Anti-infective, anti-inflammatory and antitumor drug

 

(57) Abstract:

The invention is intended for use in medical practice. The objective of the invention is the reduction of doses and duration of treatment, the expansion of the scope due to the pronounced antibacterial and antifungal activity, in addition to the above (anti-inflammatory and antitumor). The claimed means of representing Sol greenexpo acid and monosubstituted monosaccharide ester of General formula

< / BR>
where A =

< / BR>
or

< / BR>
X and Z is-OH, -H, -CH2OH or a group

W, W'= -H, alkyl-, benzyl-, (Z, W, X and W), (Z, and W, OW' and W or Z and W together form a group

R1, R2Is - H, halogen, alkyl-, carboxy-, oxyalkyl or axially, n = 1 to 4, R3, R4Is - H, alkyl, or R3and R4together with the nitrogen atom form morpholinyl, piperidinyl or pyridine heterocycle. The drug has low toxicity, a high index of therapeutic action and stable during long-term storage solutions. 2 C.p. f-crystals, 7 PL.

The technical field.

The invention relates to the field of medicine, to biologically active substances produced by chemical means, specifically to about Opletalova and antitumor agents with a wide spectrum of biological actions.

The prior art.

The basis of modern anti-infective chemotherapy are two types of medicines [ 1]:

- a means for the direct election of suppressing nodal stages of reproduction of microorganisms, development of tumors, mainly representing natural, semi - or fully-synthetic compounds (antibiotics, sulfonamides, nitrofurans, cytostatics and other) [2,3,4,5];

- antimicrobial agent in a wide spectrum of action, while suppressing the reproduction of many species of microorganisms and tumors, but indirectly, through effects on the immune system of the patient, and therefore they are called immunomodulators. While the details of the structure of the genome, enzymes and membranes foreign agents are not of fundamental importance.

This is, for example, the first reliably identified immune stimulants 1-(-)-2,3,5,6-tetrahydro-6-phenyl-imidazo-(2,1)-thiazole hydrochloride, originally used in medical practice as deworming drugs called decaris (levamisole).

Studies have shown that this compound has an extremely broad immunomodulatory effects and success of IP[ 6].

Also known a number of high-molecular Immunostimulants on the basis of polysaccharides and nucleic acids, for example Polivanova and Polinezija acid [7].

You must also specify 2,7-bis[2-(diethylamino)-ethoxy]-fluoren-9-he dihydrochloride (tilaran) that exhibits immunostimulatory effects in the treatment of a number of experimental infections (model - white mouse) [8,9].

Further research identified interferon-inducing activity (one of the types of stimulation of the immune system) from a number of low molecular weight heterocyclic compounds such as 3-amino-7-(dimethylamino)-2-methyl-5-chloro-fenotiazina [10].

Are of considerable interest attempts of some authors to obtain immune modulators on the basis of sugars with amino acid substituents [11], theoretical basis [12].

Second types of medicines (immunomodulators) from our point of view is much more interesting, because the use of such chemical and biological compounds, firstly, not addictive to him microorganisms (largely inherent means of the first type, causing a short effective COI the body of the patient.

Traditionally immunomodulators are divided into two main groups: a) high molecular weight (polysaccharides, polynucleotides and others), their molecular weight greater than 1500, b) low molecular weight (some abnormal sugars, nucleosides and other heterocycles), their molecular weight is typically less than 1000.

The most promising immunomodulating agents are low molecular weight, since they usually do not cause allergic adverse reactions.

To date, investigated a large number of low molecular weight immune modulators as potential pharmacological agents for the treatment of a number of viral, bacterial and fungal infections, as well as identify their indirect zitotoksicescoe and anti-inflammatory action.

The main disadvantages of the investigated drugs are as follows:

- high toxicity and the presence of a cumulative effect with repeated use;

- high activity against only one of the groups of microorganisms, making them ineffective in mixed infections;

- a wide range of pharmacological activity at low efficiency makes them suitable as vspomogateljno during prolonged storage in solution, what is the reason for the ambiguous results of pharmacological tests.

