The method of obtaining 3,7-dialkylamino
(57) Abstract:Usage: in medicine as an intermediate product to obtain drugs. The essence: gaining 3,7-dialkylamino by alkylation of the corresponding 3-alkylresorcinol in the two-phase mixture in the presence of a base, Quaternary ammonium and/or postoyalogo connections and linear polyether. The target compounds are obtained from very high yields with high purity. 8 C.p. f-crystals. The invention relates to a method for producing 3,7-dialkylamino, representing compounds of formula I
< / BR>Unsubstituted or substituted in position 1 with 3.7-dealkylation are the main four and intermediate products to obtain drugs. For example, the compound 3,7-dimethylxanthine (theobromine) can be used as forproduct for obtaining biologically active medicinal substance of pentoxifylline (U.S. patent 3737433) formula VIII
< / BR>and similar compounds that possess waterpainting properties.To obtain fully described pentoxifylline (VIII) you must use theobromine sufficiently high purity. Act of caffeine IX and isomeric compound theophylline X
< / BR>and coloring impurities.From the literature known methods for producing the compounds of formula I. as alkylating tools we use mainly dimethylsulfate, dimethylcarbonate and methyl chloride, ethylchloride, propylchloride, diethylsulfate, dipropylacetate, diethylcarbamyl or dipropylamine.Methods using dimethylsulfate as meteorologi means for receiving theobromine from 3-methylxanthines are summarized in the patent GDR 222026. Depending on the method used methylation get theobromine with outputs 65 - 76% of theory calculated on the pure theobromine. However, in the case of methods with high yields theobromine usually appear even larger amount of side compounds, which due to the quality requirements for obtaining biologically active medicinal substances should be removed by an additional purification process.Method using dimethylcarbonate as meteorologi tools (patent Germany 3741883) is a method, implemented at high pressure, which can be done only in special autoclaves that can withstand pressure of 80 to 160 bar. When this is achieved the outputs status is determined by HPLC.Method using methyl chloride as meteorologi means for receiving theobromine (patent Czechoslovakia 267100) in aqueous or aqueous-alcoholic medium gives high yields. But here we are talking about theobromine, which should be strongly contaminated by-products, as specified melting point is very far from the melting temperature of pure theobromine. A mixture of theobromine and approximately 5% 3-methylxanthines, for example, is always lying about 100oC above the melting temperature, as obtained according to the patent Czechoslovakia 267100 theobromine. Therefore, we must proceed from the fact that the selected product contains considerable amounts of caffeine (IX) and, if necessary, theophylline (X) that need to be removed by cleaning. The loss in output for further processing to pure theobromine can be very significant.Next, a method of obtaining 3-methyl-7-propylketone (patent Czechoslovakia 267796), and the method should be improved by adding small amounts of catalysts, operating at a phase boundary, as salts of tetraalkylammonium or dimethylbenzylamine with 8 to 18 C-atoms. However, the examples show that the addition of approximately 0,26 Ltd, obtained with catalyst and without him, the same.In addition, given in the patent Czechoslovakia 267100 examples show that in the case of large boot mixes the output is less. This fact is also described in the patent GDR 222026. Own our experiments, in which a hundred times increased the number of bootable mixture, described in the patent Czechoslovakia 267796 conditions show a significant decrease in output.The task of the invention was to develop a method of obtaining selective 3,7-dialkylamino from 3-alkylresorcinol with high outputs simultaneously very high purity and very good output per unit volume per unit time.Therefore, the invention relates to a method for producing 3,7-dialkylamino formula I
< / BR>and R1and R2independently of one another, denote a linear or branched C1-C6-alkyl,
characterized in that 3-alkylating formula II
< / BR>in which R1denotes a linear or branched C1-C6-alkyl,
