A method of treating diabetes mellitus

 

(57) Abstract:

The invention relates to medicine, in particular to endokrinologie. The invention consists in that in the method of treatment of patients, including the use of glucose-lowering medications and/or insulin and antioxidant as an antioxidant use Mexidol. The drug is administered intramuscularly and/or orally once daily at a dose of 100-200 mg within 5-7 days of treatment, which repeat in 3-4 months. The method allows for compensation of diabetes mellitus on the background of reduction of insulin doses - 1 the type of the disease, relieve insulin resistance and reduce the dose of insulin and/or glucose-lowering drugs in type II. The method makes it possible to stop the progression of late diabetic complications. 6 table.

The invention relates to medicine, namely to diabetology and can be used for the treatment of patients with I and II types of diabetes and secondary diabetes-related chronic inflammatory process (destructive pancreatitis, tumor) or resection.

There is a method of treatment of diabetes mellitus type I and insulin dependent form of type II, consisting of glycemia and severity of the disease (The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long - term complications in insulin-dependent diabetes mellitus - Vol. 14 - P. 977 - 986 ; Yki-Jarvinen H. , Kaupilla M. et al. Comperison of insulin regimens in patients with non-insulin-dependent diabetes mellitus// N. Engl. J. Med. - 1992. Vol.327 - P. 1426-1433).

However, the known method has several disadvantages: 1) multiple times during the day introduction of insulin requires a well-regulated diet and amount of physical activity, 2) the need for frequent monitoring of blood glucose for adequate insulin, 3) difficulties in finding adequate doses of insulin in labile disease, and therefore an increase in the frequency of hypoglycemia and the risk of chronic overdose of insulin, 4) prolonged use of high doses of insulin may be accompanied by allergic and autoimmune reactions.

The last few years has been applied surgical method for the treatment of diabetes associated with transplantation of the pancreas or cells (R. G. Bretzel, B. J. Hermg et al. Insulm independence in type I diabetes achived by transplantation of purified pancreatic islets // Diabetologia - 1994. Vol. 37. Suppi. 1-p (A 38), however, due to the difficulty of overcoming the incompatibility tissue, this method has not found wide application.

Also known is a method of treatment of diabetes mellitus II t the inhibitors - field of glycosidase inhibition), the dose and dosing frequency of which varies depending on the level of glycemia (Melander A. Sulfanilureas in the treatment of noninsulin-dependent diabetes // Baillier's clin. Endocr. Metabol. - 1988. -Vol. 2.-P. 443-453).

However, the method has some significant drawbacks. Due to cumulation, the drugs are derivatives of sulfonylurea may cause prolonged hypoglycemia, increase hyperinsulinemia, and therefore, increase insulin resistance, moreover, this group is not recommended to patients with obesity. The biguanide derivatives of sulfonylurea are of limited use in the pathology of the kidney. Biguanides and inhibitors - field of glycosidase inhibition cause dyspeptic symptoms and flatulence, as a result, patients refuse taking these drugs. With prolonged use of glucose-lowering drugs occurs a decrease in sensitivity to them, causing the need to increase the dose (not always possible) or switch to insulin.

For the correction of carbohydrate and lipid metabolism in type II diabetes mellitus using combination therapy: insulin and oral glucose-lowering drugs (O. Tshoj, A. Green Sulfanilureas and insulm in the treatment of non-insulin dependent diabetes mellitus // Diabetologia - 1994. - Vol. 37.-N. 11, P. 1121 - 1126).

As the prototype accepted method of treatment of diabetes mellitus type I (O. M. Smirnov, thesis for the degree of doctor of medical Sciences, 1995, , Moscow, pp. 37-38).

The method consists in the fact that the purpose of metabolic correction processes in the liver, insulin combined with oral introduction of antioxidant - tocopherol at a dose of 10 mg/kg/day for 4-6 months.

However, the known method has a number of disadvantages: the use of large doses of antioxidants can stimulate syndrome peroxidation, which leads to the background of the failure of glucose utilization, to decompensation antioxidant protection and enhancement of free radical oxidation of lipid membranes, disruption of microcirculation, increased synthesis of inflammatory mediators prostaglandins, leukotrienes. Clinically this is manifested by the development of vascular complications and impaired performance homeostasis, the tendency to thrombosis.

