Triiodide quaternary nitrogen bases and their water-soluble composition

 

(57) Abstract:

The inventive creation of new chemical compounds - triiodide Quaternary nitrogen bases containing Quaternary basic nitrogen and an associated hyperventillate anion of formula I, II, III, IV, where R1, R2, R3, R4, R8, R9is hydrogen, C1-C6alkyl; R7= -(CH)n12- (n12 = 2-4); -(CH2)n14-O-(CH2)n15- (n14 = 0-4; n15 = 0-4); -(CH2)n16-S-(CH2)n17- (n16 = 0-4; n17 = 0-4);

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(n18 = 0-4; n19 = 0-4; R20= hydrogen, C1-C6alkyl);

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(n20 = 0-4; n21 = 0-4; R21, R22= hydrogen, X-= I, I3; C1-C6alkyl); R10, R11, R12= hydrogen, C1-C6alkyl; n1, n2 = 3-4; X = I, I3. These compounds are used for the manufacture of water-soluble composition having antimicrobial activity, in the following ratio, wt.%: triode Quaternary nitrogenous bases - 1-40, extension agent - rest. As an extension agent using surface-active substance. New triiodide Quaternary nitrogen bases have antimicrobial activity and are suitable for pearlsonly compounds which part of the water-soluble composition can be used as biologically active compounds in medicine and veterinary medicine, infectious diseases of humans and animals.

Known iodoform CHI3- crystalline substance yellow, antiseptic action, was previously used to disinfect wounds (Akhmetov N. With. General and inorganic chemistry.- M.: Higher school, 1981).

A disadvantage of the known chemical compounds is inconvenient form application in the form of powder and high toxicity when applied to the wound surfaces that may cause a General poisoning.

Known iodophenyl drug immediate and long-term bactericidal action. Iodophor contains povidone-iodine and Polydextrose-iodine in a mass ratio of povidone to Polydextrose 20:80 to 80:20 (U.S. patent N 4719106, MCI AND 61 TO 31/79; NCI 424-80, the applicant Euroceltique S.A. (Luxembourg), application N 850522, 11.04.86, publ. 12.01.88).

A disadvantage of known composition is the only one outside its application.

Known antimicrobial agent is a tetracycline, a commonly used antibiotic extended-spectrum (M. D. Mashkovsky. Medicinal product. So 2, M.: Medicine, 1985).

The disadvantage of this structure is that it contains a large number of components and is only used as a disinfectant.

Most loved ones chemical compounds of the same purpose to the declared triiodide Quaternary nitrogen bases in a group of inventions on the totality of signs are according to the technical solution to the patent of the Russian Federation "Antimicrobial drug treatment" (the description of the invention to the patent of Russian Federation N 2033164, IPC6A 61 K 33/18//(a 61 K 33/18, 31:00, 31:79), 1992), triiodide 1,2,3 - triamterenetriamterene, but the characteristic "triiodide 1,2,3-dialkylanilines" can be expressed by the following structural formula:

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where R, R1, R2= H, alk.

A disadvantage of the known chemical compounds is the fact that significantly narrowed the number of members of the class of triiodide Quaternary nitrogen bases, characterized only triiodide 1,2,3-dialkylanilines. These compounds are insoluble in water.

The closest song of the same purposes of the claimed composition on a set of attributes is a water-soluble injectable form containing triiodide 1,2,3-dialkylanilines and polyvinylpyrrolidone (TU 9351-001 - 001362-RP-94). The drug is administered subcutaneously, intravenously and intramuscularly with dyspepsia young, mastitis and endometritis cows (RF patent N 2033164, IPC And 61 To 33/18//(a 61 K 33/18, 31:00, 31:79).

A disadvantage of the known water-soluble injectable form is that it narrowed its scope.

Unified technical result that can be obtained by carrying out groups of inventions: new members class triiodide Quaternary nitrogen bases, each of whom must possess antimicrobial activity.

Hekim by (chemical compound), achieved new connection - triiodide Quaternary nitrogen bases of the General formula:

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where R1, R2, R3, R4; R8, R9is hydrogen, C1-C6alkyl;

R7=-(CH)n12- (when n12= 2-4);

-(CH2)n14- O-(CH2)n15- if n14-0-4, n15=0-4);

-(CH2)n16-S-(CH2)n17(if n16-0-4, n17= 0-4);

(if n18=0-4; n19=0-4, R20=hydrogen, C1-C6alkyl);

(if n20=0-4, n21=0-4, R21, R22=hydrogen; X-= 1, 13). C1-C6alkyl;

R10, R11, R12= hydrogen, C1-C6alkyl;

n1n2=3-4

X-= 1, 13.

