RU2261243C1 - Zinc and aliphatic halogen-carboxylic acid salts for treatment of skin neoplasm and visible mucosa tissues - Google Patents

Abstract

FIELD: organic chemistry, medicine, dermatology.

SUBSTANCE: invention relates to zinc and aliphatic halogen-carboxylic acid salts that can be used in treatment of benign neoplasms of skin and visible mucosa tissues. Invention proposes the following formula of zinc and aliphatic halogen-carboxylic acid salts: (1):

wherein R means -CHal₃, -CHHal₂, -CH₂Hal and (2):

wherein R' means Alk, hydrogen atom (H); R'' means Hal; R' means Alk; R'' means H, Alk wherein in these formulae halogen atom can be represented by fluorine atom (F), chlorine atom (Cl), bromine atom (Br) or iodine atom (J). Invention provides the development of original preparation used in treatment of benign neoplasms of skin and visible mucosa tissues with low toxicity, rapid effect, expressed therapeutic effect and eliciting good tolerance, absence of complications in treatment, healing without formation of scar tissue. The development of the preparation provides expanding assortment of agents used in treatment of such diseases.

EFFECT: enhanced and valuable properties of agents.

13 ex

Description

The invention relates to medicine, in particular to dermatology, in particular to new salts of zinc and aliphatic halocarboxylic acids, which can be used to treat benign skin lesions and visible mucous membranes.

A compound of selenium with haloacetic acid or its anhydride is known (EP 1293498, 08/30/2001). The compound is intended for the treatment of benign skin neoplasms of various nature, including mucous membranes.

Also known is the use for the treatment of popillomatosis of the mucous membranes of the upper respiratory tract of a prospidin ointment, which has low toxicity (″ Prospiridin antitumor agent ″ VNIIKHFI, issue 3, M., 1973, p.115-138). The percentage of treatment effectiveness in this case is 70-75%. Prospidine is most effective in the treatment of precancerous diseases.

Given the pronounced deep tissue damage, prospidine is inappropriate to use for the treatment of benign lesions of the skin and mucous membranes.

The closest technical solution to the claimed effect and achieved effect is a preparation for local treatment of superficial lesions of the skin and mucous membrane based on the reaction between a solution of 1-5.5 M nitric acid with 45-170 mmoles of primary C ₁ -C ₅ alkanol per 1 l of nitric acid (RU 2118160, 06.23.1993). The drug, in particular, is indicated for topical treatment of superficial benign changes in the skin, such as Verrucae (e.g. Verrucae vutgares and Verrucae plantares), seborrheic and actinic keratoses and Condylomata, as well as superficial benign changes in the mucous membrane, such as benign lesions in the neck, such as erosion, Ovula nabothi polyps in the cervical canal, Condylomata.

However, with the use of the drug, recurrence is 30-40%, incomplete healing is 45%. The drug poses a certain danger to personnel and requires work with safety precautions.

The aim of the invention is the creation of an original low-toxic stable highly effective drug for the treatment of benign neoplasms of the skin and visible mucous membranes, which has good tolerance, the absence of complications during treatment, healing without scarring.

The chemical formula of zinc salts and halocarboxylic acids of an aliphatic series, having the form

where in the formulas the halogen atom may be Fluorine (F), Chlorine (Cl), Bromine (Br) or Iodine (J).

The starting materials may be various chemical products containing zinc and solutions of aliphatic halocarboxylic acids.

The final product is a solution of zinc salt and halocarboxylic acids. It is brown in color, with a pH of 2.2-3.0, and an LD50 of about 1100 mg / kg. The drug is practically non-toxic, does not penetrate the body, does not have systemic, teratogenic, embryotoxic and carcinogenic properties. The drug selectively dehydrates the tissue, has an intravital fixing effect on the tissue. After removal of the pathological tissue, healing and regeneration are completed in two weeks without significant side effects.

The concentration of zinc in the product depends on the type of starting chemical ingredients and may be between 2.5-25%. Chemically, the product is unchanged for many years when stored at room temperature in a closed dark glass vessel.

