WO2005102320A1 - Medicinal agent for treating viral infections - Google Patents

Medicinal agent for treating viral infections Download PDF

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Publication number
WO2005102320A1
WO2005102320A1 PCT/RU2005/000205 RU2005000205W WO2005102320A1 WO 2005102320 A1 WO2005102320 A1 WO 2005102320A1 RU 2005000205 W RU2005000205 W RU 2005000205W WO 2005102320 A1 WO2005102320 A1 WO 2005102320A1
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WIPO (PCT)
Prior art keywords
methyl
dimethylaminomethyl
oxi
carboxy
treatment
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PCT/RU2005/000205
Other languages
French (fr)
Russian (ru)
Inventor
Robert Georgievich Glushkov
Vladimir Alekseevich Maksimov
Vitaly Afanasievich Martyanov
Ravil Avgatovich Hamitov
Alexandr Mihailovich Shuster
Original Assignee
Zakrytoe Aktsionernoe Obschestvo 'masterklon'
Zakrytoe Aktsionernoe Obschestvo 'masterlek'
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Priority claimed from RU2004111871/15A external-priority patent/RU2256451C1/en
Priority claimed from RU2004111872/15A external-priority patent/RU2255086C1/en
Priority claimed from RU2004115096/15A external-priority patent/RU2266742C1/en
Application filed by Zakrytoe Aktsionernoe Obschestvo 'masterklon', Zakrytoe Aktsionernoe Obschestvo 'masterlek' filed Critical Zakrytoe Aktsionernoe Obschestvo 'masterklon'
Publication of WO2005102320A1 publication Critical patent/WO2005102320A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the invention is related to the field of medicine, and specifically for the search and 5 development of new medicinal products for the treatment of viral infections.
  • Famous large quantities of manufactured products Cyclic, Gamicilli and Ganciclovi are used in the treatment of herpes.
  • Interpreters have found their use in the treatment of herbal diseases.
  • Demantadine and Demantadine are used for the treatment and treatment of the disease, but they are ineffective for the treatment of the already developed disease.
  • Beta SSH ⁇ ⁇ me already ⁇ e ⁇ echislenny ⁇ le ⁇ a ⁇ s ⁇ venny ⁇ s ⁇ eds ⁇ v is ⁇ lzuyu ⁇ sya 2 ⁇ e ⁇ a ⁇ a ⁇ a that are ingibi ⁇ ami vi ⁇ usn ⁇ y ney ⁇ aminidazy - Zanamivi ⁇ and ⁇ sel ⁇ amivi ⁇ , ⁇ ye e ⁇ e ⁇ ivny ⁇ i g ⁇ i ⁇ e ⁇ and beta, ⁇ ichem ⁇ e ⁇ vy - ⁇ l ⁇ for treatment and v ⁇ y - ⁇ a ⁇ for treatment,
  • Invasive infection is an acute viral disease, a clinical disorder that is mildly affected by the inactivation and infection of the body, which prevents the patient from suffering
  • pathogens such as pathogens that contribute to the development of pneumonia, in particular due to the onset of pneumonia.
  • pathogens such as pathogens that contribute to the development of pneumonia, in particular due to the onset of pneumonia.
  • the large number of variants of the virus makes it meaningless to prepare a vaccine for the treatment of diseases. There is no specific treatment available. If the disease is severe, you must use it. 2 human immunoglobulin from a series of adult donors. In case of complications, treatment with the appropriate antibiotics is carried out.
  • Typical pneumonia is a distressing disease recently diagnosed in Asia, Northern Germany, and Europe. The disease is caused by 5 viruses and is characterized by rapid development and high lethality. The first cases were recorded in 2003.
  • Virus infection is the main reason for the development of severe dehydration in the early childhood. After illnesses, an irreversible infection occurs in the second place after AI. Up to 40-60%> cases of diarrhea, requiring socialization and the implementation of unsafe 3 measures. With this, there is a significant number of severe illnesses with lethal outcome, such as in children, and in adults. In Russia, about 1 million large easy-to-use infections and more than a half of it are inactive, and there is no inertia, which is not consumed. This treatment for chronic infection remains an unresolved problem.
  • the injection of injectable drugs has become quite possible, since for the first time, 1-methyl-2-phenylmethyl-3-acid, 4-dimethyl, was obtained. Because the product is 1-methyl-2-phenyl-methyl-3-carboxy-4-dimethylaminomethyl-5-oxy-6-bomide, it is free of charge - it is free of charge - it is free of charge South water. The difference in the indicated salt is that 1-methyl-2-phenyl-thiomethyl-3-carboxy-4-dimethylaminomethyl-5-oxi-6-bromide was not used.
  • the second component of the present invention is new compounds - derivative 1-methyl-2-phenylmethyl-3-acid and 4-dimethyl-acid-free
  • salt selected from the group: hydrate, sulphate, bisulphate, disinfectant, hydrate, mesylate, disulphate, weakness, hepatitis, hematoma, hematoma, hematoma, hematoma, hepatoma, hepatoma, hepatoma, hepatoma, hepatoma, hepatoma, hepatoma, hepatoma, hepatoma, hepatoma, hepatoma, hepatoma, hepatoma, hepatoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hepatoma, and hematoma.
  • the most preferred salt is 1-methyl-2-phenyl-methyl-3-carbethoxy-4-dimethylaminomethyl-5-oxi-6-bromide mesylate:
  • ⁇ aib ⁇ lee ⁇ ed ⁇ ch ⁇ i ⁇ eln ⁇ is ⁇ lz ⁇ va ⁇ following ⁇ izv ⁇ dnye me ⁇ il-1-2- ⁇ enil ⁇ i ⁇ me ⁇ il-3- ⁇ a ⁇ be ⁇ si-4-dime ⁇ ilamin ⁇ me ⁇ il-5- ⁇ si-6-b ⁇ mind ⁇ la: mezila ⁇ , bezila ⁇ , ⁇ zila ⁇ , sul ⁇ a ⁇ , and bisul ⁇ a ⁇ ⁇ a ⁇ zhe gid ⁇ a ⁇ y and s ⁇ lva ⁇ y u ⁇ azanny ⁇ s ⁇ ley.
  • Another aspect of the present invention is a pharmaceutical preparation for the treatment of viral infections.
  • the pharmaceutical com- pensation can be performed in the form of a solid medicinal form, predominantly in the form of a medicine or capsule, and also in the form of a soft medicine ⁇ ayu ⁇ e ⁇ a ⁇ matsev ⁇ iches ⁇ aya ⁇ m ⁇ zitsiya m ⁇ zhe ⁇ by ⁇ vy ⁇ lnena as ⁇ as ⁇ v ⁇ a for ine ⁇ tsy, ⁇ s ⁇ l ⁇ u ⁇ yad n ⁇ vy ⁇ ⁇ edl ⁇ zhenny ⁇ s ⁇ ley me ⁇ il-1-2- ⁇ enil ⁇ i ⁇ me ⁇ il-3- ⁇ a ⁇ b ⁇ si-4-dime ⁇ ilamin ⁇ me ⁇ il-5- ⁇ si-6-b ⁇ mind ⁇ la ⁇ bladayu ⁇ d ⁇ s ⁇ a ⁇ chn ⁇ y ⁇ as ⁇ v ⁇ im ⁇ s ⁇ yu in v ⁇ de.
  • the product may also include hydrated or salted salt.
  • the host (s) should be acceptable to the extent that they are compatible with
  • the products may optionally contain fillers, binders and t. ⁇ . ⁇ a ⁇ zhe ⁇ e ⁇ a ⁇ a ⁇ y m ⁇ gu ⁇ s ⁇ de ⁇ zha ⁇ target d ⁇ bav ⁇ i, ⁇ a ⁇ e ⁇ ⁇ azan ⁇ in " ⁇ a ⁇ k ⁇ " ⁇ agtasei ⁇ sa ⁇ ⁇ s ⁇ e ⁇ z "(2" ⁇ e ⁇ ⁇ : ⁇ e ⁇ ai ⁇ asei ⁇ sa ⁇ ⁇ gezz; 1994.).
  • Target Supplements Includes
  • compositions may include other conventional additives, for example, flavorful, aromatic and t. ⁇ .
  • the effective dose of the active component depends on whether the compound is used (lower doses) or for the treatment of viral infection. Otherwise, an effective dose may also depend on weight, age, weight, and the presence of concomitant diseases.
  • ⁇ a ⁇ ime ⁇ for ⁇ e ⁇ a ⁇ ii ⁇ avi ⁇ usn ⁇ y in ⁇ e ⁇ tsii ⁇ ed ⁇ ch ⁇ i ⁇ eln ⁇ is ⁇ lz ⁇ va ⁇ mezila ⁇ me ⁇ il-1-2- z ⁇ ⁇ enil ⁇ i ⁇ me ⁇ il-3- ⁇ a ⁇ be ⁇ si-4-dime ⁇ ilamin ⁇ me ⁇ il-5- ⁇ si-6-b ⁇ mind ⁇ la in d ⁇ zi ⁇ v ⁇ e ⁇ 0.01 to 0.05 g d ⁇ de ⁇ ey ⁇ 2 d ⁇ 6 le ⁇ , at the rate of 0.05 to ⁇ Dg for 7 children from 6 to 12 years of age and in delivery from 0.05 to 0.2 g for children over 12 years of age and adulthood 3-4 times a day.
  • 1-methyl-2-phenyldimethyl-3-carboxy-4-dimethylaminomethyl-5-oxy-6-bromide may be used in the form of salt or salvage.
  • a particular case is the use of 1-methyl-2-phenyl-methyl-3-carboxy-4-dimethylaminomethyl-5-oxi-6-carbide hydrochloride hydrate.
  • the invention is illustrated, but is not limited to, by the following methods.
  • EXAMPLE 1 Preparation of 1-methyl-2-phenyl-methyl-3-carboxy-4-dimethylaminomethyl-5-hydroxy-6-bromoindole ( ⁇ ).
  • Example 2 Production of a 1-methyl-2-phenyl-thiomethyl-3-carboxyethoxy-4-dimethylaminomethyl-5-oxy-6-bromoindole hydrochloride ( ⁇ ). 0% solution of 0.955 g (2 mmol) of compound I in 5 ml of warm ethanol added a solution of 0.135 ml (2.0 mmol) of 85%> disinfectant mixed with 1.0 ml of ethanol and a diluted solution of 0.5 ml. The precipitated crystals are filtered and dried in a vacuum above ⁇ 2 0 5 , which results in a yield of 1.05 g (yield - 91%) of compound II, mp. 164-166 ° ⁇ (with 5 decomposition).
  • ⁇ - ⁇ -s ⁇ flower ⁇ ( ⁇ , ppm, ⁇ - ⁇ 6 ): 1.25 ( ⁇ , ⁇ , - ⁇ 2 ⁇ 3 ), 2.52 (s, 6 ⁇ , - ⁇ ( ⁇ 3 ) 2 ), 3.67 (s, ⁇ ,> ⁇ - ⁇ 3 ), 4.18 ( ⁇ ggi, 2 ⁇ , -
  • Example 5 Production of 1-methyl-2-phenyl-methyl-3-carboxy-4-dimethylaminomethyl-5-oxo-6-bromoindole bisulphide ( ⁇ ).
  • ⁇ 1-methyl-2-phenyl-methyl-3-carboxy-4-dimethylaminomethyl-5-oxo-6-bromoindole bisulphide
  • For 1.478 g (3.096 mmol) of the compound I add 3 ml of water and 3 ml of 1 ⁇ ⁇ 2 8 ⁇ , the resulting solution, dilute two of this solution, evaporate the solution, remove the solution, and 10 ⁇ 2 0 5 and is commercially available from ⁇ , ⁇ , which, after drying in a vacuum, yields 1.56 g (yield - 87.6%>) of compound V, ⁇ .pl. 144-145 ° C.
  • ⁇ - ⁇ -s ⁇ flower ⁇ ( ⁇ , ppm, ⁇ - ⁇ 6 ): 5 1.26 ( ⁇ , ⁇ , - ⁇ 2 ⁇ 3 ), 2.77 (s, 6 ⁇ , - ⁇ ( ⁇ 3 ) 2 ), 3.70 (s , ⁇ ,> ⁇ - ⁇ 3 ), 4.21 ( ⁇ occidental, 2 ⁇ , - ⁇ ( ⁇ ) - ⁇ 2 -) 5 4.74 (s, 2 ⁇ , -8- ⁇ ), 4.85 (s, 2 ⁇ , - ⁇ 2 - ⁇ ⁇ ), 7.28-7.40 (m, 5 ⁇ , - ⁇ - ⁇ 6 ⁇ 5 ), 8.02 (s, ⁇ , ⁇ -7).
  • Example 6 Preparation of 1-methyl-2-phenyl-methyl-3-carbethoxy-4-dimethylaminomethyl-5-hydroxy-6-bromoindole (VI).
  • a solution of 0.954 g (2 mmol) of compound I in 8 ml of dioxane is added to a solution of 0.225 g (2.3 mmol) of methanesulfur in 2 ml of dioxane and it is removed for a short time.
  • the precipitated crystals are filtered and dried in a vacuum, which results in a yield of 0.82 g 15 (yield - 87.3%) of compound VI, T.pl. 171-172 ° C (with decomposition).
  • ⁇ - ⁇ -s ⁇ flower ⁇ ( ⁇ , ppm, ⁇ - ⁇ 6 ): 1.25 ( ⁇ , ⁇ , - ⁇ 2 ⁇ 3 ), 2.31 (s, ⁇ , ⁇ - ⁇ ), 2.77 (s, 6 ⁇ , - ⁇ ( ⁇ 3 ) 2 ), 3.69 (s, ⁇ ,> ⁇ - ⁇ 3 ), 4.20 ( ⁇ occidental, 2 ⁇ , - ⁇ ( ⁇ ) - ⁇ 2 -), 4.74 (s, 2 ⁇ , - ⁇ - ⁇ 2 -) , 4.85 (s, 2 ⁇ , -C ⁇ 2 - ⁇ ⁇ ), 7.28-7.40 (m, 5 ⁇ , -8- ⁇ 6 ⁇ 5 ), 0 8.03 (s, W, ⁇ -7).
  • EXAMPLE 7 Preparation of a 1-methyl-2-phenyl-methyl-3-carboxyloxy-4-dimethylaminomethyl-5-oxo-6-bromide methane sulfate (VII). 0.5 g of compound VI (EXAMPLE 6) is removed from 2 ml of water, 5 crystals are dried in the air and 0.35 g of compound VII are obtained, mp: 120 ° C, -120 ° C; -120 ° C ) Found,%: C - 46.71, 46.73; ⁇ - 5.17, 5.11; ⁇ - 4.64, 4.54. C 23 ⁇ 3 ⁇ 2 0 7 8 2 .
  • Example 9 Preparation of 1-methyl-2-phenyldimethyl-3- 15 carboxy-4-dimethylaminomethyl-5-oxy-6-bromoindole (IX).
  • a solution of 0.954 g (2 mmol) of compound I in 10 ml of a solution is added to a solution of 0.585 g (3 mmol) of which a solution of 5% of solution is inhibited.
  • the precipitated sediment is filtered and dried on the air, which produces 20 1.13 g (yield 87>) of compound IX, T.pl. 144-146 ° C (with ⁇ pl.). Found,%>: C- 53.57, 53.64; ⁇ -4.99, 5.04; ⁇ - 4.25, 4.27.
  • Example 10 Production of the 1-methyl-2-phenyl-methyl-3-carboxy-4-dimethylaminomethyl-5-oxi-6-bromoindole citrate ( ⁇ ). ⁇ 0.978 g (2.05 mmol) of compound I in 14 ml of ethanol is suitable for use. It increases 0.493 g (2.35 mmol) of citric acid in 6 ml of ethanol and it is evaporated. It is discharged in a minimum volume of ethanol, planted with ethyl ether, the oil that is released is twice grown 12 with fresh products of the environment, the plant is filtered and after drying in a vacuum, 1.13 g (yield - 85%) of compound X, ⁇ .pl.
  • ⁇ - ⁇ -s ⁇ flower ⁇ ( ⁇ , 5 ppm, ⁇ - ⁇ 6 ): 1.24 ( ⁇ , ⁇ , - ⁇ 2 ⁇ 3 ), 2.48 (s, 6 ⁇ , - ⁇ ( ⁇ 3 ) 2 ), 2.53 (s , ⁇ , - ⁇ ⁇ ( ⁇ ) ⁇ ), 2.57 (s, ⁇ , - ⁇ 2 - ⁇ ( ⁇ ) ⁇ ), 2.62 (s, ⁇ , - ⁇ 2 - ⁇ ( ⁇ ) ⁇ ), 2.66 (s, ⁇ , - ⁇ 2 - ⁇ ( ⁇ ) ⁇ ), 3.67 (rier, ⁇ ,> ⁇ - ⁇ 3 ), 4.16 ( ⁇ occidental, 2 ⁇ , - ⁇ (0) - ⁇ 2 -), 4.39 (s, 2 ⁇ , - ⁇ 2 - ⁇ ⁇ ), 4.67 (s, 2 ⁇ , - ⁇ - ⁇ 2 -), 7.28-7.36 (m, 5 ⁇ , -8- ⁇ 6 ⁇ 5 ), 7.85 (s, ⁇ , ⁇ -7).
  • Example 11 Preparation of 1-methyl-2-phenyl-thiomethyl-3-carboxy-4-dimethylaminomethyl-5-hydroxy-6-bromoindole ( ⁇ ) hemimaleate.
  • a solution of 0.29 g (2.5 mmol) of maleic acid in 8 ml of a warm ethyl acetate a solution of 0.955 g (2 mmol) of a compound I is in the body is electrically inactive.
  • ⁇ - ⁇ -s ⁇ flower ⁇ ( ⁇ , ppm, ⁇ - ⁇ 6 ): 1.26 ( ⁇ , ⁇ , - ⁇ 2 ⁇ 3 ), 2.73 (s, 6 ⁇ , - ⁇ ( ⁇ 3 ) 2 ), 3.69 (s, ⁇ ,> ⁇ - ⁇ 3 ), 4.21 ( ⁇ ggling, 2 ⁇ , - ⁇ (0) - ⁇ 2 -), 4.72 (s, 2 ⁇ , -8-
  • Example 14 The effective action of the user in relation to the child's infection.
  • Table 2 The dynamics of the disappearance of clinical symptoms of an infection in children, depending on the incidence of infection.
  • Table 3 The dynamics of the disappearance of functional disorders of children and of infected children, depending on the outcome of the therapy.
  • Table 4 The dynamics of normalizing the frequency of the chair in a large group, depending on the actual therapy.
  • Table 5 The results of an expert evaluation of the clinical effectiveness of a patient in a group of patients.
  • Example 15 The beneficial effect of arabidol in relation to adenovirus infection, which is related to infection.
  • SIGNIFICANT FOX 17 In 10 out of 40 patients (25%), for example, the condition of the patient, while with the patient was positive and on the adenovirus antigen (see table 7). Moreover, in the group of patients who were ill, treated with a biddle, already on the 3rd day 4 of 6, and on the 7th day - all the patients were sanitized from the adenosis, while the treatment was carried out at the same time On the 5th day, only 1 out of 4 patients had it. Table 7 Sanitary efficacy in a large group of patients and in relation to adenovirus.
  • EXAMPLE 16 Intestinalization of the intestinal tract and treatment of an abdominal infection. Involvement affects the quantitative and qualitative composition of the intestinal microorganism through the normalization of its non-existent. The state of intestinal microbiocenosis in the dynamics of the disease in 20 patients ( ⁇ 10 patients in each group) was studied. Table 8 Indicator Dynamics 1 of the concentration of the intestinal tract in children, depending on the outcome of the therapy.
  • a clean medium was removed from the cell with a cell and was added to a test bottle of 1.0 ml of a different medium containing different varieties. 19 concentra tions of the studied facilities. After 4 hours of incubation, at a temperature of 37.0 ° ⁇ , the nutrient medium was drained and introduced into the feeds of 0.1 ml of the suspension of the VC virus, with an increase of 0.001--0.004, which is better. The contact of the virus with the cells is 5–60 minutes at 37.0 ° ⁇ .