The objective of the invention is to provide a highly effective method of treating diabetes mellitus, which can eliminate insolidarity effect.

The invention consists in that in the method of treatment of patients, including the introduction into the organism of the patient glucose-lowering medications and/or insulin and antioxidant as an antioxidant use Mexidol, which is injected intramuscularly and/or orally once daily at a dose of 100-200 mg within 5-7 days of treatment, which repeat in 3-4 months.

The use of the invention allows to obtain the following technical result.

The method is highly effective.

It allows for compensation of diabetes mellitus on the background of reduction of insulin doses - when I type, relieve insulin resistance and reduce the dose of insulin and/or glucose-lowering drugs, as well as their complete removal in 70% of patients with type II. The method makes it possible to stabilize the course of pathological processes, controlling the path metabolic adaptation in the body of the patient with diabetes mellitus, stop the progression of late complications and thus, to improve the quality and Outlook of life.

When using the method in patients with diabetes notes: 1) normalization of the ratio of cholesterol/ triglycerides, increasing the concentration of lipopro the self-regulating system of FLOOR-AOC 4) anxiolytic and nootropic effects. This gives you the opportunity to opt-out of taking drugs, correcting lipid metabolism, normalizes microcirculation and remove sedative therapy.

The technical result is achieved due to the fact that the purpose of metabolic correction processes in the liver, the authors first used as antioxidant Mexidol.

The authors found that Mexidol - 2-ethyl-6-methyl-3-oksipiridina succinate is antihypoxic drug, antioxidant, antiplatelet agent, an anti-inflammatory drug, has immunomodulatory and hypolipidemic action, and is also anxiolytic and antidepressant.

Currently, it is shown that in diabetes mellitus type II decreases the number of insulin receptors and develops insulin resistance. Increase insulin secretion in obesity and the increase of its concentration in interstitial fluid leads to a decrease in the affinity of insulin receptors and the clinical manifestation of an even greater relative insulin deficiency. With obesity, hyperinsulinemia due to increased hormone secretion, and decrease its metabolic clearance. When I type sheerazi - cells with viral and/or autoimmune processes in the pancreas. When secondary diabetes is a decrease in the functional activity of the cells of the pancreas due to chronic inflammatory process. These derived facts was a prerequisite of the method development of metabolic correction of the drug "Mexidol".

The method is as follows.

Patient NIDDM conduct therapy with oral glucose-lowering medication and/or insulin is administered. The dose and dosing frequency in both cases individually, under the control of glycemia. Advanced drug use "Mexidol, which is administered daily once daily in doses of 100-200 mg for 5-7 days. The introduction of the drug carried out in several ways: 1. intramuscular introduction; 2. intramuscular injection of the first 3-4 days, then move to the oral ingestion of a capsulated form of the drug in the next 3-4 days; 3. oral capsules of Mexidol on for the recommended time. The treatment method is selected depending on the duration of the course and severity of illness (severity of complications and metabolic disorders), and taking into account the individual is practical tests in Endocrinology research center of RAMS in 13 patients (8 men and 5 women) aged from 23 to 68 years.

The use of Mexidol in the dose of 500-900 mg per course helped stabilize the level of blood glucose in the range of 3.5-7.8 mmol/l, was used the average therapeutic dose of glucose-lowering medication or insulin.

Patients of type II diabetes, are on maximum doses of sugar-lowering drug and in need of translation by insulin due to the absence of compensation, were translated into the minimum dose derivatives of sulfonylurea in connection with the development of hypoglycemia. The need for insulin fell away.

In patients with the first type of diabetes has decreased the need for insulin and decreased lability of the disease, i.e., improved the quality of glycemic control.

Example 1

Patient B., aged 65.

He admitted with a diagnosis of non-insulin-dependent diabetes mellitus moderate, the state of decompensation. Diabetic neuropathy, distal form, touch type. Diabetic microangiopathy: proliferative retinopathy. After laserfacial (OS). Diabetic nephropathy initial stage.