Specified single technical result in the exercise of invention the object of the composition is achieved by the fact that water-soluble composition contains triode Quaternary nitrogenous base and the extension agent, excipient surface-active character. The peculiarity lies in the fact that as triiodide Quaternary nitrogen bases use compounds of General formula:

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where the values of R1-RID Quaternary nitrogenous bases - 1-40

Extension agent - Rest

This invention covers compounds containing chetyrehkolenny nitrogen in the composition of the organic cation and the biologically-active anion I3-(triode-anion), which are interconnected electrostatic forces. Cation of nitrogen in the internal sphere, hypervalence associated with the anion of the external sphere (with triode-anion). Specified parts of the compounds in the composition of triiodide Quaternary nitrogen bases have the common property that is responsible for the functional affinity and biological activity due to the presence chetyrehjadernogo nitrogen and associated with triode-anion.

The claimed group of inventions to meet the requirement of unity of invention, since the group single object of the invention form a single inventive concept, one of the declared objects of the group - a substance obtained by chemical (chemical compound) - triiodide Quaternary nitrogen bases, intended for the manufacture of other claimed subject groups: water - soluble composition.

The difference of the invention from the prototype is the following. The analysis of the prior art, in about the equivalents of the claimed group of inventions as for the object substance, obtained by chemical means, and for object composition, allowed to set, there was no analogues for substances obtained by chemical means, and the composition of the claimed group of inventions. The list of identified unique prototype for substances obtained by chemical means, and composition, as the most similar set of features analogues, has identified a set of essential in relation to the proposed technical result of the distinctive features for each of the stated objects of the group are set out in the claims. Created new chemical compounds containing chetyrehkolenny basic nitrogen in the composition of the organic cation and hypervalent associated triode-anion (I3-- triiodide Quaternary nitrogen bases. We offer chemical compounds used for the manufacture of water-soluble antimicrobial composition as the active agent.

Thus, each of the objects of invention meets the condition of "novelty."

Proof of the suitability of the invention the term "inventive step" is as follows. the creation of the members of the class specified grounds.

The biological activity of triiodide Quaternary nitrogen bases, as new technical property, due to the presence of structures (pharmacophore) due to the strong binding of triiodide anion in triiodide Quaternary nitrogen bases chemical bond with the Quaternary nitrogen and hydrogen bond with the auxiliary substance is polyvinylpyrrolidone (PVP) eliminated toxic (burning) the action of iodine, which does not affect its biological activity.

Pathogenic microorganisms have a number of biochemical differences between healthy cells of higher organisms, such as carbohydrate and lipid components of membranes. Due to this triiodide Quaternary nitrogen bases, acting selectively on the pathogenic cells, leading to their death and eliminate the resistance of the microorganisms to the proposed biologically active compounds.

Triiodide Quaternary nitrogen bases in therapeutic doses does not adversely affect the healthy cells of higher organisms.

Triiodide Quaternary nitrogen bases are chemical compounds obtained by known techniques and methods, and their nomenclature is reflected (Banks, J. is 5; Chemist's Handbook. So 2. M.-L.: ed. Holdem, 1963).

We offer new compounds containing organic cation, including heterocyclic, have not been previously described. From knowledge of the structure of their properties were not clear; in a small part of their property was anticipated on the basis of the research prototype. Set forth in the application of antimicrobial properties identified only by study of the proposed connection.

Triiodide Quaternary nitrogen bases as the active agent are water-soluble antimicrobial composition, which become water-soluble form, with the result of their oral and parenteral application.

Thus, each of the objects of the claimed group of inventions meets the condition of "inventive step".

The expansion of the means of influence on a living organism is dictated by the peculiarities of higher organisms (e.g., individual sensitivity), contraindications of the drugs used. Proposed connection eliminates the need for determining the sensitivity of pathogenic microflora, since there is no resistance of microorganisms.

It is known that iodine preparations the possession which the impact occurs resorption products of disintegration (decay) of pathogenic cells and neutralization of the oxidized products of their metabolism, improve blood circulation, lowering blood viscosity and reduces the tone of the vascular system (Brain, I. E. Pharmacology.- M.: Kolos, 1969). The structure of the proposed chemical compounds allows for the introduction of them in the body to retain properties that are characteristic of active iodine and prolonging its action.

Triode-anion (I3-) capable of generating oppositely charged particles containing a biologically active iodine: I2; I3-; I+; IO-. In the proposed chemical compounds contained hypervalent bound iodine in the form of I3-(triode-anion). Electron cloud (density) is distributed so that the cation associated three equivalent atoms of iodine. In an aqueous solution of triiodide czetwertynski nitrogenous bases is its ionization: I-3[I+...I-] where is part.