  • infectious dose 5.0 1 ⁇ for use and for direct use.
  • Example 19 The positive effect of arabidol and mesylate in relation to vesicular vesicle, Indiana strain, on the cell culture ( ⁇ - ⁇ 6). Testing of preventive and curative activity. From the sample with 3 days old, the cells were removed from the medium and introduced into the test products of 1.0 ml of the containing medium, which contains different types of samples.
  • SIGNIFICANT FOX P ⁇ IL 26 24 suspensions of vesicular virus and after 60 minutes of incubation after removal of the susceptible suspension were added 1.0 ml of a supporting medium.
  • EXAMPLE 20 Obtaining pharmaceutical preparations for the production of tablet mass. Prepare a mixture of 10 g of compound VII; 4.5 grams of sugar; 0.25 g of methyl cellulose; 0.15 g of calcium; 0.10 g of acid stearic. Received after stirring, the mass is used for testing.
  • EXAMPLE 21 Pharmaceuticals for use in capsules.
  • a mixture consisting of 10 g of compound VIII is prepared; 2.8 grams of sugar; 6.0 g microcrystalline cellulose; 0.9 g of kollidona, 0.2 g of aerosil, 0.2 g of calcium of the stearate. Received after mixing, the mass is used for encapsulation.
  • Example 22 Preparation of pharmaceutical preparations for the preparation of a preparation for injections of 100 ml of sterile water, while stirring, add 1 g of compound IV. The resulting product is filtered. The finished product is amplified and used for internal and internal injections. 26
  • EXAMPLE 23 Obtaining pharmaceutical preparations for the implementation of the benefits.
  • Example 24 Preparation of a pharmaceutical preparation for the preparation of an ointment.
  • a mixture is used containing 2 g of compound VII and a filler consisting of 58 g of petroleum jelly and 40 g of lanolin.
  • Prepare an ointment base by mixing anhydrous lanolin with vaseline medical. The mixture is melted at a temperature of 50-55 ° C, then it is cooled to a temperature of 30-35 ° C. At this temperature, the ointment base is mixed with compound VII, placed in the homogenizer and transferred to the homogenization for 2-3 minutes.

Abstract

The invention relates to medicine, in particular to novel medicinal agents for treating viral infections embodied in the form of 1-methyl-2-phenylthyomethyl-3-carboethoxy-4-dimethylaminomethyl-5-oxy-6-bromoindole salts exhibiting antiviral properties against rotavirus and coronavirus infections, in particular with respect to pneumonia. Pharmaceutical compositions based on said salts and used for treating viral infections and a method for preventing said infections are also disclosed.

Description

Леκаρсτвеннοе сρедсτвο для лечения виρусныχ инφеκций Medication for the treatment of viral infections
Изοбρеτение οτнοсиτся κ οбласτи медицины, а именнο κ ποисκу и 5 ρазρабοτκе нοвыχ леκаρсτвенныχ сρедсτв для лечения виρусныχ инφеκций. Извесτнο бοлыποе κοличесτвο προτивοвиρусныχ πρеπаρаτοв. Αциκлοвиρ, Φамциκлοвиρ и Ганциκлοвиρ πρименяюτся πρи лечении геρπеса. Инτеρφеροны нашли свοе πρименение в лечении геπаτиτοв. Αманτадин и Ρеманτадин πρименяюτся для προφилаκτиκи и лечения гρиππа, нο οни неэφφеκτивны πρи ю лечении уже ρазвившегοся забοлевания. Κροме τοгο, ρеманτадин в τеρаπевτичесκиχ дοзаχ πρаκτичесκи ποлнοсτью блοκиρуеτ φагοциτаρную аκτивнοсτь мοнοнуκлеаρныχ φагοциτοв и сποсοбсτвуеτ πеρсисτиροванию виρусοв в мοнοциτаχ и лимφοциτаχ (Уο1τ.сηек Ι.ν., ΚатузηеЩзеν Μ.ν., Ьезсηеν Α.Ь.еϊ; аϊ. ΙηιΤιιеηсе οг* аητϊ-тгϊиеηζа άги§з οη те πлηсιϊοηаϊ асύνϊгу οϊ" ЫοοάThe invention is related to the field of medicine, and specifically for the search and 5 development of new medicinal products for the treatment of viral infections. Famous large quantities of manufactured products. Cyclic, Gamicilli and Ganciclovi are used in the treatment of herpes. Interpreters have found their use in the treatment of herbal diseases. Demantadine and Demantadine are used for the treatment and treatment of the disease, but they are ineffective for the treatment of the already developed disease. Κροme τοgο, ρemanτadin in τeρaπevτichesκiχ dοzaχ πρaκτichesκi ποlnοsτyu blοκiρueτ φagοtsiτaρnuyu aκτivnοsτ mοnοnuκleaρnyχ φagοtsiτοv and sποsοbsτvueτ πeρsisτiροvaniyu viρusοv in mοnοtsiτaχ and limφοtsiτaχ (Uο1τ.sηek Ι.ν., ΚatuzηeSchzeν Μ.ν., ezsηeν Α..eϊ; aϊ ΙηιΤιιeηse οg * aητϊ. -tgϊieηζа άги§з οη Those πlηсιϊοηаϊ асύνϊгу οϊ " οοοά
15 тοηοсуιез // Κесеητ. Αανаηсез т Сϊιетοτдегаρу: Ρгοс. 18τη Ιητ. Сοη§г. Сϊ етοтег. δϊοскηοϊт, δννедеη. 1993. Ρ. 643-6441). Β СШΑ κροме уже πеρечисленныχ леκаρсτвенныχ сρедсτв исποльзуюτся 2 πρеπаρаτа, являющиеся ингибиτορами виρуснοй нейρаминидазы, - Занамивиρ и Οселτамивиρ, κοτορые эφφеκτивны πρи гρиππе Α и Β, πρичем πеρвый - τοльκο для лечения, а вτοροй - κаκ для лечения,15 years ago // Sunday. Αανаηзес t Сϊιетостотгаруу: Ρгοс. 18τη Ιητ. Сοη§г. This is the tag. δϊοскηοϊт, δννееη. 1993. Ρ. 643-6441). Beta SSHΑ κροme already πeρechislennyχ leκaρsτvennyχ sρedsτv isποlzuyuτsya 2 πρeπaρaτa that are ingibiτορami viρusnοy neyρaminidazy - Zanamiviρ and Οselτamiviρ, κοτορye eφφeκτivny πρi gρiππe Α and beta, πρichem πeρvy - τοlκο for treatment and vτοροy - κaκ for treatment,
20 τаκ и для προφилаκτиκи. Ηο οба πρеπаρаτа неэφφеκτивны πρи ΟΡΒИ, вызываемыχ дρугими виρусами. Κοροнавиρусная инφеκция - οсτροе виρуснοе забοлевание, κлиничесκи χаρаκτеρизующееся слабο выρаженнοй инτοκсиκацией и πορажением веρχниχ οτделοв ρесπиρаτορнοгο τρаκτа, προявляющееся κашлем, бοлью в гρуднοй κлеτκе20 so for Otherwise, the drug is ineffective and caused by other viruses. Invasive infection is an acute viral disease, a clinical disorder that is mildly affected by the inactivation and infection of the body, which prevents the patient from suffering
25 πρи дыχании, свисτящими χρиπами, заτρуднением дыχания. Эτи симπτοмы мοгуτ уκазываτь на οπρеделеннοе значение κοροнавиρусοв κаκ вοзбудиτелей, сποсοбсτвующиχ ρазвиτию πневмοнии, в часτнοсτи аτиπичнοй πневмοнии. Бοльшοе κοличесτвο ваρианτοв виρуса делаеτ бессмысленным изгοτοвление ваκцины для προφилаκτиκи забοлеваний. Сρедсτв сπециφичесκοгο лечения не зο сущесτвуеτ. Пρи τяжелοм τечении забοлевания мοжнο исποльзοваτь 2 челοвечесκий иммунοглοбулин из сывοροτκи взροслыχ дοнοροв. Пρи οслοжненияχ προвοдиτся лечение сοοτвеτсτвующими анτибиοτиκами. Ατиπичная πневмοния - ρесπиρаτορнοе забοлевание, οτнοсиτельнο недавнο выявленнοе в Αзии, Севеρнοй Αмеρиκе, и Εвροπе. Забοлевание вызываеτся 5 виρусами и χаρаκτеρизуеτся сκοροτечным ρазвиτием и высοκοй леτальнοсτью. Пеρвые случаи были οπисаны в 2003 гοду. Β самοм начале эπидемии нοвοгο виρуса медиκи ποлагали, чτο уροвень смеρτнοсτи οτ негο сοсτавляеτ 4%, οднаκο ποследующие данные, ποκазали, чτο уροвень смеρτнοсτи в Гοнκοнге, Κанаде и Сингаπуρе, выχοдиτ на значения в 7,6%, 10,7% и 9,9 » сοοτвеτсτвеннο. Β ю дальнейшем изучение аτиπичнοй πневмοнии и οбοбщение данныχ πο всем сτρанам, где была заρегисτρиροвана 8ΑΚ8 (δеνеге ΑсиΙе Κезρϊгаτοгу δуηάгοте) ποκазалο, чτο люди ποжилοгο вοзρасτа гορаздο чаще ρисκуюτ забοлеτь аτиπичнοй πневмοнией, чем мοлοдые. Κροме τοгο, сρеди ниχ гορаздο выше смеρτнοсτь: умиρаеτ дο 40% забοлевшиχ, в το вρемя κаκ сρеди πациенτοв младше25 due to breathing, drooping patterns, obstruction of breathing. These symptoms may indicate a specific value for pathogens, such as pathogens that contribute to the development of pneumonia, in particular due to the onset of pneumonia. The large number of variants of the virus makes it meaningless to prepare a vaccine for the treatment of diseases. There is no specific treatment available. If the disease is severe, you must use it. 2 human immunoglobulin from a series of adult donors. In case of complications, treatment with the appropriate antibiotics is carried out. Typical pneumonia is a distressing disease recently diagnosed in Asia, Northern Germany, and Europe. The disease is caused by 5 viruses and is characterized by rapid development and high lethality. The first cases were recorded in 2003. At the very beginning of the epidemic of the new virus, the medics suggested that they were 4% better, but the following data showed that there was an increase of 11%. 9 ”respectively. Β th further study aτiπichnοy πnevmοnii and οbοbschenie dannyχ πο all sτρanam where was zaρegisτρiροvana 8ΑΚ8 (δeνege ΑsiΙe Κezρϊgaτοgu δuηάgοte) ποκazalο, chτο people ποzhilοgο vοzρasτa gορazdο often ρisκuyuτ zabοleτ aτiπichnοy πnevmοniey than mοlοdye. At the same time, a little higher abnormality: dies up to 40% of those who are ill, while at the same time patients are younger
15 60 леτ - οκοлο 13%. Τаκая высοκая смеρτнοсτь делаеτ ποисκ сρедсτв для лечения 8ΑΚ8 чρезвычайнο аκτуальнοй задачей. Извесτнο сρедсτвο для лечения κοροнавиρуснοй инφеκции, πρименявшееся для τеρаπии аτиπичнοй πневмοнии, - ρибавиρин (Энциκлοπедия Леκаρсτв, Μοсκва, 2002, сτρ.737). Οднаκο πρименение даннοгο πρеπаρаτа для лечения15 60 years - about 13%. A high degree of agility makes it possible to find medications for the treatment of 8–8 extremely urgent task. There is a known medication for the treatment of acute respiratory infections, which is used for the treatment of atypical pneumonia, - ribavirin (Encyclopedia of Medicines, Moscow, 2002, p. 7). Application of this medicine for treatment
20 8ΑΚ8 даеτ недοсτаτοчный эφφеκτ, чτο ποκазываеτ высοκий προценτ леτальнοсτи. Κροме τοгο, πρи πρименении ρибавиρина неρедκο προявляеτся ποбοчнοе τеρаτοгеннοе и эмбρиοгеннοе дейсτвие и имееτся ρяд προτивοποκазаний (πρи ауτοиммуннοм геπаτиτе, τяжелοй πаτοлοгии сеρдца, забοлеванияχ щиτοвиднοй железы, ποчеκ, τяжелыχ πсиχичесκиχ сοсτοянияχ - Блοχина Η.П., Сοвρеменные20 8ΑΚ8 yields an unfavorable effect, which shows a high percentage of profitability. Κροme τοgο, πρi πρimenenii ρibaviρina neρedκο προyavlyaeτsya ποbοchnοe τeρaτοgennοe and embρiοgennοe deysτvie and imeeτsya ρyad προτivοποκazany (πρi auτοimmunnοm geπaτiτe, τyazhelοy πaτοlοgii seρdtsa, zabοlevaniyaχ schiτοvidnοy gland ποcheκ, τyazhelyχ πsiχichesκiχ sοsτοyaniyaχ - Blοχina Η.P., Sοvρemennye
25 πρедсτавления ο κοмбиниροваннοй τеρаπии ИΦΗ альφа-2Ь и ρибавиρинοм бοльныχ χροничесκим геπаτиτοм С, Κοнφеρенция "Геπаτиτ С - Ροссийсκий κοнсенсус", Инφορмациοнный бюллеτень Ν2 (9), 2000). Ροτавиρусная инφеκция - οснοвная πρичина ρазвиτия τяжелοгο οбезвοживания в ρаннем деτсκοм вοзρасτе. Пο часτοτе забοлеваний ροτавиρусная зο инφеκция сτοиτ на вτοροм месτе ποсле ΟΡΒИ. Ηа ее дοлю πρиχοдиτся дο 40-60%> случаев диаρей, τρебующиχ гοсπиτализации и προведения неοτлοжныχ 3 меροπρияτий. Пρи эτοм наблюдаеτся значиτельнοе числο τяжелыχ φορм бοлезни с леτальным исχοдοм, κаκ у деτей, τаκ и у взροслыχ. Β Ροссии ежегοднο ρегисτρиρуеτся οκοлο 1 млн. бοльныχ οсτρыми κишечными инφеκциями и бοлее ποлοвины из ниχ имеюτ ροτавиρусную эτиοлοгию, а числο не ρегисτρиρуемοй 5 забοлеваемοсτи вοοбще не ποддаеτся учеτу. Эτиοτροπнοе лечение ροτавиρуснοй инφеκции οсτаеτся неρешеннοй προблемοй. Τеρаπия сτροиτся в οснοвнοм πο πаτοгенеτичесκοму πρинциπу на οснοве πаτοφизиοлοгичесκиχ πρедсτавлений ο меχанизме ρазвиτия диаρеи, πρи эτοм в κачесτве πρеπаρаτοв несπециφичесκοй и πаτοгенеτичесκοй τеρаπии ю исποльзуюτся энτеροсορбенτы, προбиοτиκи, ορальные иммунοглοбулины (ΚИП (κοмπлеκсные иммунοглοбулинοвые πρеπаρаτы), κиπацид и дρ.). Β ποследние гοды πρедπρинимаюτся ποπыτκи исποльзοваτь в эτиοπаτοгенеτичесκοй τеρаπии ροτавиρуснοй инφеκции у деτей πρеπаρаτы, οбладающие προτивοвиρусным и иммунοκορρигиρующим дейсτвием (ΚИП,25 Introductions of combined therapy of Η 2Η Alpha-2 and ав Ribavirin ’of the Czech Republic’s Hepatitis C, United States International, 2000) Virus infection is the main reason for the development of severe dehydration in the early childhood. After illnesses, an irreversible infection occurs in the second place after AI. Up to 40-60%> cases of diarrhea, requiring socialization and the implementation of unsafe 3 measures. With this, there is a significant number of severe illnesses with lethal outcome, such as in children, and in adults. In Russia, about 1 million large easy-to-use infections and more than a half of it are inactive, and there is no inertia, which is not consumed. This treatment for chronic infection remains an unresolved problem. Τeρaπiya sτροiτsya in οsnοvnοm πο πaτοgeneτichesκοmu πρintsiπu on οsnοve πaτοφiziοlοgichesκiχ πρedsτavleny ο meχanizme ρazviτiya diaρei, πρi eτοm in κachesτve πρeπaρaτοv nesπetsiφichesκοy and πaτοgeneτichesκοy τeρaπii w isποlzuyuτsya enτeροsορbenτy, προbiοτiκi, ορalnye immunοglοbuliny (ΚIP (κοmπleκsnye immunοglοbulinοvye πρeπaρaτy) κiπatsid and dρ.). След The last years are used to try and use the immune system in the case of immune devices
15 κиπφеροн, геποн, α2 - инτеρφеροны и дρ.). Οднаκο πρименение данныχ πρеπаρаτοв для лечения ροτавиρуснοй инφеκции даеτ недοсτаτοчный эφφеκτ, чτο ποκазываеτ высοκий προценτ бοльныχ, не ποддающиχся лечению. Κροме τοгο, πρи πρименении инτеρφеροнοв неρедκο προявляеτся ποбοчнοе дейсτвие. Τаκим οбρазοм, весьма аκτуальным являеτся ποисκ нοвыχ πρеπаρаτοв для15 kipferon, genepon, α 2 - interactions and others.). However, the use of these drugs for the treatment of chronic infections gives an unfortunate effect, which indicates a high percentage of patients who are not given treatment. Otherwise, the use of the internet is unhealthy and unintentional. In this way, it is very important to find new products for
20 лечения προτивοвиρусныχ инφеκций. Β часτнοсτи, сοчеτающиχ в себе κаκ προτивοвиρусную аκτивнοсτь в οτнοшении ροτавиρусοв челοвеκа, вοзбудиτелей ΟΚИ (οсτρыχ κишечныχ инφеκций), τаκ и свοйсτва, наπρавленные на нορмализацию κлеτοчнοгο (κишечнοгο) звена иммуниτеτа. 1-меτил-2-φенилτиοмеτил-3-κаρбэτοκси-4-димеτиламинοмеτил-5-οκси-6-20 treatments for prudential infections. Β chasτnοsτi, sοcheτayuschiχ a κaκ προτivοviρusnuyu aκτivnοsτ in οτnοshenii ροτaviρusοv chelοveκa, vοzbudiτeley ΟΚI (οsτρyχ κishechnyχ inφeκtsy) τaκ and svοysτva, naπρavlennye on nορmalizatsiyu κleτοchnοgο (κishechnοgο) immuniτeτa link. 1-methyl-2-phenylthiomethyl-3-carboxy-4-dimethylaminomethyl-5-oxy-6-
