyl. Thus, these compounds can exist in stereoisomeric forms.As mentioned above, the proposed xanthine derivatives of General formula (I) possess reduce pathological hyperactivity of eosinophilic granulocytes activity and therefore they can be an active ingredient of the pharmaceutical compositions of the respective destination.Thus, a second object of the invention is a pharmaceutical composition having reducing pathological hyperactivity of eosinophilic granulocytes activity, which in addition to at least one target of the additive contains at least one xanthine derivative of the above General formula (I) and/or a stereoisomer and/or its physiologically tolerable salt in an effective amount.The proposed pharmaceutical composition may be in the form of a standard liquid or solid dosage forms for oral, rectal, local, parenteral or inhalation use in diseases with pathologically increased activity of eosinophilic granulocytes.Suitable solid or liquid pharmaceutical forms of t is s, creams, ointments, gels, aerosols, drops or injectable solutions in this part of the form and also preparations with a slow release of biologically active substances, the manufacture of which are commonly used tools such as the media, disintegrating agents, binders for coatings, for swelling, lubricants, flavorings, sweeteners or substances that promote dissolution. As commonly used auxiliary substances include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, topic, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycol and solvents such as, for example, distilled water, alcohols, glycerol and polyhydric alcohols.Drugs preferably are made and assigned in dosage units, each unit contains as an active ingredient a specific dose of a compound of formula (I). In solid dosage forms such as tablets, capsules and suppositories, this dose can be up to 1000 mg, but preferably from 100 to 600 mg, and injection solutions in this part of the form - up to 300 mg, but pre the Oia compounds of formula (I) - daily doses of 100 to 2000 mg of biologically active substances, preferably from 300 to 900 mg for oral use and from 10 to 500 mg, preferably from 20 to 200 mg when administered intravenously.However, in some circumstances, can be set higher or lower daily doses. Getting a daily dose may be achieved by a single dose in the form of a single dosage unit or multiple, but smaller doses, as well as by repeated administration is fragmented doses at certain intervals of time.And finally, in the production of the above herbal ready forms of xanthine derivatives of the formula I, if necessary, can be used in conjunction with other suitable biologically active substances, for example, antihistamines, antiholinergicheskimi and2-mimetic agents, phosphodiesterase inhibitors, phospholipase A2and lipoxygenase, antagonists VEILS and leukotriene, corticosteroids, chromophilia, nedocromil, and cyclosporin A.Getting xanthine derivatives of General formula (I) is illustrated by the following examples.Example 1
1-(2-hydroxy-2-methylpropyl)-3-METI the thief in tetrahydrofuran and 200 ml of dry diethyl ether was added dropwise under stirring at a temperature of from 0 to 5oC solution of 46.3 g (0.5 mol) of 1-chloro-2-propanone in 50 ml of anhydrous diethyl ether. Then stirred first for 1 hour at room temperature and then 1 hour at boiling under reflux, the resulting tertiary alcoholate was dissolved by adding 50% aqueous solution of ammonium chloride, the ether layer was separated, and the aqueous layer was extracted with ether.The combined ether extracts are successively washed with aqueous solutions of sodium bisulfite and sodium bicarbonate and a small amount of water, dried over sodium sulfate, filtered, concentrated under reduced pressure and the liquid residue was subjected to fractional distillation.Yield: 31.1 g (57.3 % of theoretical.)
So Kip. 125 - 127oC
WITH4H9ClO (M. C. 108,6)-
The connection can be also obtained in a similar manner from methyl or ethyl esters of Chloroacetic acid and twice the molar amount of methylacrylamide with yields of about 60% of theoretical.b) 7-benzyl-1-(2-hydroxy-2-methylpropyl)-3-methylxanthines
A mixture of 25.6 g (0.1 mol) of potassium carbonate and 11.9 g (0.11 mol) of the tertiary alcohol from step a) in 500 ml of dimethylformamide was heated for 8 hours under stirring at a temperature of from fra, washed first with 1N. sodium hydroxide solution, then with water until neutral, dried, drove the solvent in vacuo and the solid residue precrystallization of ethyl acetate with addition of petroleum ether.Output: 26,6 g (81.0% of theoretical.)
