Iodirovannoye halides of quaternary ammonium salts, method for their production and compositions on their basis

 

(57) Abstract:

Describes the new iodized halides of Quaternary ammonium salts of General formula (I), where X=Cl, Br, J, m=1-2 and n=1-4, a, b, C together with the N means the remainder of the pyridine cycle (a), where R and R1specified in paragraph 1 of the formula, or a, b, C together with the N means the remainder of the benzimidazole series (in), where the values of R2and R3specified in paragraph 1 of the formula, or a, b, C together with the N means the remainder of urotropine (C), or a, b, C, = alkyl1-C6or Rather, In conjunction with N means the remainder of morpholinyl (d), or a, b, C together with the N means the remainder of the imidazole cycle (e), where a value of R5specified in paragraph 1 of the formula. The compounds exhibit a variety of pharmacological activity, including anti-TB, antiulcer, antiviral, antihelminthic, with low toxicity. Describes the method of their production and compositions based on compounds of the formula (I). 3 S. and 12 C.p. f-crystals, 4 PL.

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The invention relates to new derivatives in a series of Quaternary ammonium salts, namely, the iodinated halides of Quaternary ammonium salts of General formula I

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where A, B, C together with N mean OCTA is>, CON(R'1)2, COOR'1,

where R'1= C1-C6-alkyl,

a R takes on the values for m = 1:

(CH2)pPh, where p = 1-4 when R1= COOR'1n = 1, 2,

alkyl, C1-C6when R1= CONH2, CONHNC(R'1)2, CON(R'1)2, COOR'1n = 1, 2

alkyl, C1-C16when R1= hydrogen, X = Cl, Br, n = 1, 2

X = I, n = 2

alkyl, C7-C16when R1= hydrogen, X = I, n = 1, 2;

or - A, B, C together with the N means the remainder of the benzimidazole cycle

< / BR>
where R2= alkyl, C1-C6hydrogen, oxyalkyl C1-C6,

R3= alkyl, C1-C6,

a R takes values when m = 1 alkyl (C1-C6when

a) X=Cl, Br, n = 1, 2

b) X = I, n = 2

in) X = I, n = 1, except

b,1) R = CH3, R2= H, R3= C2H5,

b,2) R = CH3, R2= H, R3= CH2CH2OH,

b,3) R = CH3, R2= H, R3= C6H13,

b,4) R = C2H5, R2= H, R3= CH2CH2OH; or

- A, B, C together with the N means the remainder of urotropine

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and R takes on the values for m = 1:

alkyl, C7-C16when X = I and n = 1

alkyl, C1-C16when X = Br, Cl and n = 1, 2

X = I and n at X = Cl, Br and n = 1, 2

X = I and n = 2

alkyl, C7-C16when X = I and n = 1, 2

phenyl, oxyphenyl, group (CH2)pC6H5, (CH2)pOCOR4,

(CH2)pCOOR4, (CH2)pCON(R4)3where p = 1 to 4, R4= alkyl, C1-C6and n = 1, 2,

and R takes the value at m = 2 and n = 1-4 (CH2)pOSON2, (CH2)pwhere p = 1 to 5; or

- A, B together with the N means the remainder of morpholine

< / BR>
C takes the value alkyl, C1-C6,

R takes values when m = 1 and n = 1, 2 alkyl, C1-C16, (CH2)pCOR4,

where p = 1 to 4, R4= C6H5, alkyl (C1-C16; or

-A, B, C together with the N means the remainder of the imidazole cycle

< / BR>
where R5= alkyl (C1-C6)

and R takes values when m = 1 and n = 1, 2 alkyl, C1-C16.

The compounds exhibit a variety of pharmacological activity, including anti-TB, antiulcer, antiviral, antihelminthic.

Known halides of Quaternary ammonium salts R4N+Hal-with a variety of alkyl and aryl components exhibiting pharmacological activity: metalera 5-bromo-furan-2-carboxylic acid iodimetric), ginatilan (N,N'-bis[2-hyalinata]-succinate diode) and other /M. D. Mashkovsky, Medicines, ch. I, M, 1987, page 189, 214, 215).

