Methyluracil derivative and organic acid complex and method for production thereof
SUBSTANCE: invention relates to a novel complex of 5-hydroxy-6-methyluracil with 5-aminosalicylic acid of formula . The compound has anti-inflammatory activity and can be used as a basic active substance when producing novel medicinal preparations having anti-inflammatory action. The invention also relates to a method of obtaining said complex. The method includes reacting 5-hydroxy-6-methyluracil with 5-aminosalicylic acid in equimolar amounts in an aqueous medium at room temperature for 24 hours, followed by removal of water from the reaction mixture and obtaining the product.
EFFECT: wider range of pharmacological preparations with low toxicity, having higher anti-inflammatory activity.
2 cl, 1 tbl, 1 ex
The invention relates to medicine, in particular to pharmacology, namely to complex compounds derived methyluracil with an organic acid, specifically complex to the compound of 5-hydroxy-6-methyluracil 5-aminosalicylic acid of the formula:
exhibiting anti-inflammatory activity. This compound can be used as the main active ingredient in the creation of new drugs that have anti-inflammatory action
Known compound 6-methyluracil with succinic acid, manifesting antihypoxic activity [patent RU 2259357, CL C07D 239/22, publ. 27.08.2005,]. This compound has low toxicity and higher antihypoxic activity compared with 6-methyluracil and succinic acid. The drawback of this coupling is that the anti-inflammatory effect of 6-methyluracil expressed weaker than its derivative 5-hydroxy-6-methyluracil.
Known compound 5-hydroxy-6-methyluracil with sodium succinate [patent RU 2475482, CL C07D 239/60, OR 43/00, publ. 20.02.2013,]. This compound has a higher antihypoxic activity in models of acute himicheskoi hypoxia and acute gistologicheskoe hypoxia compared with PE is eventName drugs and low toxicity when injected into the stomach and intraperitoneally. The disadvantage of the considered complex compounds is that 5-hydroxy-6-methyluracil is mixed with sodium succinate in the ratio of 1:10, and a considerable excess of sodium succinate may cause allergic reactions.
The closest to describing the technical essence and the achieved result is a compound derived methyluracil with an organic acid, the derivative methyluracil use of 1,3-bis(2-hydroxyethyl)-5-hydroxy-6-methyluracil, and as the organic acid is fumaric acid [patent RU 2330025, CL C07D 239/60, A61K 31/513, A61P 9/10, publ. 27.07.2008,]. The complex compound has the formula:
Compound derived methyluracil with organic acid is obtained by reacting equimolar amounts of 1,3-bis(2-hydroxyethyl)-5-hydroxy-6-methyluracil with fumaric acid in the environment of a solvent at a temperature of 60-70°C for 2-3 hours, removing the solvent from the reaction mixture and the product. As the solvent used ethanol. This compound compared with the reference drugs has a higher antihypoxic activity and low toxicity when injected into the stomach and intraperitoneally. However, anti-inflammatory complex compounds 1,3-b is(2-hydroxyethyl)-5-hydroxy-6-methyluracil with fumaric acid has not been studied.
The task, which directed the claimed technical solution is to expand the Arsenal of pharmacological agents with low toxicity, which has a higher anti-inflammatory activity.
The problem is solved by obtaining the complex compounds derived methyluracil with an organic acid, where as derived methyluracil used 5-hydroxy-6-methyluracil, and organic acid - 5-aminosalicylic acid of the formula:
The method of obtaining complex compounds derived methyluracil with organic acid is in the interaction them in equimolar amounts in the environment of the solvent, the subsequent removal of the solvent from the reaction mixture with the product, as derived methyluracil using 5-hydroxy-6-methyluracil, organic acid - 5-aminosalicylic acid, and solvent - water interaction was performed at room temperature within 24 hours.
It is known that 5-hydroxy-6-methyluracil has anti-inflammatory action, which is associated with its ability to suppress the activity of proteolytic enzymes, 5-aminosalicylic acid as an inhibitor of prostaglandin synthesis, also has anti-inflammatory activity.