Complaints of dry mouth, thirst, decreased visual acuity, night pain in his legs.

When whee.

In the lungs vesicular breath, weak, diffuse dry rales in the basal regions of both lungs.

Heart sounds rhythmic, muted, accent II tone of the aorta. HELL 140/85 mm RT. Art., heart rate of 78 beats/min At the definition of ripple on the back of the arteries of the feet, there is a decrease of ripple on the right foot.

Palpation of the anterior abdominal wall pain is absent, the abdomen is soft in all departments. The bottom edge of the right lobe of the liver is on the edge of the costal arch.

The lumbar area is not visually changed, symptom tapping negative on both sides. Dysuria is not.

Clinical and laboratory studies:

(before therapy Mexidol)

CBC, ESR of 30 mm/h, the other indicators of pathology

Clinical analysis of urine - proteinuria - 0.25 g/l

Biochemical blood test: ALT 40 IU/l (4-53); ACT-41 IU/l (4 - 40); alkaline phosphatase-118 IU/l (36-92); GGT-101 IU/l (8-63); XC-4.7 mmol/l (3,3 - 6,5); TG is 1.16 mmol/l (0.00 to-2,0); HDL-0.96 mmol/l (0.7 to 2,61); LDL - 2,13 mmol/l (0,0-3,9); creatinine-130 Ámol/l (53-110)

Sample Rehberg: glomerular filtration - 63.7 ml/min (80-160); reabsorption - 99% (96-99).

Consultation of the neurologist: diabetic neuropathy, distal form touch type.

Klali (OS). Parabasal swelling of the retina of the right eye. Shown cryosurgery proliferating blood vessels in the retina of the right eye.

Specialist diabetes: diabetic foot syndrome mixed form, II-nd degree. Superficial ulcer of the proximal phalanx of the first toe. Shown antibiotic therapy and unloading of the foot.

Ongoing therapy:

(before therapy Mexidol)

diet N 8 (1800 kcal), maninil 5 mg 2 tabs. morning and evening, Enap 10 mg 1 tab. morning and evening, lincomycin 500000 IU/day in the tech. weeks, Finlepsin -1/4 tab. at night, acetylsalicylic acid 0,5 1/4 t in the morning after a meal.

The patient was treated by the proposed method.

Mexidol was appointed in a dose of 100 mg, intramuscularly 1 time a day for 7 days. In addition Mexidol patient took maninil 5 mg 2 tabs. morning and evening, Enap 10 mg 1 tab. morning and evening, lincomycin 500000 IU/day in the tech. weeks, in connection with the appointment of the drug were cancelled techniques of acetylsalicylic acid and Finlepsin.

To control for the effect of the drug the patient was determined daily blood pressure, glycemic profile, every 10 days within 2 months produced biochemical control is lubochnoy filter (creatinine clearance) and the dynamics of the pattern of the fundus.

The treatment efficacy was celebrated on the 10th day after the end of reception of Mexidol and was expressed in the following:

The glycemic profile:

on the 10th day - 900- 4,2; 1300- 3,8; 1700- 5,2; 2100- 4,0; 600- 4,7 (mmol/l)

Due to the normalization of blood glucose level, the patient reduced the dose of maynila 2 times.

The glycemic profile on the 11th day after receiving Mexidol: 900- 3,0; 1300- 3,8; 1700and 4.4; 2100- 3,5; 300- 4,3; 600- 4,0 (mmol/l)

In connection with the occurrence of hypoglycemic patient States decided to discontinue therapy glucose-lowering drug and lead the patient only on the diet (table 8, 1800 kcal). The glycemic profile:

on the 12th day of the 900- 4,7; 1300- 5,8; 1700- 6,2; 2100and 4.4; 600- 3.9 (mmol/l)

on the 14th day of the 900- 4,1; 1300- 6.8; the 1700- 4,2; 2100- 5,4; 600- 4,9 (mmol/l)

on the 15th day of the 900- 3,7; 1300- 4,8; 1700- 5,0; 2100- 6,3; 600- 4,1

Sample Rehberg on the 14th day from the start of therapy with Mexidol:

glomerular filtration - 81 ml/min,

the reabsorption is 99% on the 28th day from the beginning of therapy with Mexidol:

glomerular filtration - ml/min, reabsorption - 99%

spusta therapy Mexidol: marked decrease in parabasal retinal edema of the right eye, what makes possible the carrying out of cryosurgery. Left eye - without the negative dynamics on the 28th day from the beginning of therapy with Mexidol: patient successfully performed cryosurgery proliferating blood vessels.