The most similar structure are polymeric compounds with antibacterial activity, including fragments of R4N+I3-:

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(patent of Russian German N 2059379, C 02 F 1/76, 1984).

The technical result of the invention is to expand the Arsenal of compounds in a series of iodized halides of Quaternary ammonium salts exhibiting a wide range of pharmaceutical activity with low toxicity.

The technical result is also the method of their production and compositions based on them.

The technical result is achieved by compounds of General formula I, the method of their production and compositions based on them.

Inventive compounds I defined as new derivatives iodine halides of Quaternary ammonium salts, having a spectrum of pharmacological activity with low toxicity.

The method of obtaining the compounds of the first lies in the interaction of halides of Quaternary ammonium salts of General formula II, where A, B, C, X, R have the above values with stachio for example, lower alcohol (C1-C3), chloroform, etc.

Source halides to obtain the compounds of General formula I, where X = I, can be compounds of General formula II, where X = Br, Cl, which enter into interaction with the alkali metal iodide and iodine.

The closest in performance of the method is a method of obtaining inorganic iodine halides KI3and NaI3that lies in the interaction of potassium iodide or sodium iodide in aqueous solution (Journal of the German chemical society. Inorganic synthesis, 1957, No. 47, pp. 107-168).

Inventive step of the method is determined by the conditions of its carrying out of any process in a polar solvent or without it), the choice of which is not dictated by the known regularities.

Compounds of General formula I, taken in effective amounts may be applicable beginning pharmaceutical compositions based on them.

To improve dispersion in ointments and emulsions, solubility in injectable and oral media (water, saline solution) composition can contain surface-active substances (surfactants) from a number of lanolin, polyethylene glycol, twin, polyvinylpyrrolidone, carboxymethylthio of halide surfactant to 1:0.1 - 100.

The injectable form may contain a surfactant from a range of twin, polyvinylpyrrolidone, karboksimetilcelljuloza, dextrin, dimethylsulfoxide or a mixture of 1: 0.1 - 10 with polyvinylpyrrolidone in an amount of 50 to 99 wt.%.

Oral forms (tablets, powders) to improve the solubility may further comprise a sugar, for example lactose, or organic acid such as succinic, citric, aminouksusnoy, number, wt.%

the halide - 1,0 - 20,0

SURFACTANT - 2,0 - 50,0

acid or sugar - 30,0 - 97,0.

The oral form may also optionally contain to make sipacate sodium bicarbonate, and in the case of sugar may contain a mixture of acid with bicarbonate.

Ointments and emulsions can contain surfactants from a number of lanolin, twin, polyethylene glycol in the amount of 0.5 - 2.0 wt.%, the halide may be 0.5 - 5.0 wt. % based on the rest. The emulsion may further comprise an emulsifier, for example dimethyl sulfoxide, higher alcohol (C7) in the amount of 0.5 to 6.0 wt.%. The emulsion may contain no emulsifier or surfactant, if it contains a halide of O. F. I, where R = the higher alkyl (C7) in the amount of 0.5 to 3.0 wt.%. As ointment bases can be used, for example, VA is ICA can contain as surfactant dimethyl sulfoxide (DMSO), and optionally, solvent - ethanol or solvent in amount, wt.%:

the halide - 1,0 - 10,0

DMSO AND 0.5 - 30,0

ethanol - 40,0 - 50,0

water - the rest

or

the halide - 1,0 - 5,0

ethanol - 50,0 - 70,0

water - the rest.

The method of obtaining the composition is a mixture of components (if necessary in the presence of a polar solvent, for example from a number of dichloromethane, chloroform, chlorate, dichloroethane, lower alcohol (C1-C3), water, dimethylsulfoxide).

Examples of embodiment of the invention.