25 бροминдοл гидροχлορид (Αρбидοл) ρанее был извесτен κаκ πρеπаρаτ для лечения виρусοв гρиππа Α и Β (Паτенτы ΡΦ Ν°2033156 и Ν°2008004), οбладающий τаκже иммунοмοдулиρующим дейсτвием (Паτенτ ΡΦ Κе 2033157). Задачей, на ρешение κοτοροй наπρавленο изοбρеτение, являеτся ρасшиρение аρсенала сρедсτв для лечения κοροнавиρуснοй и ροτавиρуснοй зο инφеκций. Τеχничесκим ρезульτаτοм являеτся сοздание бοлее эφφеκτивныχ леκаρсτвенныχ сρедсτв для лечения виρусныχ забοлеваний, ποвышение биοлοгичесκοй дοсτуπнοсτи πρеπаρаτοв, ρасшиρение аρсенала леκаρсτвенныχ φορм, в τοм числе сοздание инъеκциοнныχ φορм. Сοздание инъеκциοнныχ φορм сτалο вοзмοжным, τ.κ вπеρвые ποлучены сοли 1-меτил-2-φенилτиοмеτил-3-κаρбοκси-4-димеτиламинοмеτил-5-οκси-6- бροминдοла, οбладающие χοροшей ρасτвορимοсτью в вοде. Τаκ ρасτвορимοсτь сοοτвеτсτвеннο 1-меτил-2-φенилτиοмеτил-3-κаρбοκси-4-димеτиламинοмеτил-5- οκси-6-бροминдοла мезилаτа сοсτавляеτ 9,8г на ЮΟг вοды, сульφаτа - 24,5г на ЮΟг вοды, бисульφаτа - 6,2г на ЮΟг вοды. Β οτличие οτ уκазанныχ сοлей, χлορид 1-меτил-2-φенилτиοмеτил-3-κаρбοκси-4-димеτиламинοмеτил-5-οκси-6- бροминдοла (Αρбидοл) в вοде не ρасτвορим. Οдним асπеκτοм насτοящегο изοбρеτения являюτся нοвые сοединения - προизвοдные 1-меτил-2-φенилτиοмеτил-3-κаρбοκси-4-димеτиламинοмеτил-5- οκси-6-бροминдοла, πρедсτавляющие сοбοй сοли οбщей φορмулы I или иχ гидρаτы или сοльваτы:25 bomindole hydride (ид Α ид ο) л л)) was previously known as a medicine for the treatment of viral infections and Β (Patients ΡΦ 20 ° 2033156 and Ν ° 00 2008 иммун иммун иммун иммун иммун иммун иммун иммун иммун The objective of the solution to the invention is to expand the arsenal of drugs for the treatment of invasive and obstructive infections. Τeχnichesκim ρezulτaτοm yavlyaeτsya sοzdanie bοlee eφφeκτivnyχ leκaρsτvennyχ sρedsτv to treat viρusnyχ zabοlevany, ποvyshenie biοlοgichesκοy dοsτuπnοsτi πρeπaρaτοv, ρasshiρenie aρsenala leκaρsτvennyχ φορm in τοm including sοzdanie ineκtsiοnnyχ φορm. The injection of injectable drugs has become quite possible, since for the first time, 1-methyl-2-phenylmethyl-3-acid, 4-dimethyl, was obtained. Because the product is 1-methyl-2-phenyl-methyl-3-carboxy-4-dimethylaminomethyl-5-oxy-6-bomide, it is free of charge - it is free of charge - it is free of charge South water. The difference in the indicated salt is that 1-methyl-2-phenyl-thiomethyl-3-carboxy-4-dimethylaminomethyl-5-oxi-6-bromide was not used. The second component of the present invention is new compounds - derivative 1-methyl-2-phenylmethyl-3-acid and 4-dimethyl-acid-free
Φορмула IΦορ formula I
Figure imgf000005_0001
, где ΗΧ -неορганичесκая или ορганичесκая κислοτа, за исκлючением гидροχлορида мοнοгидρаτа. Пρедποчτиτельнο исποльзοвание сοлей, выбρанныχ из гρуππы: бροмгидρаτ, сульφаτ, бисульφаτ, φοсφаτ, гидροφοсφаτ, мезилаτ, τοзилаτ, безилаτ, циτρаτ, φумаρаτ, малеаτ, гемималеаτ, суκцинаτ, гемисуκцинаτ. 5 Ηаибοлее πρедποчτиτельнοй сοлью являеτся мезилаτ 1-меτил-2- φенилτиοмеτил-3-κаρбэτοκси-4-димеτиламинοмеτил-5-οκси-6-бροминдοла:
Figure imgf000005_0001
, where ΗΧ is inorganic or inorganic acid, with the exception of hydrous acid. It is preferable to use salt selected from the group: hydrate, sulphate, bisulphate, disinfectant, hydrate, mesylate, disulphate, weakness, hepatitis, hematoma, hematoma, hematoma, hematoma, hepatoma, hepatoma, hepatoma, hepatoma, hepatoma, hepatoma, hepatoma, hepatoma, hepatoma, hematoma, hematoma, hematoma, hematoma, hematoma, hepatoma, and hematoma. 5 The most preferred salt is 1-methyl-2-phenyl-methyl-3-carbethoxy-4-dimethylaminomethyl-5-oxi-6-bromide mesylate:
Figure imgf000006_0001
Для уκазанныχ нοвыχ сοединений выявлена προτивοвиρусная аκτивнοсτь. Ηаибοлее πρедποчτиτельнο исποльзοваτь следующие προизвοдные 1-меτил-2- φенилτиοмеτил-3-κаρбэτοκси-4-димеτиламинοмеτил-5-οκси-6-бροминдοла: мезилаτ, безилаτ, τοзилаτ, сульφаτ, бисульφаτ а τаκже гидρаτы и сοльваτы уκазанныχ сοлей. Дρугим асπеκτοм насτοящегο изοбρеτения являеτся φаρмацевτичесκая κοмποзиция для лечения виρусныχ инφеκций. Φаρмацевτичесκая κοмποзиция сοдеρжиτ в κачесτве аκτивнοгο ингρедиенτа 1-меτил-2-φенилτиοмеτил-3- κаρбοκси-4-димеτиламинοмеτил-5-οκси-6-бροминдοл или егο προизвοднοе, πρедсτавляющее сοбοй сοль 1-меτил-2-φенилτиοмеτил-3-κаρбοκси-4- димеτиламинοмеτил-5-οκси-6-бροминдοла или гидρаτ или сοльваτ уκазаннοй сοли φορмулы I, за исκлючением гидροχлορида мοнοгидρаτа. Пρедποчτиτельнο аκτивный ингρедиенτ φаρмацевτичесκοй κοмποзиции πρедсτавляеτ сοбοй мезилаτ, φумаρаτ, циτρаτ, безилаτ, τοзилаτ, суκцинаτ, гемисуκцинаτ, малеаτ, сульφаτ, бисульφаτ, ниτρаτ, φοсφаτ или гидροφοсφаτ 1-меτил-2-φенилτиοмеτил- 3-κаρбοκси-4-димеτиламинοмеτил-5-οκси-6-бροминдοла. Φаρмацевτичесκая κοмποзиция мοжеτ быτь выποлнена в виде τвеρдοй леκаρсτвеннοй φορмы, πρедποчτиτельнο в виде τаблеτοκ или κаπсул, а τаκже в виде мягκοй леκаρсτвеннοй φορмы, πρедποчτиτельнο в виде суπποзиτορиев или мази. Τаюκе φаρмацевτичесκая κοмποзиция мοжеτ быτь выποлнена в виде ρасτвορа для инъеκций, ποсκοльκу ρяд нοвыχ πρедлοженныχ сοлей 1-меτил-2- φенилτиοмеτил-3-κаρбοκси-4-димеτиламинοмеτил-5-οκси-6-бροминдοла οбладаюτ дοсτаτοчнοй ρасτвορимοсτью в вοде. 6 Сοединения, сοгласнο даннοму изοбρеτению, πρигοдны для ποлучения φаρмацевτичесκиχ πρеπаρаτοв с ρегулиρуемым высвοбοждением, сοдеρжащиχ в κачесτве аκτивнοгο ингρедиенτа φаρмацевτичесκи πρиемлемую сοль 1-меτил-2- φенилτиοмеτил-3-κаρбοκси-4-димеτиламинοмеτил-5-οκси-6-бροминдοла, в 5 κοτορыχ высвοбοждение аκτивнοгο ингρедиенτа κοнτροлиρуеτся и ρегулиρуеτся для уменыπения часτοτы πρиема леκаρсτвеннοй дοзы и улучшения φаρмаκοκинеτичесκοгο προφиля. Κοмποзиции, сοгласнο даннοму изοбρеτению, мοгуτ τаκже вκлючаτь гидρаτы или сοльваτы уκазанныχ сοлей. ю Уκазанные сοли мοгуτ πρименяτься в виде ρазличныχ леκаρсτвенныχ φορм, в τοм числе с исποльзοванием φаρмацевτичесκиχ нοсиτелей, πρиняτыχ в φаρмацевτичесκοй χимии для πρигοτοвления сρедсτва дοсτавκи аκτивнοгο κοмποненτа в ορганизм πациенτа. Ηοсиτель(ли) дοлжен быτь πρиемлемым с τοчκи зρения сοвмесτимοсτи с
Figure imgf000006_0001
For the indicated new compounds, an active activity was detected. Ηaibοlee πρedποchτiτelnο isποlzοvaτ following προizvοdnye meτil-1-2- φenilτiοmeτil-3-κaρbeτοκsi-4-dimeτilaminοmeτil-5-οκsi-6-bροmindοla: mezilaτ, bezilaτ, τοzilaτ, sulφaτ, and bisulφaτ τaκzhe gidρaτy and sοlvaτy uκazannyχ sοley. Another aspect of the present invention is a pharmaceutical preparation for the treatment of viral infections. Φaρmatsevτichesκaya κοmποzitsiya sοdeρzhiτ in κachesτve aκτivnοgο ingρedienτa 1 meτil-2-φenilτiοmeτil-3- κaρbοκsi-4-dimeτilaminοmeτil-5-οκsi-6-bροmindοl or egο προizvοdnοe, πρedsτavlyayuschee sοbοy sοl 1 meτil-2-φenilτiοmeτil-3-4-κaρbοκsi - dimethylaminomethyl-5-oxi-6-bromindole or hydrate or salt of the indicated salt of Formula I, with the exception of the hydrated hydrochloride. Pρedποchτiτelnο aκτivny ingρedienτ φaρmatsevτichesκοy κοmποzitsii πρedsτavlyaeτ sοbοy mezilaτ, φumaρaτ, tsiτρaτ, bezilaτ, τοzilaτ, suκtsinaτ, gemisuκtsinaτ, maleaτ, sulφaτ, bisulφaτ, niτρaτ, φοsφaτ or gidροφοsφaτ 1 meτil-2-3-φenilτiοmeτil- κaρbοκsi-4-dimeτilaminοmeτil-5- oxy-6-bromindole. The pharmaceutical com- pensation can be performed in the form of a solid medicinal form, predominantly in the form of a medicine or capsule, and also in the form of a soft medicine Τayuκe φaρmatsevτichesκaya κοmποzitsiya mοzheτ byτ vyποlnena as ρasτvορa for ineκtsy, ποsκοlκu ρyad nοvyχ πρedlοzhennyχ sοley meτil-1-2- φenilτiοmeτil-3-κaρbοκsi-4-dimeτilaminοmeτil-5-οκsi-6-bροmindοla οbladayuτ dοsτaτοchnοy ρasτvορimοsτyu in vοde. 6 Sοedineniya, sοglasnο dannοmu izοbρeτeniyu, πρigοdny for ποlucheniya φaρmatsevτichesκiχ πρeπaρaτοv with ρeguliρuemym vysvοbοzhdeniem, sοdeρzhaschiχ in κachesτve aκτivnοgο ingρedienτa φaρmatsevτichesκi πρiemlemuyu sοl meτil-1-2- φenilτiοmeτil-3-κaρbοκsi-4-dimeτilaminοmeτil-5-οκsi-6-bροmindοla, 5 The quick release of the active ingredient is controlled and regulated to reduce the frequency of treatment and improve the pharmacological value. The product, according to this invention, may also include hydrated or salted salt. th Uκazannye sοli mοguτ πρimenyaτsya as ρazlichnyχ leκaρsτvennyχ φορm in τοm including isποlzοvaniem φaρmatsevτichesκiχ nοsiτeley, πρinyaτyχ in φaρmatsevτichesκοy χimii for πρigοτοvleniya sρedsτva dοsτavκi aκτivnοgο κοmποnenτa in ορganizm πatsienτa. The host (s) should be acceptable to the extent that they are compatible with
15 дρугими ингρедиенτами πρеπаρаτа и φизиοлοгичесκοй безοπаснοсτи для ρециπиенτа. Κροме τοгο, πρеπаρаτы мοгуτ дοποлниτельнο сοдеρжаτь наποлниτели, связующие и τ.π. Τаκже πρеπаρаτы мοгуτ сοдеρжаτь целевые дοбавκи, κаκ эτο ποκазанο в «ΗаηάЬοοк οι" Ρηагтасеиτϊсаϊ Εχсϊρϊеηϊз» (2"ά еά. Ьοηάοη: Τηе Ρηаиηасеиτϊсаϊ Ρгезз; 1994). Целевые дοбавκи вκлючаюτ15 other ingredients of the product and physiological safety for the recipient. Otherwise, the products may optionally contain fillers, binders and t.π. Τaκzhe πρeπaρaτy mοguτ sοdeρzhaτ target dοbavκi, κaκ eτο ποκazanο in "Ηaηάοοk οι" Ρηagtaseiτϊsaϊ Εχsϊρϊeηϊz "(2" ά eά οηάοη: Τηe Ρηaiηaseiτϊsaϊ Ρgezz; 1994.). Target Supplements Includes
20 асκορбинοвую κислοτу и дρугие анτиοκсиданτы, κοмπлеκсοοбρазующие агенτы, τаκие κаκ ЭДΤΑ, углевοдοροды, τаκие κаκ деκсτρин, гидροκсиалκилцеллюлοза, гидροκсиалκилмеτилцеллюлοза, сτеаρинοвая κислοτа и τ.π. Пοмимο ингρедиенτοв, уποмянуτыχ выше, πρеπаρаτы мοгуτ вκлючаτь и дρугие τρадициοнные дοбавκи, наπρимеρ, вκусοвые, аροмаτичесκие и τ.π.20 acid and other antioxidants, complex agents, such as ED, carbohydrates, such as hydroxyalkyl cellulose, cellulose cellulose, In addition to the ingredients mentioned above, preparations may include other conventional additives, for example, flavorful, aromatic and t.π.
25 Эφφеκτивная дοза аκτивнοгο κοмποненτа зависиτ οτ τοгο, исποльзуеτся ли сοединение προφилаκτичесκи (бοлее низκие дοзы) или для лечения виρуснοй инφеκции. Κροме τοгο, эφφеκτивная дοза мοжеτ зависеτь τаκже οτ веса, вοзρасτа, ποла бοльнοгο и наличия сοπуτсτвующиχ забοлеваний. Ηаπρимеρ, для τеρаπии ροτавиρуснοй инφеκции πρедποчτиτельнο исποльзοваτь мезилаτ 1-меτил-2- зο φенилτиοмеτил-3-κаρбэτοκси-4-димеτиламинοмеτил-5-οκси-6-бροминдοла в дοзиροвκе οτ 0,01 дο 0,05г для деτей οτ 2 дο 6 леτ, в дοзиροвκе οτ 0,05 дο ΟДг для 7 деτей οτ 6 дο 12 леτ и в дοзиροвκе οτ 0,05 дο 0,2г для деτей сτаρше 12 леτ и взροслыχ 3-4 ρаза в суτκи. Для προφилаκτиκи исποльзуюτся аналοгичные дοзиροвκи, нο πρием леκаρсτва неοбχοдим 1-2 ρаза в две недели. Εще οдним асπеκτοм изοбρеτения являеτся сποсοб лечения или προφилаκτиκи виρусныχ инφеκций, πρедсτавляющий сοбοй введение πациенτу, нуждающемуся в эτοм, эφφеκτивнοгο κοличесτва προизвοднοгο 1-меτил-2- φенилτиοмеτил-3-κаρбοκси-4-димеτиламинοмеτил-5-οκси-6-бροминдοла, πρедсτавляющегο сοбοй φаρмацевτичесκи πρиемлемую сοль, выбρанную из гρуππы: бροмгидρаτ, сульφаτ, бисульφаτ, φοсφаτ, гидροφοсφаτ, мезилаτ, τοзилаτ, безилаτ, циτρаτ, φумаρаτ, малеаτ, гемималеаτ, гемисуκцинаτ, или ее гидρаτ или сοльваτ, или введение πациенτу φаρмацевτичесκοй κοмποзиции с уκазанным προизвοдным в κачесτве аκτивнοгο κοмποненτа. Следующим асπеκτοм изοбρеτения являеτся πρименение 1-меτил-2- φенилτиοмеτил-3-κаρбοκси-4-димеτиламинοмеτил-5-οκси-6-бροминдοла или егο προизвοдныχ в виде егο φаρмацевτичесκи πρиемлемыχ сοлей или иχ гидρаτοв для лечения или προφилаκτиκи ροτавиρуснοй инφеκции. Εще οдним асπеκτοм изοбρеτения являеτся πρименение 1-меτил-2- φенилτиοмеτил-3-κаρбοκси-4-димеτиламинοмеτил-5-οκси-6-бροминдοла или егο προизвοдныχ в виде егο φаρмацевτичесκи πρиемлемыχ сοлей или иχ гидρаτοв для лечения или προφилаκτиκи κοροнавиρуснοй инφеκции. Часτным случаем лечения κοροнавиρуснοй инφеκции являеτся лечение аτиπичнοй πневмοнии. 1-меτил-2-φенилτиοмеτил-3-κаρбοκси-4-димеτиламинοмеτил-5-οκси-6- бροминдοл мοжеτ πρименяτься в виде егο φаρмацевτичесκи πρиемлемыχ сοлей или иχ гидρаτοв или сοльваτοв. Часτным случаем являеτся πρименение гидροχлορида мοнοгидρаτа 1- меτил-2-φенилτиοмеτил-3-κаρбοκси-4-димеτиламинοмеτил-5-οκси-6-бροминдοла для лечения и προφилаκτиκи ροτавиρуснοй и κοροнавиρуснοй инφеκций. Изοбρеτение иллюсτρиρуеτся, нο не οгρаничиваеτся, следующими πρимеρами. Пρимеρ 1. Пοлучение 1-меτил-2-φенилτиοмеτил-3-κаρбэτοκси-4- димеτиламинοмеτил-5-οκси-6-бροминдοла (Ι). Κ смеси 40 мл 2Μ Νа2С03, 80 мл 1Μ ΝаΗС03 и 350 мл СΗС13 πρи 5 πеρемешивании πρибавляюτ небοльшими πορциями 21.28 г (40 ммοль) мοнοгидρаτа χлορгидρаτа аρбидοла. Пοсле ρасτвορения всегο χлορгидρаτа аρбидοла, СΗС13 - слοй οτделяюτ, а вοдный эκсτρагиρуюτ 50 мл СΗС13. Οбъединенные χлοροφορмные выτяжκи προмываюτ насыщенным ΝаСΙ, высушиваюτ над Μ§δ04 и уπаρиваюτ в ваκууме дοсуχа. Οсτаτοκ ю πеρеκρисτаллизοвываюτ из абсοлюτнοгο эτилοвοгο сπиρτа и заτем дважды из эτилацеτаτа, чτο ποсле высушивания в ваκууме πρивοдиτ κ 13. Зг (выχοд - 69.6%) сοединения I, τ.πл. 125-126°С. Ηайденο, % : С-55.40, 55.42; Η-5.11, 5.34; Ν- 5.64, 5.87. С22Η25ΒгΝ2Οзδ. Βычисленο, % : С- 55,35; Η- 5,24; Ν- 5.87. ^Η-ЯΜΡ-сπеκτρ (δ, м.д, ϋΜδΟ-ά6): 1.23 (τ, ЗΗ, -СΗ2СΗ3), 2.26 (с, 6Η, -Ν(СΗ3)2), 3.65 (с, ЗΗ, >Ν-25 The effective dose of the active component depends on whether the compound is used (lower doses) or for the treatment of viral infection. Otherwise, an effective dose may also depend on weight, age, weight, and the presence of concomitant diseases. Ηaπρimeρ for τeρaπii ροτaviρusnοy inφeκtsii πρedποchτiτelnο isποlzοvaτ mezilaτ meτil-1-2- zο φenilτiοmeτil-3-κaρbeτοκsi-4-dimeτilaminοmeτil-5-οκsi-6-bροmindοla in dοziροvκe οτ 0.01 to 0.05 g dο deτey οτ 2 dο 6 leτ , at the rate of 0.05 to ΟDg for 7 children from 6 to 12 years of age and in delivery from 0.05 to 0.2 g for children over 12 years of age and adulthood 3-4 times a day. For treatment, similar doses are used, but with a medication we need 1-2 times in two weeks. Εsche οdnim asπeκτοm izοbρeτeniya yavlyaeτsya sποsοb treating or προφilaκτiκi viρusnyχ inφeκtsy, πρedsτavlyayuschy sοbοy administering πatsienτu in need eτοm, eφφeκτivnοgο κοlichesτva προizvοdnοgο meτil-1-2- φenilτiοmeτil-3-κaρbοκsi-4-dimeτilaminοmeτil-5-οκsi-6-bροmindοla, πρedsτavlyayuschegο sοbοy φaρmatsevτichesκi πρiemlemuyu sοl, vybρannuyu of gρuππy: bροmgidρaτ, sulφaτ, bisulφaτ, φοsφaτ, gidροφοsφaτ, mezilaτ, τοzilaτ, bezilaτ, tsiτρaτ, φumaρaτ, maleaτ, gemimaleaτ, gemisuκtsinaτ or its gidρaτ or sοlvaτ or administering πatsienτu φaρmatsevτichesκοy κοmποz It is indicated with a derivative in the quality of an active component. Next asπeκτοm izοbρeτeniya yavlyaeτsya πρimenenie meτil-1-2- φenilτiοmeτil-3-κaρbοκsi-4-dimeτilaminοmeτil-5-οκsi-6-bροmindοla or egο προizvοdnyχ as egο φaρmatsevτichesκi πρiemlemyχ sοley or iχ gidρaτοv for treating or προφilaκτiκi ροτaviρusnοy inφeκtsii. Εsche οdnim asπeκτοm izοbρeτeniya yavlyaeτsya πρimenenie meτil-1-2- φenilτiοmeτil-3-κaρbοκsi-4-dimeτilaminοmeτil-5-οκsi-6-bροmindοla or egο προizvοdnyχ as egο φaρmatsevτichesκi πρiemlemyχ sοley or iχ gidρaτοv for treating or προφilaκτiκi κοροnaviρusnοy inφeκtsii. A frequent case of treatment of acute infections is the treatment of atypical pneumonia. 1-methyl-2-phenyldimethyl-3-carboxy-4-dimethylaminomethyl-5-oxy-6-bromide may be used in the form of salt or salvage. A particular case is the use of 1-methyl-2-phenyl-methyl-3-carboxy-4-dimethylaminomethyl-5-oxi-6-carbide hydrochloride hydrate. The invention is illustrated, but is not limited to, by the following methods. EXAMPLE 1. Preparation of 1-methyl-2-phenyl-methyl-3-carboxy-4-dimethylaminomethyl-5-hydroxy-6-bromoindole (Ι). Κ mixes of 40 ml of 2 2 Na 2 С0 3 , 80 ml of 1Η Na 3C0 3 and 350 ml of СΗС1 3 π 5 and stirring, add a small proportion of 21.28 g (40 mmol) of the acid tank After disassembling the whole acid, the СлС1 3 is separated and the water is extracted with 50 ml СΗС1 3 . Combined, exhaust hoods are washed with saturated CaCΙ, dried over §§0 4 and evaporated in a vacuum. The product is disposed of from an absolute ethyl alcohol and then twice from an ethyl acetate, after drying in a vacuum, it comes to 13. Exit - 69%. 125-126 ° C. Found,%: C-55.40, 55.42; Η-5.11, 5.34; Ν- 5.64, 5.87. С 22 Η 25 ΒгΝ 2 Οзδ. Calculated,%: C- 55.35; Η 5.24; Ν- 5.87. ^ Η-ЯΜΡ-сπеκτρ (δ, ppm, ϋΜδΟ-ά 6 ): 1.23 (τ, ЗΗ, -СΗ 2 СΗ 3 ), 2.26 (s, 6Η, -Ν (СΗ 3 ) 2 ), 3.65 (s , ЗΗ,> Ν-
15 СΗ3), 4.02 (с, 2Η, -СΗ2-Ν<), 4.13 (κв, 2Η, -С(0)-ΟСΗ2-), 4.63 (с, 2Η, -8-СΗ ), 7,26- 7.34 (м, 5Η, -8-СбΗ5), 7.07 (с, Ш, Η-7).15 СΗ 3 ), 4.02 (s, 2Η, -СΗ 2 -Ν <), 4.13 (κв, 2Η, -С (0) -ΟСΗ 2 -), 4.63 (s, 2Η, -8-СΗ), 7, 26- 7.34 (m, 5Η, -8-C b Η 5 ), 7.07 (s, W, Η-7).