Despite these weaknesses in recent years conducted numerous studies, which outline a number of interesting approaches to solving problems, creating an effective low-molecular immunomodulators that can find application in medicine as a drug.

1) first of all, it should be noted derivatives acridone: N-methylene-carboxy-9-acridone (criconematina acid, MCA).

In the form of sodium salt MCA known as Caledon (neovir). The drug showed high activity in the treatment of several diseases caused by both DNA-and RNA-containing viruses, such as herpes viruses HSV 1 and HSV 2, rift valley fever, Semliki forest, Venezuelan equine encephalitis, etc.

Unfortunately, the high activity of the drug is observed only in the treatment of some viral diseases, most bacterial, fungal and mixed infections the drug is not effective [13, 14, 15].

2) Are also of considerable interest some monosubstituted esters of monosaccharides: 3-O-(N,N-dimethylamino-n-propyl)-1,2:5,6-di-O-isopropylidene - D is atento USA, The UK, Germany, Japan [16-21].

These compounds have a relatively wide range of biological activity (reliably established: anti-inflammatory, antitumor and antiviral activity), but lack of effectiveness.

This requires the use of high doses of such drugs for the treatment of diseases, which is highly undesirable due to the occurrence of side effects associated with toxicity [22].

3). It should be noted connection: hydrochloride of N,N-dimethylaminoethanol ether N-metrocable-9-acridone [23], which is of interest as an attempt to combine similar in structure fragments drugs SM-1213 and MCA presented above (N,N-dimethylaminoethyl-radical and greenboro cycle). This allowed to obtain the product, fundamentally suitable for oral use, albeit with somewhat reduced immunomodulatory properties.

4) Interesting attempt of modernization of the ARS held by the authors of the patent of Russia [L-24] . As a result of the work, managed to get a salt of SMA with a natural amino sugar (D-glucamine). From the sodium salt of SMA the compound obtained has a milder interferon-inducing soustitres, antipredatory and radioprotective activities.

Unfortunately it turned out that a parenteral dosage form of this drug has low stability in solution that, apparently, is connected with the inversion of the D-glucamine in aqueous solutions, transitioning into five similar structure of aminomonosaccharide.

A brief overview of the present status of the problem by the creation of immunomodulating drugs shows that in General it is still far from resolved. Each of these drugs has limitations in its practical use.

Disclosure of the invention.

The essence of the present invention is a medicinal product that combines the beneficial qualities of greenexpo acid and the monosubstituted esters of monosaccharides (high efficiency first, at the wide range of pharmacological activity of the second).

Closest to the claimed drug - monosubstituted esters of monosaccharides having the General formula

S-O-Y,

where

S - monosaccharides (pentoses, hexose, heptose);

Y is an organic radical of General formula

< / BR>
where

R1is an organic radical with a number perranoski radical number of carbon atoms from 1 to 7;

described in U.S. patent 4017608 [L, 16], published 12.04.77.

They selected us as a prototype for the greatest structural similarity and the main (basic) item chemical compounds.

As noted above, when all the positive properties of the prototype (latitude spectrum of pharmacological activity) it has a relatively low efficiency and require the use of high doses and long treatment, which eliminates the possibility of using these compounds in severe emerging pathology.

The objective of the invention is the obtaining of new medicines that minimize the above disadvantages, i.e. increased activity against a wide range of diseases (antiviral, antitumor and anti-inflammatory effect), in other words, reducing the required dose of the drug and treatment, as well as the expansion of the scope due to the emergence of a pronounced antibacterial and antifungal activity, a drug with low toxicity, a high index of therapeutic action and stable during long-term storage solutions.