a) in the aqueous phase using the asset transferred to it salt and
b) this salt in the presence of at least one Quaternary ammonium compound and/or the and independently from each other represent a linear or branched C1-C20-alkyl; benzyl or phenyl; and X is an anion, in the two-phase mixture is injected into the interaction with an alkylating agent with 1-6 C-atoms;
if necessary, the alkylation is carried out in the presence of a linear polyether of the formula V
R11-O-(Y)n-R12< / BR>and R11and R12are the same or different and independently from each other represents C1-C8-alkyl; Y is a residue from the group comprising-CH2-CH2-O - or-CH2-CH2-CH2-O-; and n is an integer equal to 1-8.In the proposed according to the invention, the method preferably receive 3,7-dealkylation formula I, and R1and R2independently of one another denote C1-C3-alkyl.Especially preferred 3,7-dealkylation for the method according to the invention are:
3,7-dimethylxanthine (= compound of the formula I with R1and R2= -CH3);
3-methyl-7-profilkanten (= compound of the formula I with R1= CH3and R2= -CH2-CH2-CH3);
3-ethyl-7-profilkanten (= compound of the formula I with R1= -CH2-CH3and R2= -CH2-CH2-CH3).Preferred unexpectedly high selective behaviour is ome, compounds of formula III and/or IV, and, if necessary, of the formula V, can be easily separated from the aqueous phase and be used for further interactions.Preferred basic tools are the hydroxides and/or carbonates of alkali metals such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate.Preferred used Quaternary ammonium or postname compounds of formulas III and IV, which only hard or almost insoluble in water. Preferred Quaternary ammonium or phosphonium compounds of formulas III and IV are: methyl-trioctylamine, methyl-trioctylamine, methyl-trickatilamania, methyl-triopalosheightsil, ethyl trioctylamine, ethyl trioctylphosphine and hexadecyltrimethylammonium.Preferred simple polyethers of the formula V are etilenglikolevye ether, dietilenglikoluretan ether, triethyleneglycoldinitrate ether, tetraethyleneglycol ether, diethylene glycol-ethyl tert-butyl ether, polietilenglikolmonostearat ether and polypropylenglycol eeet value equal 2-8).Preferred alkylating means are C1-C6-alkylhalogenide as alkylchloride, allylbromide, alkylphenyl or alkylated, in particular methyl chloride, ethylchloride; C1-C6-diallylsulfide as dimethyl-, diethyl-, dipropyl-, dibutil-, dipentyl or vexillologist; or C1-C6-diallylmalonate as dimethyl-, diethyl-, dipropyl-, dibutil-, dipentyl or digoxigenin.The term "anion" refers to chloride, bromide, hydrosulfate or hydroxide.The term "alkyl" is understood hydrocarbon residues as methyl, ethyl, propyl, butyl, pentyl or hexyl.3-(C1-C6)-alkalinty as starting substances for the proposed according to the invention the reaction of alkylation get known from the literature methods, for example by modified "Trauben-synthesis" (Ullmann's Enzyklopdie der Technischen Chemie, 4th ed., so 19/1180/, S. 579).Under way and doing it that first 3-(C1-C6)-alkylating in the aqueous phase using a hydroxide and/or carbonate of an alkali metal, such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate, perestaraksia or carbonate of an alkali metal.Then in stage method b) to the solution or suspension of the salt of 3-alkylating add Quaternary ammonium or postname compound of formula III or IV. You can also apply a mixture of ammonium and/or fofanah compounds. Compounds of formula III and/or IV insoluble or only trudnorastvorimy in the water. Therefore, there is formed a two-phase mixture consisting of an aqueous phase and which is formed by ammonium and/or fofanah compounds of formulas III and IV. Under the designation "two-phase mixture" is understood a mixture of two liquid phases, the water phase and which contains ammonium and/or postname compounds of formulas III and IV. A two-phase mixture does not contain, as a rule, no other boundary solid/liquid. However, it may be that at low temperatures and high salt concentrations of xanthine formed coagulates. A two-phase mixture is stirred and mixed in the usual way to ensure a good distribution of the phases.Preferably 100 mol 3-alkylating formula II using 5 to 100 mol of the compounds of formulas III and/or