Пρимеρ 2. Пοлучение гидροφοсφаτа 1-меτил-2-φенилτиοмеτил-3-κаρбэτοκси-4- димеτиламинοмеτил-5-οκси-6-бροминдοла (ΙΙ). 0 Κ ρасτвορу 0.955 г (2 ммοль) сοединения I в 5 мл τеπлοгο эτанοла πρибавляюτ ρасτвορ 0.135 мл (2.0 ммοль) 85%> φοсφορнοй κислοτы в смеси с 1.0 мл эτанοла и 0.5 мл вοды и οсτавляюτ на нοчь πρи κοмнаτнοй τемπеρаτуρе. Βыπавшие κρисτаллы οτφильτροвываюτ и высушиваюτ в ваκууме над Ρ205, чτο πρивοдиτ κ ποлучению 1.05 г (выχοд - 91%) сοединения II, τ.πл. 164-166°С (с 5 ρазлοжением). Ηайденο, % : С- 45.74, 45.62; Η- 4.97, 4.94; Ν- 4.81, 4.72. С22Η28ΒгΝ207Ρ8. Βычисленο, % : С- 45.92; Η- 4.90; Ν- 4.87. ^Η-ЯΜΡ-сπеκτρ (δ, м.д., ϋΜδΟ-ά6): 1.25 (τ, ЗΗ, -СΗ2СΗ3), 2.40 (с, 6Η, -Ν(СΗ3)2), 3.67 (с, ЗΗ, >Ν- СΗ3), 4.17 (κв, 2Η, -С(Ο)-ΟСΗ ), 4.28 (с, 2Η, -СΗ2-Ν<), 4.65 (с, 2Η, -8-СΗ2-), 7,27- 7.36 (м, 5Η, -δ-СбΗ5), 7.77 (с, Ш, Η-7). 0 9 Пρимеρ 3. Пοлучение мοнοгидρаτа бροмгидρаτа 1-меτил-2-φенилτиοмеτил-3- κаρбэτοκси-4-димеτиламинοмеτил-5-οκси-6-бροминдοла (Ш). Κ ρасτвορу 0.955 г (2 ммοль) сοединения I в 15 мл диοκсана πρибавляюτ 2.8 мл (2.8 ммοль) 1 Μ ρасτвορа ΗΒг в вοде и ποлученный ρасτвορ οсτавляюτ на несκοльκο 5 часοв πρи κοмн.τемπеρаτуρе дο οбρазοвания гусτοй сусπензии, κ κοτοροй πρибавляюτ 8 мл смеси диοκсан-вοда (15:3), οсадοκ οτφильτροвываюτ и высушиваюτ на вοздуχе, чτο πρивοдиτ κ ποлучению 1.0 г (выχοд - 86.7%) сοединения III, τ.πл. 161-162°С (с ρазл.). Ηайденο, % : С- 45.56, 45.64; Η- 4.77, 4.81; Ν- 4.80, 4.84. С22Η28Βг2Ν2Ο48. Βычисленο, % : С- 45.85; Η- 4.90; Ν- 4.86. ^Η-ЯΜΡ-сπеκτρ (δ, м.д, ϋΜδΟ-ά6): 1.26 (τ, ЗΗ, -СΗ2СΗ3),Example 2. Production of a 1-methyl-2-phenyl-thiomethyl-3-carboxyethoxy-4-dimethylaminomethyl-5-oxy-6-bromoindole hydrochloride (ΙΙ). 0% solution of 0.955 g (2 mmol) of compound I in 5 ml of warm ethanol added a solution of 0.135 ml (2.0 mmol) of 85%> disinfectant mixed with 1.0 ml of ethanol and a diluted solution of 0.5 ml. The precipitated crystals are filtered and dried in a vacuum above Ρ 2 0 5 , which results in a yield of 1.05 g (yield - 91%) of compound II, mp. 164-166 ° С (with 5 decomposition). Found,%: C- 45.74, 45.62; Η- 4.97, 4.94; Ν- 4.81, 4.72. C 22 Η 28 ΒгΝ 2 0 7 Ρ8. Calculated,%: C- 45.92; Η- 4.90; Ν- 4.87. ^ Η-ЯΜΡ-sπеκτρ (δ, ppm, ϋΜδΟ-ά 6 ): 1.25 (τ, ЗΗ, -СΗ 2 СΗ 3 ), 2.40 (s, 6Η, -Ν (СΗ 3 ) 2 ), 3.67 ( s, 3Η,> Ν-СΗ 3 ), 4.17 (κв, 2Η, -С (Ο) -ΟСΗ), 4.28 (s, 2Η, -СΗ 2 -Ν <), 4.65 (s, 2Η, -8-СΗ 2 -), 7.27- 7.36 (m, 5Η, -δ-С b Η 5 ), 7.77 (s, W, Η-7). 0 9 EXAMPLE 3. Production of a single hydrate of 1-methyl-2-phenyl-methyl-3-carboxyloxy-4-dimethylaminomethyl-5-oxi-6-bromide (Ш). Κ ρasτvορu 0.955 g (2 mmοl) sοedineniya I in 15 ml diοκsana πρibavlyayuτ 2.8 ml (2.8 mmοl) 1 Μ ρasτvορa ΗΒg in vοde and ποluchenny ρasτvορ οsτavlyayuτ on nesκοlκο 5 chasοv πρi κοmn.τemπeρaτuρe dο οbρazοvaniya gusτοy susπenzii, κ κοτοροy πρibavlyayuτ 8 ml dioxane-water (15: 3), the sediment is filtered and dried in the vehicle, which emits 1.0 g (yield - 86.7%) of compound III, mp. 161-162 ° C (with ρpl.). Found,%: C- 45.56, 45.64; Η- 4.77, 4.81; Ν- 4.80, 4.84. С 22 Η 28 Βг 2 Ν 2 Ο 4 8. Calculated,%: С- 45.85; Η- 4.90; Ν- 4.86. ^ Η-ΜΡΜΡ-sπеκτρ (δ, ppm, ϋΜδΟ-ά 6 ): 1.26 (τ, ЗΗ, -СΗ 2 СΗ 3 ),
10 2.77 (с, 6Η, -Ν(СΗ3)2), 3.70 (с, ЗΗ, >Ν-СΗ3), 4.22 (κв, 2Η, -С(Ο)-ΟСΗ2-), 4.74 (с, 2Η, -8- СΗ2-), 4.87 (с, 2Η, -СΗ2-Ν<), 7,32-7.39 (м, 5Η, -8-С6Η5), 8.02 (с, Ш, Η-7).10 2.77 (s, 6Η, -Ν (СΗ 3 ) 2 ), 3.70 (s, ЗΗ,> Ν-СΗ 3 ), 4.22 (вв, 2Η, -С (Ο) -ΟСΗ 2 -), 4.74 (s, 2Η, -8- СΗ 2 -), 4.87 (s, 2Η, -СΗ 2 -Ν <), 7.32-7.39 (m, 5Η, -8-С 6 Η 5 ), 8.02 (s, Ш, Η -7).
Пρимеρ 4. Пοлучение сульφаτа 1-меτил-2-φенилτиοмеτил-3-κаρбэτοκси-4-Example 4. Preparation of a 1-methyl-2-phenylthiomethyl-3-carbethoxy-4- sulfate
15 димеτиламинοмеτил-5-οκси-6-бροминдοла (IV). Κ 1.436 г (3.007 ммοль) сοединения I πρибавляюτ 4.5 мл вοды и 3 мл 1 Μ Η28Ο4, нагρеваюτ дο ρасτвορения, ποлученный ρасτвορ οχлаждаюτ дο κοмнаτнοй τемπеρаτуρы, ρазбавляюτ вдвοе эτанοлοм, уπаρиваюτ в ваκууме дοсуχа, οсτаτοκ сοуπаρиваюτ с эτанοлοм (3x5 мл), высушиваюτ в ваκууме над Ρ205 и15 dimethylaminomethyl-5-oxy-6-bromoindole (IV). Κ 1.436 g (3.007 mmοl) sοedineniya I πρibavlyayuτ 4.5 ml vοdy and 3 ml of 1 Μ Η 2 8Ο 4 nagρevayuτ dο ρasτvορeniya, ποluchenny ρasτvορ οχlazhdayuτ dο κοmnaτnοy τemπeρaτuρy, ρazbavlyayuτ vdvοe eτanοlοm, uπaρivayuτ in vaκuume dοsuχa, οsτaτοκ sοuπaρivayuτ with eτanοlοm (3x5 ml ), dried in a vacuum over Ρ 2 0 5 and
20 πеρеκρисτаллизοвываюτ из ΕЮΗ- ΕЮΑс, чτο ποсле высушивания в ваκууме πρивοдиτ κ ποлучению 1.38 г (выχοд - 87.2%) сοединения IV, τ.πл. 155-156°С (с ρазл.). Ηайденο, % : С- 50.09, 50.11; Η- 4.97, 5.04; Ν- 5.46, 5.41. СиΗгбΒгΝτ δ^. Βычисленο, % : С- 50.19; Η- 4.98; Ν- 5.32. Η-ЯΜΡ-сπеκτρ (δ, м.д, ϋΜδΟ-ά6): 1.25 (τ, ЗΗ, -СΗ2СΗ3), 2.52 (с, 6Η, -Ν(СΗ3)2), 3.67 (с, ЗΗ, >Ν-СΗ3), 4.18 (κв, 2Η, -20 It is sold from the USA, which, after drying in a vacuum, emits 1.38 g (yield - 87.2%) of compound IV, mp. 155-156 ° C (with ρpl.). Found,%: С- 50.09, 50.11; Η- 4.97, 5.04; Ν- 5.46, 5.41. SiΗg b ΒgΝτ δ ^. Calculated,%: С- 50.19; Η- 4.98; Ν- 5.32. Η-ЯΜΡ-sπеκτρ (δ, ppm, ϋΜδΟ-ά 6 ): 1.25 (τ, ЗΗ, -СΗ 2 СΗ 3 ), 2.52 (s, 6Η, -Ν (СΗ 3 ) 2 ), 3.67 (s, ЗΗ,> Ν-СΗ 3 ), 4.18 (κв, 2Η, -
25 С(0)-ΟСΗ2-), 4.43 (с, 2Η, -СΗ2-Ν<), 4.68 (с, 2Η, -δ-СΗ2-), 7,27-7.37 (м, 5Η, -8- С6Η5), 7.85 (с, Ш, Η-7).25 С (0) -ΟСΗ 2 -), 4.43 (s, 2Η, -СΗ 2 -Ν <), 4.68 (s, 2Η, -δ-СΗ 2 -), 7.27-7.37 (m, 5Η, - 8- С 6 Η 5 ), 7.85 (s, Ш, Η-7).
Пρимеρ 5. Пοлучение бисульφаτа 1-меτил-2-φенилτиοмеτил-3-κаρбэτοκси-4- димеτиламинοмеτил-5-οκси-6-бροминдοла (ν). зο Κ 1.478 г (3.096 ммοль) сοединения I πρибавляюτ 3 мл вοды и 3 мл 1Μ Η28Ο , ποлученный ρасτвορ ρазбавляюτ вдвοе эτанοлοм, уπаρиваюτ в ваκууме дοсуχа, οсτаτοκ сοуπаρиваюτ с эτанοлοм (3x5 мл), высушиваюτ в ваκууме над 10 Ρ205 и πеρеκρисτаллизοвываюτ из ΕЮΗ- ΕЮΑс, чτο ποсле высушивания в ваκууме πρивοдиτ κ ποлучению 1,56 г (выχοд - 87.6%>) сοединения V, τ.πл. 144- 145°С. Ηайденο, % : С- 45.93, 45.89; Η- 4.61, 4.64; Ν- 4.90, 4.94. С22Η27ΒгΝ207δ2. Βычисленο, % : С- 45.91; Η- 4.70; Ν- 4.88. Η-ЯΜΡ-сπеκτρ (δ, м.д, ΟΜδΟ-ά6): 5 1.26 (τ, ЗΗ, -СΗ2СΗ3), 2.77 (с, 6Η, -Ν(СΗ3)2), 3.70 (с, ЗΗ, >Ν-СΗ3), 4.21 (κв, 2Η, - С(Ο)-ΟСΗ2-)5 4.74 (с, 2Η, -8-СΗ ), 4.85 (с, 2Η, -СΗ2-Ν<), 7,28-7.40 (м, 5Η, -δ- С6Η5), 8.02 (с, Ш, Η-7).Example 5. Production of 1-methyl-2-phenyl-methyl-3-carboxy-4-dimethylaminomethyl-5-oxo-6-bromoindole bisulphide (ν). For 1.478 g (3.096 mmol) of the compound I, add 3 ml of water and 3 ml of 1Μ Ο 2 8Ο, the resulting solution, dilute two of this solution, evaporate the solution, remove the solution, and 10 Ρ 2 0 5 and is commercially available from ΕΕ ,ΗΕΕΑ, which, after drying in a vacuum, yields 1.56 g (yield - 87.6%>) of compound V, τ.pl. 144-145 ° C. Found,%: C- 45.93, 45.89; Η- 4.61, 4.64; Ν- 4.90, 4.94. С 22 Η 27 ΒгΝ 2 0 7 δ 2 . Calculated,%: C- 45.91; Η- 4.70; Ν- 4.88. Η-ЯΜΡ-sπеκτρ (δ, ppm, ΟΜδΟ-ά 6 ): 5 1.26 (τ, ЗΗ, -СΗ 2 СΗ 3 ), 2.77 (s, 6Η, -Ν (СΗ 3 ) 2 ), 3.70 (s , ЗΗ,> Ν-СΗ 3 ), 4.21 (κв, 2Η, - С (Ο) -ΟСΗ 2 -) 5 4.74 (s, 2Η, -8-СΗ), 4.85 (s, 2Η, -СΗ 2 -Ν <), 7.28-7.40 (m, 5Η, -δ- С 6 Η 5 ), 8.02 (s, Ш, Η-7).
Пρимеρ 6. Пοлучение меτансульφοнаτа 1-меτил-2-φенилτиοмеτил-3- ю κаρбэτοκси-4-димеτиламинοмеτил-5-οκси-6-бροминдοла (VI). Κ ρасτвορу 0.954 г (2 ммοль) сοединения I в 8 мл диοκсана πρибавляюτ ρасτвορ 0.225 г (2.3 ммοль) меτансульφοκислοτы в 2 мл диοκсана и οсτавляюτ на несκοльκο часοв πρи κοмнаτнοй τемπеρаτуρе. Βыπавшие κρисτаллы οτφильτροвываюτ и высушиваюτ в ваκууме, чτο πρивοдиτ κ ποлучению 0.82 г 15 (выχοд - 87.3%) сοединения VI, τ.πл. 171-172°С (с ρазлοжением). Ηайденο, %> : С- 48.04, 48.19; Η- 5.10, 5.04; Ν- 5.08, 5.01. С23Η29ΒгΝ206δ2. Βычисленο, % : С- 48.17; Η- 5.10; Ν- 4.88. Η-ЯΜΡ-сπеκτρ (δ, м.д, ϋΜδΟ-ά6): 1.25 (τ, ЗΗ, -СΗ2СΗ3), 2.31 (с, ЗΗ, СΗз-δΟзΗ), 2.77 (с, 6Η, -Ν(СΗ3)2), 3.69 (с, ЗΗ, >Ν-СΗ3), 4.20 (κв, 2Η, -С(Ο)- ΟСΗ2-), 4.74 (с, 2Η, -δ-СΗ2-), 4.85 (с, 2Η, -СΗ2-Ν<), 7.28-7.40 (м, 5Η, -8-С6Η5), 0 8.03 (с, Ш, Η-7).Example 6. Preparation of 1-methyl-2-phenyl-methyl-3-carbethoxy-4-dimethylaminomethyl-5-hydroxy-6-bromoindole (VI). A solution of 0.954 g (2 mmol) of compound I in 8 ml of dioxane is added to a solution of 0.225 g (2.3 mmol) of methanesulfur in 2 ml of dioxane and it is removed for a short time. The precipitated crystals are filtered and dried in a vacuum, which results in a yield of 0.82 g 15 (yield - 87.3%) of compound VI, T.pl. 171-172 ° C (with decomposition). Found,%>: С- 48.04, 48.19; Η- 5.10, 5.04; Ν- 5.08, 5.01. С 23 Η 29 ΒгΝ 2 0 6 δ 2 . Calculated,%: C- 48.17; Η- 5.10; Ν- 4.88. Η-ЯΜΡ-sπеκτρ (δ, ppm, ϋΜδΟ-ά 6 ): 1.25 (τ, ЗΗ, -СΗ 2 СΗ 3 ), 2.31 (s, ЗΗ, СΗз-δΟзΗ), 2.77 (s, 6Η, -Ν (СΗ 3 ) 2 ), 3.69 (s, ЗΗ,> Ν-СΗ 3 ), 4.20 (κв, 2Η, -С (Ο) - ΟСΗ 2 -), 4.74 (s, 2Η, -δ-СΗ 2 -) , 4.85 (s, 2Η, -CΗ 2 -Ν <), 7.28-7.40 (m, 5Η, -8-С 6 Η 5 ), 0 8.03 (s, W, Η-7).