There are fast electron exchange interaction between the anion and the iodine molecule. The atoms of iodine in triode-anion indistinguishable because of the excess electron is non-localized plates of three-centered orbitals: In the aquatic environment are formed oppositely charged particles containing a biologically active form of iodine: I2; I3the specified electron (biochemical substances).

Water-soluble composition of the proposed connection allows you to prolong the biological effect of triiodide Quaternary nitrogen bases in the tissue fluids of higher organisms long enough to transport the active agent (proposed connections) and having a positive impact on the disease site.

The possibility of carrying out the invention is confirmed by the following information. The structural formula of triiodide Quaternary nitrogen bases:

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where the values of R1-R12n2n2above.

The proposed compounds derived from organic compounds, which comprises a Quaternary basic nitrogen, by joining hypervalent associated anion in the form of I3-one of the following methods.

Method A. the replacement of the anion in the Quaternary ammonium salts.

It heated up to 50-60oC solution of 0.01 m of Quaternary ammonium salt in 20-30 ml of ethanol are added under stirring 10-10,5 ml of an aqueous solution containing a 2.0 of 2.08 g of potassium iodide (or equivalent amount of dihydrate sodium iodide) and 2.5-2.58 g (0.01 m) of crystalline iodine. After the Ute, washed and dried.

Method B. Iodization iodine Quaternary nitrogen bases.

To 0.01 m iodide Quaternary nitrogenous bases dissolved when heated to 50-70oC in 20-30 ml of ethanol, added with stirring to 2.5-2.58 g (0.01 m) of crystalline iodine. In the case of obtaining bis-triiodide Quaternary ammonium use double the amount of crystalline iodine. The mixture is boiled for 5-10 min under reflux, cooled, diluted with 20 ml of water, filtered and dried.

Examples of the synthesized triiodide Quaternary nitrogen bases are given in table. 1.

Justification of the selected limits is the following.

Method A.

When heated solution of the Quaternary ammonium salt is less than 50oC will not react.

The heating of the specified solution over 60oC leads to waste of energy.

When the consumption of ethanol is less than 20 ml dissolve ingredients, at a flow rate of ethanol more than 30 ml of reduced yield.

Adding an aqueous solution of potassium iodide less than 10 ml is not enough water on the dissolution of iodine. Adding the specified solution more than 10.5 ml of the excess solution will be reflected ng, derived from the reaction equations for obtaining triiodide Quaternary nitrogen bases.

Method B.

When heated solution of iodide Quaternary nitrogenous base in ethanol less than 50oC will not go the iodination reaction. The heating of the specified solution over 70oC leads to waste of energy.

When the consumption of ethanol is less than 20 ml is not completely dissolve the original components. At a flow rate of ethanol more than 30 ml reduced the yield of the final product.

The amount of crystalline iodine, 2.5-2.58 g, calculated on the basis of reaction equations for obtaining triiodide Quaternary nitrogen bases by ladirovannye iodine Quaternary nitrogen bases.

When boiling less than 5 min, the reaction will not be until the end. The boiling mixture over 10 min leads to waste of energy.

Example 1.

It heated up to 55oC to a solution of 0.01 mol of iodide of Tetramethylammonium in 25 ml of ethanol is added with stirring 10 ml of an aqueous solution containing 2 g of potassium iodide and 2.5 g of crystalline iodine. Stirred for 30 minutes After cooling the mixture is diluted with equal amount of water. Fallen triode of Tetramethylammonium filtered off, washed with whom NASA, confirmed by elemental analysis.

Found, %: I 81,9; 10.1; N 2,1; N 3,4.

Calculated, %: I 83,8; 10,5; H 2,6; N 3,1.

The structure is also confirmed by molecular weight equal to 455, the IR spectrum of metainformation due to the high iodine content (see table. 1).

The connection is characterized by simultaneous content in the molecule, the nitrogen atom with a positive charge, the four methyl groups and triiodide anion I3-.

Example 2.

To 0,01 mol of iodide N-methylate urotropine, dissolved by heating to 60oC in 20 ml of ethanol, added with stirring, 2.5 g (0.01 mol) of crystalline iodine. The mixture is boiled for 5-10 min under reflux, cooled, diluted with 20 ml of water, filtered and dried.

The structure of the obtained compounds (triometric urotropine) confirmed by elemental analysis.

Found, %: I 73,8; 17,4; H 2,9; N 11,1.

Calculated, %: I 75,0; 17.2; H 3,0; N 11,5.