1.5 months: VOD = 0,5 sph +0,5D= 0,9; VOS=0,3 sph + 0,7D= 0,8 Anterior segment of the eye is not changed. Environment transparent.

The fundus of the eye: optic disc pale pink color, border clear. Veins are moderately dilated, caliber uneven, macular region is not changed, OS - single parabasal microaneurysms. On OS and OD are determined by the scars of cryosurgery and laserfacial.

Specialist diabetic foot: monitoring stops were carried out in a day. Shows good healing of the wound, redness, swelling feebly, purulent discharge is absent. Patient cancelled lincomycin permitted circulation.

The patient was discharged from the clinic with a diagnosis of diabetes mellitus type II, moderate in state compensation. Diabetic microangiopathy: retinopathy III, after laserfacial and cryosurgery. Initial diabetic nephropathy. Diabetic polyneuropathy distal form, touch type. Syndrome diabeticmedicine.

Patient recommended: a diet low in animal fats and refined carbohydrates (1800 kcal), Enap - tab. morning and evening. A second course of Mexidol is expected to spend in 3 months. Frequency of courses will depend on the condition of the patient (assessment of blood glucose level, the picture of the fundus).

Example 2.

Patient Century, 60 years.

Was admitted with complaints of pains in the legs at night.

At survey: growth 156 see Weight 80 kg, the skin is a normal color, dry. In the lungs vesicular breathing, wheezing no. Heart sounds rhythmic, muted, accent of II tone of the aorta. AD-170/100 mm RT.article HR-56 beats/min Abdominal palpation painless and soft in all departments, the liver is not enlarged. The lumbar area is not visually changed, symptom tapping negative on both sides, dysuria no.

Diagnosis : diabetes II type, moderate, insulin dependent (?). The phase of decompensation.

Clinical and laboratory studies:

(before treatment with Mexidol)

CBC - without pathology

Clinical urine analysis showed no pathology

Blood biochemistry: ALT - 47 IU/l, ACT - 20 IU/l, alkaline phosphatase - 77 IU/l, XC -6,47 IMO to 59.8 ml/min reabsorption - 98%

Consultation of the neurologist: diabetic neuropathy, distal form, touch type.

Consultation of the oculist: Diabetic pathology of the ocular fundus is not revealed. Palpate both eyes.

Ongoing therapy: Diet N 8 (1700 kcal), glurenorm 0.3 2 tab. morning and evening, Enap 10 mg 1 tab. in the morning and 2 in the evening, atenolol -100 mg on 1/4 tab. in the morning, mevacor - 1 tab./day, acetylsalicylic acid on 1/4 tab. morning.

Given the lack of effect of therapy glucose-lowering drugs, the patient was offered a transfer to insulin. In connection with failure patients on insulin therapy, it was decided to appoint Mexidol. Mexidol has appointed intramuscularly at a dose of 200 mg/day for 3 days, followed by oral administration of 100 mg in over the next 3 days (900 mg per treatment). To assess therapeutic effect of Mexidol were cancelled mevacor and acetylsalicylic acid. The patient continued to take glurenorm 0.3 2 tab. morning and evening, Enap 10 mg 1 tab. in the morning and 2 in the evening, atenolol 100 mg on 1/4 tab. in the morning. The study was conducted by the same procedure as in example 1.

The treatment efficacy was celebrated on the 7th day after the end in the - 6,8; 1700-5,7; 2100- 8,0; 600- 7.7 (mmol/l)

The glycemic profile on the 9th day after receiving Mexidol: 900- 5,0; 1300- 4,8; 1700- 6,4; 2100- 5,5; 300- 4,3; 600- 6,0 (mmol/l)

In connection with the normalization of glycemia decided to reduce the dose glyurenorma 2 times (tab. morning and evening).