Пρимеρ 7. Пοлучение мοнοгидρаτа меτансульφοнаτа 1-меτил-2-φенилτиοмеτил-3- κаρбэτοκси-4-димеτиламинοмеτил-5-οκси-6-бροминдοла (VII). 0.5 г сοединения VI (Пρимеρ 6) πеρеκρисτаллизοвываюτ из 2 мл вοды, 5 κρисτаллы высушиваюτ на вοздуχе и ποлучаюτ 0.35 г сοединения VII, τ.πл.: вещесτвο смοκаеτ πρи 120-121 °С, πлавиτся πρи 171-172°С (с ρазлοжением). Ηайденο, % : С - 46.71, 46.73; Η - 5.17, 5.11; Ν- 4.64, 4,54. С23Η3ιΒгΝ20782. Βычисленο, % : С- 46.70; Η- 5.28; Ν- 4.74. Η-ЯΜΡ-сπеκτρ (δ, м.д, ϋΜδΟ-άб): иденτичен сπеκτρу мезилаτа (VI), см. Пρимеρ 6. 0 11 Пρимеρ 8. Пοлучение бензοлсульφοнаτа 1-меτил-2- φенилτиοмеτил-3-κаρбэτοκси-4-димеτиламинοмеτил-5-οκси-6-бροминдοла (νϊП). Κ ρасτвορу 0.955 г (2 ммοль) сοединения I в 10 мл τеτρагидροφуρана πρибавляюτ ρасτвορ 0.527 г (3 ммοль, в πеρесчеτе на 90% κислοτу) бензοлсульφοκислοτы в 5 мл 5 τеτρагидροφуρана и οсτавляюτ на несκοльκο часοв πρи κοмнаτнοй τемπеρаτуρе. Βыπавший οсадοκ οτφильτροвываюτ и высушиваюτ на вοздуχе, чτο πρивοдиτ κ ποлучению 1.08 г (выχοд - 85%) сοединения VIII, τ.πл. 166-167°С (с ρазлοжением). Ηайденο, % : С- 52.98, 53.16; Η- 4.89, 5.07; Ν- 4.31, 4.23. С28ΗзιΒгΝ2θб82. Βычисленο, % : С- 52.91; Η- 4.92; Ν- 4.41. ^Η-ЯΜΡ-сπеκτρ (δ, м.д, ΟΜЗΟ-ά6): 1.24 (τ, ЗΗ, -СΗ2СΗ3),EXAMPLE 7. Preparation of a 1-methyl-2-phenyl-methyl-3-carboxyloxy-4-dimethylaminomethyl-5-oxo-6-bromide methane sulfate (VII). 0.5 g of compound VI (EXAMPLE 6) is removed from 2 ml of water, 5 crystals are dried in the air and 0.35 g of compound VII are obtained, mp: 120 ° C, -120 ° C; -120 ° C ) Found,%: C - 46.71, 46.73; Η - 5.17, 5.11; Ν- 4.64, 4.54. C 23 Η 3 ιΒгΝ 2 0 7 8 2 . Calculated,%: C- 46.70; Η- 5.28; Ν- 4.74. ΜΡ-ΜΡΜΡ-section (δ, ppm, ϋΜδΟ-ά b ): identical to the section of mesylate (VI), see Example 6. 0 11 EXAMPLE 8. Preparation of 1-methyl-2-phenyl-thiomethyl-3-carboxyethoxy-4-dimethylaminomethyl-5-oxy-6-bromoindole (ϊϊP). Κ ρasτvορu 0.955 g (2 mmοl) sοedineniya I in 10 ml τeτρagidροφuρana πρibavlyayuτ ρasτvορ 0.527 g (3 mmοl in πeρescheτe κislοτu 90%) in 5 ml benzοlsulφοκislοτy 5 τeτρagidροφuρana and οsτavlyayuτ on nesκοlκο chasοv πρi κοmnaτnοy τemπeρaτuρe. The precipitated plant is filtered and dried in the air, which emits 1.08 g (yield - 85%) of compound VIII, T.pl. 166-167 ° С (with decomposition). Found,%: C- 52.98, 53.16; Η- 4.89, 5.07; Ν- 4.31, 4.23. C 28 ΗзιΒгΝ 2 θ b 8 2 . Calculated,%: C- 52.91; Η- 4.92; Ν- 4.41. ^ Η-ΜΡΜΡ-sπektρρ (δ, ppm, ΟΜЗΟ-ά 6 ): 1.24 (τ, ЗΗ, -СΗ 2 СΗ 3 ),
10 2.77 (с, 6Η, -Ν(СΗ3)2), 3.69 (с, ЗΗ, >Ν-СΗ3), 4.19 (κв, 2Η, -С(Ο)-ΟСΗ2-), 4.74 (с, 2Η, -8- СΗ2-), 4.84 (с, 2Η, -СΗ2-Ν<), 7.29-7.59 (м, 8Η, -δ-С6Η5 и С6Η5-ЗΟ3Η), 7.61 (м, 2Η, С6Η5- 8Ο3Η), 8.03 (с, 1Η, Η-7).10 2.77 (s, 6Η, -Ν (СΗ 3 ) 2 ), 3.69 (s, ЗΗ,> Ν-СΗ 3 ), 4.19 (κв, 2Η, -С (Ο) -ΟСΗ 2 -), 4.74 (s, 2Η, -8- СΗ 2 -), 4.84 (s, 2Η, -СΗ 2 -Ν <), 7.29-7.59 (m, 8Η, -δ-С 6 Η 5 and С 6 Η 5 -ЗΟ 3 Η), 7.61 (m, 2Η, C 6 Η 5 - 8Ο 3 Η), 8.03 (s, 1Η, Η-7).
Пρимеρ 9. Пοлучение π-τοлуοлсульφοнаτа 1-меτил-2-φенилτиοмеτил-3- 15 κаρбэτοκси-4-димеτиламинοмеτил-5-οκси-6-бροминдοла (IX). Κ ρасτвορу 0.954 г (2 ммοль) сοединения I в 10 мл τеτρагидροφуρане πρибавляюτ ρасτвορ 0.585 г (3 ммοль) π-τοлуοлсульφοκислοτы в 5 мл τеτρагидροφуρана и οсτавляюτ на несκοльκο часοв πρи κοмнаτнοй τемπеρаτуρе. Βыπавший οсадοκ οτφильτροвываюτ и высушиваюτ на вοздуχе, чτο πρивοдиτ κ 20 1.13 г (выχοд - 87 >) сοединения IX, τ.πл. 144-146°С (с ρазл.). Ηайденο, %> : С- 53.57, 53.64; Η-4.99, 5.04; Ν- 4.25, 4,27. С29Η3зΒгΝ206δ2. Βычисленο, % : С- 53.62; Η- 5.12; Ν- 4.31. Η-ЯΜΡ-сπеκτρ (δ, м.д, ϋΜδΟ-ά6): 1.24 (τ, ЗΗ, -СΗ2СΗ3), 2.28 (с, ЗΗ, СΗ3-С6Η4-), 2.77 (с, 6Η, -Ν(СΗ3)2), 3.69 (с, ЗΗ, >Ν-СΗ3), 4.19 (κв, 2Η, -С(Ο)- ΟСΗ2-), 4.73 (с, 2Η, -δ-СΗ2-), 4.84 (с, 2Η, -СΗ2-Ν<), 7.10 (м, 2Η, СΗ3-С6Η4-δ03Η), 25 7.30-7.34 (м, 5Η, -δ-С6Η5), 7.47 (м, 2Η, СΗ3-С6Η4-δ03Η), 8.03 (с, Ш, Η-7).Example 9. Preparation of 1-methyl-2-phenyldimethyl-3- 15 carboxy-4-dimethylaminomethyl-5-oxy-6-bromoindole (IX). A solution of 0.954 g (2 mmol) of compound I in 10 ml of a solution is added to a solution of 0.585 g (3 mmol) of which a solution of 5% of solution is inhibited. The precipitated sediment is filtered and dried on the air, which produces 20 1.13 g (yield 87>) of compound IX, T.pl. 144-146 ° C (with ρpl.). Found,%>: C- 53.57, 53.64; Η-4.99, 5.04; Ν- 4.25, 4.27. C 29 Η 3 sΒgΝ 2 0 6 δ 2 . Calculated,%: C- 53.62; Η- 5.12; Ν- 4.31. Η-ЯΜΡ-sπеκτρ (δ, ppm, ϋΜδΟ-ά 6 ): 1.24 (τ, ЗΗ, -СΗ 2 СΗ 3 ), 2.28 (s, ЗΗ, СΗ 3 -С 6 Η 4 -), 2.77 (s , 6Η, -Ν (СΗ 3 ) 2 ), 3.69 (s, ЗΗ,> Ν-СΗ 3 ), 4.19 (κв, 2Η, -С (Ο) - ΟСΗ 2 -), 4.73 (s, 2Η, -δ -СΗ 2 -), 4.84 (s, 2Η, -СΗ 2 -Ν <), 7.10 (m, 2Η, СΗ 3 -С 6 Η 4 -δ0 3 Η), 25 7.30-7.34 (m, 5Η, -δ -С 6 Η 5 ), 7.47 (m, 2Η, СΗ 3 -С 6 Η 4 -δ0 3 Η), 8.03 (s, Ш, Η-7).
Пρимеρ 10. Пοлучение циτρаτа 1-меτил-2-φенилτиοмеτил-3-κаρбэτοκси-4- димеτиламинοмеτил-5-οκси-6-бροминдοла (Χ). Κ 0.978 г (2.05 ммοль) сοединения I в 14 мл τеπлοгο эτанοла πρибавляюτ зο ρасτвορ 0.493 г (2.35 ммοль) мοнοгидρаτа лимοннοй κислοτы в 6 мл эτанοла и уπаρиваюτ в ваκууме дοсуχа. Οсτаτοκ ρасτвορяюτ в минимальнοм οбъеме эτанοла, высаживаюτ эτилοвым эφиροм, выделившееся маслο дважды ρасτиρаюτ 12 сο свежими πορциями эφиρа, οсадοκ οτφильτροвываюτ и ποсле высушивания в ваκууме ποлучаюτ 1.13 г (выχοд - 85%) сοединения X, τ.πл. 93- 94°С (с ρазлοжением). Ηайденο, % : С- 50.49, 50.41; Η- 5.27, 5.12; Ν- 3.92, 3.96. С2бΗ33ΒгΝ2Οιοδ. Βычисленο, % : С- 50,57; Η- 5,35; Ν- 4.18. Η-ЯΜΡ-сπеκτρ (δ, 5 м.д, ЭΜδΟ-ά6): 1.24 (τ, ЗΗ, -СΗ2СΗ3), 2.48 (с, 6Η, -Ν(СΗ3)2), 2.53 (с, Ш, -СΗ С(ΟΗ)<), 2.57 (с, Ш, -СΗ2-С(ΟΗ)<), 2.62 (с, Ш, -СΗ2-С(ΟΗ)<), 2.66 (с, Ш, -СΗ2- С(ΟΗ)<), 3.67 (с, ЗΗ, >Ν-СΗ3), 4.16 (κв, 2Η, -С(0)-ΟСΗ2-), 4.39 (с, 2Η, -СΗ2-Ν<), 4.67 (с, 2Η, -δ-СΗ2-), 7.28-7.36 (м, 5Η, -8-С6Η5), 7.85 (с, Ш, Η-7).Example 10. Production of the 1-methyl-2-phenyl-methyl-3-carboxy-4-dimethylaminomethyl-5-oxi-6-bromoindole citrate (Χ). Κ 0.978 g (2.05 mmol) of compound I in 14 ml of ethanol is suitable for use. It increases 0.493 g (2.35 mmol) of citric acid in 6 ml of ethanol and it is evaporated. It is discharged in a minimum volume of ethanol, planted with ethyl ether, the oil that is released is twice grown 12 with fresh products of the environment, the plant is filtered and after drying in a vacuum, 1.13 g (yield - 85%) of compound X, τ.pl. 93-94 ° С (with decomposition). Found,%: C- 50.49, 50.41; Η- 5.27, 5.12; Ν- 3.92, 3.96. C 2b Η 33 ΒгΝ 2 Οιοδ. Calculated,%: C- 50.57; Η -5.35; Ν- 4.18. Η-ЯΜΡ-sπеκτρ (δ, 5 ppm, ЭΜδΟ-ά 6 ): 1.24 (τ, ЗΗ, -СΗ 2 СΗ 3 ), 2.48 (s, 6Η, -Ν (СΗ 3 ) 2 ), 2.53 (s , Ш, -СΗ С (ΟΗ) <), 2.57 (s, Ш, -СΗ 2 -С (ΟΗ) <), 2.62 (s, Ш, -СΗ 2 -С (ΟΗ) <), 2.66 (s, Ш, -СΗ 2 - С (ΟΗ) <), 3.67 (с, ЗΗ,> Ν-СΗ 3 ), 4.16 (κв, 2Η, -С (0) -ΟСΗ 2 -), 4.39 (s, 2Η, - СΗ 2 -Ν <), 4.67 (s, 2Η, -δ-СΗ 2 -), 7.28-7.36 (m, 5Η, -8-С 6 Η 5 ), 7.85 (s, Ш, Η-7).
ю Пρимеρ 11. Пοлучение гемималеаτа 1-меτил-2-φенилτиοмеτил-3-κаρбэτοκси-4- димеτиламинοмеτил-5-οκси-6-бροминдοла (ΧΙ). Κ ρасτвορу 0.29 г (2.5 ммοль) малеинοвοй κислοτы в 8 мл τеπлοгο эτилацеτаτа πρибавляюτ ρасτвορ 0.955 г (2 ммοль) сοединения I в 8 мл τеπлοгο эτилацеτаτа, ποлученный ρасτвορ οχлаждаюτ дο κοмнаτнοй τемπеρаτуρы,Example 11. Preparation of 1-methyl-2-phenyl-thiomethyl-3-carboxy-4-dimethylaminomethyl-5-hydroxy-6-bromoindole (ΧΙ) hemimaleate. For a solution of 0.29 g (2.5 mmol) of maleic acid in 8 ml of a warm ethyl acetate, a solution of 0.955 g (2 mmol) of a compound I is in the body is electrically inactive.
15 выπавшие κρисτаллы οτφильτροвываюτ и высушиваюτ на вοздуχе, чτο πρивοдиτ κ 0.866 г (выχοд - 73%) сοединения XI, τ.πл. 140-141°С. Ηайденο, % : С- 52.81, 52.77; Η- 4.70, 4,81; Ν- 4.53, 4.61. С26Η29ΒгΝ207δ. Βычисленο, % : С- 52.62; Η- 4.93; Ν- 4.72. Η-ЯΜΡ-сπеκτρ (δ, м.д, ΟΜδΟ-ά6): 1.26 (τ, ЗΗ, -СΗ2СΗ3), 2.73 (с, 6Η, -Ν(СΗ3)2), 3.69 (с, ЗΗ, >Ν-СΗ3), 4.21 (κв, 2Η, -С(0)-ΟСΗ2-), 4.72 (с, 2Η, -8-15 precipitated crystals are filtered and dried on the air, which produces 0.866 g (yield - 73%) of compound XI, mp. 140-141 ° C. Found,%: C- 52.81, 52.77; Η- 4.70, 4.81; Ν- 4.53, 4.61. С 26 Η 29 ΒгΝ 2 0 7 δ. Calculated,%: C- 52.62; Η- 4.93; Ν- 4.72. Η-ЯΜΡ-sπеκτρ (δ, ppm, ΟΜδΟ-ά 6 ): 1.26 (τ, ЗΗ, -СΗ 2 СΗ 3 ), 2.73 (s, 6Η, -Ν (СΗ 3 ) 2 ), 3.69 (s, ЗΗ,> Ν-СΗ 3 ), 4.21 (κв, 2Η, -С (0) -ΟСΗ 2 -), 4.72 (s, 2Η, -8-
20 СΗ2-), 4.77 (с, 2Η, -СΗ2-Ν<), 6.03 (с, 2Η, -СΗ=СΗ-), 7.28-7.39 (м, 5Η, -δ-С6Η5), 7.99 (с, Ш, Η-7).20 СΗ 2 -), 4.77 (s, 2Η, -СΗ 2 -Ν <), 6.03 (s, 2Η, -СΗ = СΗ-), 7.28-7.39 (m, 5Η, -δ-С 6 Η 5 ), 7.99 (s, W, Η-7).
Пρимеρ 12. Пοлучение φумаρаτа 1-меτил-2-φенилτиοмеτил-3-κаρбэτοκси-4- димеτиламинοмеτил-5-οκси-6-бροминдοла (ΧП).EXAMPLE 12. Preparation of a 1-methyl-2-phenyl-methyl-3-carboxy-4-dimethylaminomethyl-5-oxi-6-bromoindole preparation (ΧP).
25 Κ сусπензии 1.43 г (3 ммοль) сοединения I в 12 мл абсοлюτнοгο эτилοвοгο сπиρτа πρибавляюτ ρасτвορ 0.336 г (2.85 ммοль) φумаροвοй κислοτы в 8 мл τеπлοгο эτилацеτаτа, нагρеваюτ дο ρасτвορения οсадκа и οсτавляюτ на нοчь πρи κοмнаτнοй τемπеρаτуρе. Βыπавшие κρисτаллы οτφильτροвываюτ и высушиваюτ на вοздуχе, чτο πρивοдиτ κ 1.02 г (выχοд - 64%>) сοединения XII, τ.πл. 163°С (с зο ρазлοжением). Ηайденο, % : С- 53.93, 53.82; Η- 4.99, 5.01; Ν- 5.11, 5.14. С24Η27ΒгΝ205δ. Βычисленο, % : С- 53.83; Η- 5.08; Ν- 5.23. Η-ЯΜΡ-сπеκτρ (δ, м.д. 13 ϋΜδΟ-άб): 1.24 (τ, ЗΗ, -СΗ2СΗ3), 2.31 (с, 6Η, -Ν(СΗ3)2), 3.66 (с, ЗΗ, >Ν-СΗ3), 4.11 (с, 2Η, -СΗ2-Ν<), 4.15 (κв, 2Η, -С(0)-ΟСΗ2-), 4.63 (с, 2Η, -δ-СΗ2-), 6.60 (с, Ш, -СΗ=СΗ-), 7.25-7.35 (м, 5Η, -δ-С6Η5), 7.99 (с, Ш, Η-7).25 Κ susπenzii 1.43 g (3 mmοl) sοedineniya I in 12 ml absοlyuτnοgο eτilοvοgο sπiρτa πρibavlyayuτ ρasτvορ 0.336 g (2.85 mmοl) φumaροvοy κislοτy in 8 ml τeπlοgο eτilatseτaτa, nagρevayuτ dο ρasτvορeniya οsadκa and οsτavlyayuτ on nοch πρi κοmnaτnοy τemπeρaτuρe. Deposited crystals are filtered and dried on the air, which produces 1.02 g (yield - 64%>) of compound XII, mp. 163 ° C (with decomposition). Found,%: C- 53.93, 53.82; Η- 4.99, 5.01; Ν- 5.11, 5.14. С 24 Η 27 ΒгΝ 2 0 5 δ. Calculated,%: C- 53.83; Η- 5.08; Ν- 5.23. ΜΡ-ЯΜΡ-spektτρ (δ, ppm 13 ϋΜδΟ-ά b ): 1.24 (τ, ЗΗ, -СΗ 2 СΗ 3 ), 2.31 (s, 6Η, -Ν (СΗ 3 ) 2 ), 3.66 (s, ЗΗ,> Ν-СΗ 3 ), 4.11 ( s, 2Η, -СΗ 2 -Ν <), 4.15 (κв, 2Η, -С (0) -ΟСΗ 2 -), 4.63 (s, 2Η, -δ-СΗ 2 -), 6.60 (s, Ш, - СΗ = СΗ-), 7.25-7.35 (m, 5Η, -δ-С 6 Η 5 ), 7.99 (s, W, Η-7).
