Quinone therapeutic agent for treatment of liver disease

FIELD: medicine, oncology, pharmacy.

SUBSTANCE: invention describes a medicament used in treatment of liver disease by prevention of invasion onset of portal vein. This agent represents the effective medicament containing menatetrenone as an active component used in treatment/prophylaxis of liver disease. Indicated agent used in treatment/prophylaxis of liver disease is the effective medicament against liver cancer, in particular, against DCP (des-γ-carboxyprothrombin)-positive liver cancer. Agent used in aims for treatment/prophylaxis of liver disease contains menatetrenone as an active component, it improves prognosis significantly after carrying out the anticancer therapy and possesses the excellent effect directed on prevention of liver cancer relapses.

EFFECT: valuable medicinal property of agent.

4 cl, 2 tbl, 10 dwg, 2 ex

 

The scope to which the invention relates.

The present invention relates to a tool for the treatment of liver diseases, and more specifically to a tool that improves the prognosis of liver cancer and containing menatetrenone as the active ingredient.

Prior art

It is known that in patients with hepatocellular carcinoma (hereinafter referred to as "FCC") has a high level of invasion of the portal vein (also called "TRS"), and after the TRS forecast becomes very bad. It is known that high levels of des-γ-carboxyprothrombin (hereinafter referred to as "DCP") in patients with HCC is closely associated with the subsequent development of the TRS (see Y. Koike engineering Germany, Cancer 2001, 91:561-9). DCP is also indicated PIVKA-II (protein induced by the absence of vitamin K or antagonist II). DCP is a prothrombin, which has no normal coagulating activity, it is known that in case of deficiency of vitamin K (hereinafter referred to as "VK"), its level increases; thus, the DCP is a protein used as a marker of deficiency VK or breach absorption VK.

In addition, it was reported that after the introduction of VK patients with HCC with a high level of DCP, the DCP level in serum was decreased (see Cancer 1992, 69:31-8), and after administration of vitamin K-II (hereafter referred to as "VK-II) DCP-producing cell line HCCin vitrowatched the camping inhibition of cell proliferation (see Hepatology, 1995, 22:876-82).

But still not received any clinical data indicating that prevent the TRS and recurrence of hepatocellular carcinoma by introducing VK-II patients after treatment of HCC, where such introduction would lead to a better prognosis of this disease.

In accordance with the above, the aim of the present invention to provide a highly effective means for treating or preventing liver disease.

Description of the invention

The present invention was supposed to, mainly, the discovery of the authors of the fact that oral administration of the drug VK-II patients suffering from HCC with DCP production, leads to inhibition of the TRS after treatment of HCC and to improve the prognosis of this disease, as well as to the suppression of recurrence of liver cancer after treatment.

The above objective is achieved by the use of means for the treatment or prevention of liver diseases, containing menatetrenone as the active ingredient.

In accordance with a preferred aspect of the present invention, the above tool is used in the case when the specified liver disease is liver cancer.

In accordance with a preferred aspect of the present invention, vishey the above tool is used in the case when specified liver cancer is liver cancer, which is produced by desγ-carboxyprothrombin (DCP).

In accordance with a preferred aspect of the present invention, the above tool improves the prognosis of liver cancer after treatment.

In accordance with a preferred aspect of the present invention, the above-mentioned means is a means which prevents invasion of the portal vein (TRS).

In addition, the above objective is achieved by the use of means to prevent the invasion of the portal vein (TRS), where the specified product contains menatetrenone as the active ingredient.

In addition, the above aim is achieved with the use of funds to increase survival of the patient after the treatment of liver cancer, where the specified product contains menatetrenone as the active ingredient.

In addition, the above aim is achieved with the use of funds to prevent the recurrence of hepatocellular carcinoma containing menatetrenone as the active ingredient.

In addition, the above objective is achieved by using a means of reducing the level of DCP and containing menatetrenone as the active ingredient.

In addition, the above objective is achieved by applying the method of preventing invasion of the portal in the us (TRS), includes introduction to the patient an effective dose of a medicinal product containing menatetrenone as the active ingredient.

In addition, the above objective is achieved by applying the method of preventing recurrence of hepatocellular carcinoma, comprising the administration to a patient an effective dose of a medicinal product containing menatetrenone as the active ingredient.

In addition, the above objective is achieved by the application of the method of regulation of the level of DCP in the blood of a patient, comprising the administration to a patient an effective dose of a medicinal product containing menatetrenone as the active ingredient.