Acute toxicity of complex compound 5-hydroxy-6-methyluracil 5-aminosalicylic acid has been studied in 12 mice weighing 16-18 g compound was dissolved in TWEEN-85 and distilled water, was administered orally in two doses: 5000 mg/kg 8000 mg/kg during the first day of the animals in both groups were alive with no visible signs of toxicity of the complex. On the basis of the received data according to the classification GOST 12.1.007-76 compound 5-hydroxy-6-methyluracil 5-aminosalicylic acid belongs to the class IV hazardous compounds.
Anti-inflammatory activity of complex compound 5-hydroxy-6-methyluracil 5-aminosalicylic acid was studied on a model of acute inflammation caused by the introduction under the aponeurosis of the foot mice 1% solution carragenin. Experiments were performed on 48 outbred mice of both sexes weighing 18-20 g compound 5-hydroxy-6-methyluracil 5-aminosalicylic acid is administered orally in doses of 50 mg/kg and 100 mg/kg 1 hour before and 1 and 2 hours after playing inflammation. As comparative drugs were used starting compound: 5-hydroxy-6-methyluracil and 5-aminosalicylic acid, which was introduced in a similar way at a dose of 50 mg/kg Control animals were injected intragastrically equivalent volume of water. After until is reaches a "peak" moment of swelling, animals were euthanized ether anesthesia. Feet cut off in the area of the ankle joint and weighed. About anti-inflammatory activity was assessed by the severity of swelling experienced paws compared with healthy foot and inhibition of inflammation compared to the control without treatment (table).
|The influence of compounds on acute swelling of the paws of mice caused a 1% solution carragenin (N=8)|
|Connection||Dose, mg/kg||The severity of edema, %||Inhibition of inflammation, %|
|Compound(5-hydroxy-6-methyluracil: 5-aminosalicylic acid =1:1)||50||56,6±4,1*||26,4|
|Compound (5-hydroxy-6-methyluracil: 5-||100||49,1±2,2||36,2|
|aminosalicylic acid =1:1)|
|Compound (5-hydroxy-6-methyluracil:5-amines illowa acid =1:2)||50||55,7±3,1||23,0|
|Note: N - number of animals in the group.|
|* - Significantly relative to the control at P<0,01, where P is the signicance level|
The study showed that in the groups of animals that were injected compound 5-hydroxy-6-methyluracil 5-aminosalicylic acid in doses of 50 mg/kg and 100 mg/kg, the percentage of the severity of edema was, respectively, 1.4 and 1.6 times less than that of the control group. The claimed compound in a dose of 50 mg/kg inhibited inflammation by 26.4%, and at a dose of 100 mg/kg - 36.2%. Comparators (5-hydroxy-6-methyluracil and 5-aminosalicylic acid) reduces the severity of swelling, respectively, 1.2 and 1.3 times in comparison with control. The percentage inhibition of inflammation in these groups accounted for the Il of 13.3% and 20.0%, respectively.
Thus, the model carragenine inflammation compound 5-hydroxy-6-methyluracil 5-aminosalicylic acid in doses of 50 mg/kg and 100 mg/kg showed anti-inflammatory activity (P<0.01) compared with the parent compounds.
As follows from table 5-aminosalicylic acid showed a higher tendency to inhibition of inflammation than 5-hydroxy-6-methyluracil, therefore, was investigated anti-inflammatory activity of complex compound 5-hydroxy-6-methyluracil 5-aminosalicylic acid in which the molar ratio of the components 5-hydroxy-6-methyluracil:5-aminosalicylic acid is 1:2 (table). The table shows that the percent severity of edema and inhibition of inflammation was at the level of complex compound 5-hydroxy-6-methyluracil 5-aminosalicylic acid in which the molar ratio of the components 5-hydroxy-6-methyluracil: 5-aminosalicylic acid is 1:1.
The essence of the technical solution is illustrated by the following example.
To a solution of 2.0 g (0,013 mol) of 5-aminosalicylic acid in 200 ml of water was added 1.8 g (0,013 mol) of 5-hydroxy-6-methyluracil. The reaction mixture was stirred for 1 day at room temperature. From the reaction mixture water was removed by evaporation and was obtained with quantitative yield of integrated the e compound 5-hydroxy-6-methyluracil 5-aminosalicylic acid.