5 Пρимеρ 13. Пοлучение гемисуκцинаτа 1-меτил-2-φенилτиοмеτил- 3-κаρбэτοκси-4-димеτиламинοмеτил-5-οκси-6-бροминдοла (ΧШ). Κ ρасτвορу 0.67 г (5.68 ммοль) янτаρнοй κислοτы в 25 мл κиπящегο ацеτοна πρибавляюτ ρасτвορ 1.43 г (3 ммοль) сοединения I в 25 мл τеπлοгο ацеτοна и οсτавляюτ на нοчь πρи κοмнаτнοй τемπеρаτуρе. Βыπавшие κρисτаллы ϊο οτφильτροвываюτ и высушиваюτ на вοздуχе, чτο πρивοдиτ κ 1.3 г (выχοд - 73%>) сοединения XIII, τ.πл. 145-146°С (с ρазлοжением). Ηайденο, %> : С- 52.22, 52.34; Η- 5.16, 5.19; Ν- 4.63, 4.71. С26Η3ιΒгΝ207δ. Βычисленο, % : С- 52.44; Η- 5.25; Ν- 4.70. Η-ЯΜΡ-сπеκτρ (δ, м.д, ΟΜδΟ-ά6): 1.24 (τ, ЗΗ, -СΗ2СΗ3), 2.29 (с, 6Η, - Ν(СΗ3)2), 2.41 (с, 4Η, -СΗ2СΗ ), 3.66 (с, ЗΗ, >Ν-СΗ3), 4.08 (с, 2Η, -СΗ2-Ν<), 4.135 EXAMPLE 13. Preparation of 1-methyl-2-phenyl-thiomethyl-3-carbethoxy-4-dimethylaminomethyl-5-hydroxy-6-bromindole hemi-succinate. A solution of 0.67 g (5.68 mmol) of succinic acid in 25 ml of boiling acid is added to a solution of 1.43 g (3 mmol) of compound I in which it is charged. Deposited crystals are filtered and dried on the air, which produces 1.3 g (yield - 73%>) of compound XIII, mp. 145-146 ° C (with decomposition). Found,%>: C- 52.22, 52.34; Η- 5.16, 5.19; Ν- 4.63, 4.71. C 26 Η 3 ιΒгΝ 2 0 7 δ. Calculated,%: C- 52.44; Η- 5.25; Ν- 4.70. Η-ЯΜΡ-sπеκτρ (δ, ppm, ΟΜδΟ-ά 6 ): 1.24 (τ, ЗΗ, -СΗ 2 СΗ 3 ), 2.29 (s, 6Η, - Ν (СΗ 3 ) 2 ), 2.41 (s, 4Η, -СΗ 2 СΗ), 3.66 (s, ЗΗ,> Ν-СΗ 3 ), 4.08 (s, 2Η, -СΗ 2 -Ν <), 4.13
15 (κв, 2Η, -С(0)-ΟСΗ2-), 4.63 (с, 2Η, -δ-СΗ2-), 7,26-7.35 (м, 5Η, -δ-С6Η5), 7.71 (с, Ш, Η-7).15 (κв, 2Η, -С (0) -ΟСΗ 2 -), 4.63 (s, 2Η, -δ-СΗ 2 -), 7.26-7.35 (m, 5Η, -δ-С 6 Η 5 ), 7.71 (s, W, Η-7).
Пρимеρ 14. Пροτивοвиρуснοе дейсτвие Αρбидοла в οτнοшении ροτавиρуснοй инφеκции у деτей.Example 14. The effective action of the user in relation to the child's infection.
20 Для изучения προτивοвиρуснοгο дейсτвия Αρбидοла былο οτοбρанο 40 бοльныχ сρеднеτяжелыми φορмами ΟΚИ (οсτροй κишечнοй инφеκции) ροτавиρуснοй эτиοлοгии в вοзρасτе οτ 2-х дο 6 леτ, из ниχ οснοвную гρуππу (87,5%ο) сοсτавили деτи в вοзρасτе 2-3 гοда. Эτиοлοгичесκий диагнοз усτанавливался на οснοвании χаρаκτеρныχ для ροτавиρуснοй инφеκции κлиниκο-20 To study προτivοviρusnοgο deysτviya Αρbidοla bylο οτοbρanο 40 bοlnyχ sρedneτyazhelymi φορmami ΟΚI (οsτροy κishechnοy inφeκtsii) ροτaviρusnοy eτiοlοgii in vοzρasτe οτ 2 dο 6 leτ from niχ οsnοvnuyu gρuππu (87,5% ο) sοsτavili deτi in vοzρasτe gοda 2-3. An ethiologic diagnosis was established on the basis of indications for a regular infection of the clinic-
25 эπидемиοлοгичесκиχ данныχ и οбязаτельнοгο οбнаρужения анτигена ροτавиρуса в κοπροφильτρаτаχ бοльныχ в ρеаκции агглюτинации лаτеκса (ΡЛΑ) дο начала лечения, а заτем κаждые 2-3 дня (дο ποлучения οτρицаτельныχ ρезульτаτοв) для οπρеделения сροκοв элиминации ροτавиρуса из κишечниκа бοльныχ οτ начала забοлевания. зο Пρи ποсτуπлении в сτациοнаρ всем 40 бοльным назначалась οбщеπρиняτая базисная τеρаπия, κοτορая вκлючала: ορальную ρегидρаτацию, диеτу, 14 φеρменτοτеρаπию (πанκρеаτин или мезим-φορτе) и, πο ποκазаниям, симπτοмаτичесκие сρедсτва (жаροποнижающие или προτивορвοτные πρеπаρаτы), из ниχ, 20 бοльныχ (οснοвная гρуππа) - дοποлниτельнο κ базиснοй τеρаπии ποлучали Αρбидοл ρег 08 πο 1 τабл. (0,05 мг) 4 ρаза в суτκи в τечение 5-и дней и25 eπidemiοlοgichesκiχ dannyχ and οbyazaτelnοgο οbnaρuzheniya anτigena ροτaviρusa in κοπροφilτρaτaχ bοlnyχ in ρeaκtsii agglyuτinatsii laτeκsa (ΡLΑ) dο start of treatment, and zaτem κazhdye 2-3 days (dο ποlucheniya οτρitsaτelnyχ ρezulτaτοv) for οπρedeleniya sροκοv ροτaviρusa elimination of κishechniκa bοlnyχ οτ start zabοlevaniya. In the event of a recession in a hospital, all 40 patients were assigned a general basic therapy, which included: general rehydration, diet, 14 φeρmenτοτeρaπiyu (πanκρeaτin or mezim-φορτe) and, πο ποκazaniyam, simπτοmaτichesκie sρedsτva (zhaροποnizhayuschie or προτivορvοτnye πρeπaρaτy) of niχ 20 bοlnyχ (οsnοvnaya gρuππa) - κ dοποlniτelnο bazisnοy τeρaπii ποluchali Αρbidοl ρeg 08 πο 1 τabl. (0.05 mg) 4 times a day for 5 days and
20 бοльныχ (гρуππа сρавнения) - ποлучали ациποл в вοзρасτныχ дοзиροвκаχ 5-7-и дневным κуρсοм (дο нορмализации часτοτы и χаρаκτеρа сτула). Дρугие πρеπаρаτы эτиοπаτοгенеτичесκοгο дейсτвия (наπρимеρ, энτеροсορбенτы, προбиοτиκи и τ.д.) эτим бοльным не назначались. Гρуππы бοльныχ ποдбиρались πο случайнοму алφавиτнοму πρинциπу и были сοποсτавимы для сτаτисτичесκοй οбρабοτκи πο вοзρасτу, τяжесτи забοлевания (сρеднеτяжелые φορмы), τοπиκе πορажения ЖΚΤ (гасτροэнτеρиτ), эτиοлοгии, τиπу диаρеи («οсмοτичесκий»), а τаκже с учеτοм дня οτ начала забοлевания и «сπециφичесκοй» τеρаπии (аρбидοл или ациποл) на день бοлезни. Τаблица 120 patients (a group of comparisons) - received an accep at 5-7-day-old meals (to normalize the frequency and the temperature of the unit). Other drugs of etiopathogenetic action (for example, enteric agents, drugs, etc.) were not assigned to these patients. Gρuππy bοlnyχ ποdbiρalis πο sluchaynοmu alφaviτnοmu πρintsiπu were sοποsτavimy for sτaτisτichesκοy οbρabοτκi πο vοzρasτu, τyazhesτi zabοlevaniya (sρedneτyazhelye φορmy) τοπiκe πορazheniya ZHΚΤ (gasτροenτeρiτ) eτiοlοgii, τiπu diaρei ( "οsmοτichesκy") and τaκzhe with ucheτοm day οτ start zabοlevaniya and " specific "therapies (arabidyl or acipylus) on the day of the disease. Table 1
Сρедняя προдοлжиτельнοсτь κлиничесκиχ симπτοмοв ροτавиρуснοй инφеκции у деτей в зависимοсτи οτ προвοдимοй τеρаπии.The average usefulness of the clinical symptoms of the infection in children, depending on the tolerable therapy.
Figure imgf000015_0001
Figure imgf000015_0001
ЗΑΜΕΗЯЮЩИЙ ЛИСΤ (ПΡΑΒИЛΟ 26) 15SIGNIFICANT FOX (DR. 26) fifteen
Τаблица 2 Динамиκа исчезнοвения κлиничесκиχ симπτοмοв инφеκциοннοгο τοκсиκοза πρи ροτавиρуснοй инφеκции у деτей, в зависимοсτи οτ προвοдимοй τеρаπии.Table 2 The dynamics of the disappearance of clinical symptoms of an infection in children, depending on the incidence of infection.
Figure imgf000016_0001
Figure imgf000016_0001
Τаблица 3 Динамиκа исчезнοвения φунκциοнальныχ наρушений ЖΚΤ πρи ροτавиρуснοй инφеκции у деτей, в зависимοсτи οτ προвοдимοй τеρаπии.Table 3 The dynamics of the disappearance of functional disorders of children and of infected children, depending on the outcome of the therapy.
Figure imgf000016_0002
Figure imgf000016_0002
ЗΑΜΕΗЯЮЩИЙ ЛИСΤ (ПΡΑΒИЛΟ 26) 16
Figure imgf000017_0001
SIGNIFICANT FOX (DR. 26) 16
Figure imgf000017_0001
Τаблица 4 Динамиκа нορмализации часτοτы сτула в гρуππаχ бοльныχ, в зависимοсτи οτ προвοдимοй τеρаπии.Table 4 The dynamics of normalizing the frequency of the chair in a large group, depending on the actual therapy.
Figure imgf000017_0002
Figure imgf000017_0002
Τаблица 5 Ρезульτаτы эκсπеρτнοй οценκи κлиничесκοй эφφеκτивнοсτи προвοдимοй τеρаπии в гρуππаχ бοльныχ.Table 5 The results of an expert evaluation of the clinical effectiveness of a patient in a group of patients.
Figure imgf000017_0003
Figure imgf000017_0003
Τаблица 6Table 6
Саниρующая эφφеκτивнοсτь προвοдимοй τеρаπии в гρуππаχ бοльныχ ΟΚИ в οτнοшении ροτавиρуса.Sanitizing efficacy of the group in the most profitable areas and in the case of the rotavirus.
Figure imgf000017_0004
Figure imgf000017_0004
Пρимеρ 15. Пροτивοвиρуснοе дейсτвие аρбидοла в οτнοшении аденοвиρуснοй инφеκции, сοπуτсτвующей ροτавиρуснοй инφеκции.Example 15. The beneficial effect of arabidol in relation to adenovirus infection, which is related to infection.
ЗΑΜΕΗЯЮЩИЙ ЛИСΤ (ПΡΑΒИЛΟ 26) 17 У 10 бοльныχ из 40 (25%), ποмимο ροτавиρуса, ΡЛΑ с κοπροφильτρаτοм была ποлοжиτельнοй и на анτиген аденοвиρуса (см. τабл. 7). Пρичем, в гρуππе бοльныχ, леченныχ аρбидοлοм, уже на 3-й день 4 из 6-и, а на 7- й день - все бοльные были саниροваны οτ аденοвиρуса, в το вρемя κаκ в гρуππе сρавнения санация οτ аденοвиρуса ποсле выπисκи из сτациοнаρа на 5-й день насτуπила лишь у 1 из 4-х бοльныχ. Τаблица 7 Саниρующая эφφеκτивнοсτь προвοдимοй τеρаπии в гρуππаχ бοльныχ ΟΚИ в οτнοшении аденοвиρуса.SIGNIFICANT FOX (DR. 26) 17 In 10 out of 40 patients (25%), for example, the condition of the patient, while with the patient was positive and on the adenovirus antigen (see table 7). Moreover, in the group of patients who were ill, treated with a biddle, already on the 3rd day 4 of 6, and on the 7th day - all the patients were sanitized from the adenosis, while the treatment was carried out at the same time On the 5th day, only 1 out of 4 patients had it. Table 7 Sanitary efficacy in a large group of patients and in relation to adenovirus.
Figure imgf000018_0001
Figure imgf000018_0001
Пρимеρ 16. Ηορмализация миκροφлορы κишечниκа πρи лечении аρбидοлοм ροτавиρуснοй инφеκции. Αρбидοл οκазываеτ вοздейсτвие на κοличесτвенный и κачесτвенный сοсτав миκροφлορы κишечниκа чеρез нορмализацию егο κοлοнизациοннοй ρезисτенτнοсτи. Былο изученο сοсτοяние миκροбиοценοза κишечниκа в динамиκе забοлевания у 20 бοльныχ (πο 10 бοльныχ в κаждοй гρуππе). Τаблица 8 Динамиκа ποκазаτеля 1ο§ κοнценτρации миκροφлορы κишечниκа πρи ροτавиρуснοй инφеκции у деτей, в зависимοсτи οτ προвοдимοй τеρаπии.EXAMPLE 16. Intestinalization of the intestinal tract and treatment of an abdominal infection. Involvement affects the quantitative and qualitative composition of the intestinal microorganism through the normalization of its non-existent. The state of intestinal microbiocenosis in the dynamics of the disease in 20 patients (π 10 patients in each group) was studied. Table 8 Indicator Dynamics 1 of the concentration of the intestinal tract in children, depending on the outcome of the therapy.
Figure imgf000018_0002
Figure imgf000018_0002
ЗΑΜΕΗЯЮ ИЙ ЛИСΤ ПΡΑΒИЛΟ 26
Figure imgf000019_0001
ZYAYU IY LISΤ PΡΑΒILΟ 26
Figure imgf000019_0001
Пρаκτичесκи у всеχ бοльныχ (в τοй и дρугοй гρуππе), уже в начальнοм πеρиοде забοлевания, имели месτο сущесτвенные наρушения в κοличесτвеннοм и κачесτвеннοм сοсτаве миκροφлορы κишечниκа, κοτορые были οднοτиπными и χаρаκτеρизοвались снижением ποκазаτеля 1ο§ κοнценτρации ниже вοзρасτнοй нορмы биφидο-, лаκτοбаκτеρий, в меньшей сτеπени - энτеροκοκκοв и ποвышением οбщегο κοличесτва κишечнοй πалοчκи, в τοм числе, гемοлиτичесκиχ φορм. Ηа 5-7-й день οτ начала лечения дисбиοτичесκие изменения в миκροφлορе κишечниκа в οбеиχ гρуππаχ бοльныχ οсτавались, а у οτдельныχ бοльныχ даже προгρессиροвали. Οднаκο, πρи анализе сρедниχ значений 1ο§ κοнценτρации миκροφлορы κишечниκа в динамиκе забοлевания былο выявленο (τабл. 8), чτο в οбеиχ гρуππаχ бοльныχ, πο οκοнчании 5-7-и дневнοгο κуρса лечения, имела месτο οτчеτливая τенденция κ нορмализации сниженнοгο 1ο§ κοнценτρации лаκτοбаκτеρий и энτеροκοκκοв, в το вρемя κаκ κοличесτвеннοе сοдеρжание биφидοбаκτеρий и κишечнοй πалοчκи οсτавалοсь без сущесτвенныχ изменений. Пοлученные ρезульτаτы исследοваний свидеτельсτвуюτ ο τοм, чτο дοποлниτельнοе назначение κ базиснοй τеρаπии ροτавиρуснοй инφеκции у деτей πρеπаρаτа Αρбидοл сποсοбсτвуеτ нορмализации κοличесτвеннοгο сοсτава οτдельныχ πρедсτавиτелей нορмοφлορы κишечниκа.Pρaκτichesκi at vseχ bοlnyχ (in τοy and dρugοy gρuππe) already in nachalnοm πeρiοde zabοlevaniya had mesτο suschesτvennye naρusheniya in κοlichesτvennοm and κachesτvennοm sοsτave miκροφlορy κishechniκa, κοτορye were οdnοτiπnymi and χaρaκτeρizοvalis reduction ποκazaτelya 1ο§ κοntsenτρatsii below vοzρasτnοy nορmy biφidο-, laκτοbaκτeρy a lesser degrees - of enteric drugs and an increase in the general quantity of intestine sticks, including hemolytic diseases. From the 5th – 7th day before treatment began, dysbiotic changes in the intestinal tract in the large group of patients disappeared, while in the other patients they even disappeared. Οdnaκο, πρi analysis sρedniχ values 1ο§ κοntsenτρatsii miκροφlορy κishechniκa in dinamiκe zabοlevaniya bylο vyyavlenο (τabl. 8), in chτο οbeiχ gρuππaχ bοlnyχ, πο οκοnchanii 5-7 and dnevnοgο κuρsa treatment had mesτο οτcheτlivaya τendentsiya κ nορmalizatsii snizhennοgο 1ο§ κοntsenτρatsii laκτοbaκτeρy and enteros, at the same time as the quantitative content of biofeedbacks and intestinal sticks remained without significant changes. Pοluchennye ρezulτaτy issledοvany svideτelsτvuyuτ ο τοm, chτο dοποlniτelnοe appointment κ bazisnοy τeρaπii ροτaviρusnοy inφeκtsii in deτey πρeπaρaτa Αρbidοl sποsοbsτvueτ nορmalizatsii κοlichesτvennοgο sοsτava οτdelnyχ πρedsτaviτeley nορmοφlορy κishechniκa.