IV, preferably 10 to 60 mol, in particular from 10 to 50 mol.If necessary to further accelerate the reaction, you can add simple linear the CSOs polyester of the formula V, preferably 5 to 80 mol, in particular from 10 to 50 mol.Additionally, for improved separation of two-phase above the reaction mixture of compounds of formulas III, IV and V add an organic solvent, such as heptane, cyclohexane, dimethylcyclohexane, butyl acetate, amylacetate, dioxane, anisole or amyl alcohol. However, it is preferable to work without additional solvent.The added solvent is preferably only it is soluble in water or completely insoluble in it. The used amount of solvent can vary within wide limits and can easily determine a specialist.Then add the alkylating agent. For methylation, for example, 100 mol 3-methylxanthines need 102 to 150 mol of methyl chloride, in particular 105 - 140 mol, preferably 108 to 120 mol; or 102 - 150 mol of dimethylsulfate, especially 105 - 130 mol, preferably 110 to 120 mol.The reaction temperature may vary within wide limits. In General it is minus 10oC - 140oC, preferably 40 to 110oC.In the method of alkylation with methyl chloride in the reaction vessel reaches high pressure up to 5 bar, which is in General 1 - 4 o'clockWhen alkylation reaction using dimethylsulfate formed during the reaction metallinou acid is neutralized by slowly adding a hydroxide of an alkali metal, a carbonate of an alkali metal, hydroxide of alkaline-earth metal or carbonate of alkaline-earth metal.After a reaction time phase two-phase mixture is separated from each other. Then, first in the form of a coagulate 3,7-dealkylation formula I is mixed with alkaline hydroxide and/or alkaline-earth metal and/or carbonate of an alkali metal until, until emulsion is formed. For this, generally, you need about 80 to 120 mol of the above mixture.Phase two-phase mixture is separated from each other now standard ways. The organic phase, which contains mainly the compounds of formula III and/or IV, and, if necessary, the compound of formula V, can directly or after washing with water again be used for the alkylation reaction. The aqueous phase, which now contains a salt of 3,7-dialkylamino and impurities, mixed with auxiliary means for filtering based on cellulose or silicic acid or activated carbon and hotfil the nogo for separation of by-products, and deposited pure 3,7-dealkylation. As inorganic acids, for example, include: hydrochloric acid, sulfuric acid or nitric acid. You can also use carbonic acid.The temperature of deposition is about 50 - 110oC, in particular 75 - 105oC, preferably 85 - 95oC. After deposition, the pH of the solution is 7 to 10.Consumption of inorganic acid is a total of 88 - 110 mol.The solid is then allocate by suction and washed with water to remove by-products.Proposed in the invention method is now explained in more details by the following examples.Example 1. In a reactor placed in 2000 ml of water, 400 g of 3-methylxanthines, 310 g of a 33% aqueous sodium hydroxide solution, 20 g of sodium bicarbonate and 200 g of methyl-trioctylamine. After the reactor was tightly closed, at about 50oC enter 135 g of methyl chloride. Then leave another to react at about 110oC up until the pressure inside the reactor will not fall. The reactor is cooled to approximately the 60oC and quickly dehydrate. After that add 310 g of a 33% aqueous hydroxide solution natrenovany methyl-trioctylamine can be used again for the next methylation. The aqueous phase is mixed with active charcoal and the solution is filtered. Then, by addition, in General, 252 g of 37% hydrochloric acid at a temperature of 85 - 95oC precipitated theobromine. After cooling, theobromine sucked off and optionally washed with water. After drying to constant weight gain 367 g of theobromine content of theobromine = 99,5% (HPLC). So pl. = 350,5 - 351oC. It is 84,5% of theoretically calculated values, based on the original product 3-methylxanthines.HPLC-determination (determination by high performance liquid chromatography).The sample preparation. 50 mg of theobromine (sample) is suspended in 90 ml of water, add 1 ml of 1 M sodium hydroxide solution and the sample is easily dissolved. Then, the sample is acidified with 2 ml of 1 M acetic acid in a volumetric flask and topped up to 100 ml with water.Comparative solutions: 1 mg of caffeine, 3-methylxanthines and theophylline dissolved as described above.Condition analysis:
injection amount: 10 μl;
column: RP 8,250 - 4,10 μm, lichrosorb (firm E. Merck, Darmstadt);
the degree of fluidity: 1 ml/min;
mobile phase: 80% vol. 0.1% solution KH2PO4, 20 vol.% methanol;
detection: UV date min, caffeine - minutes of 11.15Determination of the yield point. Yield point is determined by differential thermal analysis using system Mettler TA3000.Example 2. In the reactor serves 2000 ml of water, 400 g of 3-methylxanthines, 310 g of a 33% aqueous sodium hydroxide solution, 20 g of sodium bicarbonate and 200 g of methyl-trioctylamine and 100 g dietilaminoetilovogo simple ether. After the reactor was tightly closed, at about 50oC enter 134 g of methyl chloride. Then at around 90oC leave more to respond to until the internal pressure will not fall. The reactor is cooled to approximately the 50oC and quickly obzharivayut. After that add 310 g of a 33% aqueous sodium hydroxide solution and then the organic phase is separated. It additionally washed with 100 ml of water. Thus, the newly allocated methyl-trioctylamine and dietilenglikoluretan simple air can re-enter for the next methylation. The aqueous phase is mixed with active charcoal and the solution is filtered. Then at 85 - 95oC by addition is generally about 252 g of 37% hydrochloric acid precipitated theobromine. After drying to constant weight gain 376 g of theobromine with the content of the t 3-methylxanthines.Example 3. In the apparatus with stirrer serves pre-2000 ml of water, 400 g of 3-methylxanthines, 294 g of a 33% aqueous sodium hydroxide solution, 200 g of methyl-trioctylamine and 100 g triethyleneglycoldinitrate simple ether. Then at about 50 - 60oC was added dropwise 351 g dimethylsulfate. After adding to the reaction mixture was added dropwise addition of 16 g of 33% sodium hydroxide solution. Then leave approximately at 60oC doragonball. Cool and then add 310 g of a 33% aqueous sodium hydroxide solution. Then the organic phase is separated. It is washed with 100 ml of water. Thus, the newly allocated methyl-trioctylamine and triethyleneglycoldinitrate simple air can re-enter for the next methylation. The aqueous phase is mixed with active charcoal and filtered. Then at 85 - 95oC by addition is generally about 250 grams of 37% hydrochloric acid precipitated theobromine. After cooling, theobromine sucked off and optionally washed with water. After drying to constant weight gain 361 g of theobromine content of theobromine of 99.5% (HPLC). This accounts for 83.2% of theoretically calculated values in the calculation of the original product 3-methylxanthines.Example 4. In etilenpropilendienovogo ether (n = 3-5) and 100 g of chloride ethyltrichlorosilane. After the tight closure of the reactor is injected 135 g of methyl chloride at a temperature of about 50oC. and Then at a temperature of approximately 90oC give to react until the internal pressure will not cease to fall. The reactor is cooled to 50oC and soon evacuated. After that add 310 g of 33% sodium liquor and separated then the organic phase. The latter was washed with 100 ml of water. Regenerated thus the catalyst can be re-used for the next methylation. The aqueous phase is mixed with activated carbon and diazelam and the solution is filtered. Then precipitated theobromine, adding dropwise at 85 - 95oC 252 g of 37% hydrochloric acid. After cooling, theobromine is sucked off and washed with water. After drying to constant weight get 376,5 g theobromine content of 99.5% (liquid chromatography high pressure). This is 86.6% of theoretical value, considering the original product - 3-methylxanthines.Example 5. Charged to the reactor 2000 ml of water, 400 g of 3-methylxanthines, 310 g of 33% sodium lye, 20 sodium bicarbonate, 200 polyethylenglykolmonobutylether ether (n = 3-5) and 70 g of bromide hexadecyltrimethylammonium. After the tight closure of the reactor is injected 138 g of methyl chloride at temperature stop falling. The reactor is cooled to 50oC and soon evacuated. After that add 310 g of 33% sodium liquor and separated then the organic phase. The latter