The task R is faridul General formula

< / BR>
where

A =

< / BR>
or

< / BR>
X and Z = -OH,-H, -CH2OH or a group

< / BR>
W, W1Is-H, alkyl, benzyl, (Z, W, X and W), (Z, and W, OW1and W or Z and W together form a group

< / BR>
R1, R2= -H, halogen, alkyl-, carboxy-, oxyalkyl or axially, n = 1 to 4, R3, R4= -H, alkyl, or R3and R4together with the nitrogen atom form morpholinyl, piperidinyl or pyridine heterocycle.

The best implementation of the proposed drug, according to the authors

(A) when used as anion: N - greenexpo acid as cation: 1,2:5,6-di-O-isopropylidene 3-O (NN-dimethylamino-n-propyl) ,D - glucofuranose, forming a compound of the formula

< / BR>
This connection is a special case of the General formula (1)

Gross formula C32H42N2O9< / BR>
Molecular weight 598,94

Chemical name: 1,2:5,6-di-O-isopropylidene-3-O-(N,N-dimethylamino-n-propyl)- ,D-glucofuranose 10'-methylanthracene-9'-acridan.

B) when used as the anion of 3-chloro-10-methylanthracene-9-acridone, and as a cation - 1,2:3,4-di - O-isopropylidene 6-O (N,N-dimethylaminoethyl) ,D-galactopyranose,

forming a compound of the formula

< / BR>
This coedCl

Molecular weight 619,11.

Chemical name: 1,2:3,4-di-O-isopropylidene-6 - O-(N,N-dimethylaminoethyl), D-galactopyranose-3'-chloro-10'-methylanthracene-9'-acridan.

The invention is illustrated below, including:

the results of a comprehensive study of therapeutic characteristics of the claimed medicinal product;

- total technology of obtaining the claimed compounds;

- 6 examples of manufacturing specific products;

- 7 tables of comparative tests of the proposed drug, where table. 1 - comparative characteristics of the activities of the claimed compounds and source components; PL. 2 - the results of the radiation of the proposed drugs in experimental models of smallpox infection in comparison with the prototype, comedonal and ribamidil; PL. 3 - the results of the radiation of the proposed drugs in experimental models of rift valley fever in comparison with the prototype, sodium 3-chloro-N-carboxymethyl-9-acridone and ribamidil; PL. 4 - the impact of the introduction of the proposed products on the parameters characterizing the antifungal activity of macrophages against Candida albicans; PL. 5 is a comparative study of antibacterial activity of tawlae the CSOs cancer Ehrlich in comparison with the prototype and acridinium component; table. 7 - the influence of the proposed products on the growth of leukemia P-388 in comparison with the prototype and acridinium component.

Applicants conducted a synthesis of all the above compounds. In General, it was conducted in the following way. Equimolecular amounts of both components are mixed in anhydrous acetone, the mixture is refluxed for 20 to 40 min, protected from moisture. The obtained clear solution is evaporated in a vacuum to the extent necessary for the precipitation of salt. Dropped the precipitate was separated by filtration, dried and then recrystallized from anhydrous methanol. The recrystallized precipitate dried in a vacuum at a temperature not exceeding 35oC. any significant difference in the technological process of obtaining various salts of formula (1) and (2) not found. As a rule, the compounds obtained are large hygroscopic crystals of pale yellow, soluble in water, dimethylacetamide, dimethyl sulfoxide, glycerol in hot ethanol, sparingly soluble in ether and chloroform, practically insoluble in hydrocarbons.

The synthesized compounds are fully characterized using elemental analysis, demetrii.

All the salts are soluble in water and are suitable for manufacturing of all types of dosage forms.

The solutions obtained dosage forms have a pH close to physiological, stable when stored in solution for 1.5 to 2.0 years (observation period), 20oC, without access of light.