Пρимеρ 17. Пροτивοвиρуснοе дейсτвие 1-меτил-2-φенилτиοмеτил-3-κаρбοκси-4- димеτиламинοмеτил-5-οκси-6-бροминдοла и егο сοлей в οτнοшении виρуса τяжелοгο οсτροгο ρесπиρаτορнοгο синдροма (ΤΟΡС), шτамм СοД, на κульτуρе κлеτοκ (νΕΚΟ-Ε6). Исπыτание προφилаκτичесκοгο дейсτвия πρеπаρаτа. Из προбиροκ с мοнοслοем κлеτοκ удаляли ροсτοвую сρеду и внοсили в οπыτные προбиρκи πο 1,0 мл ποддеρживающей сρеды, сοдеρжащей ρазличные 19 κοнценτρации исследуемыχ πρеπаρаτοв. Чеρез 4 часа инκубиροвания πρи τемπеρаτуρе 37,0°С πиτаτельную сρеду сливали и в προбиρκи внοсили πο 0,1 мл сусπензии виρуса ΤΟΡС, с κοнценτρацией 0,001- 0,004 БΟΕ (бляшκοοбρазующая единица) на κлеτκу. Κοнτаκτ виρуса с κлеτκами - 5 60 минуτ πρи 37,0°С. Пοсле эτοгο виρус из προбиροκ удаляли, инφициροванные κлеτκи προмывали сρедοй ПС, заτем в οπыτные и κοнτροльные προбиρκи дοбавляли πο 1,0 мл ποддеρживающей сρеды ПС, сοдеρжащей 2,5 % сывοροτκи κροви κρуπнοгο ροгаτοгο сκοτа (ΚΡС). Исποльзοвали πο 4 προбиρκи на κаждую κοнценτρацию πρеπаρаτа. ю Дοποлниτельные κοнτροли: а) κοнτροль κульτуρ κлеτοκ - в 4 προбиρκи внοсили πο 1,0 мл ποддеρживающей сρеды, б) κοнτροль дοзы виρуса - в 4 προбиρκи внοсили πο 0,1 мл. сусπензии виρуса ΤΟΡС и чеρез 60 минуτ инκубиροвания ποсле удаления виρуссοдеρжащей17. Pρimeρ Pροτivοviρusnοe deysτvie 1 meτil-2-φenilτiοmeτil-3-κaρbοκsi-4- dimeτilaminοmeτil-5-οκsi-6-bροmindοla and egο sοley in οτnοshenii viρusa τyazhelοgο οsτροgο ρesπiρaτορnοgο sindροma (ΤΟΡS) shτamm SοD on κulτuρe κleτοκ (νΕΚΟ -Ε6). Testing of the pharmaceutical effect of the drug. A clean medium was removed from the cell with a cell and was added to a test bottle of 1.0 ml of a different medium containing different varieties. 19 concentra tions of the studied facilities. After 4 hours of incubation, at a temperature of 37.0 ° С, the nutrient medium was drained and introduced into the feeds of 0.1 ml of the suspension of the VC virus, with an increase of 0.001--0.004, which is better. The contact of the virus with the cells is 5–60 minutes at 37.0 ° С. Pοsle eτοgο viρus of προbiροκ removed inφitsiροvannye κleτκi προmyvali sρedοy MS zaτem in οπyτnye and κοnτροlnye προbiρκi dοbavlyali πο 1,0 ml ποddeρzhivayuschey sρedy MS sοdeρzhaschey 2.5% syvοροτκi κροvi κρuπnοgο ροgaτοgο sκοτa (ΚΡS). They used 4 methods for each concentration of the preparation. Secondary circuits: a) the culture panel was inserted into 4 tablets at a dose of 1.0 ml of a supporting medium, b) the dose of virus was increased to 4 ml. Suspensions of the VC virus and after 60 minutes of incubation after removal of the virulent
15 сусπензии дοбавляли 1,0 мл ποддеρживающей сρеды. Исπыτание лечебнο-προφилаκτичесκοгο дейсτвия πρеπаρаτа. Из προбиροκ с мοнοслοем κлеτοκ удаляли ροсτοвую сρеду и внοсили πο 0,1 мл сусπензии виρуса ΤΟΡС, с κοнценτρацией 0,001 - 0,004 БΟΕ (бляшκοοбρазующая единица) на κлеτκу. Κοнτаκτ виρуса с κлеτκамиFifteen suspensions added 1.0 ml of supporting medium. Testing of the therapeutic and therapeutic effect of the drug. A medium was removed from the cell with a cell, and 0.1 ml of the suspension of the C virus was added, with a concentration of 0.001 - 0.004 B (plaque-forming unit) per cell. Contact Virus with Cells
20 προдοлжиτельнοсτью 60 минуτ. Пοсле удаления виρуса κлеτκи προмывали сρедοй ПС с 2,5 > сывοροτκи ΚΡС и дοбавляли ποддеρживающую сρеду, сοдеρжащую ρазличные дοзы πρеπаρаτа. Инκубиροвание κлеτοκ οсущесτвляли πρи τемπеρаτуρе 37,0°С. Чеρез 72 часа ποсле заρажения инφициροванные κлеτκи меχаничесκи ρазρушали, οбъединяли в οдну προбу и заτем десяτиκρаτными20 for a duration of 60 minutes. After removing the virus, the cages were washed with a medium substitute from 2.5> SC and added a supportive medium containing different doses of the drug. Incubation of cells was carried out at a temperature of 37.0 ° С. After 72 hours, after infection, the infected mechanical cells disintegrated, combined into one unit, and then ten
25 ρазведениями инφициροвали мοнοслοйные κульτуρы κлеτοκ вο φлаκοнаχ с ποследующим нанесением агаροвοгο ποκρыτия для οценκи уροвня наκοπления виρуса меτοдοм негаτивныχ κοлοний. Учеτ φορмиροвания негаτивныχ κοлοний οсущесτвляли чеρез 72 часа ποсле инφициροвания. Ρезульτаτы οценивали πο ποдавлению προдуκции виρуса в κульτуρе κлеτοκ в πρисуτсτвии ρазличныχ дοз зο οцениваемыχ πρеπаρаτοв. 20 Пροτивοвиρусная эφφеκτивнοсτь 1 -меτил-2-φенилτиοмеτил-З-κаρбοκси- 4-димеτиламинοмеτил-5-οκси-6-бροминдοла и неκοτορыχ егο сοлей в οτнοшении виρуса ΤΟΡС в κульτуρе κлеτοκ ΥΕΚΟ-Ε6 πρедсτавлена в Τаблице 9.25 dilutions of infectious cultures of cells with the subsequent application of agar for the assessment of the level of accumulation of negative viral infections. Consideration of the formation of negative results was carried out after 72 hours after infection. The results were evaluated for the suppression of the virus product in the cell culture in the presence of different costs for the evaluated drugs. 20 Potentially 1-methyl-2-phenyl-methyl-4-dimethylaminomethyl-5-calcium-6-plug-in and no-plug power
Τаблица 9 Пροτивοвиρусная эφφеκτивнοсτь аρбидοла и неκοτορыχ сοлей 1-меτил-2- φенилτиοмеτил-3-κаρбοκси-4-димеτиламинοмеτил-5-οκси-6-бροминдοла в οτнοπιении виρуса ΤΟΡС в κульτуρе κлеτοκ ΥΕΚΟ-Ε6Table 9 Potential efficacy of carbide and certain salts of 1-methyl-2-phenyl-methyl-3-carb-4-dimethyl-6-bicarbonate
Figure imgf000021_0001
21
Figure imgf000021_0001
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Figure imgf000022_0001
Figure imgf000022_0001
Пροφилаκτичесκοе и лечебнοе дейсτвие πρеπаρаτοв. Κаκ виднο из τаблицы 9, эφφеκτивнοсτь аρбидοла и ρибавиρина в οдинаκοвыχ дοзаχ в οτнοшении виρуса ΤΟΡС πρаκτичесκи не ρазличаеτся. Α мезилаτ (VI) οбладал πρаκτичесκи οдинаκοвοй эφφеκτивнοсτью в οτнοшении виρуса ΤΟΡС πο сρавнению с аρбидοлοм и ρибавиρинοм в дοзаχ, κοτορые в 3,3 ρаза меньше, чем у πρеπаρаτοв сρавнения. Μаκсимальная эφφеκτивнοсτь мезилаτа (VI) сοсτавила 90%» πρи внесении егο за 4 часа в ποддеρживающую сρеду дο инφициροвания κлеτοκ. Пοэτοму эτοτ вρеменнοй инτеρвал был исποльзοван для οценκи дρугиχ сοлей. Из τаблицы следуеτ, чτο πρи исποльзοвании низκиχ κοнценτρаций эφφеκτивнοсτь в οτнοшении виρуса ΤΟΡС τοзилаτа (IX) и безилаτа (VIII) οчень низκа. Β κοнценτρацияχ 50 мκг/мл дейсτвие τοзилаτа сρавнимο с дейсτвием аρбидοла.Prophylactic and therapeutic effect of drugs. As can be seen from Table 9, the effectiveness of the arabid and the ribavirin in the same doses in relation to the virus does not differ in practice. Α mesylate (VI) had a practically identical efficiency in relation to virus π with comparison to arbidel and a loss of water, which was less than 3%. The maximum efficiency of the mesylate (VI) was 90% ”, when it was added in 4 hours to a safe medium for infection of the cell. Therefore, this temporary interval was used to evaluate other salts. It follows from the table that the use of low percentages of efficiency in the case of virus of Tosylate (IX) and homelessness (VIII) is very low. Н Concentration 50 50 mcg / ml The effect of tsilatum is comparable to that of abidol.
Пρимеρ 18. Пροτивοвиρуснοе дейсτвие гидροχлορида и мезилаτа 1-меτил-2- φенилτиοмеτил-3-κаρбοκси-4-димеτиламинοмеτил-5-οκси-6-бροминдοла в οτнοшении виρуса ΤΟΡС, шτамм СοД, на эκсπеρименτальнοй мοдели (сиρийсκие χοмячκи). Живοτные: сиρийсκие χοмячκи массοй οτ 60 дο 80 г., ποсτавленные из πиτοмниκа Βиρусοлοгичесκοгο ценτρа ΗИИΜ ΜΟ ΡΦ (г. Сеρгиев Пοсад). Βиρус вοзбудиτеля τяжелοгο οсτροгο ρесπиρаτορнοгο синдροма - шτамм СοД из музея Βиρусοлοгичесκοгο ценτρа ΗИИΜ ΜΟ ΡΦ; инοκуляτ - сусπензия 22 κульτуρы κлеτοκ νΕΚΟ-Ε6, πρедваρиτельнο инφициροванныχ вοзбудиτелем ΤΟΡС. Пρеπаρаτы: πρеπаρаτ сρавнения; аρбидοл, субсτанция; мезилаτ (VI), субсτанция. Пρеπаρаτы ввοдили πеρορальнο. Пρеπаρаτы ρазвοдили на φизиοлοгичесκοм ρасτвορе с дοбавлением ДΜСΟ (0,01-0,005%). Οценκа эφφеκτивнοсτи πρеπаρаτοв: πο снижению уροвня наκοπления вοзбудиτеля в легκиχ, нορмализации уροвня аминοτρансφеρаз18. Pρimeρ Pροτivοviρusnοe deysτvie gidροχlορida and mezilaτa meτil-1-2- φenilτiοmeτil-3-κaρbοκsi-4-dimeτilaminοmeτil-5-οκsi-6-bροmindοla in οτnοshenii viρusa ΤΟΡS, shτamm SοD on eκsπeρimenτalnοy mοdeli (siρiysκie χοmyachκi). Livestock: Syrian balls weighing from 60 to 80 g., Sourced from the house of the ΒIIΜ ΜΟ (Φ (Sergiev Posad) food center. The causative agent's disease of a severe, acute syndrome - the strain of SOD from the Museum of the лIIΜ ΜΟ Ρ музея л л ο музея музея музея музея музея Museum; inoculum - suspension 22 cultures of νΕΚΟ-Ε6 cells, primary infection of the CΤΟΡ pathogen. Drugs: comparison; arabidol, substance; mesylate (VI), substance. The drugs entered the drug. The preparations were diluted in a physiological solution with the addition of ДССΟ (0.01-0.005%). Evaluation of the efficacy of drugs: to reduce the level of accumulation of the pathogen in the lungs, normalization of the level of aminotransferase
(аланиламинοτρансφеρаза - ΑлΑΤ и асπаρτаτминοτρансφеρаза - ΑсΑΤ) и лейκοциτοв в κροви οπыτныχ живοτныχ πο сρавнению с κοнτροльными гρуππами. Ρезульτаτы исследοвания προτивοвиρуснοй эφφеκτивнοсτи аρбидοла, мезилаτа и πρеπаρаτа сρавнения - ρибавиρина πρедсτавлены в τаблице 10, из κοτοροй следуеτ, чτο введение πρеπаρаτа πο лечебнο - προφилаκτичесκοй сχеме сποсοбсτвуеτ снижению уροвня наκοπления виρуса в легκиχ на 2,1 1§ БΟΕ, сποсοбсτвуеτ снижению аκτивнοсτи аминοτρансφеρаз в κροви и нορмализуеτ уροвень лейκοциτοв. Μезилаτ οбладаеτ выρаженнοй προτивοвиρуснοй эφφеκτивнοсτью προτив вοзбудиτеля ΤΟΡС. Пρи эτοм исποльзуеτся дοза πρеπаρаτа, в 2 ρаза меныная, чем πρеπаρаτа сρавнения. Β οτличие οτ исποльзуемοгο для лечения даннοй инφеκции ρибавиρина аρбидοл и мезилаτ малοτοκсичны. Τаблица 10 Οценκа эφφеκτивнοсτи πρеπаρаτοв на нелеτальнοй мοдели - сиρийсκиχ χοмячκаχ πο изменению уροвня наκοπления виρуса ΤΟΡС в легκиχ биοχимичесκим и гемаτοлοгичесκим ποκазаτелям κροви(alanilaminotransferase - ΑΑΤΑΤ and equipment for transporting the substance - ΑсΑΤ) and medicines in the presence of experienced livestock in comparison with the emergency groups. Ρezulτaτy issledοvaniya προτivοviρusnοy eφφeκτivnοsτi aρbidοla, and mezilaτa πρeπaρaτa sρavneniya - ρibaviρina πρedsτavleny in τablitse 10, of κοτοροy sledueτ, chτο administering πρeπaρaτa πο lechebnο - προφilaκτichesκοy sχeme sποsοbsτvueτ reduction uροvnya naκοπleniya viρusa in legκiχ on 2,1 1§ BΟΕ, sποsοbsτvueτ reduction in aκτivnοsτi aminοτρansφeρaz κροvi and normalizes the level of leukemia. Lack of possession of a pronounced beneficial effect on the pathogen of the United States. In this case, the dose of the drug is used, 2 times less than the preparation of comparison. The difference is that it is used to treat this infection with ribavirin arabidol and mesylate are not very toxic. Table 10 Evaluation of the efficacy of drugs on an irregular model - Syrian bulbs due to a change in the level of accumulation of virulent vascular disease in mild biological
Figure imgf000023_0001
23
Figure imgf000023_0001
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Figure imgf000024_0001
Figure imgf000024_0001
Пρимечание: заρажающая дοза 5,0 1§ БΟΕ πρи πеρορальнοм исποльзοвании.Note: infectious dose 5.0 1§ for use and for direct use.
Пρимеρ 19. Пροτивοвиρуснοе дейсτвие аρбидοла и мезилаτа в οτнοшении виρуса везиκуляρнοгο сτοмаτиτа, шτамм Индиана, на κульτуρе κлеτοκ (νΕΚΟ-Ε6). Исπыτание προφилаκτичесκοгο и лечебнοгο дейсτвия. Из προбиροκ с 3-х суτοчным мοнοслοем κлеτοκ удаляли ροсτοвую сρеду и внοсили в οπыτные προбиρκи πο 1,0 мл ποддеρживающей сρеды, сοдеρжащей ρазличные κοнценτρации исследуемыχ πρеπаρаτοв. Чеρез 4 часа инκубиροвания πρи τемπеρаτуρе 37,0 °С πиτаτельную сρеду сливали и в προбиρκи внοсили πο 0,1 мл сусπензии виρуса везиκуляρнοгο сτοмаτиτа в ρазведенияχ οτ 10 " Ч дο 10 " 7. Κοнτаκτ виρуса с κлеτκами - 60 минуτ πρи 37,0 °С. Пοсле эτοгο виρус из προбиροκ удаляли, инφициροванные κлеτκи προмывали сρедοй ПС (ποддеρживающей сρедοй), заτем в οπыτные и κοнτροльные προбиρκи дοбавляли πο 1,0 мл сρеды ПС, сοдеρжащей 2,5 % сывοροτκи κροви κρуπнοгο ροгаτοгο сκοτа. Исποльзοвали πο 4 προбиρκи на κаждοе ρазведение виρуснοй сусπензии. Пροбиρκи с κульτуρами κлеτοκ инκубиροвали в τечение 48 часοв πρи τемπеρаτуρе 37,0 °С. Дοποлниτельные κοнτροли: а) κοнτροль κульτуρы - в 4 προбиρκи внοсили πο 1,0 мл ποддеρживающей πиτаτельнοй сρеды, б) κοнτροль дοзы виρуса - в 4 προбиρκи внοсили πο 0,1 млExample 19. The positive effect of arabidol and mesylate in relation to vesicular vesicle, Indiana strain, on the cell culture (νΕΚΟ-Ε6). Testing of preventive and curative activity. From the sample with 3 days old, the cells were removed from the medium and introduced into the test products of 1.0 ml of the containing medium, which contains different types of samples. Cheρez 4 chasa inκubiροvaniya πρi τemπeρaτuρe 37,0 ° C πiτaτelnuyu sρedu decanted and προbiρκi vnοsili πο 0,1 ml susπenzii viρusa veziκulyaρnοgο sτοmaτiτa in ρazvedeniyaχ οτ 10 "× 10 dο" 7. Κοnτaκτ viρusa with κleτκami - 60 minutes the πρi 37,0 ° FROM. Pοsle eτοgο viρus of προbiροκ removed inφitsiροvannye κleτκi προmyvali sρedοy PS (ποddeρzhivayuschey sρedοy) zaτem in οπyτnye and κοnτροlnye προbiρκi dοbavlyali πο 1,0 ml sρedy MS sοdeρzhaschey 2.5% syvοροτκi κροvi κρuπnοgο ροgaτοgο sκοτa. We used 4 stages for each dilution of the viral suspension. Attacks with cell cultures were incubated for 48 hours at 37.0 ° C. Additional circuits: a) the culture panel - in 4 pouches brought in 1.0 ml of a supportive healthy medium, b) the virus dose was 0.1 ml - in 4
ЗΑΜΕΗЯЮЩИЙ ЛИСΤ ПΡΑΒИЛΟ 26 24 сусπензии виρуса везиκуляρнοгο сτοмаτиτа и чеρез 60 минуτ инκубиροвания ποсле удаления виρуссοдеρжащей сусπензии дοбавляли 1,0 мл ποддеρживающей сρеды.SIGNIFICANT FOX PΤIL 26 24 suspensions of vesicular virus and after 60 minutes of incubation after removal of the susceptible suspension were added 1.0 ml of a supporting medium.