was washed with 100 ml of water. Regenerated thus the catalyst can be re-used for the next methylation. The aqueous phase is mixed with activated carbon and diazelam and the solution is filtered. Then precipitated theobromine, adding dropwise at 85 - 95oC 252 g of 37% hydrochloric acid. After cooling, theobromine is sucked off and washed with water. After drying to constant weight get 371,7 g theobromine content of 99.5% (liquid chromatography high pressure). This accounts for 85.5% of theoretical value, considering the original product - 3-methylxanthines.Example 6. a 10-fold amount of the mixture in comparison with example 1 of the CS-PS 26 7796, 83 g of dry 3-methyl-3,7-dihydro-1H-purine-2,6-dione (BUX), which is 0.5 mol, is heated with an 80.2 g K2CO3(99%) (corresponds 0,575 mol) and 1000 ml of water up to 80oC and maintain at this temperature for 1 h in a reverse flow. The solution is cooled to 30oC. then add 52,3 ml of n-propyl bromide (0,575 mole) dissolved in 500 ml of ethanol (96%).The initial mixture after heating and p is analyzed by chromatography high pressure.The result: 40,7% 3-methyl-7-propyl-3,7-dihydro-1H-purine-2,6-dione, 42,3% BUX, 12,0% 3-methyl-1,7-dipropyl-3,7-dihydro-1H-purine-2,6-dione, or 1.9% 1-propanol. 1. The method of obtaining 3,7-dialkylamino formula I
< / BR>in which R1and R2independently from each other - FROM1-C6-alkyl, linear or branched,
characterized in that 3-alkylating formula II
< / BR>in which R1- C1-C6-alkyl, linear or branched,
transferred to the aqueous phase using the asset in its salt and this salt is subjected to interaction in the presence of at least one Quaternary ammonium compound and/or postoyalogo the compounds of formula III or IV
< / BR>in which R3- R10the same or different and independently of one another denote WITH1-C20-alkyl, linear or branched, benzyl or phenyl;
X - anion,
in the two-phase mixture with an alkylating agent containing 1-6 carbon atoms, and carry out the alkylation in the presence of a linear polyether of the formula V
R11- O - (Y)n- R12,
in which R11and R12the same or different and independently from each other - FROM1-C8-alkyl;
Y is the residue of g is .1, characterized in that the gain of 3.7-dealkylation formula I, where R1and R2independently from each other, WITH1-C3-alkyl.3. The method according to p. 1 or 2, characterized in that the gain of 3.7-dimethylxanthine, 3-ethyl-7-profilkanten or 3-methyl-6-profilkanten.4. The method according to PP.1 to 3, wherein introducing at least one ammonium compound of the formula III, fashonable compound of formula IV, a simple polyester of the formula V or an organic solvent, which trudnorastvorimy in water, not soluble in it.5. The method according to PP.1 to 4, characterized in that as the primary means use the hydroxide and/or carbonate of an alkali metal such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate, as Quaternary ammonium or postoyalogo compounds of formulas III and IV injected methyl-trioctylamine, methyl-trioctylamine-hydroxide, methyl-trickatilamania, methyl-tricaprylate-hydroxide, ethyl trioctylamine, ethyl trioctylphosphine or hexadecyltrimethylammonium and as a polyether of the formula V used etilenglikolevye ether, di is jingleball-ethyl tert-butyl ether, propilenglikolmonostearata ether, dipropyleneglycol ether, polietilenglikolmonostearat ether or polypropylenglycol ether.6. The method according to PP.1 to 5, characterized in that the alkylating tools use1-C6-alkylhalogenide,1-C6-dialkylamides or1-C6-dialkylamino, in particular methyl chloride, ethylchloride, propylchloride or dimethylsulfate.7. The way PP. 1 - 6, characterized in that per 100 mol of 3-alkylating formula II using 5 to 100 mol of the compounds of formula III and/or IV, preferably 10 to 60 mol, in particular from 10 to 50 mol, and, if necessary, add 3 to 100 mol of a linear polyether of the formula V, preferably 5 to 80 mol, in particular from 10 to 50 mol.8. The method according to PP.1 to 7, characterized in that the alkylation is carried out at temperatures from -10 to +140oC, preferably at 40 - 110oC.9. The method according to PP.1 to 8, characterized in that the molar ratio of 3-acylcarnitine to the alkylating agent is 1 : of 1.02 to 1.5, preferably 1 : 1,08 - 1,2.
