Antimicrobial, anti-inflammatory and analgesic agent of n-4-nitrophenylbenzamidine

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is an antimicrobial, anti-inflammatory and analgesic agent of a benzamidine derivative of empirical formula (C13H11N3O2), namely N-4-nitrophenylbenzamidine (I) as an active substance. It is shown that N-4-nitrophenylbenzamidine is low-toxic; it possess antimicrobial (on Gram-positive and Gram-negative bacteria), anti-inflammatory and analgesic activity.

EFFECT: these properties make it possible to suggest that N-4-nitrophenylbenzamidine may be used in medicine, as an ingredient of the drug preparation for specified application.

2 tbl, 5 ex

 

The invention relates to medicine and pharmacy and the new antimicrobial, anti-inflammatory and analgesic based tools derived benzamidine, namely N-4-nitrophenylacetylene (C13H11N3O2) formula I:

N-Substituted benzamidine, among which N-4-nitrophenylarsonic known [Masa-aki Kakimoto, Shin-ichi Ogata, Yo-shio Imai // Chemistry Letters. 1984. P.821-824; Panayiotis A.Koutentis, Styliana I.Mirallai // Tetrahedron. 2010. V.66. P.5134-5139; Kuvaev, E.V. Amidine. Synthesis and structure / Avicularia, Avedoere, Aggostino, Ipekoglu, Yevlanova, Overath // Vědeký pokrok na rozmezi tisícileti. - 2010: Materialy VI mezinárodni vědeko-praktická conference 27.05.2010-05.06.2010. Praha, 2010. Dil 22. P.66-67].

However, the toxicity and biological activity of N-4-nitrophenylacetylene not studied that does not allow to speak about the availability of the medicinal product based on it.

It is known that amidine are biologically active components of funds for various purposes (inhibitors of coagulation factors, anti-cancer). Aydinbey fragment (usually consisting of heterocycle) included in the structure of many drugs, such as naphazoline, galazolin, fentolamina, hlordiazepoksida. The analysis of literary sources is not possible to identify a correlation between biological properties and structure of the molecule is substituted by the CSO of amidine.

Known antimicrobial activity of derivatives of benzamidine General formula II:

,

where A - represents a linear or branched alkyl chain containing from 3 to 9 carbon atoms, and X is an oxygen atom or a direct link [U.S. Pat. The USSR 1319784, IPC 123/00. The way to obtain pharmaceutically acceptable salts of the derivatives of benzamidine, prior. Dem. 2550192 FR; see also Pat. 4,720,581 US. Benzamidine derivatives].

Minimum inhibitory concentration (MIC) salts of these derivatives of benzamidine against Escherichia coli high and ranges from 4000-16000 µg/ml against Staphylococcus aureus 2000-20000 µg/ml.

Known antimicrobial activity of p-methylsulfonylbenzoyl hydrochloride and p-guanylyltransferase hydrochloride, but in the description of the patent does not see the value of the minimum inhibitory concentration of these compounds [pat. GB 580,884. Improvements in and relating to therapeutically active compounds of the amidine type].

Most similar in structure and pharmacological properties to the claimed means are N-halogenation General formula III (prototype)

,

where X=Cl (a); I (b)

possessing antimicrobial activity against Escherichia coli (IIIa - 250-500 μg/ml; IIIB - 1000-2000 μg/ml) and Staphylococcus aureus (IIIa - 250 µg/ml; IIIB - 1000 µg/ml) [pat. EP 0076430. Compositions having antimicrobial activity].

The disadvantages of the compounds II, III is low the antimicrobial activity.

The task of the invention is to expand the Arsenal of antimicrobial, anti-inflammatory and analgesic means, find a new one based on benzamidine, assets that have low toxicity, having antimicrobial activity and additionally exhibiting anti-inflammatory and analgesic properties comparable to existing separately applied in clinical practice, drugs, and significantly more pronounced antimicrobial activity than the closest analogue (prototype).

This task is achieved by creating antimicrobial, anti-inflammatory and analgesic funds on the basis of N-4-nitrophenylacetylene.

The invention is illustrated by examples of the synthesis and study of pharmacological properties.

Example 1. The technique of synthesis of N-4-nitrophenylacetylene

To the mixture 46,92 g (0.34 mol) of 4-nitroaniline and 34.8 ml (0.34 mol) of benzonitrile under stirring portions as to obtain a homogeneous mixture 45,39 g (0.34 mol) of anhydrous aluminum chloride. The mixture is rapidly heated to 180°C and in the molten state is slowly poured into 800 ml of 1.2%HCl solution. The total time of the process is no more than 30 minutes. Next, add 10.0 g of activated carbon, the resulting suspension is filtered through a diatomaceous earth filter. The filtrate is poured to 600 ml of 15.5%-leg the NaOH solution. The precipitation is filtered off and dried. The resulting product does not require additional purification.