The claimed substance can be used only for local use. As a medicine, it can be in the form of a solution in a concentration of 5 to 45%. The recommended dose for one lesion is from 0.1 to 2.0 cm ² in liquid form - from 0.03 to 0.2 ml. For multiple lesions, the dose may be from 0.2 to 2.00 ml.

The achieved technical result consists in the creation of an original drug for the treatment of benign neoplasms of the skin and visible mucous membranes, low-toxic, fast-acting with a pronounced therapeutic effect, with good tolerance, the absence of complications in treatment, healing without the formation of scar tissue. The creation of the drug allows you to expand the range of products for the treatment of such diseases.

The drug is easy to use, safe for patients and medical staff, and also does not require special restrictions on the behavior regimen.

From the patent and scientific and technical information, the chemical formula of zinc salts and aliphatic halocarboxylic acids is not known, which could be used for topical treatment of benign skin tumors and visible mucous membranes.

The synthesis of the claimed substance is based on the use of affordable and inexpensive raw materials and is simple.

The claimed substance is obtained by the reaction of an oxide, or hydroxide, or zinc carbonate with halocarboxylic acids in an aqueous medium and stabilization of the resulting solutions by adding 0.72-1.36% salts of succinic or citric acids.

The structure of the new substance is confirmed by elemental analysis.

Example 1. Di- (bromoacetate) zinc.

To a suspension of 2.44 g (0.03 mol) of zinc oxide in 30 ml of distilled water, 8.34 g (0.06 mol) of bromoacetic acid is added in one portion. The reaction mixture is stirred until the precipitate is almost completely dissolved (about 15 min) at room temperature, a slight mixture is filtered through a paper filter on a Buchner funnel. 32 ml of a 23.8% solution of bromoacetic acid and zinc salt are obtained. After lyophilization of an aliquot of the solution, a dry salt was obtained and its elemental composition was determined. C ₄ H ₄ Br ₂ O ₄ Zn. To stabilize the solution, succinic acid was added to it in an amount of 0.3 g. Calculated,%: C 14.06; H 1.17; Br 46.87; Zn 19.16. Found,%: C 13.95; H 1.12; Br 46.55; Zn 19.24.

Example 2. Di- (trichloroacetate) zinc.

Obtained in example 1 from 2.44 g (0.03 mol) of zinc oxide, 9.81 g (0.06 mol) of trichloroacetic acid and 20 ml of distilled water. The concentration of salt obtained is 36.3%. C ₄ Cl ₆ O ₄ Zn. To stabilize, 0.3 g of citric acid was added to the solution.

Calculated,%: C 12.30; Cl 54.56; Zn 16.75.

Found,%: C 12.39; Cl 54.47; Zn 16.62.

Example 3. Di- (chloroacetate) zinc.

To a suspension of zinc hydroxide obtained from 4.1 g (0.03 mol) of zinc chloride and 2.4 g (0.06 mol) of sodium hydroxide, add a solution of 5.67 g (0.06 mol) of chloroacetic acid in 25 ml distilled water. It is stirred at room temperature until the precipitate is almost completely dissolved, filtered through a paper filter on a Buchner funnel and a 22.5% solution of chloroacetic acid and zinc salt is obtained. After lyophilization of an aliquot, a dry salt was obtained and its elemental composition was determined. C ₄ H ₄ Cl ₂ O ₄ Zn. The solution is stabilized by the addition of 0.3 g of succinic acid.

Calculated,%: C 19.02; H 1.59; Cl 28.13; Zn 25.91.

Found,%: C 19.89; H 1.63; Cl 28.01; Zn 26.03.

Example 4. Di- (2-chloropropionate) zinc.

Obtained according to example 3 of 4.1 g (0.03 mol) of zinc chloride, 2.4 g (0.06 mol) of sodium hydroxide, followed by treatment of zinc hydroxide with a solution of 6.5 (0.06 mol) of 2-chloropropionic acid in 20 ml of distilled water. The concentration of salt obtained is 28.5%. C ₆ H ₈ Cl ₂ O ₄ Zn. The solution is stabilized by the addition of 0.3 g of citric acid.