IR spectrum (ν, cm1): 646, 790, 1070(=N-), 1090, 1228, 1276, 1318 (ν CN), 1378 (δsCH3), 1426, 1462 (CH2CH3), 1600, 1650, 1690, 1710 (C=O, =N-C=O), 2536, 2854, 2938 (ν CH), 2950, 3082, 3560 (HE).
13C NMR spectrum (δ, M. D.): 18.22 (CH3), 153.04, 164.22 (C=O), 171.83 (COOH), 156.93 (C-OH), 131.31 (C-NH2).
The optimal condition for the process of obtaining complex compound 5-hydroxy-6-methyluracil 5-aminosalicylic acid is room temperature and duration of interaction 24 hours. Temperatures above and below room require additional energy costs for heating and cooling the reaction mixture, respectively. The interaction of reagents with a duration of less than 24 hours is not enough for the formation of complex compounds and the process for more than 24 hours is impractical because of the additional time and energy costs.
The optimal molar ratio of the components in the complex compound is the molar ratio of 5-hydroxy-6-methyluracil: 5-aminosalicylic acid is 1:1. Complex compounds of other elements (table). have the same anti-inflammatory properties, but to receive them spent more reagents.
Thus, it follows from the presented results of the research, the proposed compound 5-hydroxy-6-methyluracil 5-aminosalicylate acid of the formula:
has a higher anti-inflammatory activity than the original 5-hydroxy-6-methyluracil and 5-aminosalicylic acid, low toxicity and allows you to expand the Arsenal of pharmacological agents with low toxicity, which has a higher anti-inflammatory activity.
1. Compound derived methyluracil with an organic acid, characterized in that as a derivative methyluracil used 5-hydroxy-6-methyluracil, and organic acid - 5-aminosalicylic acid of the formula:
2. The method of obtaining complex compounds derived methyluracil with organic acid is in the interaction them in equimolar amounts in the environment of the solvent, the subsequent removal of the solvent from the reaction mixture to obtain the product, characterized in that as a derivative methyluracil using 5-hydroxy-6-methyluracil, organic acid - 5-aminosalicylic acid, and solvent - water interaction is carried out at room temperature for 24 hours.
SUBSTANCE: preparation shows an antitoxic activity, and can be used as an antidote for nitrite and nitrate poisoning. A complex compound of 5-hydroxy-6-methyluracil with ascorbic acid (5-hydroxy-6-methyluracil ascorbate) is described by formula: The preparation contains the complex compound in an amount of 0.3-0.4 wt %, and ascorbic acid - the rest. The method for producing the preparation consists in a reaction of 5-hydroxy-6-methyluracil and ascorbic acid taken in the relation of ascorbic acid: 5-hydroxy-6-methyluracil equal to 1:(0.0015-0.0022), in water as a solvent at a temperature of 20-40°C for 30-60 minutes. The complex compound is produced as shown by infra-red and NMR spectra. The antitoxic activity of 5-hydroxy-6-methyluracil on nitrite has been unknown before.
EFFECT: water removal from the reaction mixture under low pressure.
2 cl, 2 tbl, 1 ex
SUBSTANCE: invention relates to a novel complex of 5-hydroxy-6-methyluracil with sodium succinate (5-hydroxy-6-methyluracil succinate) of formula: , which exhibits antihypoxic activity. The disclosed compound widens the range of pharmacologically active compounds with low toxicity and high antihypoxic activity, which increase body resistance to certain types of hypoxia and in conditions influenced by other extreme environmental factors. The invention also relates to a method of producing the complex. The method involves mixing 5-hydroxy-6-methyluracil and sodium succinate in ratio of 1:10 in distilled water and then mixing the reaction mixture until dissolution of 5-hydroxy-6-methyluracil, removing the solvent from the reaction mixture and extracting the product.
EFFECT: output of the end product reaches 98%.