As a result of studying the claimed chemical compounds in acute experiments determined the thresholds of toxic effects on the body as in the overall index of mortality, and the impact on the major vital systems: blood, SS, and Central nervous system. It is shown that these drugs do not cause hemolysis of erythrocytes. Intramuscular and intravenous use them in the doses of 10 and 100 mg/kg not have a negative impact on hemodynamics, heart and Central nervous system. At doses of 300 mg/kg none of the claimed compounds did not cause the death of animals and manifestations of toxicity in mice and rats.

These drugs do not have strong cumulative properties.

Intravenous drugs to rats in increasing doses in chronic experiments did not lead to accumulation of toxic effect (the coefficient of accumulation greater than 5).

the C 20 - 50 minutes

The elimination half-life (T 50%) is typically 100 - 130 min, are eliminated from the body primarily through renal excretion. After 24 h after intravenous injection in doses of 10 to 100 mg/kg they are almost completely excreted in the blood is either not defined or present in trace quantities.

Substances A and B were injected daily for 15 and 30 days intramuscularly and intravenously to rabbits and dogs at doses of 10 and 50 mg/kg did not affect the condition of the animals, their body weight, the pattern of blood, liver, kidneys, pancreas, heart activity, and was not accompanied by pronounced pathological changes of internal organs. Drugs A and B in all the ways did not mestnorazdrajatego and pyrogenic action.

LD 50 of the synthesized compounds were 2 - 2.5 times lower than the amount of LD 50 components of their components taken separately.

Experiments have shown that these substances do not have embryotoxic and teratogenic when injected into the entire pregnancy to rats in doses of 10 and 100 times greater than therapeutic.

All these results confirm that the proposed chemicali, have a high therapeutic index 50 - 100 or more, which allows the use of these substances in a wide range of doses.

It was unexpectedly found that the compounds obtained in animal experiments and tissue culture showed strong antibacterial and antifungal activities, not seen as derivative greenexpo acid, and the monosubstituted esters of monosaccharides, which allows the use of these substances as a potential universal medicines in mixed infections.

It was also detected a stronger antiviral properties: index of protection (OF) animals infected with 10 - 100 LD 50 both RNA-and DNA - genome viruses was 70 - 85% as in treatment-and-prophylactic and therapeutic scheme the introduction of these drugs.

Study of anti-inflammatory activity of the synthesized compounds was carried out on the model of healing polnoletnyh skin wounds and serotonin edema (exudative phase of inflammation), showed a high efficacy of these drugs.

The study of antitumor activity in models of transplantable tumors (solid tumors: cancer Ehrlich, melanoma B-16 and ascitic leucosolenia response to the introduction of the proposed drugs suggests, they are not direct cytotoxic agents, and effectively act to slow down the growth of tumors through the immune system.

Comparative characteristics of the activities of the claimed compounds and reference compounds are given in table. 1.

Examples of specific methods of obtaining the claimed compounds are given below:

Example 1. 20 g of 3-O-(N,N-dimethylamino-n-propyl)- 1,2:5,6 - di-O-isopropylidene - D-glucofuranose representing a transparent, viscous, hydrophobic liquid, mixed with 14.5 g of N-greenexpo acid in 150 ml of anhydrous acetone. The mixture is heated to boiling and refluxed for 30 minutes During this time, the precipitated N-greenexpo acid is completely dissolved, the mixture becomes homogeneous. The solution was concentrated in vacuo to a total volume of 95 ml, cooled to +5oC, kept at this temperature for 7 hours the precipitation is filtered and dried. The obtained light-yellow crystalline precipitate is recrystallized from anhydrous methanol (1/3), is separated from the solution by filtration and dried in vacuum (5 mm RT.CT.) at a temperature of not more than 32oC. Obtain 29 g (yield of 84%) of the final product.

Henichesk is he.

Gross formula C32H42N2O9.

Purity (chromatographic) - 98.5 per cent.

Molecular weight 598,76.

Elemental analysis:

calculated - C - 64,19 H 7,08 N 4,71,

found - C - 64,26 H 7,15 N 4,63.