The product is a reddish-brown color, the output of 36.3 g, 67% of theoretical based on benzonitrile. Melting point 165-167°C. Chromatographic homogeneity of the target product was confirmed by chromatography was carried out solution in DMSO in the system ethyl acetate-hexane 7:4 (Rf=0,81). The composition of the synthesized compounds was confirmed by elemental analysis. Brutto-formula: C13H11N3O2. Found, %: C - 63,77; N Was 4.42%; N - 17,29%; O - 14,52%. Calculated, %: C - 63,67%; N - 4,45%; N - 17,19%; O - 14,69%.

The structure of the synthesized substance was proved by physico-chemical methods of identification of organic compounds: NMR1H and13C, UV-, IR-spectroscopy, mass spectrometry and two-dimensional spectrum15N-HSQC.

In the IR spectra of the substance (KBr tablet) most characteristic are the field 1620-1610 cm-1and 3500-3410 cm-1where there are absorption bands corresponding to the stretching vibrations of C=N-bond and NH2groups, respectively.

UV spectrum of N-4-nitrophenylacetylene in 96%ethanol has 3 maximum absorption in the wavelength 207,6; 227,6 and 333,6 nm.

An NMR spectrum1N. the compounds obtained in DMSO-d6characterized by the presence of resonance signals of protons aroma is practical rings (δ 6,76-8,14 ppm (m, N)), as well as broadened signal in the region of 6.4 ppm (s, 2H) NH2group.

An NMR spectrum13With this connection is characterized by the signals of the nuclei of the carbon rings (δ 124,5-150,9 ppm) and the signal C group-C=N(-N) (δ 155,45 ppm).

The structure of the obtained substance was confirmed using mass spectrometry. The calculated molecular mass coincided with the experimentally obtained (M+=245).

Structure of N-4-nitrophenylacetylene (compound I) is proved using two-dimensional correlation spectroscopy15N-HSQC. In the spectrum visible to only one correlation peak between the signal of the nitrogen atom15N and a signal related atoms protons in the corresponding NMR spectrum.

Example 2. Determination of acute toxicity

Acute toxicity of the synthesized compounds were determined by nonlinear white mice-males weighing 18-20, Animals were divided into equal numbers and body weight groups of 10 animals each. Suspension of the compounds in water, stabilized by tween-80 was administered once intraperitoneally at doses of 50 mg/kg 3160 mg/kg Survival of animals was determined by observing 24 hours and 48 hours from the moment of introduction of the investigated compounds. Observation of the animals was carried out within 72 hours. Recorded the development of the main symptoms and time of death of the animals.

<> Calculation sredneseriynoe dose (LD50) was performed using a rapid method Webprotector [Prozorovsky V.B. have been, Prozorovsky BTW, Demchenko VI // Pharmacology and toxicology. 1978. No. 4. S-502] and probit analysis according to the method of Miller-Tainter [Belenky, M. elements of a quantitative evaluation of the pharmacological effect, 2nd ed., supplementary and Rev. L: Medgiz, 1963]. The toxicity of the inventive substance is 2642 mg/kg According to the classification of the toxicity of preparations of compound 1 belongs to the class of practically non-toxic substances [Izmerov IVAN, Sanotski I., Sidorov, K.K. Settings toxicometric industrial poisons. M.: Medicine, 1977. S-197]. It is more than 30 times less toxic diclofenac - product comparison-inflammatory activity.

Example 3. Determination of antimicrobial activity

The minimum inhibiting concentration was determined by the method of serial dilutions in liquid nutrient medium - mesopatamia broth (BCH) followed by plating on agar medium. The investigated compound is not soluble in water, so as the solvent used 20%aqueous solution of DMSO, not overwhelming growth of any of the used test cultures at concentrations of more than 1000 ág/ml as the test microorganisms were selected gram-positive bacteria Staphylococcus aureus strain R 209 and gram-negative bacteria Esherichia coli ATCC 25922. Strains of test organisms were selected in accordance with the recommendations of the global Fund XI [State Pharmacopoeia of the USSR: In 2 vol. V.2. M.: Medicine, 1989. P.194]. Microbial load was 1000 cells/ml To achieve the appropriate concentration of microbial cells prepared suspension of microorganisms in saline solution in accordance with the turbidity standard of 10 UNITS (1 billion cells/ml), and then through a series of serial dilutions received final concentration of microbial cells.

In a series of test tubes were filled to 1 ml BCH for bacteria. In the first test tube was introduced 1 ml of a solution of tested compound and perform serial dilutions in a series of tubes (transferring 1 ml from the previous in the following), then in each tube of the series were made in 0.1 ml of microbial suspension (104 cells/ml)test tubes were cultured at 37°C for 24 hours.