3 cl, 2 tbl, 4 ex
SUBSTANCE: invention refers to new biologically active high-immunotropic compound -N,N'-(sulphonyldi-1,4-phenylene)bis[(N",N'"-dimethyl)methyliminomethane]1,2,3,4-tetrahydro-6-methyl-2,4-dioxo-5-pyrimidinesulphonate of formula stated below to be used in treatment of, e.g., patients suffering from leprosy, allergic dermatosis, dermatitis herpetiformis. .
EFFECT: new compound is characterised with useful biological activity.
2 tbl, 1 ex
SUBSTANCE: invention relates to the new complex compound of 1,3-bis(2-hydroxyethyl)-5-hydroxy-6-methyluracil with fumaric acid of the formula which can be used in medicine as the substance capable of raising the survival rate in conditions under the influence of extreme environmental factors, particularly hypoxia. The new complex compound 1,3-bis(2-hydroxyethyl)-5-hydroxy-6-methyluracil with fumaric acid is obtained with 94% output by mixing equimolar quantities of 1,3-bis(2-hydroxyethyl)-5-hydroxy-6-methyluracil with fumaric acid in organic solvent with the subsequent heating of the reaction mixture for 2-3 hours, preferably at a temperature of 60-70°, removal of the solvent from the reaction mixture and the isolation of the product.
EFFECT: it makes it possible to increase the survival rate in harsh environmental conditions.
3 cl, 3 tbl, 5 ex
FIELD: organic chemistry, chemical technology.
SUBSTANCE: invention relates to the improved method for preparing 4,6-dimethoxy-2-(methylsulfonyl)-1,3-pyrimidine. Method involves reaction of 4,6-dichloro-2-(methylthio)-1,3-pyrimidine with alkaline metal methoxide in inert organic solvent, transfer of prepared 4,6-dimethoxy-2-(methylthio)-1,3-pyrimidine in aqueous acid medium and the following oxidation of this compound in the presence of catalyst if necessary, preferably, with an interphase catalyst, such as tricaprylmethylammonium chloride. Then method involves carrying out the purification stage wherein pH value of the aqueous acid reaction mixture is brought about to the value from 5 to 8 with aqueous base, such as alkaline metal hydroxide, for example, sodium hydroxide at temperature 10-90°C and stirring in the presence of absence of organic solvent, for example, aromatic hydrocarbon, such as benzene, toluene or isomeric xylenes, or alcohol, such as methanol or ethanol. Also, invention relates to using the prepared compound as an intermediate substance for synthesis of herbicide, in particular, 7-[(4,6-dimethoxypyrimidin-2-yl)thio]-3-methylphthalide by reaction of 7-mercapto-3-methylphthalide of compound in preparing herbicides, for example, 7-[(4,6-dimethoxypyrimidin-2-yl)thio]-3-methylphthalide.
EFFECT: improved preparing method.
24 cl, 2 sch, 1 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to 4,4'-sulfonyl-bis-(N,N'-dimethylammoniomethyleneaniline)-chloride, 6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-sulfonate of the formula (I) eliciting antibacterial, antimycobacterial and immunotropic activities. Also, invention describes a pharmaceutical composition based on compound of the formula (I).
EFFECT: valuable medicinal properties of compounds and composition.
3 cl, 7 tbl, 2 ex
FIELD: organic chemistry, biochemistry, pharmacy.