So pl. 115-117oC
C17H20N4O3(M. C. 328,4)
Analysis: Calculated: 62,18%; H 6,14%, N 17,06%.Found: 62,60%; H 6,18%; N 17,00%.The compound was also obtained by way of 7-benzyl-3-methylxanthines first of the above conditions by interaction with 1-chloro-2-propanone or a methyl or ethyl ester, Chloroacetic acid was converted to 7-benzyl-3-methyl-1-(2-oxopropyl)-xanthine or 7-benzyl-1-meth (or EB)oxycarbonyl-3-methylxanthines and then oxopropyl or alkoxycarbonylmethyl side chain of recovery has metilirovanie methylmagnesium in anhydrous diethyl ether as described in stage a).C) 1-(2-hydroxy-2-methylpropyl)-3-methylxanthines
of 13.1 g (0.04 mol) of 7-Benzylcyanide from stage b) in 200 ml of glacial acetic acid was first made when shaken over 1.5 g of palladium (10%) on charcoal at 60oC and 3.5 bar for 100 hours. After cooling, was purged with nitrogen, Otti is ethyl acetate.Yield: 7.8 g (81.8% of theory.)
So pl. 215-217oC
C10H14M4O3(M. C. 238,3)
Analysis: Calculated: 50,41%; H Of 5.92%, N 23,52%.Found: 50,10%; H 5,90%; N 23,40%.Example 2
To a suspension of 90 g (0.5 mol) of 3-metilksantina in 500 ml of methanol was added 20 g (0.5 mol) dissolved in 200 ml of water sodium hydroxide and stirred for 1 hour at 70oC, was added dropwise at the same temperature to 69.6 g (0.55 mol) of benzylchloride and withstand the reaction mixture for 3 hours at a temperature between 70 and 80oC. and Then cooled, the cold was filtered on a suction filter, washed product on the suction filter with water, was dissolved in 1000 ml of hot 1H. caustic soda, filtered and using 4 N. hydrochloric acid slowly, with stirring, brought to a pH of 9.5. The product crystallized, was filtered from the still warm solution, washed bichloride water and dried in vacuum.Output: 131 g (96.9 % of theoretical.)
So pl. 217-218oC
C14H14N4O2(M. C. 270,3)
The reaction of interaction of 7-benzyl-3-metilksantina from stage a) with 1-chloro-2-hydroxy-2-methylpropanol from example 1A) with the od: 46,1% of theoretical. ) and his subsequent gidrodinamicheskim dibenzylammonium (yield: 97.9% from theory. in accordance with example 1B) was obtained crude final product, purified by recrystallization from ethanol.So pl. 217-219oC
C11H16N4O3(M. C. 252,3)
Analysis: Calculated 52,37%; H 6,39%; N 22,21%,
Found: 52,19%; H 6.29 Per Cent; N Of 21.75%.Example 3
a) 1-chloro-3-hydroxy-methylbutane.The connection was obtained from methylacrylamide and 1-chloro-3-butanone (which can be obtained by attaching hydrogen chloride to methyl vinyl ketone are in diethyl ether) or from methylacrylamide and ethyl ester 3-chloropropionic acid in dichloromethane as the reaction medium analogously to example 1 (a).Output: 60 - 70% of theory.So Kip (18 mbar) 66 - 68oC
C5H11ClO (M. C. 122,6).b) 7-benzyl-1-(3-hydroxy-3-methylbutyl)-3-methylxanthines
is obtained analogously to example 1B) from 7-benzyl-3-methylxanthines and tertiary alcohol from step a).Yield: 70% of theory.So pl. 92-94oC
C18H22N4O3(M. C. 342,4)
Analysis: Calculated: 63,14%; H 6,48%; N 16,36%.Found: 63,10%; H To 6.43%; N 16.28 Per Cent.Output: 87,27% of theory.So pl. 203 - 205oC
C11H16N4O3(M. C. 252,3)
Analysis: Calculated: 52,37%; H 6,39%; N 22,21%.Found: 52,13%; H, 6.52 Per Cent; N 22,08%.Example 4
Is obtained analogously to example 1B) from 7-benzyl-3-metilksantina (example 2A) and 1-chloro--hydroxy-3-methylbutane (example 3A).Output: 71,8% of theory
So pl. 133-135oC
C19H24N4O3(M. C. 356,4)
b) 3-ethyl-1 -(3-hydroxy-3-methylbutyl)-xanthine
Obtained in accordance with example 1B) by gidrodinamicheskogo dibenzylamine of the product from step a).Yield: 88.2% of theory.So pl. 241 to 243oC
C19H18N4O3(M. C. 266,3)
Analysis: Calculated: 54,12%; H 68,1%; N 21,04%.Found: 53,89%; H 6,86%; N 21,03%.Example 5
First of 38.4 g (0.15 mol) of 7-benzyl-3-methylxanthines, 22,4 g (rate £ 0.162 mol) of potassium carbonate and 26.7 g (rate £ 0.162 mol) of atelectasia 1-chloro-4-pentanone in 600 ml of dimethylformamide as described in example 1B) were converted to 7-benzyl-1-(4,4-Atlasova heating under reflux in 600 ml of 1N. of hydrochloric acid. The resulting ketone after neutralization of the mixture with concentrated sodium hydroxide solution was extracted with chloroform and the chloroform extract was washed with water, dried over sodium sulfate and one stripped off to dryness under reduced pressure.Output: of 50.4 g (98,7% of theoretical.)