Example 1. Getting iodobromide 1 cetylpyridinium

of 38.4 g (0.1 m) Bromide 1 cetylpyridinium (obtained by the method of A. S. USSR N 121544, 1959) is placed in 100 ml of chloroform and the resulting suspension is added under stirring 25.4 g (0.1 m) of crystalline iodine. Stand for 10 minutes and diluted with 100 ml of petroleum ether. The precipitation is filtered off. The output 62 g (97%), brown needles with TPL63oC (from ethanol). UV-range, nm: 227, 298, 368. The infrared spectrum, cm-1: 1620, 1580, 767, 727, 673.

Elemental analysis of C21H38NBrI2,%:

found N = 2,33, total halogen = 51,84

calculated N = 2,19, total halogen = 52,35.

Similarly, the compounds 1, foreign 1 cetylpyridinium grind with 25.4 g (0.1 m) of crystalline iodine. Further operations, output, and data analysis and spectra similar to example 1.

Similarly, the compounds 14, 25, 26, 30 (table 1).

Example 3. Getting triiodide N-cetylpyridinium

To a suspension of 38.4 g (0.1 m) of bromide of cetylpyridinium in 100 ml of alcohol, add one scoop of 100 ml aqueous solution of 25.4 g (0.1 m) of iodine in 20 g of potassium iodide. The mixture is stirred and the precipitated triode of cetylpyridinium filtered. The yield of the desired product 65 g (95%), brown needles with TPL66o(from methanol). Range of PMR, M. D.: 8,9 (d, 2H); 8,6 (t, N); 8,2 (t, 2H); 4.75 V (t, 2H); 2,12 (m, 2H); 1,0-1,7 (m, 14N); of 0.85 (t, 3H). UV-range, nm: 260, 295, 367.

Elemental analysis of C21H38NI3,%:

found N = 2,18 I = 53,12

calculated N = 2,04 I = 55,62.

Similarly, the compound obtained 27 (table 1).

Example 4. Getting pentaiodide N-decylpyrimidine

To a suspension of 3.5 g (0.01 m) iodide N-cetylpyridinium in 20 ml of methylene chloride is added in one time of 5.1 g (0.02 m) of iodine. The mixture is stirred for 15 minutes and the solvent is distilled off. The residue is a viscous dark brown mass, RUB clean with alcohol. The output of 8.1 g (94%), black crystals with TPL21-23oC. the infrared spectrum, cm-1: 1620, 1580, 1470, 765. UV spectrum. nm: 220, 294, 368. PMR-spectrum, ppm: 8,9 (s, 2H); 8,6 (C, H); 8.2 PERCENT:

found N = 1,83; I = 73,39;

calculated N = 1,64; I = 74,27.

Similarly, the compounds 10, 21,22 (PL.1).

All the above compounds elemental analysis data on nitrogen and halogen correspond to the calculated. Electronic spectra do not contain strips of charge transfer free iodine (420 nm in ethanol solutions) and contain the absorption band of the complex anions ClI2-; when 360-368 nm, BrI2-when 362-370 nm, I3-at 360-370 nm. In the PMR spectra of iodine halides observed characteristic of complexation shift meso-heterocyclic proton in the region of strong field at 1.0-1.5 m) for compounds 24, 26, 27, 30 2, b pyridine protons for compounds 1-8 - 0.3 to 0.8 M. D. relative to the source of halides. The introduction of a second molecule of iodine in the complex anion does not change the position of the signals of protons, but leads to a significant broadening and disappearance of the multiplicity. The position signals of alkyl ammonium protons at the center remains constant. The IR spectra of compounds I are the same under the provisions of the bands with the corresponding parent compounds and do not have the characteristic peaks in the area 600-3600 cm-1associated with nature hypervalent anion.