In addition, the above objective is achieved using menatetrenone in order to obtain means to prevent the TRS.

In addition, the above objective is achieved using menatetrenone in order to prevent recurrence of hepatocellular carcinoma.

In addition, the above aim is achieved with the use of tools for the treatment or prevention of liver disease, where the specified product contains vitamin K as an active ingredient.

The tool containing menatetrenone, for the treatment of liver diseases in accordance with the present invention has a high activity, a warning TRS when Zabol the processes in the liver, in particular, DCP-positive liver cancer, and, in addition, has a high effect of improving the prognosis after treatment of liver cancer. In addition, the tool containing menatetrenone, for the treatment of liver diseases in accordance with the present invention is most suitable for the prevention of liver cancer after treatment.

Brief description of the graphical material

Figure 1 presents a block diagram illustrating the selection of patients.

Figure 2 presents a graph illustrating the change in the level of DCP in the serum.

Figure 3 presents a graph illustrating the change in frequency of the TRS.

Figure 4 presents a graph illustrating changes of survival.

Figure 5 presents a graph illustrating the inhibitory effect of the introduction of VK-II aimed at preventing recurrence of liver cancer (50% recurrence).

Figure 6 presents a graph illustrating the results only in the case of HCV infections in the tests conducted in order to confirm the inhibitory effect of the introduction of VK-II, aimed at preventing recurrence of liver cancer (50% recurrence).

Figure 7 presents a graph illustrating results if you exclude the appearance of local recurrence in trials in order to confirm the inhibitory effect of the introduction of VK-II, aimed at preventing the eldivan liver cancer (50% recurrence).

On Fig presents a graph illustrating results if you exclude the occurrence of relapses within 6 months of the trials in order to confirm the inhibitory effect of the introduction of VK-II, aimed at preventing recurrence of liver cancer (50% recurrence).

Figure 9 is a diagram illustrating the results of the assessment of the relative risk (RR) of disease recurrence using the model is proportional to the risk of Coke and

Figure 10 presents a graph illustrating the results of the analyses on the level of the DCP prior to the treatment and after the occurrence of relapses.

The best embodiments of the present invention

Below is a more detailed description of the present invention with reference to examples, which, however, should not be construed as limiting the invention.

Liver cancer often occurs in patients with chronic hepatitis and cirrhosis of the liver, the treatment of which the present invention is directed, and upon the completion of courses such treatment often its recurrence. So, for example, hepatitis type C or type-b hepatitis leads to cirrhosis of the liver, and after cutting out the tumor relapse. Using the present invention for the treatment of liver disease prognosis after treatment of liver cancer can be mean is Ino improved (i.e., the recurrence can be prevented or removed). In addition, using the specified tool can be successfully prevented the invasion of the portal vein (TRS), which is a form of recurrence of liver cancer with a poor prognosis.

Menatetrenone used in the present invention has the chemical name 2-methyl-3-tetraphenyl-1,4-naphthoquinone, and its structural formula is represented below.

Menatetrenone is a yellow crystalline or oily substance, which has neither taste nor smell and easily decomposing under the action of light. In addition, menatetrenone is almost insoluble in water. Menatetrenone also called vitamin K-II (VK-II), and with regard to its pharmacological action, in the process of protein synthesis of coagulation factors (prothrombin, VII, IX and X) menatetrenone involved in the carboxylation reaction, where the remains of glutamic acid into physiologically active γ-carboxyglutamic acid, and also stimulates the synthesis of normal prothrombin in the liver, etc. and activates the mechanism of hemostasis in vivo, i.e. facilitates hemostasis in the body.

Menatetrenone, which is the active ingredient in the pharmaceutical preparation of the present invention, may be present in the form of an anhydride or hydrate. In addition, menatetrenone has to istoricheskie polymorphs, but not limited to; menatetrenone may be present in any of the crystalline forms, which include, but are not limited to, crystalline form or a mixture. In addition, the metabolite produced by menatetrenone of the present invention and degradable in a living organism, is also in the scope of claims of the present invention.