From the tube, where it is not observed crop growth (turbidity), did the seed in Petri dishes on mastopathy agar (MPA) for Staphylococcus aureus and Escherichia coli.

Cups were cultured at 37°C for 24 hours.

The minimum inhibiting concentration of N-4-nitrophenylacetylene for E. coli and St. aureus are 0,049 µg/ml, which is at or below widely used in practice, antibiotics (aminoglycosides of 0.2 to 3.2 μg/ml (E. coli) and 0.1 to 1.6 µg/ml (St. aureus)and fluoroquinolones (0,016-0.5 μg/ml (E. coli) and 0.06-0,52 mg/ml (St. aureus)) iznachalno below, than that of the prototype (250-2000 mg/ml). In addition, preparations of a series of fluoroquinolones latest generation inaccessible for the price.

Example 4. Determination of anti-inflammatory activity

Anti-inflammatory activity was studied on screening models - formalin swelling of the paws of rats.

In the experience used outbred rats-males weighing 200-240 g in the amount of 30 pieces. Of them were formed 3 groups of 10 animals each. Individuals in the control group was injected only phlogogenic agent. Animals of the experimental group received the study drug and the comparator drug, which was administered intraperitoneally 1 hour before the creation of the swelling.

Aqueous 2%solution of formalin was injected subplantar in an amount of 0.1 ml for each animal.

Studied native solution of N-4-nitrophenylacetylene was administered to rats intraperitoneally at a dose of 50 mg/kg of the Drug comparison - diclofenac - was administered at a dose of 25 mg/kg

For each animal were performed experimental procedure in the following sequence:

- intraperitoneal injection of the sample: in the acute experience once 1 hour prior to the introduction of flogging substances;

- measurement of the volume of the foot right hind legs of the animal (raw data);

- subplantar introduction of formalin (0.1 ml of 2%solution) in the right hind paw of the animal through one hour after the last introduction the studied sample;

- measurement of the volume of the foot right hind paw of the rat after a certain period of time after the introduction of phlogogenic agent (1 and 24 hour).

Measurement of the volume of paw was measured with a glass of oncamera by volume of the displaced water after immersion of the feet in a special tank.

Obtained from each animal results were averaged within groups and calculated the percentage inhibition of inflammation in the experimental group relative to the control. The results of measurements of the volume of the paws of rats are summarized in table 1.

Intraperitoneal single preventive introduction N-4-nitrophenylacetylene helps curb the development of the inflammatory response after a day or 64.8%, which is at the level commonly used in practice of diclofenac at a much lower toxicity of the proposed drug.

Example 5. Determination of analgesic activity of N-4-nitrophenylacetylene

For the experimental evaluation of the analgesic activity of N-4-nitrophenylacetylene used the model generation acetic acid "cramps" in mice-males. Convulsions in animals caused by using intraperitoneal administration of 3%-aqueous solution of acetic acid. The experiment was carried out on nonlinear white mice-males body weight 15-22 g for 10 in the group. A suspension of the compounds of untili intraperitoneally and after 40 minutes wew is brusino were injected with 0.2 ml of 3%solution of acetic acid, watched the animals for 20 minutes. During the experiment recorded the start time of the seizures and the number of seizures for the time interval. Drug comparison was Metamizole sodium (100 mg/kg). The results are given in table 2.

A single intraperitoneal injection of N-4-nitrophenylacetylene reduces the manifestation of seizures 64.9% in comparison with control while reducing the number of seizures by 50% is considered a good result.

Thus, the inventive tool is low-toxic, shows significantly greater antimicrobial activity than the prototype, and comparable effectiveness with which can be used alone, antimicrobial, anti-inflammatory or analgesic drugs.

N-4-nitrophenylarsonic can be used for the synthesis of new biologically active compounds and in medicine as an active ingredient of the antimicrobial, anti-inflammatory and analgesic funds in an effective dose.

Table 1
Evaluation of anti-inflammatory activity of N-4-nitrophenylacetylene
ConnectionBefore the introduction of phlogogenic agentAfter 1 cha is After 24 hours
1,41,91,9
1,41,61,4
1,01,51,6
1,61,81,7
1,31,61,5
Diclofenac1,41,81,4
1,51,61,6
1,41,71,8
1,31,71,5
1,51,61,6
Cf. 1,38Cf. 1,68Cf. 1,6
1,31,61,4
1,21,61,6
1,11,31,2
1,51,71,7
N-4-Nitrophenylarsonic1,11,61,4
1,21,61,5
1,11,51,4
1,11,31,4
1,41,61,5
1,41,81,5
Cf. 1,24Cf. 1,56Cf. 1,46

Table 2
Evaluation of analgesic activity of N-4-nitrophenylacetylene
ConnectionDose (mg/kg)The start time of the seizures, minThe number of seizures observed within 20 min% number of seizures to the controlEfficiency, %
Control-a 3.937100-
Metamizole
sodium100at 7.55513,586,5
N-4-nitrophenylarsonic
2647,81335,164,9

Antimicrobial, anti-inflammatory and analgesic agent comprising N-4-nitrophenylarsonic as active substances.