Prepared compositions of pharmaceutically acceptable components, wt. %:

1.

the connection 15 - 0,7

twin - 1,0

vaseline - rest

(ointment)

2.

the connection 22 - 0,9

lanolin - 0,7

a mixture of polyethylene glycol with water 1:1 - rest

(ointment)

3.

connection 19 - 2,5

the glycol - 1,2

a mixture of polyetheramine with water 1:1 - rest

(ointment)

4.

the connection 31 - 1,5

twin - 0,6

dimethyl sulfoxide - 1,8

vaseline - rest

(emulsion)

5.

connection 1 - 2,8

lanolin - 1,1

oktilovom alcohol - 4,0

a mixture of polyetheramine with water 1:0.5 to rest

(emulsion)

6.

connection 9 - 1,0

dimethyl sulfoxide - 2,5

vaseline - rest

(emulsion)

7.

connection 12 - 20,0

polyvinylpyrrolidone (PVP) 80,0

8.

connection 9 - 40,0

carboximetilceluloza - 60,0

9.

connection 13 - 35,0

dextrin - 65,0

composition 7 ID (DMSO) - 75,0

11.

the connection 30 - 10,0

a mixture of PVP and DMSO 1:1 to 90.0

12.

connection 5 - 1,0

twin - 99,0

13.

connection 21 - 5,0

DMSO - 1,0

ethanol - 35,0

water - the rest

14.

the connection 29 - 3,0

ethanol - 60,0

water - the rest

song 10 - 14 - solutions reddish-brown color

15.

connection 4 - 15,0

PVP - 30,0

glucose - 30,0

NaHCO3- 10,0

citric acid - 15,0

powder, light brown, soluble in water.

As can be seen from the above materials, compositions composed of pharmaceutically acceptable components, represent, or ointments or tinctures, or water-soluble forms.

The compounds of O. F. I felt tubulations, antiulcer, anthelmintic, antiviral activity.

Biological tests

Acute toxicity was determined on the adult mice of both sexes weighing from 18 to 20, the target compound was administered in injection form with polyvinylpyrrolidone intraperitoneally. Observation of animals should be performed within 14 days after a single injection of the compounds. Investigated the effect of doses from 500 to 5000 mg/kg animal mass. Achiev what xinou more than 1500 mg/kg (more than 5000 mg/kg), which corresponds to a low-toxic (or practically non-toxic) substances according to Sidorov, K. K.

Example 5. Definition topolitical compounds

In the experience of use 110 pigs with an average weight of 350 g, infected subcutaneously in the region of the right groin 0.001 mg/ml culture of Mycobacterium tuberculosis strain H37Ry. Treatment begin within 2 weeks after infection and spend 5 times a week for 60 days.

Connections give Guinea pigs at a dose of 20 mg/kg per day, control the drug tubazide give the equivalent dose. Organs and tissues are subjected to pathological and bacteriological study. The results are presented in table. 2.

From table. 2 shows that the studied animals that received compound 1 significantly differ in weight from the control, the increase of mass on 48-71 g greater than that of the control. There are differences in the mass of bodies. All control animals tuberculous lesions localized predominantly in the introduction.

In animals treated with the synthesized compounds or tubazide, morphologically tuberculous changes it is not revealed.

Given the toxicity of tubazide, LD50which is 363 mg/kg, Terada.

Example 6. Research antiulcer activity

Pharmacological studies showed that compounds 2, 9,15, 22, 31 have high antiulcer activity.

Pharmacological data

1. Pre-treatment compounds shows chitosamine (gastronomiczne) effect against damage in the stomach caused by acidified ethanol: CD50= 1 - 6 mg/kg orally.

2. Compounds prevent the development of stomach ulcers, induced by indomethacin (U50= 1,0 - 2,0 mg/kg orally); aspirin (U50= 1,0 - 3,0 mg/kg orally); aspirin + stress (U50= 8,0 - 20,0 mg/kg orally).

3. Connection speed up the healing of chronic gastric ulcers induced in rats with acetic acid at doses of 1 mg/kg per day in 73-92% of the animals.