So pl. 104 - 105oC
C18H20N4O3(M. C. 340,4)
b) 7-benzyl-1-(4 hydroxy-4-methylpentyl)-3-methylxanthines
A mixture of 9 g (0.12 mol) of methylmagnesium as the standard 20% solution in tetrahydrofuran and 300 ml of dichloromethane was cooled to -25oC and then added dropwise to a solution of 34 g (0.1 mol) of the product from step a), the temperature was increased to 20oC. Stirring is continued for one further hour at room temperature, then was added a saturated solution of ammonium chloride, the organic layer was separated, the aqueous layer was extracted several times with dichloromethane, the combined dichloromethane extracts were washed with water, sushena and one stripped off and the solid residue recrystallized from ethyl acetate.Output: 28,3 g (79,4 % of theoretical.)
So pl. 132-133oC
C19H24N4O3(M. C. 356,4)
Obtained with theory.So pl. 188 - 189oC
C12H18N4O3(M. C. 266,3)
Analysis: Calculated: 54,12%; N For 6.81%; N 21,04%.Found: 53,86%; N 6,88%; N 20,93%.Example 6
Obtaining carried out as described in example 5a), using as the starting material 7-benzyl-3-ethyl-xanthine from example 2a)
Output: 82,4 % of theory.So pl. 139-141oC
C19H22N4O3(M. C. 354,4)
b) 7-benzyl-3-ethyl-1-(4-hydroxy-4-methylpentyl)-xanthine.The reaction product of stage (a) was entered into interaction with methylmagnesium similar to that described in example 5B).Output: 81,1 % of theory.So pl. 155-157oC
C20H26N4O3(M. C. 370,5)
Analysis: Calculated: 64,84%; H 7,07%; N 15,12%.Found: 64,95%; H 7,18%; N 15,10%.C) 3-ethyl-1-(4-hydroxy-4-methylpentyl)-xanthine.The connection obtained by gidrodinamicheskogo dibenzylamine of the reaction product of stage b) analogously to example 1B).Output: 71,3% of theory.So pl. 214-216oC
C13H20N4O3(M. C. 280,3)
Analysis: Calculated: the-methylxanthines
To purged with nitrogen a mixture of 264 g (1.2 mol) of trimethylsulfonium and 28.8 g (1.2 mol) of sodium hydride was added dropwise over 10 minutes under stirring at 40oC 1000 ml of anhydrous dimethyl sulfoxide. After the evolution of gas (about 2 hours) was added dropwise a solution of 134,6 g (1 mol) of 1-chloro-5-hexanone in 30 ml of dimethylsulfoxide. Was stirred for two hours at room temperature, while cooling with ice was slowly mixed with 500 ml of ice water and the resulting 1-chloro-5,6-epoxy-5-methylhexan was extracted with diethyl ether (yield: 130,5 g (87.8% of theory.); C7H13ClO (M cent. of 148.6)). For hydrolytic cleavage of amoxicilina it was stirred in a mixture of 60 ml of water, 600 ml of tetrahydrofuran and 1 ml of 70% perchloro acid for 5 days at room temperature. Then neutralize soda solution, drove tetrahydrofuran and the resulting 1-chloro-5,6-dihydroxy-5-methylhexan was extracted with chloroform (yield: of 124.8 g (85.3% of theory. ); C17H15ClO2(M. C. 166,6)). Then in the usual way by the action of 2,2-dimethoxypropane in acetone under conditions of acid catalysis diol was converted into a dioxolane.Yield: 67.2% of theoretical.So Kip. (0.5 bar) 84R> Diol from step a) was subjected to interaction with 7-ethoxymethyl-3-methyl-xanthine similar to that described in example 1B) with the quantitative formation of 7-ethoxymethyl-1-(5,6-isopropylidenedioxy-5-etylhexyl)-3-methylxanthines (C19H30N4O5, M. C. 394,5) by acidic hydrolysis with simultaneous disclosure dioxolane cycle and defined in condition 7-ethoxymethylene group received the final product. For this to 19.7 g (0.05 mol) of the compound of xanthine in a mixture of 300 ml of 1N. hydrochloric acid and 30 ml of glacial acetic acid was heated for 15 hours under stirring to 70oC, after cooling, was podslushivaet sodium carbonate and washed with chloroform, then neutralize 1H. hydrochloric acid and was extracted with chloroform. The residue from evaporation after filtration through a column of silica gel using as mobile phase a mixture of chloroform/methanol (10:1) and recrystallized from ethyl acetate.Output: 11.5g (77,6 % of theoretical.)