These NMR (1 H); DMSO d 6):

1,1 - 1,5 M. D. - 4 groups-CH3 in dioxolane give 3 cycles of singlet: (1.25 M. D.; s(6H)); (1.31 memorial plaques; s(3H)); (1,40 M. D.; s (3H)).

1,5 - 3,7 M. D. - region signals of the protons of N,N-dimethylamino-propyl - Deputy: -N(CH3)2 (2,47 memorial plaques ; s(6H)); -CH2-N (2,78 M. D.; t(2H); -CH2- (1,78 M. D.; q(2H)); -CH2-O- (3,3,was 3.7 the cross. m).

3,5 - 6,0 m D. the signals of the protons glucofuranose: H1-H6 (3,5 - 4,5 M. D.; m; H2 (4,62 M. D.; d(1H)); H1 (of 5.83 M. D. d(1H));

4,98 m D. the signals of the protons of the N-medienkombination: (s(2H)).

a 7.2 to 8.5 M. D. - region signals of aromatic protons of acridone (7,35 M. D.; t(2H)); (7,7 M. D.; d(2H)); (7,83 M. D.; t(2H)); (8,4 M. D.; d(2H)).

Example 2. 25 g of 6-O-(N,N-dimethylaminoethyl-1,2:3,4-di-O-isopropylidene - D-galactopyranose representing a transparent, viscous, hydrophobic liquid, mixed with 21.6 g of 3-chloro-N-greenexpo acid in 170 ml of anhydrous acetone. The mixture is refluxed for 40 minutes During this time, the precipitated 3-chloro-N-greenexpo acid is completely dissolved, the solution gets what at this temperature for 2 hours The formed precipitate is filtered and dried. The obtained crystalline precipitate a yellow-green color is recrystallized from anhydrous methanol (1/3), is separated from the solution by filtration and dried in vacuum (5 mm RT.cent.), at a temperature not exceeding 25oC. Obtain 41.5 g (yield 89 percent) of the final product:

Chemical name: 6-O-(N,N-dimethylaminoethyl)-1,2:3,4-di-O-isopropylidene - D-galactopyranose 3'-chloro-N-methylanthranilate-9'-acridan.

Gross formula C31H39N2O9Cl.

Purity (chromatographic) - 98%.

Molecular weight 619,11.

Elemental analysis:

calculated - C - 60,14 H 6,35 to 4.52 N Cl 5,73,

found - C - 60,05 H 6,41 N 4,63 Cl 5,70.

These NMR (1 H); DMSO d 6):

of 1.15 to 1.5 M. D. - 4 groups-CH3 in dioxolane give 3 cycles of singlet: (1.23 memorial plaques; s(6H)); (1.37 memorial plaques; s(3H)); (1.48 memorial plaques; s(3H));

2,3 - 3,7 M. D. - region signals of the protons of N,N-dimethylaminoethyl-Deputy: -N(CH3)2 (2.5 M. D.; s(6H)); -CH2-N-CH2-O-(2,7 - 3,5 cross. m).

3,5 - 6,0 m D. the signals of the protons galactopyranose: H2-H6 (3,5 - 4,8 M. D.; m); H1 (5,71 M. D.; d(1H));

5.0 memorial plaques - region signals of the protons of the N-medienkombination: (s(2H)).

of 7.2 and 8.6 m D. - region signals of aromatic protons of acridone.

Primidone, mixed with 19.5 g of 3-chloro-6-methyl-N-greenexpo acid in 250 ml of anhydrous acetone. The mixture is heated to boiling and refluxed for 20 minutes the Obtained clear solution is evaporated in vacuum to a total volume of 100 ml, cooled to 0oC, kept at this temperature for 4 hours the precipitate is filtered, dried and recrystallized from anhydrous methanol (1/3), is separated from the solution by filtration and dried in vacuum (5 mm RT. Art. ), at a temperature not exceeding 25oC. Get to 36.7 g (yield - 88,4%) of the final product:

Chemical name: 3-O-(1'-ethyl-2'-(N-morpholinyl)-1,2-O-isopropylidene - D - glucofuranose 3"-chloro-6"-methyl-N-methylanthranilate-9-acridone.