4. The compounds inhibit caused by indomethacin gut ulcer.

Example 7. Research anthelminthic activity

In experiments in gimenolepidoze white mice revealed that compound I in a single oral dose of 100 mg/kg cause a full (100%) exemption mice from hymenolepis. The minimum effective dose (MED) for compounds I in gimenolepidoze mice ranges from 22 to 60 drug oral dose of 100 mg/kg (see table. 3).

Example 8

Drugs have significant chemotherapeutic activity in influenza pneumonia mice caused by influenza virus A2 (England 042/72), at a dose of 5 mg/kg, and entered through the mouth once a day for 5 days significantly (P<0,01) protects from death 50-80% of mice infected with 10 LD70. When infected mice 10 LD 80 connection I significantly (P<0,01) protects from death 35-50% of the animals. In addition, the use of compounds 2, 9, 15, 22, 31 at a dose of 5 mg/kg significantly increases the life expectancy of treated mice. The effectiveness of the compounds is confirmed by pathological study of the lungs of mice and establishing patania accumulation of influenza virus in the lungs of immunized mice in comparison with the accumulation of virus in the lungs of untreated (control) mice.

Example 9

Tested the effectiveness of compounds 2, 9, 15, 22, 31 when parenteral introduction.

Mice weighing 7-10 g infected with herpes simplex virus (HSV) type 1 by intraperitoneal injection veronicadelgado material at a dose of 100 LD50. All infected mice were divided into groups of 10-20 individuals in each. Groups of immunized animals substance was administered in doses of from 20 to 0.1 mg/kg for 7 days.

It was shown that the treated LM is enhanceability. At the same time in the control group animals death reached 80,95 + 8,8%, the obtained results are valid - P<0,001 (PL.4). The introduction of drugs in doses of 1.0-0.1 mg/kg was accompanied by a significant reduction in mortality with 80.95 + 8.85 untreated animals to 8.7 - 25,0 have treated, but the full protection of animals, as noted in the application of higher doses was not observed. The activity of the preparations was reached only with dose reduction to 0.01 mg/kg, but here the mortality rate of treated animals relative to controls did not reach statistical significance.

Tests have shown that the proposed compounds have a range of pharmacological activity: topolitical, antiulcer, anthelmintic, anti-virus with low toxicity. Connection is stable during storage. It can be assumed that the proposed connection by analogy with iodine are bactericidal, anti-inflammatory, together with immunomodulating and other activities. Unlike active I2the proposed compounds have low toxicity and prolonged action.

1. Iodirovannoye halides of Quaternary ammonium salts of General formula I

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where A, B, C together with the N means the remainder of the pyridine cycle/SUB>, COOR'1where R'1= C1- C6-alkyl,

R takes on the values for m = 1:

(CH2)pPh, where p = 1 to 4 if R1= COOR'1n = 1, 2,

alkyl, C1- C6when R1= CONH2, CONHNC(R'1)2, CON(R'1)2, COOR'1n = 1, 2,

alkyl, C1- C16when R1= hydrogen, X = Cl, Br, n = 1, 2, X = I, n = 2, alkyl (C7- C16when R1= hydrogen, X = I, n = 1, 2;

or A, B, C together with the N means the remainder of the benzimidazole cycle

< / BR>
where R2= alkyl, C1- C6hydrogen, oxyalkyl C1- C6;

R3= alkyl, C1- C6,

R takes values when m = 1 alkyl (C1- C6when

a) X = Cl, Br, n = 1, 2,

b) X = I, n = 2,

in) X = I, n = 1, except

b, 1) R = CH3, R2= H, R3= C2H5,

b, 2) R = CH3, R2= H, R3= CH2CH2OH,

b, 3) R = CH3, R2= H, R3= C6H13,

b, 4) R = C2H5, R2= H, R3= CH2CH2OH;

or A, B, C together with the N means the remainder of urotropine

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R takes on the values for m = 1:

alkyl, C7- C16when X = I and n = 1,

alkyl, C1- C16when X = Br, Cl, and n = 1, 2, X = I and n = 2;

or A, B, C = alkyl, C1- C7- C16when X = I and n = 1, 2,

phenyl, oxyphenyl, group (CH2)pC6H5, (CH2)pOCOR4, (CH2)pCOOR4, (CH2)pCON(R4)3where p = 1 to 4, R4= alkyl, C1- C6and n = 1, 2,