So pl. 181-182oC
C13H20N4O4(M. C. 296,3)
Analysis: Calculated: 52,69%; H, 6.80 per cent; N 18,91%;
Found: 52,46%; H 6,90%; N 18,66%.Example 8
7-benzyl-3-methyl-1-(5-oxagile has atelierul ketogroup ethylmagnesium in accordance with example 5B) and the resulting 7-benzyl-1-(5-hydroxy-5-methylheptan)-3-methylxanthines were dibenzylamine in the conditions of example 1B).Output: 70,2% of theory.So pl. 169 - 170oC
C14H22N4O3(M. C. 294,4)
Analysis: Calculated: 57,13%; H 7,53%; N OF 19.03%,
Found: 56,90%; H, 7.55 per cent; N 18,96%
7-benzyl-3-ethyl-1-(5-hydroxy-5-methylhexan)-xanthine, obtained from 7-benzyl-3-metilksantina (example 2A) and 1-chloro-5 - hydroxy-5-methylhexane according to example 1B) with the release of 65% of theory. (C21H28N4O3; M. C. 384,5; so pl. 112 - 114oC), hydrogenations was dibenzylamine using ammonium formate as a hydrogen source. To do this, of 3.84 g (0.01 mol) of benzyl derivative and 1.0 g (to 0.016 mol) of ammonium formate in 30 ml of ethanol was stirred for several days on 2 g of palladium (10%) on charcoal at the 35oC, when it gave a good result of the gradual introduction of additional quantities of ammonium formate to its total amount of 4.4 g (0.07 mol). The reaction mixture was filtered, the filtrate was evaporated, the residue was transferred into a solution of sodium carbonate, washed with chloroform, the aqueous layer was brought hydrochloric acid to pH 4, the product was dissolved in chloroform and after drying and evaporation perekristalizovanny of ethyl acetate.Yield: 67.9 % of theory.
%.Found: 56,77%; H 7,66%; N18,93%
7-benzyl-3-Edilkamin (example 2A) and 1-chloro-5-hexanone analogously to example 16) was converted into 7-benzyl-3-ethyl-1-(5 - oxohexyl)-xanthine (C20H24N4O3; M. C. 368,4; output: 81,7% of theoretical.; so pl. 123-125oC). Restoration of atilirovanie ketogroup ethylmagnesium according to example 5B) resulted in a 7-benzyl-3-ethyl-1-(5-hydroxy-5-methylheptan)-xanthine (C22H30N4O3, M. C. 398,5; output: 86,9% of theoretical.; so pl. 93-94oC), which hydrogenations was dibenzylamine analogously to example 9. The final product was recrystallized from ethanol.Yield: 66.5% of theory.So pl. 165 - 166oC
C15H24N4O3(M. C. 308,4)
Analysis: Calculated: 58,42%; H 7,84%; N 18,17%,
Found: 58,30%; H 8,05%; N 18,33%.Example 11
7-benzyl-1-(6-hydroxy-6-methylheptan)-3-methylxanthines (C21H28N4O3, M. C. 384,5; so pl.: 83-85oC, obtained with the yield of 77.5% of 7-benzyl-3-methylxanthines and 1-bromo-6-hydroxy-6-methylheptane analogously to example 1B), hydrogenations was dibenzylamine according to example 1B).Yield: 82.2% of theory.