Gross formula C31H39N2O10Cl.

Purity (chromatographic) - >98%.

Molecular weight 635,17.

Elemental analysis:

calculated - C - 58,62 H 6,20 to 4.41 N Cl 5,58

found - C - 58,73 H 6,21 N 4,37 Cl 5,62

These NMR (1 H); DMSO d 6):

1,2 - 1,5 m D. - 2 group-CH3 in dioxolane cycle give 2 singlets, intensity 3 protons each.

1,5 - 3,9 M. D. - region signals of the protons of the N-ethylmorpholine: -CH2-N - CH2-N-CH2-research (2,7 - 3,1 M. D.; m(6H)); -CH2-O - and-CH2-N-CH2-research (3 (5,8 M. D. d(1H));

4.99 memorial plaques - region signals of the protons of the N-medienkombination: (s(2H)).

7,0 - 8,5 m D. - region signals of aromatic protons of acridone.

Example 4. 15 g of 3-O-(N,N-diethylamino-(2'-isobutyl)-1,2-O-isopropylidene-D - allopurino, representing a clear yellowish viscous liquid is mixed with 12.8 g of 2'-carboxy-N-methylanthranilate-9'-acridone acid in 100 ml of anhydrous acetone. The mixture is heated to boiling and refluxed for 20 minutes Then proceed analogously to the method described in example 2. Get 21 g (yield - 75,5%) of the final product.

Chemical name: 3-O-(N,N-diethylamino-(2'-isobutyl)-1,2-O-isopropylidene - D - glucofuranose 2"-carboxy-N-methylanthranilate-9-acridone.

Gross formula C33H44N2O11.

Purity (chromatographic) - 98%.

Molecular weight 644,83.

Elemental analysis:

calculated - C - 61,47 H 6,88 N 4,36,

found - C - 61,35 H 6,91 N 4,42.

Example 5. 30 g of 1-O-ethyl-5-O-(1'-butyl-4'-(N-pyridinyl)-D-ribofuranose mix from 25.5 g of 2-oxyethyl-7-carboxyethyl-N-greenexpo acid in 150 ml of anhydrous acetone under reflux for 40 minutes Then proceed similarly e: 1-O-ethyl-5-O-(1'-butyl-4'-(N-pyridinyl)-D-ribofuranoside 2 '-oxyethyl-7"-carboxyethyl N-methylanthranilate-9-acridone.

Gross formula C36H45N2O11.

Purity (chromatographic) - 97%.

Molecular weight 681,83.

Elemental analysis:

calculated - C - 63,41 H 6,67 N 4,11,

found - C - 63,49 H 6,58 N 4,12.

Example 6. 75 g of 5-O-benzyl-3-O-(1'-ethyl-2'-(N-piperidinyl)-1,2-O-isopropylidene - D-xylofuranose mix from 74.2 g of 2-(1'-ethyl-2'-benzyloxy)-N-greenexpo acid in 350 ml of anhydrous acetone. After boiling for 20 minutes the solution is evaporated in vacuum to a volume of 180 ml are similar to the method described in example 2. Obtain 122 g (yield - 82%) of the final product.

Chemical name: 5-O-benzyl-3-O-(1'-ethyl-2'-(N-piperidinyl)-1,2-O-isopropylidene - D-xylofuranose 2"-(1"'-ethyl-2"'-benzyloxy) N-methylanthranilate-9-acridone.

Gross formula C46H54N2O9.

Purity (chromatographic) - 97%.

Molecular weight 779,02.

Elemental analysis:

calculated - C - 70,92 H 7,00 N 3,60,

found - C - 70,47 H 7,05 N 3,66.

Industrial applicability.