R takes the value at m = 2 and n = 1 to 4 (CH2)pOCOCH2, (CH2)pwhere p = 1 to 5;

or

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A, B together with the N means the remainder of morpholine,

C takes the value alkyl, C1- C6,

R takes values when m = 1 and n = 1, 2 alkyl, C1- C16, (CH2) = COR4where p = 1 to 4, R4= C6H5, alkyl (C1- C16,

or A, B, C together with the N means the remainder of the imidazole cycle

< / BR>
where R5= alkyl, C1- C6,

R takes values when m = 1 and n = 1, 2, alkyl (C1- C16.

2. Iodirovannoye halides of Quaternary ammonium salts on p. 1 of General formula I, where A, B, C together form a residue of benzimidazole cycle

< / BR>
where R2= alkyl, C1- C6hydrogen, oxyalkyl C1- C6;

R3= alkyl, C1- C6,

R takes values when m = 1 alkyl (C1- C6when

a) X = Cl, Br, and n = 1, 2,

b) X = I and n = 2,

in) X = I and n = 1, except SUB>5,

b, 3) R = CH3, R2= H, R3= CH2CH2OH,

b, 4) R = CH3, R2= CH3, R3= CH3,

b, 5) R = R3= CH3, R2= C2H5,

b, 6) R = CH3, R2= H, R3= C6H13,

b, 7) R = R3= C2H5, R2= H

in, 8) R = R3= C2H5, R2= CH3,

V, 9) R = C2H5, R2= H, R3= CH2CH2OH.

3. The method of obtaining yugirovannykh halides of Quaternary ammonium salts on the PP.1 and 2, characterized in that the halides of Quaternary ammonium salts of General formula II

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where A, B, C, R, X, and m have the above values,

enter into interaction with the stoichiometric amount of iodine.

4. The method according to p. 3, characterized in that to obtain the compounds of General formula I, where X = I, the halides of General formula II

< / BR>
where X = Br, Cl, enter into interaction with potassium iodide and iodine or c solution of iodine and iodide of an alkali metal.

5. The method according to PP. 3 and 4, characterized in that the process is carried out in the presence of a polar solvent.

6. Pharmaceutical composition comprising the active principle - idatabase substance otlica formula I on PP.1 and 2 in an effective amount.

7. The pharmaceutical composition according to p. 6, characterized in that it additionally contains a surface-active substances (surfactants), such as number of: lanolin, polyethylene glycol, twin, polyvinylpyrrolidone, karboksimetilcelljuloza, dextrin, a sulfoxide, a mixture of polyvinylpyrrolidone with dimethylsulfoxide 1 : 0.1 to 10 at a ratio of halide to surfactant of 1 : 0.1 to 100 weight. h

8. The pharmaceutical composition according to paragraphs.6 and 7 for use in the form of ointments, characterized in that it contains as a surfactant or lanolin, or polyethylene glycol, or twin and additionally ointment base in the following ratio, wt.%:

The halide - 0,5 - 5,0

SURFACTANT IS 0.5 TO 2.0

Ointment base - Rest

9. The pharmaceutical composition according to paragraphs. 6 and 7 for use in the form of an emulsion, characterized in that it contains as a surfactant or a twin, or lanolin, or polyethylene glycol, and optionally an emulsifier of a number of dimethylsulfoxide, alcohol C7- C16and emulsion base in the following ratio, wt.%:

The halide - 0,5 - 5,0

SURFACTANT IS 0.5 TO 2.0

Emulsifier - 0,5 - 6,0

Emulsion base - Rest

10. The pharmaceutical composition according to p. 6 for use in the form of an emulsion, otlichalsa based on the ratio of the components, wt.%:

The halide - 0,5 - 3,0

Emulsion base - Rest

11. The pharmaceutical composition according to paragraphs.8 - 10 for use in the form of ointment or emulsion, characterized in that as ointment bases it contains petrolatum, and as an emulsion Foundation, a mixture of polyethylene glycol or polyetheramine with water in a ratio of 1 : 0,5 - 3,0.

