RU2193883C1 - Medicinal preparation and method of its preparing - Google Patents

Abstract

FIELD: medicine, pharmacy, pharmaceutical technology. SUBSTANCE: invention relates to medicinal preparation comprising chlorocresoxyacetic acid sodium salt and eliciting immunomodulating, anti-inflammatory and antitumor properties. Method of medicinal preparation preparing involves bubbling cresoxyacetic acid with chlorine and the following contact with sodium hydrocarbonate aqueous solution. Distilled water heated to temperature 80-100 C is added to chlorocres-oxyacetic acid prepared by bubbling and kept at this temperature up to dark precipitate preparing and after decantation precipitate is mixed with sodium hydrocarbonate aqueous solution. Prepared composite is cooled to temperature 4-10 C obtaining the end product as precipitated white or slightly yellowish crystalline powder. Heated distilled water is added in the ratio, wt.%: chlorocresoxyacetic acid, 0.002-0.21; water, the balance. EFFECT: improved method of preparing. 3 cl, 5 ex

Description

 The present invention relates to medicine, namely to drugs that affect the immune system, and to the production of such drugs.

 Known drug "Sodium nucleonate" - a sodium salt of nucleic acid, which is an immunological drug, which is white or slightly yellowish, readily soluble in water with the formation of opalescent solutions, with the ability to stimulate the migration and cooperation of T and B lymphocytes, increase phagocytic activity macrophages and activity of factors of non-specific resistance (see, for example, M. D. Mashkovsky "Medicines". M., Medicine, 1985, v. 2, p. 172).

 This drug has a wide spectrum of biological activity, however, the injection of this drug causes pain, which leads to the need for simultaneous administration of painkillers to patients.

 The closest prototype analogue is Leucomax, produced in the form of a sterile lyophilized water-soluble powder, which has a pronounced effect on blood formation and functional activity of leukocytes, stimulating the growth of granulocytes, monocytes and T-lymphocytes, without affecting the growth of B- lymphocytes (see, for example, the reference book "Medicinal products of foreign firms in Russia", M., Astrafarmservis, 1993, p. 351).

 This drug is used in the treatment of leukopenia with bone marrow failure, to restore myeloid hemopoiesis during infections due to neutropenia, as well as to accelerate hematopoiesis after chemotherapy, in AIDS, but its use causes an increase in temperature and allergic reactions.

 The sodium salt of chlorocresoxyacetic acid is known, which is part of the adduct of crystalline hydrates of sodium salts of chlorocresoxyacetic acid, cresoxyacetic acid and sodium bicarbonate, which has biostimulating properties, but due to its toxicity is limited in use (see, for example, USSR copyright certificate 6140875 with priority 30 to priority No. 30 from G., IPC: A 01 N 9/24, bull. 25 dated 05/05/78). In this case, information on the use of the sodium salt of chlorocresoxyacetic acid outside the above adduct was not found in the relevant sources of information.

 A known method for producing a medicinal product is 2-amino-1,2,3,4-tetrahydrophthalazine-1,4-dione sodium dihydrate salt, which comprises obtaining a starting product, for example 3-aminophthalhydrazide, which is subjected to a molecular rearrangement reaction followed by exposure to sodium hydroxide and the selection of the target product (see, for example, patent of the Russian Federation 2138264 with priority from 05/06/99, IPC: A 61 K 31/50, bull. 27 from 09/27/99).

 This method allows to increase the yield of the target product, however, its use is limited by the possibility of obtaining only the specified drug.

 The closest analogue to the prototype is a method for producing the adduct of crystalline hydrates of sodium salts of chlorocresoxyacetic, cresoxyacetic acids and sodium bicarbonate (see, for example, USSR Authors Certificate 614087 with priority dated 12.30.75, IPC: A 01 N 9/24, bull. 25 dated 05.07.78 g), including the passage (sparging) of a mixture of chlorosilane acetic acid and glacial acetic acid (70-80)% of the total chlorination required for complete chlorination and treatment of the resulting mixture with an aqueous solution of sodium bicarbonate taken in molar excess of the mixture following by removing unbound water.