Study of antiviral activity of the claimed compounds were carried out on experimental orthopox viral infection caused by cotton rats (weighing 50 - 7 is La standardization of the conditions of experience infection in all cases held constant dose of the virus, equal to 10 LD 50.

The drugs were injected in a dose of 50 mg/kg to rats for 4 h before and on the second day after infection of laboratory animals, using intramuscular and intraperitoneal administration methods.

The experiments were considered significant only when 100% mortality in the control. In each experience as refinenc drug used ribamidil (virazole), which was given to rats orally at a dose of 100 mg/kg for standard medical scheme.

The results of the study are given in table. 2.

From the data table. 2 should conclude that the claimed compounds exhibit a high antiviral activity, especially pronounced when injecting a drug (=80%), and are promising antiviral drugs, far surpassing the prototype, Caledon and ribamidil (reference drug).

The effectiveness of the proposed drugs in experimental rift valley fever were studied in outbred mice weighing 10 to 12 d after subcutaneous infection and white rats weighing 35 - 50 g infected vnutribruchinno. For the reproduction of infection used virulent virus rift valley fever, simmered in a multilayer ku is expressed by the viral dose of 250 BATTLE. The drugs were injected intraperitoneally scheme emergency prevention (2 hours after infection and then 1 time per day for 3 days). The experiments were considered significant only when 100% mortality in the control. In the experience as the reference drug used ribamidil (virazole), which was administered to animals at a dose of 100 mg/kg according to the same scheme.

The results of the study claimed drugs in experimental rift valley fever are given in table. 3.

From the data table. 3 it follows that the claimed compounds exhibit extremely high antiviral activity in experimental rift valley fever, far greater than the activity of the source components.

Antifungal activity of the inventive preparations of 3-O-(N,N-dimethylamino-n-propyl)-1,2: 5,6-di-O-isopropylidene - D-glucofuranose N-methylanthranilate-9-acridone (1 in table. 4) and 3-O-(N,N-diethylamino-(2'-isobutyl)-1,2-O-isopropylidene - D-allopurino 2"-carboxy-N-methylanthranilate-9-acridone (2 in the table. 4) studied in outbred mice. The drugs were injected intraperitoneally in doses of 25, 50 and 75 mg/kg animal body weight. As Comparators in the experiments used a 3-O-(N,N-diethylamino-(2'-isobutyl)-1,2-O-of the table. 4), the component included in the compound (2) in doses of 25 and 75 mg/kg of a Suspension of cells of C. albicans (strain N 13 grown on medium Saburo at 37oC for 2 days), prepared according to the standard 50 million, after 1 h was introduced 1 ml of a suspension of the mice that received the tested preparations.

In animals after 7 h after injection of C. albicans was extirpable glands and prepared film preparations, which were stained with PAS reaction. Then counted the number of yeast cells with growth tubes in the chamber Goryaeva.

The results are shown in table. 4. As can be seen from the data table. 4, the multiplication of the pathogen in the film packing of animals treated with the drugs (1) and (2) sharply decreased in comparison with control. The most pronounced reduction of vegetation C. albicans observed after 7 h after intraperitoneal administration at doses of 25 and 50 mg/kg, which indicates the antifungal efficacy of the inventive compounds, whereas the compound (3), which is the prototype, did not show a reliable anti-fungal properties. The compound (4) was also inactive.

Antibacterial action of the claimed drugs were studied in a model of chronic staphylococcal sepsis caused by intravenous introduction zolotas per day for 5 days) and treatment-and-prophylactic scheme: up to 2 days before infection, and continued for 5 days after infection.

After treatment, animals were scored, dissected kidneys, homogenized and produced seed on agar of Chistovich for counting the number of cells St. aureus. After 72 h incubation at 37oC was determined by the number of grown colonies of Staphylococcus. The results of a comparative study of antibacterial activity of the claimed compounds are given in table. 5.