SUBSTANCE: invention relates to new heterocyclylsulfonyl alkylcarboxylic acids and their derivatives of the general formula (1): or their pharmaceutically acceptable salts, N-oxides or hydrates possessing the inhibitory effect on kinase activity and to the focused library for search of active leader-compounds comprising at least abovementioned compound. In the general formula 91) W represents optionally substituted heterocyclic radical, among them: pyrrole-3-yl, thiophene-2-yl, isooxazole-4-yl, pyrazole-4-yl, imidazole-4-yl, pyridine-3-yl, 1H-2,4-dioxopyrimidine-5-yl, 2,3-dihydro-1H-indole-5-yl, 2,3-dihydro-1H-indole-7-yl, 1,3-dihydro-2-oxoindole-5-yl, 2,3-dioxo-1H-indole-5-yl, 2-oxo-3H-benzoxazole-6-yl, benzothiazole-6-yl, 1H-benzimidazole-5-yl, benzo[1,2,5]oxadiazole-4-yl, benzo[1,2,5]thiadiazole-4-yl, 1,2,3,4-tetrahydroquinoline-6-yl, 3,4-dihydro-2-oxo-1H-quinoline-6-yl, quinoline-8-yl, 1,4-dihydro-2,3-dioxoquinoxaline-6-yl, 3-oxo-4H-benzo[1,4]oxazine-7-yl, 3-oxo-4H-benzo[1,4]thiazine-7-yl, 2,4-dioxo-1H-quinazoline-6-yl, 2,4-dioxo-1,5-dihydrobenzo[b][1,4]diazepine-7-yl or 2,5-dioxo-3,4-dihydrobenzo[b][1,4]diazepine-7-yl; Y represents optionally substituted methylene group; R1 represents chlorine atom, optionally substituted hydroxyl group, optionally substituted amino-group, optionally substituted azaheterocyclyl; n = 1, 2 or 3; or Yn represents carbon atom of optionally substituted (C3-C7)-cycloalkyl or optionally substituted (C4-C7)-heterocyclyl. Also, invention relates to a pharmaceutical composition in form of tablets, capsules or injections placed into pharmaceutically acceptable package.
EFFECT: valuable properties of compounds.
5 cl, 3 sch, 5 tbl, 6 ex
< / BR>where R denotes cyclopropyl, cyclobutyl, cyclohexyl, phenyl, unsubstituted or mono -, di - or tizamidine group selected from hydroxy, C1-C4of alkyl, C1-C4alkoxy, halogen, trifloromethyl, ceanography and amino groups; 1-or 2-naphthyl, 9-anthracene; 2-anthrachinone, Persil, unsubstituted or substituted group selected from1-C4of alkyl, C1-C4alkoxy, ceanography and halogen; 2-, 3 - or 4-chinoline, oxiranyl, 1-benzotriazolyl, 2-benzoxazolyl, furanyl, substituted C1-C4alkoxycarbonyl; C1-C4alkylsulphonyl or benzoyl; R1denotes halogen or1-C4alkyl, R2and R3independently represent hydrogen or C1-C4alkyl; X denotes an oxygen atom and Y represents an oxygen atom, a sulfur atom or a carbonyl, or their pharmaceutically acceptable salts, method of production thereof and pharmaceutical composition having antiviral activity, containing antiviruse-effective amount of compounds of General formula I
SUBSTANCE: invention relates to an improved method of producing diethyl ether of 5-amino-2-hydroxy-4,6-dimethylisophthalic acid. The method involves cyclocondensation of diethyl ether with acetone dicarboxylic acid with isonitrosoacetyl acetone followed by reduction of the obtained diethyl ether of 2-hydroxy-4,6-dimethyl-5-nitrosoisophthalic acid with hydrogen on a palladium catalyst in ethyl acetate medium until the end product is obtained.
EFFECT: method cuts the number of process steps, increases output of the end product and makes the process safer.
SUBSTANCE: present invention relates to versions of the method of producing a derivative of tetrafluorobenzyl-5- aminosalicylic acid of formula I where R1, R2 and R3 can independently denote hydrogen or halogen, which can be used to prevent or treat acute and chronic neurodegenerative diseases, particularly focal brain ischemia, and to a method of producing pharmaceutically acceptable salts of this derivative. One version of the method of producing the tetrafluorobenzyl-5-aminosalicylic acid derivative of formula I involves the following steps: a) oxidation of tetrafluorobenzyl alcohol of formula I to tetrafluorobenzaldehyde of formula 2 b) conversion of tetrafluorobenzaldehyde to a tetrafluorobenzylidine-5-aminosalicylic acid derivative of formula II through a dehydration-condensation reaction between tetrafluorobenzaldehyde and 5-aminosalicylic acid of formula 3 and c) hydrogenation of the tetrafluorobenzylidine-5-aminosalicylic acid derivative to a tetrafluorobenzyl-5-aminosalicylic acid derivative of formula I.
EFFECT: efficient method of producing tetrafluorobenzyl-5-aminosalicylic acid derivative.