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: organic chemistry, biochemistry.
SUBSTANCE: invention proposes compound of the formula (1) in free form or as a salt wherein R1, R2, R3, R4 and R5 have values given in the invention claim. The claimed compounds are selective inhibitors of enzyme PDE-5 and show the high selectivity in inhibition of activity of 3',5'-cycloguanosine monophosphate phosphodiesterase being activity of PDE-5 first of all.
EFFECT: valuable biochemical properties of derivatives.
6 cl, 3 tbl, 87 ex
FIELD: organic chemistry, pharmaceutical chemistry, pharmacology, medicine.
SUBSTANCE: invention relates to novel derivatives of 3-methyl-7-(thietanyl-3)-xanthine of formulae (Ia, b, c, d): wherein R means C2H5, R1 means , n = 1 (Ia); R means n-C3H7, R1 means Br, n = 1 (Ib); R means hydrogen atom (H), R1 means -SCH2CONHNH2, n = 0 (Ic); R means H, R1 means -SCH2CONHNH2, n = 2 (Id). Proposed compounds possess the greater hemorheological activity as compared with that of pentoxyphylline and lower toxicity. Invention provides synthesis of novel and not described previously derivatives of 3-methyl-7-(thietanyl-3)-xanthine of formulae (Ia, b, c, d) possessing hemorheological activity.
EFFECT: improved method of synthesis, valuable medicinal property of compounds.
2 tbl, 4 ex
FIELD: organic chemistry, medicine, pharmacology.
SUBSTANCE: invention relates to compound of the formula (I): or (II): wherein R1 and R2 are chosen independently from hydrogen, optionally substituted alkyl or the group: -D-E wherein R represents a covalent bond or alkylene; E represents optionally substituted alkoxy-group, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkenyl or optionally substituted alkynyl under condition that if D represents a covalent bond then E can't represents alkoxy-group; R3 represents hydrogen atom, optionally substituted alkyl or optionally substituted cycloalkyl; X represents optionally substituted arylene or heteroarylene; Y represents a covalent bond or alkylene wherein one carbon atom can be substituted optionally for -O-, -S- or -NH-, and optionally substituted hydroxy-, alkoxy-, optionally substituted amino-group or -COR wherein R represents hydroxy-, alkoxy- or amino-group under condition that if an optional substitute represents hydroxy- or amino-group then it can't be adjacent with a heteroatom; Z represents hydrogen atom, optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl under condition that Z represents hydrogen atom only under condition that Y represents a covalent bond, and X represents optionally substituted 1,4-pyrazolene, and under condition that if X represents optionally substituted arylene then Z represents optionally substituted monocyclic heteroaryl. Also, invention describes a method for treatment of the morbid state by inhibition of adenosine receptors describes as A2B based on compounds of the formula (I) or the formula (II). Invention provides synthesis of novel compounds possessing useful biological properties.
EFFECT: valuable medicinal properties of compounds.