Calculated,%: C 25.68; H 2.85; Cl 25.32; Zn 23.32.

Found,%: C 25.75; H 2.71; Cl 25.42; Zn 23.27.

Example 5. Di- (2-methyl-3-bromopropionate) zinc.

Obtained in example 1 from 2.44 g (0.03 mol) of zinc oxide, 10 g (0.06 mol) of 2-methyl-3-bromopropionic acid and 25 ml of distilled water. The concentration of salt obtained is 30.3%. C ₈ H ₁₂ Br ₂ O ₄ Zn. The solution is stabilized with 0.3 g of succinic acid.

Calculated,%: C 24.16; H 3.02; Br 40.26; Zn 16.46.

Found,%: C 24.03; H 3.15; Br 40.37; Zn 16.38.

Example 6. Di- (3-bromopropionate) zinc.

To a suspension of 3.76 g (0.03 mol) of zinc carbonate in 30 ml of distilled water, 9.18 g (0.06 mol) of 3-bromopropionic acid are added in one portion with stirring. The reaction mixture is stirred until the carbon dioxide evolution is completely stopped, the turbidity is filtered through a paper filter on a Buchner funnel. A 25.9% solution of the salt of 3-bromopropionic acid and zinc is obtained. After lyophilization of an aliquot of the solution, a dry salt was obtained and its elemental composition was studied. C ₆ H ₈ Br ₂ O ₄ Zn. The solution is stabilized with 0.3 g of citric acid.

Calculated,%: C 19.49; H, 2.17; Br 43.31; Zn 17.71.

Found,%: C 19.58; H 2.29; Br 43.22; Zn 17.62.

Example 7. Di- (2,3-dibromopropionate) zinc.

Obtained in example 6 from 3.76 g (0.03 mol) of zinc carbonate, 13.92 g (0.06 mol) of 2,3-dibromopropionic acid and 25 ml of distilled water. The concentration of salt obtained is 36.9%. C ₆ H ₆ Br ₄ Zn. The solution is stabilized with 0.3 g of succinic acid.

Calculated,%: C 13.65; H 1.14; Br 60.68; Zn 12.40.

Found,%: C 13.53; H 1.19; Br 60.54; Zn 12.51.

Example 8. Di - (...- iodoacetate) zinc.

Obtained in example 1 from 2.44 g (0.03 mol) of zinc oxide, 12 g (0.06 mol) of ... -iodoacetic acid and 30 ml of distilled water. The concentration of salt obtained is 30.1%. C ₄ H ₄ J ₂ O ₄ Zn. The solution is stabilized with 0.3 g of citric acid.

Calculated,%: C 11.02; H 0.92; J 58.34; Zn 15.02.

Found,%: C 10.91; H 1.01; J 58.01; Zn 15.14.

Example 9. Di- (trifluoroacetate) zinc.

Obtained in example 1 from 2.44 g (0.03 mol), 6.84 g (0.06 mol) of trifluoroacetic acid and 15 ml of distilled water. The concentration of salt obtained is 33.8%. C ₄ F ₆ O ₄ Zn ...

Calculated,%: C 16.47; F 39.12; Zn 22.44.

Found,%: C 16.56; F 39.24; Zn 22.32.

Example 10. Di- (fluoroacetate) zinc.

Obtained in example 6 from 3.76 (0.03 mol) of zinc carbonate, 4.68 g (0.06 mol) of fluoroacetic acid and 15 ml of distilled water. The concentration of salt obtained is 27.3%. C ₄ H ₄ F ₂ O ₄ Zn ...

Calculated,%: C 21.88; H 1.82; F 17.32; Zn 29.81.

Found,%: C 21.82; H 1.73; F 17.44; Zn 29.69.

Example 11. Di- (dichloroacetate) zinc.