In accordance with example 12 carried out the sequence of reactions from 7-benzyl-3-ethyl-xanthine from example 2a), and gidrodinamicheskoe dibenzylamine by ammonium formate was carried out similarly to example 9.Output: 72,4% of theory.So pl. 163-165oC
C15H24N4O3(M. C. 308,4)
Analysis: Calculated: 58,42%; H 7,84%; N 18,17%.Found: 57,83%; H Of 7.64%; N 18,04%.Pharmacological experiments and results
1. Inhibitory activity against proinflammatory mediators reactions early phase
Inhibiting activity of the compounds according to the formula 1 against proinflammatory mediators early phase of histamine, VEILS and leukotriene D4(LTD4) was investigated on isolated segments of the respiratory tract of Guinea pigs-albinos, and the measurement parameter was the inhibition caused by these mediators cuts.For conducting experiments every time used svezhepriobretenny the male organs. The trachea was cut into circles, of which in each case 5 cartilaginous rings of the trachea, SUP>oC and probabtionary with Carbogen solution of Tyrode and by adding histamine dihydrochloride (concentration in the bath: 310-7/ml) in the absence (control experiment) or in the presence of the tested substances was made to reduce.Easy cut lengthwise into 2 - 3 bands that did the same thing as described above, however, the tensile stress was 1 g and the reduction was caused FOP or LTD4when the concentration in the bath 10-9or 10-8g/ml.Each experiment consisted of a parallel study 6 billet bodies (n=6).Assessment of the activity of the drug was performed using the values IR50, i.e. the concentration, expressed in µg/ml, which is caused in the control experiment the reduction of the authority decreased by half. The results are summarized in table 1.Guinea pigs - albinos of both sexes with body weight from 180 to 220 g were sensitized by subcutaneous injection every time 1 mg of ovalbumin (0.1% solution in physiological sodium chloride solution) for two consecutive days. The experiment was carried out in 20 days according to the method of Konzett and Rossler (Arch. exp. Path. und Pharmak. (1940) 195: 75). For this purpose animals were narcoticyou pentobarbital, did they artif the animals in each. By intravenous injection of ovalbumin as an antigen in a dose of 1 mg/kg caused a prolonged asthma attack as a result of acute bronchospasm induced by mediators within the early asthmatic reaction, the intensity of which is characterized by the amplitude of contractions in taragram.The tested drugs were used each time intravenously 15 minutes before the antigen provocation. Instead, the animals of control group received net of 0.9% sodium chloride solution. For evaluating the effect of the drug was established the number of animals of this group, whose asthmatic reaction in the control group was reduced at least by 40%.The results are summarized in table 2. 1. Xantina derivatives of General formula I
< / BR>where R1is methyl or ethyl;
R2is alkyl with 1 to 4 carbon atoms;
X is a hydrogen atom or hydroxyl;
n is an integer from 1 to 5;
moreover, when R1is methyl, R2is methyl, X is a hydrogen atom, n represents the number 1, 2, 3, 5,
their stereoisomers and the physiologically tolerated salts.2. Xantina derivatives of General formula I under item 1, in which R2means methyl or ethyl.3. Derivatives Xuly I on p. 1, in which R1is methyl, R2is methyl or ethyl, X is hydrogen atom, n is an integer from 1 to 5.5. Pharmaceutical composition having reducing pathological hyperactivity of eosinophilic granulocytes activity containing the active substance on the basis of xanthine derivatives and at least one additive, characterized in that the active substance it contains at least one compound of General formula I
< / BR>where R1is methyl or ethyl; R2is alkyl with 1 to 4 carbon atoms;
X is a hydrogen atom or hydroxyl;
n is an integer from 1 to 5,
moreover, when R1is methyl, R2is methyl, X is a hydrogen atom, n is 1, 2, 3, 5,
and/or its stereoisomer, and/or its physiologically tolerable salt in an effective amount.
SUBSTANCE: the present innovation deals with antiviral preparations that contain aliphatic alcohol C21-C28 in combination with either nucleoside or nucleotide analog or phosphoformic acid in pharmaceutically acceptable carrier. It is necessary to mention that n-docosanol is considered to be a preferable aliphatic alcohol. Concentration of aliphatic alcohol C21-C28 corresponds to 0.05% to 40% by weight. Concentration of either nucleoside or nucleotide analog or phosphoformic acid corresponds to 0.1% to 10% by weight. The innovation, also, deals with the ways to treat viral infections due to applying such compositions. Aliphatic alcohols C21-C28 synergistically intensify antiviral activity of nucleoside analogs directed against replication of several herpetic viruses and that of cow's pox.
EFFECT: higher efficiency of inhibition.
28 cl, 13 dwg, 21 ex, 6 tbl
FIELD: organic chemistry, chemical technology, medicine, pharmacy.