 The known method does not provide the possibility of obtaining the sodium salt of chlorocresoxyacetic acid without mixture with other components of the above adduct.

 The essence of the invention consists in the use of the sodium salt of chlorocresoxyacetic acid as a drug having immunomodulatory, anti-inflammatory and antitumor properties.

The essence of the invention lies in the fact that in the method for producing a medicinal product - sodium salt of chlorocresoxyacetic acid, including bubbling cresoxyacetic acid with chlorine, followed by exposure to an aqueous solution of sodium bicarbonate, distilled water heated to a temperature of (80-100) ^o C is added after sparging with chlorocresoxyacetic acid and, while stirring, kept at this temperature until a dark precipitate is obtained, which after decantation is mixed with an aqueous solution of sodium bicarbonate, and Acquiring the composition is cooled to a temperature of (4-10) ^o C to give the desired product as a precipitated then precipitate as a white or slightly yellowish crystalline powder.

 In this case, the heated distilled water is added in the ratio, wt.%: Chlorocresoxyacetic acid - (0.002-0.2); water is the rest.

 Studies have shown that the drug - the sodium salt of chlorocresoxyacetic acid has anabolic activity, stimulates cellular and humoral defense factors of the body, and has anti-inflammatory and antitumor effects.

 This is confirmed by instrumental laboratory examinations of patients by conducting a blood test to check the immunological parameters of their (patients) leukocyte and lymphocytic systems.

 This drug can be taken orally in the form of a powder or tablets during or after a meal, and its use in a wide dosage range (from 20 mg to 2 g) does not cause allergic reactions or other side effects, and its effectiveness (in the treatment of relevant diseases) higher than, for example, the drug selected as a prototype.

 The drug is prepared as follows.

Initially when reacting molten (100-120) ^o C cresol mixture (C ₇ H ₈ O) and glacial acetic acid (C ₂ H ₄ O ₃₎ is prepared krezoksiuksusnuyu acid (C ₉ H ₁₀ O _3), from which, after sparging over a period of 30 to 50 minutes, with chlorine gas (Cl ₂ ) and cooling of the reaction mixture, chlorocresoxy acetic acid (Cl ₉ H ₉ O ₃ ) is obtained in the form of a crystalline powder, which is washed off from acetic acid and dried. This powder is poured with boiling distilled water and kept until a dark precipitate appears, but no more (20-40) min, at a temperature of (80-100) ^o C, and then decantation is carried out, followed by treatment of this precipitate with a solution of sodium bicarbonate (NaHCO ₃ ) in water, obtaining the desired product as the corresponding precipitate, the chlorocresoxyacetic acid sodium salt (ClC ₉ H ₈ O ₃ Na) in the form of a white or slightly yellowish powder, which is washed with distilled water, then dried in an oven and Packed.

 It should be noted that distilled water heated to a boil is added taking into account the ratio, wt.%: Powder - (0.002-0.2); water is the rest.

For a chemically pure powder of sodium salt of chlorocresoxyacetic acid - found,%: C 48.54; H 3.59; Cl 15.95; Na 10.34. C ₉ H ₈ O ₃ Cl Na. Calculated,%: C 48.34; H 3.50; Cl 15.85; Na 10.64.

 The chemical individuality of the chlorocresoxyacetic acid sodium salt was proved by thin layer chromatography on Culefol UV-254 plates by the presence of one spot on the chromatogram in the butanol: ethanol system: 25% aqueous ammonia solution at a ratio of 1: 1: 1 Rf = 0.60.

 The chromatograms were developed by calcining these plates over a gas burner, as well as over iodine vapors.

 The possibility of using the proposed drug is confirmed by examples.

 Example 1

 Patient A., 35 years old.

 Diagnosis: Hodgkin's disease. Conducted several chemotherapy courses. The condition is serious.

 When handling: in the neck area on the left, a dense formation of 10x12 cm, painfully fused with adjacent tissues. On the roentgenogram in the mediastinum, the tumor formation is 5x5 cm. Paroxysmal cough and suffocation.

 Blood test: white blood cells up to 30 thousand, red blood cells - 2.5 million, platelets - 19 thousand units.