Menatetrenone used in the present invention can be easily produced well-known method, and a representative example of the method of its production is described in application laid on the Japan patent No. 49-55650; or, alternatively, such menatetrenone can be purchased from chemical manufacturers. In addition, menatetrenone can be purchased as a pharmaceutical preparation in the form of capsules or drugs for injection. As for the drug of the present invention, menatetrenone can be used in pure form, or it can be prepared by a standard method in the form of a pharmaceutical preparation by mixing with ingredients that are usually used as starting materials for pharmaceuticals, such as the well known pharmaceutically acceptable carriers and the like (for example, fillers, binders, disintegrators, lubricating agents, kr is the bearers, the corrigentov, stabilizers, emulsifying agents, stimulants absorption, surfactants, pH regulators, preservatives, antioxidants, etc.). In addition, if necessary, can be mixed and other ingredients such as vitamins and amino acids. Examples of forms of pharmaceutical preparations are tablets, powders, granules, capsules, syrups, suppositories, injectable preparations, ointments, poultices, etc.

In addition, according to the present invention, the method of introducing menatetrenone has no particular limitation, although preferred is oral administration. This menatetrenone capsules can be purchased in capsule form called "capsules Kaytwo" (patented the name given Eisai Co., Ltd.) and in the form of capsules called "capsules Glakay" (patented the name given Eisai Co., Ltd.), menatetrenone syrup can be purchased in the form of a syrup called "syrup Kaytwo" (patented the name given Eisai Co., Ltd.), as preparation for injection can be purchased in the form of a drug called "Kaytwo N" (patented the name given Eisai Co., Ltd.).

Menatetrenone drug of the present invention can be used for treating or preventing liver disease. The preferred dose menatetrenone is mainly 10-200 mg/day, more FAV is preferably 30-135 mg/day.

Examples

The following are examples of tests of the present invention, but these examples are only for illustrative purposes and should not be construed as limiting the present invention. Each specialist can implement the present invention not only in accordance with the following examples of tests, but it may also make various modifications without leaving the scope of the claims, and such modifications are also included in the scope of claims of the present invention.

The test example I

Clinical trials (randomized prospective controlled trials) was performed as follows.

In this trial included patients with hepatocellular carcinoma with DCP level above 60 IU/l (DCP-positive liver cancer). On the other hand, from this test were excluded patients with invasion of the portal vein and patients who have already experienced the metabolism VK due to the introduction VK funds or antagonist VK. Detailed description of the tests is given in table 1.

Table 1

Individuals participating in the test:

In the test included the following individuals:

1. Patients with liver cancer.

2. Patients whose level of DCP in serum was ≥ 60 IU/L.

Of the trials were excluded for the following individuals:

1. Individuums invasion of the portal vein.

2. Individuals with metastatic cancer of the liver to peripheral organs.

3. Individuals with uncontrolled production of ascites.

4. Individuals with serum bilirubin > 3.0 mg/DL.

5. Individuals who took the drug of vitamin K, warfarin.

The group, which was introduced VK-II:

Patients who received 45 mg of vitamin K-II (Glakay) three times after treatment of liver cancer.

Groups that do not have introduced the K-II:

The patients who underwent only the treatment of liver cancer.

Evaluation criteria:

1. The emergence of invasion of the portal vein.

2. Death.

Figure 1 presents a block diagram illustrating the selection of patients. 126 patients with liver cancer were treated from February 1999 to November 2001. Treatment of liver cancer was in therapy against HCC by percutaneous cauterization (RFA and/or PEIT); treatment through the blood vessels (tai or TAI); or in the surgery. From this test was excluded 5 patients.

Then the rest (121 patients) were randomly divided into a group of patients who took VK-II (n = 60), and a group of patients (control group)who did not take VK-II (n = 61). The group that took the drug VK-II oral received 45 mg/day of VK-II (patented name Glakay, this Eisai Co., Ltd.) after treatment of liver cancer and the control group did not receive VK-II.

P the following treatment of liver cancer conducted surveillance of patients. This observation patients was ultrasound every 3 months (abdominal ultrasound), computed tomography every 6 months and assessing the levels of tumor markers, alpha-fetoprotein and DCP, through every month.

Table 1 shows the clinical data for the study patients. Any significant differences between the clinical parameters for the group, consider taking the drug, and for a group who were not taking such drugs, was not observed.