32 cl, 35 ex
SUBSTANCE: invention concerns new derivatives of 1- and 7-[ω-(benzhydryl-4-piperazinyl-1)alkyl]-3-alkyloxantines of the general formulae I and II, including their pharmaceutically acceptable salts and/or salt hydrates, the derivatives showing antihistaminic and antiallergenic effect. In the general formulae I and II : R = H, Me, CH2Ph; R1 = Me, "н" - C4H9; n = 0-3; X = H, OH, OCOCH2CH2COOH; Y = Y1 = H, Cl, F; on the condition that R and R1 are not both methyl. Compounds of the invention feature high antihistaminic and antiallergenic activity. E.g., 7-[4-(benzhydryl-4-piperazinyl-1)butyl]-3-methyloxantine dihydrochloride surpasses most efficient antihistaminic and antiallergenic medications, such as cetirizine, loratadine and azelastine, in activity and lasting effect.
EFFECT: obtaining a compound with high antihistaminic and antiallergenic activity.
2 cl, 3 tbl, 8 ex
SUBSTANCE: present invention refers to substituted 8-heteroarylzantines of general formula where R represents hydrogen, (C1-C5)alkyl or halogen(C1-C8)alkyl; R1 is chosen from (C3-C6)cycloalkyl or (C3-C6)cycloalkyl(C1-C4)alkyl-; R2 is chosen from (C1-C8)alkyl, (C3-C8)alkenyl, (C3-C8)alkinyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C8)alkyl- or (C6-C10)aryl(C1-C8)alkyl-; X represents 3-pyridyl substituted in 6th position with Z; Z represents -NR4R5 or (C4-C10)heterocycle where heterocycle is optionally substituted with 1, 2, 3 or 4 substitutes independently chosen from (C1-C8)alkyl; each Z1 independently represents halogen or -NR7R8; R5 is chosen from -C(O)R6, -CO2R6 or -C(O)NHR7; R4 is chosen from hydrogen, (C1-C8)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C8)alkyl-, (C3-C10)heterocycle(C1-C8)alkyl-, (C6-C10)aryl, (C6-C10)aryl(C1-C8)alkyl-, (C5-C10)heteroaryl, (C5-C10)heteroaryl(C1-C8)alkyl-, -((CH2)2-4)Y)q-(CH2)2-4-X1, -C(O)R6, -CO2R6 or -C(O)NR7R8; or R4 and R5 together with atoms whereto attached form saturated mono-or bicyclic ring with 5, 6, 7 or 8 ring atoms and optionally containing 1 or 2 heteroatoms chosen of non-peroxide oxy (-0-) and amine -N(R9)- in the ring where the ring is optionally substituted by 1, 2, 3 or 4 substitutes independently chosen from -C(O)Ra and -C(O)NRbRc; X1 represents -OR6; and Y represents oxy (-O-); where alkyl, alkenyl, cycloalkyl, alkinyl, aryl, heterocyclic or hetero aryl groups from R1, R2, R3, R4 and R5 groups are optionally substituted by one or more substitutes independently chosen from (C1-C8)alkyl, -ORa, (C6-C10)aryl, hydroxy(C1-C8)alkyl and RbRcN(C1-C8)alkyl; where R6 represents (C1-C8)alkyl or (C4-C10)heteroaryl; where heteroaryl is optionally substituted by 1, 2, 3 or 4 substitutes independently chosen from halogen, -ORa and halogen(C1-C8)alkyl; where R7, R8 and R9 independently represent (C1-C8)alkyl, RaO(C1-C8)alkyl, (C6-C10)aryl or (C4-C10)heteroaryl; where heteroaryl or aryl are optionally substituted by 1, 2, 3 or 4 substitutes independently chosen from halogen and -ORa; Ra represents hydrogen or (C1-C6)alkyl; each Rb and Rc independently represents hydrogen or (C6-C10)aryl; and where n is equal to 0, 1 or 2; and q is equal to 1; or its pharmaceutically acceptable salt. In addition, the invention concerns pharmaceutical composition based on compound of formula I.