12. The pharmaceutical composition according to paragraphs.6 and 7, suitable for injection, characterized in that it contains as a surfactant or polyvinylpyrrolidone, or twin, or carboximetilzellulozu, or dextrin, or dimethylsulfoxide, or a mixture of polyvinylpyrrolidone with dimethylsulfoxide 1 : 0.1 to 10 in the following ratio, wt.%:

The halide is 1 - 50

SURFACTANT - 50 - 99

13. The pharmaceutical composition according to paragraphs.6 and 7, suitable for oral administration, characterized in that the surfactant contains, or polyvinylpyrrolidone, or twin, or carboximetilzellulozu, or dextrin, or dimethylsulfoxide, or a mixture of polyvinylpyrrolidone and DMSO in a ratio of 1 : 0.1 to 10, and optionally sugar, for example lactose, or organic acid, for example from a number of amber, aminouksusnoy, lemon, in the following ratio, wt.%:

The halide - 1.0 to the project in the form of a tincture for external use, characterized in that it contains as a surfactant dimethyl sulfoxide (DMSO) and optionally the solvent is ethanol and water in the following ratio, wt.%:

The halide - 1,0 - 5,0

DMSO - 0,5 - 3,0

Ethanol - 50 - 40

Water - the Rest

15. The pharmaceutical composition according to p. 6 for use in tincture form for topical use, characterized in that it additionally contains a solvent of ethanol and water in the following ratio, wt.%:

The halide - 1,0 - 5,0

Ethanol - 50,0 - 70,0

Water - The Rest

 

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< / BR>
in which: R1is hydrogen, CI/C1-C4/ alkylamino,

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B is hydrogen, COR4or SO2R5with the proviso that when B is COR4or SO2R5, R1is other than hydrogen or a cation, and R9different from hydrogen;

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X, Y and Z each independently is CR6, CR7R8, N or NR9with the proviso that at least one of X, Y and Z must be N or NR9;

configuration is either a simple bond or double bond with the proviso that when any of X, Y or Z is CR7R8or NR9then === configuration, attached to it, is a simple connection, with one proviso that at least one of the === configuration represents a simple bond;

R6, R7and R8are independently hydrogen, halogen, C1-C4alkoxy or C1-C4the alkyl may be substituted one is;

R9is hydrogen or C1-C4the alkyl possibly substituted by hydroxy or one to three halogen, C1-C4alkoxy groups, or C1-C4alkylthio groups;

Q is hydrogen, halogen, C1-C4alkoxy or C1-C4the alkyl, possibly substituted by one to three of the following substituents: halogen, C1-C4alkoxy, C1-C4alkylthio or C2-C4alkenyl;

their optical isomers, when R2and R3not the same or when R7and R8unequal;

their tautomers and geometric isomers, and their attached salts of acids, except when R1is salabrasion cation

The invention relates to chemical-pharmaceutical industry, namely to new biologically active substances on the basis of which can be created drugs with hypotensive and analepticheskih activity

The invention relates to a method for producing L-isomers derived propargylamine General formula I

< / BR>
where Y is hydrogen or fluorine atom, by decomposition of a D-tartrate-L-isomer amine of General formula II

< / BR>
where Y is specified above, and interaction obtained L-isomer amine of General formula II in the presence of a base, with a halide of General formula Vwhere X is halogen, followed by the interaction of the thus obtained L-isomer of General formula III

< / BR>
with hydrogen chloride in an organic solvent
The invention relates to methods of producing Quaternary ammonium compounds

The invention relates to means for biochemical protection of cellulose-containing materials from blue stain fungi and mildew and can be used in timber and woodworking industry
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