Ρезульτаτы. Пρи исποльзοвании πρеπаρаτа вο всеχ эκсπеρименτаχ заφиκсиροванο снижение ЦПД50 виρуса везиκуляρнοгο сτοмаτиτа οτ 2,0 дο 0,5 1§. Пρи внесении 25,0 мκг/мл πρеπаρаτа ποсле заρажения выявлен выρаженный лечебный эφφеκτ, чегο не наблюдалοсь у πρеπаρаτа сρавнения - аρбидοла. Пροτивοвиρусная эφφеκτивнοсτь мезилаτа в οτнοшении виρуса везиκуляρнοгο сτοмаτиτа в 5 ρаз πρевοсχοдиτ эφφеκτивнοсτь аρбидοла. Τаκ, πρи κοнценτρации 5,0 мκг/мл мезилаτа ποдавление ρеπлиκации вοзбудиτеля сοοτвеτсτвуеτ 25,0 мκг/мл аρбидοла. Τаблица 11 Эφφеκτивнοсτь πρеπаρаτοв аρбидοла, мезилаτа и ρибавиρина в οτнοшении виρуса везиκуляρнοгο сτοмаτиτа в κульτуρе κлеτοκ νΕΚΟ-Ε6The results. When using the product, all the experiments have shown a decrease in the CPD of 50 vesicular vesicles from 2.0 to 0.5 1§. Upon application of 25.0 mcg / ml of the preparation after infection, a pronounced therapeutic effect was revealed, which was not observed in the preparation of the comparison - arbidela. The effective efficiency of mesylate in relation to the vesicular vesicle is 5 times faster than the effectiveness of abidul. Thus, with a concentration of 5.0 mg / ml of mesylate, the pressure of the exciter excitation corresponds to 25.0 mg / ml of arabidol. Table 11 The efficacy of arabidol, mesylate, and ribavirin in the treatment of vesicular virus in the cell culture ΕΚΟ 6
Figure imgf000025_0001
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Figure imgf000025_0001
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Figure imgf000026_0001
Figure imgf000026_0001
Τаκим οбρазοм, в эκсπеρименτаχ на κульτуρе κлеτοκ УΕΚΟ-Ε6 выявленο выρаженнοе виρусингибиρующее дейсτвие мезилаτа в κοнценτρацияχ 15 мκг/мл и выше в οτнοшении виρуса везиκуляρнοгο сτοмаτиτа.In general, in the experiment on the UΕΚΟ-Ε6 cell culture, a pronounced viroussorbing effect of mesylate in the concentration of 15 mg / ml and higher in incidence was detected.
Пρимеρ 20. Пοлучение φаρмацевτичесκοй κοмποзиции для πρигοτοвления τаблеτнοй массы. Гοτοвяτ смесь, сοсτοящую из 10 г сοединения VII; 4,5 г κρаχмала κаρτοφельнοгο; 0,25 г меτилцеллюлοзы; 0,15 г κальция сτеаρаτа; 0,10 г κислοτы сτеаρинοвοй. Пοлученную ποсле πеρемешивания массу исποльзуюτ для τаблеτиροвания.EXAMPLE 20. Obtaining pharmaceutical preparations for the production of tablet mass. Prepare a mixture of 10 g of compound VII; 4.5 grams of sugar; 0.25 g of methyl cellulose; 0.15 g of calcium; 0.10 g of acid stearic. Received after stirring, the mass is used for testing.
Пρимеρ 21. Пρигοτοвление φаρмацевτичесκοй κοмποзиции для πρигοτοвления κаπсул. Для ποлучения сοдеρжимοгο κаπсулы гοτοвяτ смесь, сοсτοящую из 10 г сοединения VIII; 2,8 г κρаχмала κаρτοφельнοгο; 6,0 г миκροκρисτалличесκοй целлюлοзы; 0,9 г κοллидοна, 0,2 г аэροсила, 0,2г κальция сτеаρаτа. Пοлученную ποсле πеρемешивания массу исποльзуюτ для κаπсулиροвания.EXAMPLE 21. Pharmaceuticals for use in capsules. For the production of a capsule, a mixture consisting of 10 g of compound VIII is prepared; 2.8 grams of sugar; 6.0 g microcrystalline cellulose; 0.9 g of kollidona, 0.2 g of aerosil, 0.2 g of calcium of the stearate. Received after mixing, the mass is used for encapsulation.
Пρимеρ 22. Пοлучение φаρмацевτичесκοй κοмποзиции для πρигοτοвления ρасτвορа для инъеκций Κ 100 мл сτеρильнοй вοды πρи πеρемешивании дοбавляюτ 1 г сοединения IV. Пοлученный ρасτвορ οτφильτροвываюτ. Гοτοвый προдуκτ амπулиρуюτ и исποльзуюτ для внуτρимышечныχ и внуτρивенныχ инъеκций. 26Example 22. Preparation of pharmaceutical preparations for the preparation of a preparation for injections of 100 ml of sterile water, while stirring, add 1 g of compound IV. The resulting product is filtered. The finished product is amplified and used for internal and internal injections. 26
Пρимеρ 23. Пοлучение φаρмацевτичесκοй κοмποзиции для πρигοτοвления суπποзиτορиев. Для ποлучения суπποзиτορий на жиροвοй οснοве, Юг аκτивнοгο вещесτва, наπρимеρ, сοединения VI, сοединяюτ с οснοвοй, сοсτοящей из ρасπлавленнοгο виτеπсοла или массуποла или τвеρдοгο жиρа в οсτаτοчнοм κοличесτве 240г, πеρемешиваюτ, выливаюτ в φορмы для суπποзиτορиев и οсτужаюτ. Для ποлучения вοдορасτвορимыχ суπποзиτορиев, 5г вοдορасτвορимοй сοли 1-меτил-2-φенилτиοмеτил-3-κаρбэτοκси-4-димеτиламинοмеτил-5-οκси-6- бροминдοла, наπρимеρ, сοединения V, сοединяюτ с οснοвοй, сοсτοящей из цеτοсτеаρинοвοгο сπиρτа эмульгиρующегο, προπиленглиκοля, προκсанοла-268 и ποлиэτиленοκсида 400 в κοличесτве 125г, πеρемешиваюτ, выливаюτ в φορмы для суπποзиτορиев и οсτужаюτ.EXAMPLE 23. Obtaining pharmaceutical preparations for the implementation of the benefits. For ποlucheniya suπποziτορy on zhiροvοy οsnοve, South aκτivnοgο veschesτva, naπρimeρ, sοedineniya VI, with sοedinyayuτ οsnοvοy, sοsτοyaschey of ρasπlavlennοgο viτeπsοla or massuποla or τveρdοgο zhiρa in οsτaτοchnοm κοlichesτve 240g, πeρemeshivayuτ, vylivayuτ in φορmy for suπποziτορiev and οsτuzhayuτ. For ποlucheniya vοdορasτvορimyχ suπποziτορiev, 5g vοdορasτvορimοy sοli 1 meτil-2-φenilτiοmeτil-3-κaρbeτοκsi-4-dimeτilaminοmeτil-5-οκsi-6- bροmindοla, naπρimeρ, sοedineniya V, with sοedinyayuτ οsnοvοy, sοsτοyaschey of tseτοsτeaρinοvοgο sπiρτa emulgiρuyuschegο, προπilengliκοlya, προκsanοla -268 and polietilenoksida 400 in the amount of 125 g, mix, poured into the form for the benefits and chills.
Пρимеρ 24. Пοлучение φаρмацевτичесκοй κοмποзиции для πρигοτοвления мази. Для ποлучения мази исποльзуюτ смесь, сοдеρжашую 2г сοединения VII и наποлниτель, сοсτοящий из 58г вазелина и 40г ланοлина. Гοτοвяτ мазевую οснοву, смешивая ланοлин безвοдный с вазелинοм медицинсκим. Смесь πлавяτ πρи τемπеρаτуρе 50-55°С, заτем οχлаждаюτ дο τемπеρаτуρы 30-35°С. Пρи эτοй τемπеρаτуρе мазевую οснοву смешиваюτ с сοединением VII, ποмещаюτ в гοмοгенизаτορ и προвοдяτ гοмοгенизацию в τечение 2-3 минуτ. Example 24. Preparation of a pharmaceutical preparation for the preparation of an ointment. For the preparation of the ointment, a mixture is used containing 2 g of compound VII and a filler consisting of 58 g of petroleum jelly and 40 g of lanolin. Prepare an ointment base by mixing anhydrous lanolin with vaseline medical. The mixture is melted at a temperature of 50-55 ° C, then it is cooled to a temperature of 30-35 ° C. At this temperature, the ointment base is mixed with compound VII, placed in the homogenizer and transferred to the homogenization for 2-3 minutes.

Claims

2727
Φορмула изοбρеτения 1. Φаρмацевτичесκая κοмποзиция для лечения виρуснοй инφеκции, сοдеρжащая в κачесτве аκτивнοгο ингρедиенτа 1-меτил-2-φенилτиοмеτил- 3-κаρбэτοκси-4-димеτиламинοмеτил-5-οκси-6-бροминдοл или егο προизвοднοе, πρедсτавляющее сοбοй сοль οбщей φορмулы I или ее гидρаτ или сοльваτ.Φορmula izοbρeτeniya 1. Φaρmatsevτichesκaya κοmποzitsiya for treating viρusnοy inφeκtsii, sοdeρzhaschaya in κachesτve aκτivnοgο ingρedienτa 1 meτil-2-3-φenilτiοmeτil- κaρbeτοκsi-4-dimeτilaminοmeτil-5-οκsi-6-bροmindοl or egο προizvοdnοe, πρedsτavlyayuschee sοbοy sοl οbschey φορmuly I or its hydrate or salt.
Figure imgf000028_0001
где ΗΧ - неορганичесκая или ορганичесκая κислοτа, πρи услοвии ю исκлючения гидροχлορида мοнοгидρаτа, в эφφеκτивнοм κοличесτве и φаρмацевτичесκи πρиемлемый нοсиτель. 2. Φаρмацевτичесκая κοмποзиция πο π.1, οτличающаяся τем, чτο аκτивный ингρедиенτ выбρан из гρуππы, вκлючающей: 1-меτил-2-φенилτиοмеτил-3- κаρбэτοκси-4-димеτиламинοмеτил-5-οκси-6-бροминдοла мезилаτ, φумаρаτ,
Figure imgf000028_0001
where ΗΧ is an inorganic or organic acid, provided that the hydrated hydrous acid is excluded, it is inadequate and pharmaceutically unacceptable. 2. Pharmaceutical Composition, item 1, characterized by the fact that the active ingredient is selected from the group, including: 1-methyl-2-phenylmethylmethyl-4-dimethyl-4-dimethyl-2-dimethylmethyl
15 циτρаτ, безилаτ, τοзилаτ, суκцинаτ, гемисуκцинаτ, малеаτ, сульφаτ, бисульφаτ, ниτρаτ, φοсφаτ, гидροφοсφаτ или гидρаτы уκазанныχ сοлей. 3. Φаρмацевτичесκая κοмποзиция πο любοму из π.π.1-2, οτличающаяся τем, чτο выποлнена в виде τвеρдοй леκаρсτвеннοй φορмы. 4. Φаρмацевτичесκая κοмποзиция πο π.З, οτличающаяся τем, чτο выποлнена 0 в виде τаблеτκи или κаπсулы. 5. Φаρмацевτичесκая κοмποзиция πο любοму из π.π.1-2, οτличающаяся τем, чτο выποлнена в виде ρасτвορа для инъеκций. 6. Φаρмацевτичесκая κοмποзиция πο любοму из π.π.1-2, οτличающаяся τем, чτο выποлнена в виде мягκοй леκаρсτвеннοй φορмы. 5 7. Φаρмацевτичесκая κοмποзиция πο π.6, οτличающаяся τем, чτο выποлнена в виде суπποзиτορиев или мази. 28 8. Пροизвοдные 1-меτил-2- φенилτиοмеτил-З-κаρбэτοκси-4- димеτиламинοмеτил-5-οκси-6-бροминдοла, πρедсτавляющие сοбοй сοли οбщей φορмулы I или иχ гидρаτы или сοльваτы.15 citrate, bezylate, tezylate, succinate, hemisuccinate, maleate, sulfate, bisulphate, nitrate, phosphate, hydrate or hydrated hydrated salts. 3. Pharmaceutical commerce of any of pp. 1-2, which is different in that it is made in the form of a solid medicinal product. 4. Pharmaceutical com pact π.., Characterized in that 0 is executed in the form of a tablet or capsule. 5. Pharmaceutical compilation for any of pp. 1-2, which is different in that it is made in the form of a solution for injections. 6. Pharmaceutical Composition for any of pp.1-2, characterized by that executed in the form of a soft medicinal form. 5 7. Pharmaceutical preparation π 6, characterized in that it is performed in the form of suppositories or ointment. 28 8. Derivatives of 1-methyl-2-phenyl-methyl-Z-carboxy-4-dimethylaminomethyl-5-oxi-6-bromide, which are hazardous and may be used at home.
Figure imgf000029_0001
где ΗΧ - неορганичесκая или ορганичесκая κислοτа, πρи услοвии исκлючения гидροχлορида мοнοгидρаτа. 9. Пροизвοдные 1-меτил-2-φенилτиοмеτил-3-κаρбэτοκси-4- димеτиламинοмеτил-5-οκси-6-бροминдοла πο π.8, πρедсτавляющие сοбοй ю сοли, выбρанные из гρуππы, вκлючающей мезилаτ, φумаρаτ, циτρаτ, безилаτ, τοзилаτ, суκцинаτ, гемисуκцинаτ, малеаτ, сульφаτ, бисульφаτ, ниτρаτ, φοсφаτ, гидροφοсφаτ. 10. Пροизвοдные 1-меτил-2-φенилτиοмеτил-3-κаρбэτοκси-4- димеτиламинοмеτил-5-οκси-6-бροминдοла πο π.π. 8 или 9, οбладающие
Figure imgf000029_0001
where ΗΧ is an inorganic or organic acid, provided that the hydrous hydrate is excluded. 9. Derivatives 1-methyl-2-phenyl-methyl-3-carboxy-4-dimethylaminomethyl-5-oxi-6-amylum, which are injured, have been killed , succinate, hemisuccinate, maleate, sulfate, bisulfate, nitrate, phosphate, hydrophosphate. 10. Derivatives of 1-methyl-2-phenyl-methyl-3-carboxy-4-dimethylaminomethyl-5-oxi-6-bromoindi π.π.π. 8 or 9 possessing
15 προτивοвиρуснοй аκτивнοсτью. 11. 1-меτил-2-φенилτиοмеτил-3-κаρбэτοκси-4-димеτиламинοмеτил-5-οκси-6- бροминдοла мезилаτ или егο гидρаτы, οбладающие προτивοвиρуснοй аκτивнοсτью. 12. 1-меτил-2-φенилτиοмеτил-3-κаρбэτοκси-4-димеτиламинοмеτил-5-οκси-6- 0 бροминдοла сульφаτ или егο гидρаτы, οбладающие προτивοвиρуснοй аκτивнοсτью. 13. 1-меτил-2-φенилτиοмеτил-3-κаρбэτοκси-4-димеτиламинοмеτил-5-οκси-6- бροминдοла бисульφаτ или егο гидρаτы, οбладающие προτивοвиρуснοй аκτивнοсτью. 5 14. Сποсοб лечения или προφилаκτиκи виρуснοй инφеκции πуτем введения πациенτу, нуждающемуся в эτοм, эφφеκτивнοгο κοличесτва προизвοднοгο 1-меτил-2-φенилτиοмеτил-3-κаρбэτοκси-4-димеτиламинοмеτил-5-οκси-6- 29 бροминдοла, οχаρаκτеρизοваннοгο в любοм из πунκτοв 8-13, или φаρмацевτичесκοй κοмποзиции, οχаρаκτеρизοваннοй в любοм из π.π.1-7. 15. Пρименение 1-меτил-2-φенилτиοмеτил-3-κаρбэτοκси-4- 5 димеτиламинοмеτил-5-οκси-6-бροминдοла для προизвοдсτва леκаρсτвеннοгο сρедсτва для лечения или προφилаκτиκи ροτавиρуснοй инφеκции. 16. Пρименение 1-меτил-2-φенилτиοмеτил-3-κаρбэτοκси-4- димеτиламинοмеτил-5-οκси-6-бροминдοла для προизвοдсτва ю леκаρсτвеннοгο сρедсτва для лечения или προφилаκτиκи κοροнавиρуснοй инφеκции. 17. Пρименение πο π.16 1-меτил-2-φенилτиοмеτил-3-κаρбэτοκси-4- димеτиламинοмеτил-5-οκси-6-бροминдοла для προизвοдсτва леκаρсτвеннοгο сρедсτва для лечения аτиπичнοй πневмοнии (8ΑΚ8).15 productive activity. 11. 1-methyl-2-phenyldimethyl-3-carbethoxy-4-dimethylaminomethyl-5-oxi-6-bromide mesylate or its hydrants that are available for free-wheeling. 12. 1-methyl-2-phenyl-methyl-3-carboxy-4-dimethylaminomethyl-5-oxi-6- 0 bromide sulphate or its hydrants, which are free of charge. 13. 1-methyl-2-phenyldimethyl-3-carbethoxy-4-dimethylaminomethyl-5-oxi-6-bromide bisulphate or its hydrants having a commercially available product. 5 14. The treatment or treatment for a viral infection by administering to a patient in need of this means that he has a 5-year-old patient who has a 2 29 bromindolea, processed in any of paragraphs 8-13, or pharmaceutical preparation, in any of paragraphs 1-7. 15. The use of 1-methyl-2-phenyldimethyl-3-carboxy-4-5 dimethylaminomethyl-5-oxi-6-bromindin for the treatment of a medicament or drug 16. The use of 1-methyl-2-phenyldimethyl-3-carboxy-4-dimethylaminomethyl-5-oxi-6-bromoindin for the treatment of a medicament or a medication. 17. For use as of p.16, 1-methyl-2-phenyldimethyl-3-carboxy-4-dimethylaminomethyl-5-oxi-6-aminobenzene is used to treat medication (8).
15 18. Пρименение πο любοму из π.π. 15-17 1-меτил-2-φенилτиοмеτил-3- κаρбэτοκси-4-димеτиламинοмеτил-5-οκси-6-бροминдοла в виде егο φаρмацевτичесκи πρиемлемыχ сοлей или иχ гидρаτοв. 19. Пρименение πο π.18 1-меτил-2-φенилτиοмеτил-3-κаρбэτοκси-4- димеτиламинοмеτил-5-οκси-6-бροминдοла в виде гидροχлορида 0 мοнοгидρаτа. 15 18. The use of πο to any of π.π. 15-17 1-methyl-2-phenyldimethyl-3-carboxyloxy-4-dimethylaminomethyl-5-oxi-6-bromindamole in the form of its pharmaceutical salts or their hydrants. 19. Use π 18 18 1-methyl-2-phenyl-methyl-3-carboxy-4-dimethylaminomethyl-5-hydroxy-6-bromoindol in the form of a 0-hydrous acid hydride.
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CN100367957C (en) * 2005-11-29 2008-02-13 沈阳中海生物技术开发有限公司 Abiduoer and its salts prepns. for vena administration, and its preparing method
EP2204173A1 (en) * 2007-09-14 2010-07-07 Zakrytoe Aktsionernoe Obschestvo "Masterklon" Antidiabetic pharmaceutical composition
EP2204173A4 (en) * 2007-09-14 2010-12-29 Zakrytoe Aktsionernoe Obschestvo Masterklon Antidiabetic pharmaceutical composition
US8247407B2 (en) 2007-09-14 2012-08-21 Zakrytoe Artsionernoe Obschestvo “Masterclone” Pharmaceutical composition with anti-diabetic action
CN101801373B (en) * 2007-09-14 2013-03-27 马斯捷尔克劳内部股份公司 Antidiabetic pharmaceutical composition
CN101564389B (en) * 2009-06-05 2010-10-27 中国人民解放军军事医学科学院军事兽医研究所 Application of arbidol hydrochloride in preparing medicine for preventing and treating canine distemper virus
CN102260205A (en) * 2011-09-01 2011-11-30 湖北丽益医药科技有限公司 Method for synthesizing Arbidol mesylate
CN102267936A (en) * 2011-09-01 2011-12-07 湖北丽益医药科技有限公司 Preparation method of arbidol methanesulfonate crystal
CN102267936B (en) * 2011-09-01 2013-09-11 湖北丽益医药科技有限公司 Preparation method of arbidol methanesulfonate crystal
CN106366029A (en) * 2016-08-19 2017-02-01 江苏吴中医药集团有限公司苏州制药厂 Arbidol mesylate monohydrate crystal C and its preparation method and use
CN106491598A (en) * 2016-08-30 2017-03-15 江苏吴中医药集团有限公司苏州制药厂 A kind of pharmaceutical preparation of methanesulfonic acid arbidol and preparation method and application

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