EFFECT: new substituted 8-heteroarylxantines are selective antagonists of A2B adenosine receptors.
38 cl, 1 tbl, 1 ex
SUBSTANCE: method involves alkylation of 7-potassium salt of 3-methylxanthine with 1,4-dibromobutane, with subsequent reaction of the formed 7-(4-bromobutyl)-3-methylxanthane with 1-benzhydrylpiperazine and neutralisation of the obtained base 7-/4-(4-benzhydrylpiperazinyl-1)butyl/-3-methylxanthane with organic or inorganic acid.
EFFECT: obtained compounds have better pharmacotherapeutic properties than current antihistaminic drugs.
2 cl, 1 dwg, 2 ex
SUBSTANCE: invention relates to an improved method of producing compounds of formula I, which are antagonists of adenosine receptors A2B, and useful in treating different conditions, including asthma and diarrhoea, as well as intermediate compounds for their production. In formula (I) R1 and R2 are independently optionally substituted alkyl; X is pyrazol-4-yl; Y is a covalent bond or a lower alkylene; and Z is optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl. The method involves ring closure of the compounds of formula (3): , in which R1, R2, X, Y and Z are as described above, in the presence of a base. In the method new intermediate compounds are obtained, which makes the method of producing compounds of formula I more cost effective since the primary products used are obtained using simple technology.
EFFECT: design of a simple method of obtaining said compounds.
47 cl, 6 dwg, 30 ex
SUBSTANCE: invention relates to 3-methyl-8-piperazino-7-(thiethanyl-3)-1-ethylxanthine hydrochloride of formula .
EFFECT: novel compound which can be used in medicine as an antiaggregation and disaggregation agent is obtained and described.
3 cl, 2 tbl, 1 ex
SUBSTANCE: invention relates to compounds of formula in which R1 and R2 independently denote C1-6alkyl; R4 denotes phenyl, substituted with trifluoromethyl if necessary; X denotes hydrogen or methyl; and Y denotes -C(O)R, where R denotes C1-6alkyl; or Y denotes -P(O)(OR5)2, where R5 denotes hydrogen or C1-6alkyl; or pharmaceutically acceptable salts thereof. Said compounds are prodrugs of adenosine A2B receptor. The invention also relates to a pharmaceutical composition which is an adenosine A2B receptor antagonist based on the compound of formula I.
EFFECT: formula I compounds and the pharmaceutical composition can be used in treating different diseases in mammals, such as gastrointestinal disorders, immunological disorders, allergic disorders, neurological disorders, cardiovascular disorders and diseases associated with cell hyperproliferation.
13 cl, 1 tbl, 15 ex
SUBSTANCE: disclosed agent is a xanthine derivative of formula 1
, where R1 denotes CH3, R2 denotes CH3; R3 denotes halogens: F,Cl, Br, I; R4 denotes hydrogen; R1 denotes CH3, R2 denotes CH3; R3 denotes hydrogen, halogens: F, Cl, Br, I; R4 denotes CH2COOH; R1 denotes hydrogen, R2 denotes CH3; R3 denotes halogens: F, Cl, Br, I; R4 denotes CH3. The preferred compounds of the said agent are 8-chlorotheophylline, 8-bromotheophylline and theophylline-7-acetate. The invention also relates to a method of slowing down proliferation of tumour cells and a method of inducing differentiation in mouse melanoma B16-F10 cells. Each of the methods involves addition of an effective amount of the said agent in an effective amount, preferably in amount of 1 mM.
EFFECT: improved properties of the derivatives.
8 cl, 4 tbl, 12 dwg
SUBSTANCE: nucleic base (e.g. uracil, cytosine, adenine, guanine, hypoxanthine, xanthine or similar) reacts with perfluoroalkyl halide in the presence of sulphoxide, peroxide and an iron compound to obtain a perfluoroalkyl-substituted nucleic base.
EFFECT: high cost effectiveness as an intermediate compound for producing medicinal agents.
15 cl, 6 tbl