 The drug was treated with sodium chloride of chlorocresoxyacetic acid: 300 mg 2 times a day with meals for a month.

 A sharp improvement was noted after the first 10 days of taking the drug. The attacks of suffocation ceased.

 After the course of treatment: the tumor on the neck almost disappeared (this area is painless on palpation), the tumor is also not detected on the roentgenogram. Blood test: white blood cells - 5.5 thousand, red blood cells - 6.5 million, platelets 350 thousand units.

 Example 2

 Patient V., 52 years old.

 Diagnosis: carcinoma (3-4) degree of lung with metastases in the liver and brain.

 When handling a state of extreme severity.

 The treatment with a drug - sodium salt of chlorocresoxyacetic acid was carried out for 2 months.

 The first 7 days, 450 mg 3 times a day with meals, then for 3 weeks, 300 mg 3 times a day, then for a month 200 mg 2 times after meals.

 On the fifth day after the start of treatment, an improvement in the general condition was noted, the use of painkillers was canceled.

 In the course of further treatment, positive dynamics were observed. After 2 months, the patient's condition returned to normal, with an ultrasound, the primary tumor and metastases were not determined.

 Example 3

 Patient T., 28 years old.

 Diagnosis: AIDS with damage to the skin of the lower body and legs. Profuse diarrhea.

 The patient preceding treatment was treated with injections of a complex of drugs: leukomax and zidovudine.

 The drug was treated with sodium chloride of chlorcresoxyacetic acid, 500 mg 3 times a day, an additional injection of the drug Tamerit 1 time per day in a single dose of 250 mg. On the 5th day, the symptoms of diarrhea disappeared, on the 7th day the injections of Tamerite were canceled, the drug was 300 mg of chlorocresoxyacetic acid sodium 2 times a day. By the end of the 3rd week after the start of treatment, the manifestations of the disease of the skin were eliminated, the patient began to walk. Blood counts returned to normal at the 3rd week of treatment; the presence of the virus on test systems is not determined.

 Example 4

 Patient S., 49 years old.

 Diagnosis: viral infection, astheno-vegetative syndrome, prolonged diarrhea.

 Sick for 3 months, extreme degree of exhaustion, previous treatment with known agents did not give effect.

 The drug was treated with sodium salt of chlorocresoxyacetic acid 250 mg2 times a day for 10 days.

 According to the patient’s examination: two weeks after the start of treatment with this drug, the symptoms of diarrhea are relieved, the condition is normal.

 Example 5

 Patient K., 60 years old.

 Diagnosis: neutropenic fever due to cytostatic chemotherapy for chronic leukemia.

 The drug was treated with sodium salt of chlorocresoxyacetic acid 150 mg2 times a day with meals during the first 2 weeks of treatment, and then for another 2 weeks at 100 mg2 times a day.

 After a month of treatment, the patient's condition returned to normal, according to the results of blood tests, the number of neutrophils (in%): stab - 6.0 (at admission - 5.3), segmented - 79.0 (at admission - 47.6).

 With the continuation of chemotherapy, the patient is recommended during treatment prophylactic administration of the indicated drug at (50-100) mg (1-2) times a day.

Claims (3)

 1. A drug having immunomodulatory, anti-inflammatory and antitumor properties, characterized in that it contains the sodium salt of chlorocresoxy acetic acid. 2. A method of obtaining a medicinal product of the sodium salt of chlorocresoxy acetic acid, comprising bubbling cresoxy acetic acid with chlorine, followed by exposure to an aqueous solution of sodium bicarbonate, characterized in that distilled water heated to a temperature of (80-100) ^o C is added to the resulting sparging of chlorocresoxy acetic acid and stirring , maintained at this temperature until a dark precipitate is obtained, which after decantation is mixed with an aqueous solution of sodium bicarbonate, and the resulting composition is about lazhdayut to a temperature (4-10) ^o C to give the desired product as a precipitated then precipitate as a white or slightly yellowish crystalline powder.  3. The method according to p. 2, characterized in that the heated distilled water is added in the ratio, wt. %: chlorocresoxyacetic acid 0.002-0.2, water - the rest.