SUBSTANCE: invention describes derivatives of 8-phenyl-6,9-dihydro[1,2,4]-triazolo[3,4-I]purine-5-one of the general formula:
wherein R1 means hydrogen atom, group -CH2-R6 wherein R6 means phenyl; R2 means (C1-C5)-alkyl or group -(CH2)n-R6 wherein n= 1 or 2; R6 means (C1-C4)-alkoxy-group or pyridyl group; R3 means (C1-C6)-alkyl; R4 means hydrogen atom or (C1-C4)-alkyl; R5 means -(CH2)n-R7 wherein n = 0-4; R7 means 3-7-membered ring comprising 1-3 heteroatoms taken among nitrogen atom (N) and oxygen atom (O), (C3-C7)-cycloalkyl or phenyl wherein indicated groups can be substituted with different substitutes; or R4 and R5 mean independently hydrogen atom (H), (C2-C6)-alkynyl or (C1-C6)-alkyl that can be substituted possibly; or R4 and R5 in common with nitrogen atom (N) form 4-7-membered ring comprising 1-2 heteroatoms taken among N and O and substituted possibly. Also, invention relates to their pharmaceutically acceptable salts, methods for preparing these compounds, intermediate substances, pharmaceutical composition and a to a method for treatment of different diseases mediated by activity of phosphodiesterase-5 (PDE-5). Described compounds of the formula (I) are inhibitor of PDE-5.
EFFECT: improved preparing method and treatment, valuable properties of compounds.
20 cl, 5 tbl, 149 ex
FIELD: vitamins, chemical technology, food industry, pharmacy.
SUBSTANCE: invention relates to crystalline alkaline-earth salts of 5-methyl-(6R,S)-, -(6S)- and -(6R)-tetrahydrofolic acid with the content of at least one equivalent of crystallizing water per equivalent of 5-methyltetrahydrofolic acid, in particular, 5-methyl-(6R)-tetrahydrofolic acid crystalline calcium salt or to different types of 5-methyl(6S)-tetrahydrofolic acid crystalline calcium salts. These salts can be used in preparing medicinal agents or as a nutrition supplement for treatment or prophylaxis of folic acid-mediated diseases. Also, invention relates to a method for preparing crystalline salts of 5-methyl-(6R,S)-, -(6S)- and -(6R)-tetrahydrofolic acid by crystallization of the corresponding salt of 5-methyl-(6R,S)-, -(6S)- or -(6R)-tetrahydrofolic acid from a polar medium by using heat treatment at temperature above 60°C followed, if necessary, by drying the prepared product. Also, invention relates to a composition for pharmaceutical agents or nutrition supplements.
EFFECT: improved preparing method, valuable properties of salts and composition.
13 cl, 5 dwg, 4 tbl, 11 ex
FIELD: medicine, gerontology.
SUBSTANCE: the present innovation deals with rehabilitation therapy of cerebrovascular diseases. One should introduce microcirculators and nootropic preparations to conduct training neuropsychological procedures. Moreover, microcirculatory and nootropic preparations should be introduced as intravenous infusions for 10 d, ten during 1 mo it is necessary to introduce tableted forms of the same preparations at simultaneous neuropsychological training directed to improving household skills valuable for a patient that deal with memorizing different names, important dates, names of medicinal preparations and location of domestic articles. On achieving a success the tasks should be complicated. Training should last for 30 min carried out thrice weekly: therapy course includes 12 trainings. The innovation widens the number of preparations for treating elderly and senile patients at discirculatory encephalopathy stage III and coarse cognitive deficiency.
EFFECT: higher efficiency of therapy.
3 ex, 1 tbl
FIELD: medicine, oncology.
SUBSTANCE: one should carry out chemoradiation therapy at applying a cytostatic preparation followed by distance and intracavitary irradiation. Depending upon development of tumor lesion during the first 3 or 6 d it is necessary to conduct monochemotherapy only due to introducing proxiphen together with dimethyl sulfoxide at weight ratio of 4.5-5.0 : 0.5-1.5, correspondingly by applications in "Coletex" napkins. Moreover, a napkin should be pre-impregnated in 20%-dimethylsulfoxide solution and fixed with a tough vaginal tamponade by changing napkins every 24 h. Then since the 4th d or the 7th d simultaneously with application it is necessary to carry out contact irradiation and distance impact onto minor pelvis every 4-6 h at single focal dosage (SFD) being 2 Gy at 10 seances 5 times/weekly with high-activity sources of SFD 2 Gy. The innovation provides tumor regress under conditions of no therapeutic complications, thus, improving patients' quality of life.
EFFECT: higher therapy.
FIELD: medicine, infectious diseases, psychotherapy.