 

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EFFECT: compounds may be used as raw products for synthesis of new heterocyclic systems in pharmacology as potential drug preparations possessing analgesic activity.

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new imidazo[4,5-b]pyrazine derivatives of general formula or to its pharmaceutically acceptable salt wherein: R1 represents either aryl unsubstituted or substituted by one of the groups: halogen, hydoxyl, C1-6alkyl, C1-6alkoxyl, NH2, NHC1-6alkyl, N(C1-6alkyl)2, NHC1-6alkylC1-6alkoxy, C1-6alkylhydroxy, -C(O)NH2, -C(O)OC1-6alkyl, -C(O)NH C1-6alkyl, cyano, carboxy, heteroaryl and heterocycloalkyl; or heteroaryl unsubstituted or substituted by one of the groups: C1-6alkoxy, hydroxy, -C1-6alkyl, NH2 and NHC1-6alkyl; heterocycloalkyl unsubstituted or substituted by one group =O; and R2 represents H; unsubstituted C3-4alkyl; C1-4alkyl substituted by C5-6cycloalkyl unsubstituted or substituted by one group specified in amino, hydroxyl, C1-6alkoxy, or heterocycloalkyl unsubstituted or substituted by 1-2 groups specified in =O, C1-6alkyl; or C5-6cycloalkyl substituted by one group specified in hydroxyl, C1-6alkoxyl, C1-6alkylC1-6alkoxy, C1-6alkylhydroxy, CONH2; or substituted ir unsubstituted heterocycloalkyl; wherein aryl represents an aromatic structure consisting of 6-10 carbon atoms containing one ring or two condensed rings; wherein heteroaryl represents a 5-10-member aryl ring system containing 1-2 heteroatoms specified in nitrogen, oxygen and sulphur; wherein heterocycloalkyl represents a 5-9-member nonaromatic cycloalkyl wherein 1-2 heteroatoms specified in nitrogen and oxygen; provided the compound does not represent 1,3-dihydro-5-phenyl-2H-imidazo[4,5-b]pyrazin-2-one. Also, the invention refers to the specific imidazo[4,5-b]pyrazine derivatives, to a based pharmaceutical composition, to a method of treating or preventing cancer, inflammatory conditions, immunological diseases, metabolic conditions, and to a method of kinase inhibition in a cell expressing said kinase.

EFFECT: there are produced new imidazo[4,5-b]pyrazine derivatives showing effective biological properties.

17 cl, 2 tbl, 210 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new derivatives of ((phenyl)imidazolyl)methylheteroaryl of formula wherein A represents pyridyl or thienyl having 0 or 1 substitute; B represents phenyl having 0, 1 or 2 substitutes; wherein each substitute independently represents alkyl having 1 to 8 carbon atoms, -F, -Cl, -Br or -CF3. Also, the invention refers to the use of the declared compounds for the purpose of preparing a therapeutic agent, a pharmaceutical composition on the basis of the declared compounds, and to a kit containing the pharmaceutical composition above.

EFFECT: there are prepared new derivatives of ((phenyl)imidazolyl)methylheteroaryl effective in pain management.

10 cl, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to cyclohexane derivatives presented by general formula wherein the substitute A is a group of general formula or wherein the radicals and symbols are presented in the patent claim. The compounds of formula (I) possess strong analgesic action both on nociceptive pain, and on neuropathic pain, and to a lesser degree side effects. Their pharmaceutical use is also described.

EFFECT: cyclohexane derivative and its pharmaceutical use is presented.

17 cl, 42 tbl, 7 dwg, 177 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to gynaecology, and may be used for treating inflammatory pelvic diseases. That is ensured by intramuscular administration of amoxicillin in a single dose of 1.2 g 2 times a day. It is added by vaginal administration of one suppository two times a day containing the ingredients in the following ratio, g per a suppository: 5% alcoholic extract of wax moth larvae 0.09, 5% alcoholic extract of propolis 0.09 Lutrol F68 0.75, Polyethylene glycol 4000 1.0, Cremophor RH-40 1.25, and amoxicillin is administered intramuscularly in a single dose of 1.2. The therapeutic course is 10 days.

EFFECT: method provides extended therapeutic range of treatment and reduces the length of treatment ensured by immunomodulatory, anti-stress, antioxidant, regenerating and antibacterial action, and improved microcirculation, blood rheology and uterine blood circulation, and reduces the drug load.

2 ex

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