The glycemic profile on the 11th day of the 900- 4,7; 1300- 5,1; 1700- 6,2; 2100and 4.4; 600- 4,9 (mmol/l)

on the 14th day of the 900- 4,1; 1300- 6.8; the 1700- 4,2; 2100- 5,4; 600- 4,9 (mmol/l)

on the 15th day of the 900- 3,7; 1300- 4,8; 1700- 5,0; 2100- 5,3; 600- 4.1 (mmol/l)

Sample Rehberg

the 14th day from the start of therapy with Mexidol:

glomerular filtration - 86 ml/min, reabsorption - 99%

on the 28th day from the beginning of therapy with Mexidol:

glomerular filtration - 92 ml/min, reabsorption - 98%

after 1.5 months: glomerular filtration - 89 ml/min, reabsorption - 99%

Examination by ophthalmologist:

Negative dynamics in the fundus of the eye during the test observations.

The patient was discharged from the hospital with a diagnosis of diabetes mellitus type II, moderate in state compensation. Diabetic neuropathy dis is descent and refined carbohydrates (1800 kcal), pragian on tab. morning and evening; Enap 10 mg 1 tab. in the morning and 2 in the evening, atenolol 100 mg on 1/4 tab. in the morning. A second course of Mexidol is expected to spend in 3 months. Frequency of courses will depend on the condition of the patient ( assessment of the level of glycemia and lipid spectrum).

Example 3.

Patient K., 23 years.

Was admitted with complaints of decreased visual acuity, decrease in body weight of 3 kg, aching pain in the legs at night.

During examination: height 178 see weight 64 kg, pale skin, dry. In the lungs vesicular breathing, wheezing no. Heart sounds rhythmic, clear accent of II tone of the aorta. AD-140/100 mm RT.article Heart rate is 70 beats/min

Abdomen palpation painless and soft in all departments, the liver is not enlarged. The lumbar area is not visually changed, symptom tapping negative on both sides, dysuria no.

Diagnosis: Diabetes mellitus type I, moderate in the phase of decompensation. Diabetic microangiopathy: retinopathy (St. ), the initial nephropathy. Diabetic distal polyneuropathy.

Clinical and laboratory studies:

(before treatment with Mexidol)

CBC - without pathology

Clinical is 70 IU/l, XC -4,27 mmol/l, TG is 1.58 mmol/l, creatinine - 116 Ámol/l, urea and 4.3.

Sample Rehberg: glomerular filtration rate - 62,0 ml/min) - 99 %

Consultation of the neurologist: diabetic neuropathy, distal form, touch type.

Consultation of the oculist: VOD =0,8 sph +0,3D= 0,9; VOS=0,6 sph + 0,5D= 0,9. Anterior segment of the eye is not changed. Environment transparent.

The fundus of the eye: optic disc pale pink color, border clear. Veins are moderately dilated, caliber uneven, macular region is not changed, OS and OD - microaneurysms, single hemorrhage.

Ongoing therapy: Diet N 9 (2500 kcal), insulin: 900- Actrapid - 8 Ed. , monotard - 12 Ed., 1400- Actrapid 10 Ed., 1800- Actrapid 8 Ed., 2200- monotard 12 Ed., Enap 10 mg 1/2 tab. in the morning and 1 tab. night

The patient was assigned Mexidol orally 1 capsule (100 mg) daily for 5 days. (Dose scheme and the introduction of insulin in the beginning did not change)

The survey was conducted under the above scheme.