Table 1

Description of clinical data for patients
The group, who consider drug

(n = 60)
The group, who didn't consider drug

(n = 61)
P
Age66,9 ± 7,067,3 ± 7,50,8
Gender (male/female)36/2445/160,12
Virus (HCV/no HCV)50/1052/90,81
Tumor size (mm)32 ± 1135 ± 180,27
The number of tumors4,0 ± 3,24,3 ± 3,50,66
Kindergartens is s hepatitis, the class (And/or)18/4227/340,13
Albumin (g/DL)3,4 ± 0,53,5 ± 0,50,3
Bilirubin (mg/DL)1,2 ± 0,71,1 ± 0,90,4
ALT (IU/l)55 ± 3861 ± 470,47
Prothrombin (%)78 ± 1678 ± 140,99
The blood platelets (104/mm3)10,8 ± 6,011,5 ± 6,60,52
AFP (ng/l)2668 ± 76661539 ± 70360,42
DCP (IU/l)985 ± 26391178 ± 51080,80
MOUTH with reception/no reception medicines48/1241/200,15
average ± cf. square from. (median)

Figure 2 presents a graph illustrating changes in the level of DCP in the serum. The solid line corresponds to the group taking the drug, and the dotted line means a group not treated with this drug. For both groups, after treatment of liver cancer, the level of DCP after decreased. Then DCP, the group taking the drug, the OST is also approximately constant during the 12 months while the level of DCP in the group not treated with this drug, gradually increased.

Figure 3 presents a graph illustrating changes in the frequency of cases TRS. As shown in figure 3, the group who considered the drug, the number of cases TRS was 2% after 1 year, and 23% in 2 years. On the other hand, the group who considered the drug, the number of cases TRS was 23% at 1 year and 47% after 2 years (P=0,018).

4 shows a graph illustrating the change in survival. As shown in figure 4, the survival of patients in the treated group, considered the drug was 66% after 2 years, whereas survival of patients in the group not taking this particular drug was 28% (P=0,044).

Performed statistical analysis on the incidence of TRS and survival of patients in the two groups. That is, the calculation was performed using a model of proportional risk of Coke, and this test was performed using lagrangeville criterion. The average observation period was 12 ± 8 months.

Based on the above results, it was assumed that the oral administration of the drug VK-II there was a very sharp decline in the number of cases TRS in patients with DCP-positive HCC, and, in addition, the survival rate for these patients is much the age of the aircraft, and, therefore, significantly improved the prognosis after treatment of liver cancer.

Sample test 2

The test was performed, as described below, in order to study inhibitory effect of VK-II aimed at the prevention of recurrence of hepatocellular carcinoma after treatment, and its security.

For the period from March 1999 to March 2001 was compiled the list, which included 61 patients diagnosed with hepatocellular carcinoma and followed by a complete necrosis after treatment (or surgery), which was indicated contrast-enhanced CT scan; and patients who were included in this list were divided into two groups, namely, the group that took VK-II and in which a finite number of ID patients was odd, and the group that did not receive the VK-II (control group) and in which a finite number of ID patients was even; thus patients VK-II-group oral introduced VK-II (patented name Glakay, this Eisai Co., Ltd.) at a dose of 45 mg/day. Then every 3 months spent contrast computed tomography or magnetic resonance tomography, and performed statistical analysis of the period of time until relapse. In particular, comparisons were made using the criterion of Kaplan-Meier (lagrangeville test) and assessment of the relative risk of recurrence with COI is whether the model is proportional to the risk of Coke.

As shown in table 2, the average period of observation 61 participant test (32 patients in the treated group, VK-II, and 29 patients in the group not treated with VK-II) was 19.6 months (7-32).

Table 2
IndividualsThe group, which took the VK-II (32 cases)The control group (29 cases)
Age63,3±7,5(48-75)64,5±67(45-74)
Gender (male/female)23/918/11
Factor causing the disease (type a/type b/type b+C)28/3/126/2/1
Background alcohol consumption (alcoholic/non-alcoholic)10/223/26
Primary tumor/relapse15/1714/15
Tumor size (mm)17,7±5,1(10-30)19,4±6,9(10-38)
The number of tumors1,50±0,88(1-4)1,48±0,74(1-3)
Log AFP (ng/ml)1,47±0,61

(0,60-3,09)
1,72±0,91

(0,48-3,88)
PIVKA-II (may/ml)41,8±65,4

(8-346)
70,3±104,1

(7-417)
Liver function (LD A/B/C)15/16/113/15/1
The method of treatment (surgical/nonsurgical)1/313/26
The average follow-up period (months)24,3±7,1(13-37)24,2±8,3(12-37)

After counting the total number of cases of recurrence was found that the number of relapses at 1 year after treatment in patients group, taking VK-II, was 12.5%, while patients in the control group is 55.2%, while the number of relapses in 2 years after treatment in patients group, taking VK-II amounted to 39.6%, while patients in the control group of 85.5%. From these results, it was found that, compared with the control group, the group who took VK-II, there was a statistically significant decrease in the overall incidence of recurrence of liver cancer.