The structure is also confirmed by molecular weight equal to 508. The IR spectrum of metainformation due to the high iodine content (see table. 1).

The connection is characterized by simultaneous content in the molecule, the nitrogen atom with a positive charge, and e is connected to the nitrogen atom; content triiodide anion I3-.

Study of the antimicrobial action of the proposed compounds listed in table. 1, was performed ten-fold serial dilutions in saline solution with successive planting in appropriate nutrient medium (Lewicki C. I. et al. Clinical laboratory diagnostics. 1998, No. 1, p. 44). As test objects used the following microorganisms occupying different systematic position according to the determinant of Berga: gram-positive cocci - St. aureus-R; gram-negative Bacillus - E. coli-88; spore-forming Bacillus - Cl.difficile-4938 and fungi C. albicans-674. The results are given in table. 2.

Are given in table. 2 data show that the proposed compounds for antimicrobial activity are not inferior to widely used antibiotics.

Some biological activity in inflammatory processes accompanying, for example, syphilis, have previously used (oral and intravenous) salt itestosterone acid - iodine: potassium iodide and sodium iodide, which is explained by the presence in the body of the iodide-oxidase, which converts the iodine anion (I-in biologically active form - cation of iodine (I+), which is OK the response.- Leningrad: Nauka, 1968).

The proposed triiodide Quaternary nitrogen bases allow you to enter into the body iodine directly into its biologically active form, thereby strengthening its action, while reducing toxicity.

Triiodide Quaternary nitrogen bases are insoluble in water. A significant amount of organic cation in them contributes to the stabilization of compounds in General, but affects the solubility of the proposed compounds. Derivatives of organic triiodide weak surface-active substances (surfactants) due to differences in hydrophobicity and hydrophilicity of the cation and anion. To increase the solubility of the used surfactants, such as twins, in the presence of which the dissolution occurs due to the formation of cluster complexes.

To obtain water-soluble compositions of triiodide Quaternary nitrogen bases are mixed extension agent (surfactant) in an amount of 60-99 wt.% with one triiodide Quaternary nitrogen bases in the amount of 1-40 wt.% and autoclave at a temperature of 100-150oC and a pressure of 1-1 .5 psi for 0.5 to 1.5 hours

You can obtain a water-soluble composition without autoclaving, when a mixture of the above components are dissolved in the shock from light yellow to reddish yellow. For solution powder dissolved in boiled, distilled water or saline solution. The surfactant is used to stabilize aqueous solution, preventing the precipitation of the Quaternary nitrogen bases, as well as for prolonging their action.

Justification of the selected limits is the following.

If triiodide Quaternary nitrogenous bases take less than 1 wt.% to obtain water-soluble composition that decreases the biological activity of the latter. If the proposed connection (one of them) take more than 40 wt. % falls dark residue. The possibility of carrying out the invention the object composition is confirmed by the following information.

Example 1.

Take 1 wt. % crystalline triiodide of Tetramethylammonium and 99 wt.% polyvinylpyrrolidone (PVP) (Pharmacopeia 42-1194-78), mix and autoclave at a temperature of 100-150oC and a pressure of 1-1 .5 psi for 0.5 to 1.5 hours Obtained crystalline powder light yellow color Packed in sealed containers. The obtained water-soluble composition possesses antimicrobial activity.

Example 2.

Take 40 wt. % crystalline readmetadata urotropine the shock of reddish-yellow color Packed in sealed containers. The obtained water-soluble composition possesses antimicrobial activity.

Proof of compliance of the claimed invention, the condition of "industrial applicability" is as follows.

When using the claimed group of inventions made the following sets of conditions:

a) a means of embodying the invention in its implementation, is intended for use as biologically active substances in medicine and veterinary medicine, infectious diseases of humans and animals;

b) for the claimed group of inventions, as described in independent clauses set forth in the claims, confirmed the possibility of their implementation using the above in the application of tools and techniques.

The invention in its implementation ensures the achievement of the envisaged in the proposal of a unified technical solution consists in creating a new members class triiodide Quaternary nitrogen bases, each of whom must possess antimicrobial activity.

Therefore, the claimed group of inventions meets the condition of "industrial applicability".

R10, R11, R12= hydrogen, C1- C6alkyl;

n1n2= 3 - 4;

X = I, I3.

2. Water-soluble composition having antimicrobial activity, containing triiodide Quaternary nitrogenous base and the extension agent, excipient surface-active character, characterized in that as triiodide Quaternary nitrogen bases use connections under item 1 in the following ratio, wt.%: triode Quaternary nitrogenous bases 1 to 40; extension agent else.

 

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CH3(CH2)mCH2-CH2-,< / BR>
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