The level of contamination renal tissue of mice treated with the inventive compounds decreased more in the 10,000 - to 100,000-fold compared with the control, the prototype also found weak antibacterial activity, significantly less than the claimed compounds, greenboro forming activity was not detected.

The influence of the proposed synthesized compounds:

1. 3-O-(N, N-dimethylamino-n-propyl)-1,2:5,6-di-O-isopropylidene - D-glucofuranose-N-carboxymethylation,

2. 1-O-ethyl-5-O-(1'-butyl-4'-(N-pyridinyl)-D-ribofuranoside 2 '-oxyethyl-7"carboxyethyl N-methylanthranilate-9-acridone in comparison with

3. 1-O-ethyl-5-O-(1'-butyl-4'-(N-pyridinyl)-D-ribofuranose (prototype)

4. 2-oxyethyl-7-carboxyethyl N-methylanthranilate-9-acridone (acridinium component substances (2) private leukemia P-388 (PL. 7).

Solid tumor (ES) transplanted into the pillow hind legs of male mice weighing 18 to 20 g line SHR and C57B1, respectively, in the number 10(6) cells re. Leukemia P-388 transplanted intraperitoneally to mice-males line DBA at 106cells. Starting from the 3rd day of inoculation re (at the time of formation of tumor and stromal elements) and from the 2nd day after inoculation of P-388, mice control groups daily intraperitoneally injected in 0.1 ml of saline and the animals in the experimental groups were administered the drug at doses of 20, 100 and 250 mg/kg

It follows from the presented results (table. 6 and 7), the claimed compounds possess strong ability to inhibit the growth of transplantable tumors and its activity is considerably larger than the prototype and acridology component. The results are shown in table. 2 - 7, clearly confirm the achievement of pharmacological targets - increased pharmacological activity and expanding the range of indications of the new drug.

From the above it follows that the resulting new chemical compounds, salts monosubstituted esters of monosaccharides and derivatives of greenexpo acid, which is an effective therapeutic drugs, with Shiro is narcotic.

We present methods of synthesis of these compounds is easily feasible on an industrial scale, do not require scarce raw materials and non-standard equipment. Given all this, began development on their basis of dosage forms for parenteral, oral and outdoor use.

Thus, it can be argued that the proposed solution is new, not obvious and industrially applicable, i.e., satisfy the requirements of the inventions.

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17. Patent UK 1497409, class A 61 K 31/33, publ. 12.01.1978.

18. The Japan patent 62-149694, class C 07 H 15/12 A 61 K 31/70.

19. The application Germany 2455026, class A 61 K, publ. 03.07.1975.

20. The application Germany 2612717, CL 07 N 15/04, publ. 14.10.1976.

21. U.S. patent 4735934, class A 61 K 31/70, publ. 05.04.1988.

22. Nishikava Y. , Yoshimoto K., Chem. Pharm. Bul., 1987, -35, N 7, p. 2894 - 2899.

23. Patent Poland 139805, class C 07 D 219/16, publ. 31.07.1987.

24. Russia's bid N 93017260/04 from 1.04.93.

1. Vehicle anti-infective, anti-inflammatory and antitumor actions, representing Sol greenexpo acid and monosubstituted monosaccharide ester of General formula

< / BR>
where AND

< / BR>
or

< / BR>

< / BR>
R1, R2= -H, halogen, alkyl-, carboxy-, oxyalkyl or axially;

n = 1 to 4;

R3, R4= -H, alkyl-, or R3and R4together with the nitrogen atom form morpholinyl, piperidinyl or pyridine heterocycle.

2. Means under item 1, which represents the salt of the N-th greenexpo acid and 3-0-(N,N-dimethylamino-n-propyl)-1,2:5,6-di-O-isopropylidene-

< / BR>
3. Means under item 1, which represents a salt of 3-chloro-10-methylanthracene-9-acridone and 1,2: 3,4-0-diisopropylidene-6-O-(N, N-dimethylamino-ethyl)-,D-galactopyranose General formula

< / BR>


 

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