Obtained in example 1 from 2.44 g (0.03 mol) of zinc oxide, 7.74 g (0.06 mol) of dichloroacetic acid and 20 ml of distilled water. The concentration of salt obtained is 30.2%. C ₄ H ₂ Cl ₄ O ₄ Zn.

Calculated,%: C 14.94; H 0.62; Cl 44.18; Zn 20.35.

Found,%: C 14.83; H 0.57; Cl 44.27; Zn 20.00.

Example 12. Treatment of 11 patients with a diagnosis of cervical ectopia (pseudo-erosion), in which recurrent pseudo-erosion was observed (age from 26 to 32 years). For the treatment of ectopias, a 30% solution of the zinc salt of halocarboxylic acid was used. Depending on the volume of the pathological focus, the number of applications of the drug was different. With ectopia not exceeding a diameter of 0.5-0.8 mm, the treatment was carried out 1 time for 2 days. For large lesions, the application was used 1 time by double application, then daily or every other day, for a total of 3-4 applications. The drug was applied using cotton swabs as an application to the affected area. The immediate effect was manifested in the appearance of a whitish-yellow color of the tissue with a clear, white color ischemic ridge around the affected area, the tissue became gray-white in 2-3 days, from 3 days there was a decrease in the size of the scab and its rejection. At the site of rejection, the cervical mucosa acquired a reddish tint. The duration of epithelization was from 10 to 14 days, during which regeneration of the cervical mucosa by young epithelium occurred. With extensive lesions of the cervix, requiring deep tissue destruction, the duration of epithelization increased to 3-5 weeks. As side effects, a slight burning sensation was noted at the time of treatment.

On the control examination 3-4 days after the last treatment, in almost all cases, scab rejection and the presence of a reddish-purple color of the cervical mucosa were noted.

At the control examination after 2 weeks, the cervical mucosa acquired a pink-red tint, i.e. approached the normal color of the cervical mucosa. Colposcopic examination showed the appearance of metaplastic (young) epithelium over the entire surface, i.e. epithelialization process. Cytological examination revealed stratified squamous epithelium.

The terms of observation of patients with ectopia ranged from 12 days to 2 months. During this observation period, only one (9.1%) patient in the presence of a previously extensive erosive surface on the cervix and probably due to the depth of the lesion did not show complete epithelialization of the mucosa.

Thus, the effectiveness of using a solution of the zinc salt of halocarboxylic acid allows in 90% of cases to achieve a positive result in the treatment of ectopia (background diseases) of the cervix.

Example 13. Treatment of 7 patients with a diagnosis of genital warts of papillovirus infection (papilloma) (age from 20 to 68 years). For the treatment of patients with papillomas, a 30% solution of the zinc salt of halocarboxylic acid was used, 3-4 applications were performed daily, with large papillomas up to 6. Directly during the treatment, a decrease in the volume of formation of “shrinkage” was observed, i.e. dehydration, mummification with the formation of a whitish-yellow coating. Before each subsequent treatment, dead tissue was removed. After gradual rejection, dark cyanotic-brown spots remained on the skin for 7-14 days.

Cytological examination at the end of treatment revealed the presence of squamous epithelium without signs of pathology.

Of the 7 patients with papillomas, after 2 months, a relapse of the disease was observed in 1 patient, who initially had a papilloma in diameter of at least 4 cm.

Thus, the primary effect in the treatment of papillomas is 100%.

As follows from the examples, the use of the drug of zinc salt and halocarboxylic acids shows its high effectiveness in the treatment of ectopia of the cervix and papillomatous skin lesions of the genitals.

The advantages of the drug include its good tolerance, the absence of complications, healing without the formation of cicatricial changes, ease of implementation, safety for patients and medical staff, as well as the absence of special restrictions on the behavior regimen.

Thus, the claimed chemical substance - zinc salts and aliphatic halocarboxylic acids - can be effectively used as a drug for the treatment of benign neoplasms of the skin and visible mucous membranes.

Claims (1)

Aliphatic zinc salts and halocarboxylic acids

where in the formulas the halogen atom may be fluorine (F), chlorine (Cl), bromine (Br), or iodine (J).