The treatment efficacy was celebrated on the 4th day of reception of Mexidol and was expressed in the following:

The glycemic profile: day 2 - 900- 3,2; 1300- 4,3; 170000- Actrapid - 6 Ed., monotard - 10 Ed., 1400attrelid 8 Ed., 1800- Actrapid 8 Ed., 2200- monotard 10 Ed.,

The glycemic profile on the 5th day of reception of Mexidol: 900- 4,1; 1300- 4,2; 1700- 3,4; 2100- 5,8; 600- 5,8 (mmol/l)

The glycemic profile on the 7th day after the end of the course: 900- 4,7; 1300- 3,1; 1700- 4,0; 2100- 3,4; 600- 4,9 (mmol/l)

The dose of insulin required further adjustments: 900- Actrapid - 6 Units. , monotard - 8 Ed., 1400- Actrapid 6 Ed., 1800- Actrapid 4 Ed., 2200- monotard 8 Ed.

on the 14th day after the end of the course: 900- 4,1; 1300- 4,3; 1700- 4,2; 2100- 5,4; 600- 5,9 (mmol/l)

on the 28th day after the end of the course of Mexidol: 900- 5,1; 1300- 5,8; 1700- 7,2; 2100and 4.4; 600- 4,3 (mmol/ l)

Sample Rehberg

on the 14th day from the start of therapy with Mexidol:

glomerular filtration - 79 ml/min, reabsorption - 98%

on the 28th day from the beginning of therapy with Mexidol:

glomerular filtration - 86 ml/min, reabsorption - 99%

after 1.5 months: glomerular filtration - 89 ml/min, reabsorption - 99%

Examination by ophthalmologist:

Negative dynamics in the fundus of the eye when conducting kontana of gravity in a state of subcompensation. Diabetic microangiopathy: retinopathy 1 tbsp. Diabetic distal polyneuropathy form touch type.

Patient recommended : 1) diet with restriction of refined carbohydrates (2500 - 3000 kcal) 2) daily 3-5 single glycemic control, 3) insulin therapy (schema and dose to pick up depending on the schedule, the quality and quantity of food.

A method of treating diabetes, comprising introducing into a patient insulin and/or glucose-lowering drug and an antioxidant, wherein in use as an antioxidant Mexidol, which is injected intramuscularly and/or orally once daily at a dose of 100 - 200 mg for 5 to 7 days, repeat the treatment after 3 to 4 months.

 

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FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I):

wherein X means group of the formula (X-1) wherein R15 means halogen atom, (lower)-alkyl and perfluoro-(lower)-alkyl; R16 means hydrogen, halogen atom and (lower)-alkyl; or X means group of the formula (X-2) wherein Het means 5- or 6-membered heteroaromatic ring comprising 1 or 2 heteroatoms as nitrogen (N) atom; R15 and R16 have values indicated above for (X-1); R30 means hydrogen atom or (lower)-alkyl; p means a whole number from 0 to 1; or X means group of the formula (X-3) wherein R18 means aryl; R19 means unsubstituted arylalkyl or heteroarylalkyl representing 6-membered heteroaromatic ring comprising nitrogen (N) atom as a heteroatom; R20 means unsubstituted (lower)-alkanoyl; Y means group of the formula (Y-1) wherein R22 and R23 mean independently from one another hydrogen atom, (lower)-alkyl, halogen atom or perfluoro-(lower)-alkyl and at least one of radicals R22 and R23 doesn't mean hydrogen atom; R24 means hydrogen atom; or Y means group of the (Y-3) wherein R25 means group of the formula: R26-(CH2)e- wherein R26 means (lower)-alkoxy-group, (lower)-alkylthio-group, (lower)-alkylsulfonyl; or R26 means group of the formula: -NR28R29 wherein R28 means hydrogen atom; R29 means (lower)-alkanoyl or (lower)-alkylaminocarbonyl; Q means -(CH2)f- wherein e means a whole number from 0 to 4; f means a whole number from 1 to 3; a bond denoted as a dotted line can be hydrogenated optionally; and to its pharmaceutically acceptable salts and esters. Also, invention proposes a pharmaceutical composition designated for treatment or prophylaxis of rheumatic arthritis, cerebrospinal sclerosis, intestine inflammatory disease and asthma and containing compound of the formula (I) or its pharmaceutically acceptable salt or ester in combination with a compatible pharmaceutical carrier. Invention proposes derivatives of thioamide inhibiting interaction between α4-comprising integrins and VCAM-1.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 1 tbl, 86 ex

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

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