4 cl, 9 tbl, 1 dwg, 11 ex
SUBSTANCE: invention relates to novel hexa-substituted para-aminophenols with ester groups in the 2,6-positions relative a hydroxyl group of general formula I, which can be used as intermediate products in synthesis of pharmaceutical preparations. In general formula I
1) R=CH3, R1=CH3, 2) R=C2H5; R1=CH3; 3) R=C3H7, R1=CH3; 4) R=C4H9, R1=CH3.
EFFECT: high efficiency of using the composition.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to the pharmaceutical industry, particularly to a preparation possessing anti-inflammatory, analgesic and wound-healing action. The preparation possessing the anti-inflammatory, analgesic and wound-healing action represents a mixture of an alcoholate of lilac blossom and plantain leaves with honey and extracted juice of unpeeled pomegranate.
EFFECT: preparation possesses the pronounced anti-inflammatory, analgesic and wound-healing action.
SUBSTANCE: present invention refers to compounds having formula III such as below, wherein: Q represents C(Y3) or N; R represents H, -R1, -R1-R2-R3, -R1-R3 or -R2-R3; R1 represents heteroaryl or heterocyclyl each of which is optionally substituted by one or more C1-6alkyls, hydroxyC1-6alkyls, oxogroups or halogenC1-6alkyls; R2 represents -C(=O), -O, -C(R2')2, -C(R2')2C(=O), -C(R2')2C(=O)NR2', C(R2')2 N(R2')C(=O), -C(=NH), -C(R2')2NR2' or -S(=O)2; each R2' independently represents H or C1-6alkyl; R3 represents H or R4; R4 represents C1-6alkyl, C1-6alkoxygroup, aminogroup, C1-6alkylaminogroup, di(C1-6alkyl)aminogroup, heterocyclyl, C1-10alkylheterocycloalkyl, heterocycloalkylC1-10alkyl each of which is optionally substituted by one or more C1-6alkyls, C1-6alkylaminogroups, di(C1-6alkyl)aminogroups, hydroxygroups, hydroxyC1-6alkyls, C1-6alkoxygroups, oxogroups or halogenC1-6alkyls; X represents CH; X' represents CH; and the rest symbols have values as specified in the patent claim. The compounds of formula III inhibit Bruton's tyrosine kinase (Btk). There are also described compositions containing the compounds of formula III, and at least one carrier, thinner or excipient, and a method for producing the compound of formula X in accordance with the following procedure.
EFFECT: compositions are effective for modulating Btk activity and treating diseases related to Btk hyperactivity, and can be used for treating inflammatory and autoimmune diseases related to disturbed B-cell proliferation, such as rheumatoid arthritis.
22 cl, 2 tbl, 260 ex
SUBSTANCE: method for preparing an agent possessing anti-inflammatory, diuretic and antioxidant activity, involving milling Spiraea salicifolia shoots representing a mixture of leaves, blossom and shoots, extracting them three times by gradual maceration, mixing in infusing, filtering, condensing, separating, drying in the certain environment.
EFFECT: agent shoes the pronounced anti-inflammatory, diuretic and antioxidant activity.
2 dwg, 12 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to medicine and represents a controlled-release preparative form of diacerein administered once a day for treating or autoimmune diseases or their complications. The preparative form contains a core, an active layer, a sustained-release film layer and a delayed-release film layer, wherein the active layer is followed by the sustained-release film, and the delayed-release film layer thereafter. The sustained-release film layer contains ethyl cellulose polymer, povidone, triethylacetate and talc; the delayed-release film layer contains Eudragit polymer, triethylacetate and talc.
EFFECT: reducing the negative side action of diacerein.
18 cl, 23 ex, 33 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: present invention refers to microbiology, namely to using bacteria, and describes a composition containing microorganisms, a method for preparing probiotics with the anti-inflammatory action and a method for preparing an anti-inflammatory composition containing the probiotics. The composition according to the invention is characterised by the microorganism count subject to the short-time high-temperature processing at 120-140°C for 5-15 seconds.
EFFECT: invention can be used for preparing the compositions for treating or preventing the inflammatory disorders for the probiotics for dairy products.
10 cl, 7 dwg