SUBSTANCE: method involves antiviral therapy, immune correction with thymus hormones and interferon inductors. Since the first day the relapse symptom method involves prescription of antiox+ (1 capsule per a day) and detox+ (1 capsule, 2 times per a day) for 30 days, profluzak (20 mg, 3 times per a day for 5 days) and then in the dose 20 mg, 1 time per a day for 20 days. Derinate is prescribed topically as installation into urethra in the dose 3-5 ml or with tampon into vagina and with simultaneous prescription of microenemas in the dose 10-40 ml for 10 days. Since 10-14 day in exacerbation period in the proliferative stage of an antiherpetic immune response derinate is prescribed by intramuscular injections in the dose 5 ml, 1 time in a day, 10 injections in total number. Then since 6-th day of exacerbation and intake of profluzak psychotherapy seances are carried out. The first seance of rational psychotherapy involves explanation to a patient in available form mechanism of the disease, the necessity of prolonged treatment and motivation for treatment is enhanced by suggestion. The second psychotherapy seance involves neurolinguistic programming wherein a patient colorful and detailed description of desirable function when he imagines achievement of the desire result, and positive emotional and vegetative symptoms are notes and the conditional-reflect association is formed by tactile contact. Under psychotherapist control a patient imagines "part of person" responsible for achievement of the desire result the patient attention is accented for the desire result and arisen physiological responses are fixed by using tactile contact. Also, new behavior methods are proposed to take for a patient that are directed for achievement of the desire result - avoiding sexual contacts during exacerbation of genital herpes in one of partner and during every month hormonal cycles, avoiding stress situations, and in case of each stress situation significant for patient profluzak has to be intake in a single dose 40 mg, using a condom in sexual contact in the exacerbation period. Patient analyzes the proposed new behavior methods that help avoiding relapses, provide good state of health, promotes to recovery process of genitals recovery and selects at least three the most rationally available for him behavior methods. In the case of the positive response that is controlled by physiological symptoms the result is fixed by tactile contact. The third seance involves the suggestive psychotherapy directed for fixing the attained result. The suggestive therapy seance is carried out once per a week for 6 months. Method provides declining the treatment time, to reduce relapse frequency of genital herpes and to recover the emotional state of patient.
EFFECT: improved treatment method.
2 cl, 3 tbl, 1 ex
SUBSTANCE: invention relates to a granulated pharmaceutical composition comprising granulated material and erythritol. Granulated material comprises a medicinal substance of unpleasant taste and wax. Also, invention relates to a pharmaceutical product for oral using that comprises the indicated granulated composition. The composition masks unpleasant taste of a medicinal agent and provides good feeling in oral using. The granulated composition can be swallowed easily by elderly humans, children and patients suffering with dysphagia. Except for, the product is useful for administration by using a tube.
EFFECT: improved and valuable properties of composition.
15 cl, 5 tbl, 6 ex
SUBSTANCE: method involves applying antiherpetic therapy using Phamcyclovir. Then, Trental is sequentially introduced during 5 days with 2-5 ml of cerebrolysin being concurrently intratissularly introduced behind mastoid process tip. Mexidol is administered for 10 days. The treatment is finished by introducing Polyoxydonium.
EFFECT: combined microcirculation improvement; high neurotrophic and antioxidant activity; secondary immune deficiency adjustment; eliminated labyrinth hydrops.
FIELD: organic chemistry, neurology, medicine.
SUBSTANCE: invention relates to a new medicinal agent used in treatment of feeble-mindedness comprising a derivative of 2-aryl-8-oxodihydropurine, namely, a derivative of 2-aryl-8-oxodihydropurine that comprises acetamide group at position 7 or 9 of purine ring. Invention proposes compounds of formulae (Ia) and (Ib) wherein radicals X1, Y1, R12, R13, R22, R23, R32, R42 and R43 have the corresponding values, or their pharmaceutically acceptable acid-additive salt. Also, invention proposes using compounds of the formulae (Ia) and (Ib) or their pharmaceutically acceptable acid-additive salt for preparing a medicinal agent used in treatment or prophylaxis of feeble-mindedness wherein feeble-mindedness represents deterioration of the teaching process, dysmnesia, dysmnesia-based disorientation, mental dysfunction, Alzheimer's disease, cerebrovascular feeble-mindedness and/or senile feeble-mindedness, and in treatment or prophylaxis of higher cerebral dysfunction. Invention provides the development of a medicinal preparation for prophylaxis or treatment of feeble-mindedness symptoms associated with diseases that can induce feeble-mindedness and higher cerebral dysfunction.
EFFECT: valuable medicinal properties of agents.
12 cl, 3 tbl, 5 ex
FIELD: medicine, cardiology.
SUBSTANCE: the present innovation deals with treating patients with ischemic cardiac disease at the background of type II diabetes. For this purpose, in case of stenocardia of functional class II and type II diabetes of average severity degree one should introduce enalapril at the dosage of 20 mg/d in combination with trental at the dosage of 400 mg/d, and at stenocardia of functional class III and type II diabetes of severe flow one should introduce enalapril at the dosage of 30 mg/d in combination with trental at the dosage of 400 mg/d. The innovation suggested normalizes monocytic-macrophageal link of immune system.
EFFECT: higher efficiency of correction.
2 ex, 4 tbl
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new derivatives of indolylpiperidine of the formula (I): wherein A1 means (C1-C7)-alkylene, (C1-C7)-alkyleneoxy-, (C1-C7)-alkylenethio-, (C1-C7)-alkanoyl, hydroxy-(C1-C7)-alkylene; A2 means a single bond, (C1-C7)-alkylene, (C2-C5)-alkenylene; W means a single bond, phenylene, furanylene that is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkoxy- and/or alkyl groups; R1 means hydrogen atom (H), (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C2-C5)-alkoxyalkyl, (C3-C7)-alkenyloxyalkyl, (C3-C7)-alkynyloxyalkyl, (C3-C7)-alkoxyalkoxyalkyl, phenyl-(C1-C7)-alkyl wherein phenyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy- or arylalkoxy- (preferably with phenylalkoxy-) groups, or means (C3-C10)-cycloalkyl-(C1-C7)-alkyl wherein cycloalkyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy-groups; R2 means hydrogen atom (H), halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-; R3 means carboxyl, tetrazolyl, and to their pharmaceutically acceptable salts. Compounds of the formula (I) elicit antihistaminic and anti-allergic activity that allows their using in composition used for treatment of allergic diseases including bronchial asthma, rhinitis, conjunctivitis, dermatitis and nettle rash. Also, invention describes methods for preparing compounds of the formula (I).
EFFECT: valuable medicinal properties of compounds.
15 cl, 2 sch, 3 tbl, 162 ex
FIELD: organic chemistry, biochemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new aminobenzophenones of the formula (I):
or their pharmaceutically acceptable salts. These compounds elicit properties of inhibitors of cytokines secretion, in particular, 1β-interleukin (IL-1β) and tumor necrosis α-factor (TNF-α) and to secretion of polymorphonuclear superoxide that are useful for treatment of inflammatory diseases, for example, skin diseases, such as psoriasis, atopic dermatitis. In the formula (I) R1 is taken among the group consisting of halogen atom, hydroxy-, mercapto-group, trifluoromethyl, amino-group, (C1-C3)-alkyl, (C2-C3)-olefinic group, (C1-C3)-alkoxy-, (C1-C3)-alkylthio-, (C1-C6)-alkylamino-group, (C1-C3)-alkoxycarbonyl, cyano-group, carbamoyl, phenyl or nitro-group under condition that when R1 means a single substitute then it at ortho-position, and when R1 means more one substitute then at least one substitute of R1 is at ortho-position; R2 means one substitute at ortho-position being indicated substitute is taken among the group consisting of (C1-C3)-alkyl, (C1-C3)-alkoxy-group; R3 means hydrogen, halogen atom, hydroxy-, mercapto-group, trifluoromethyl, amino-group, (C1-C3)-alkyl, (C2-C3)-olefinic group, (C1-C3)-alkoxy-, (C1-C3)-alkylthio-, (C1-C6)-alkylamino-group, (C1-C3)-alkoxycarbonyl, phenyl, cyano-, carboxy-group or carbamoyl; R4 means hydrogen atom or (C1-C3)-alkyl; Q means a bond or -SO2-; Y means (C1-C15)-alkyl, (C3-C10)-carbocyclic group or phenyl being each of them can be substituted optionally with one or some similar or different substitutes designated by the formula R5; R5 means halogen atom, (C1-C4)-alkyl, amino-, (C1-C3)-alkoxy-group, (C1-C3)-alkoxycarbonyl or -COOH; X means oxygen or sulfur atom. Also, invention relates to a pharmaceutical composition and to a method for treatment and/or prophylaxis of inflammatory diseases.
EFFECT: valuable medicinal properties of compounds and composition.
9 cl, 2 sch, 2 tbl, 29 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: the suggested pharmaceutical composition includes formoterol and its pharmaceutically acceptable salt and flucticason propionate at their weight ratio being, correspondingly, 1 : 5 to 1 : 50. Combined application of flucticason propionate and formoterol fumarate provides synergistic therapeutic action that enables to decrease the dosage of flucticason propionate for achieving concrete antiphlogistic action that leads to possible unfavorable side effects.
EFFECT: higher efficiency of application.
10 cl, 216 ex