Figure 5 presents a graph illustrating the effect of the introduction of VK-II, aimed at preventing the recurrence of liver cancer (50% recurrence). As shown in figure 5, the period of time until recurrence of liver cancer (50% of relapses) in the group that took VK-II was 26 months and in control group it was 10 months.

Moreover, after counting the total number of cases of recurrence with only HCV-cases (hepatitis C), it was found that the appearance of recurrence 1 year after treatment in patients group, taking VK-II, was 7.1%, and in patients contact Olney group - 61.5%, and the occurrence of relapse after 2 years of treatment in patients who took VK-II, was 37.8 percent, while patients in the control group - 87,2%. From these results, it was found that, compared with the control group the group, which took VK-II, there was a statistically significant reduction in the overall incidence of recurrence of liver cancer when considering only HCV-cases.

Figure 6 presents a graph illustrating the results obtained in the test for HCV-cases conducted in order to confirm the inhibitory effect of the introduction of VK-II, aimed at preventing recurrence of liver cancer (50% recurrence). As shown in Fig.6, the period of time until recurrence of liver cancer (50% of relapses) in the group that took VK-II was 26 months and in control group it was 10 months.

Figure 9 is a diagram illustrating the results of the assessment of the relative risk (RR) of occurrence of relapses in the model is proportional to the risk of Coke. As shown in Fig.9, if we take the relative risk for control group 1, the relative risk for the group, taking VK-II was approximately one third, i.e. 0,329; in particular, for HCV-cases relative risk was 0,210, i.e. for the group, taking VK-II, this risk was reduced five times.

On Fig presents a graph to illustrate the results for the cases of exclusion of local recurrence in trials in order to confirm the inhibitory effect of the introduction of VK-II, aimed at preventing recurrence of liver cancer (50% recurrence) (treated group, VK-II: 29 patients; group not treated with VK-II: 22 patients). In addition, Fig presents a graph illustrating results if you exclude the occurrence of relapses within 6 months of when the tests carried out in order to confirm the inhibitory effect of the introduction of VK-II, aimed at preventing recurrence of liver cancer (50% recurrence) (treated group, VK-II: 31 patients; group not treated with VK-II: 22 patients). As shown in Fig.7 and 8, in these cases, again, it was found that the group that took VK-II, there was a statistically significant reduction in the overall incidence of recurrence of liver cancer compared with the control group.

Figure 10 presents a graph illustrating the results of the analyses on the level of the DCP prior to the treatment and after the occurrence of relapses. As shown in figure 10, in all cases, the occurrence of relapse in patients treated group VK-II, DCP was not detected, and, in addition, there were no side effects and cases of failure of test.

Action VK-II of the present invention on the development of invasion/metastasis of liver cancer cells was study the ANO in vitro. The ability to impact on the invasion was investigated using analysis on the invasion using cells G2 and camera Matrigel. The results showed that the number of cells that passed through the chamber Matrigel, was decreased by adding VK-II, and this reduction was dependent on the concentration of VK-II. The ability to impact on metastasis was investigated the influence of VK-II on the expression of the intercellular matrix metalloproteinases (MMP) using Western blot analysis. After research on the protein expression of MMP-1 and MMP-3 by adding VK-II in cancer cells of the liver was found that in this case the expression inhibited. Based on these results, though they were receivedin vitrowe can assume that VK-II inhibits invasion/metastasis of liver cancer cells.

Industrial application

As described above, menatetrenone a tool used for treating or preventing liver disease in accordance with the present invention has excellent inhibitory effect on TRS with liver disease, and in particular, DCP-positive liver cancer, and, in addition, it has excellent action from the point of view of prognosis after treatment of liver cancer.

In addition, menatetrenone a tool used for treating or preventing liver disease in accordance with the present invention, I have provided is very effective for preventing recurrence of liver cancer after treatment.

1. Means for inhibiting the recurrence of hepatocellular carcinoma after treatment of liver cancer containing menatetrenone as the active ingredient.

2. Means for reducing the level of des-γ-carboxyprothrombin and containing menatetrenone as the active ingredient.

3. Method of inhibiting recurrence of hepatocellular carcinoma, comprising the administration to the patient after the treatment of liver cancer, an effective dose of a medicinal product containing menatetrenone as the active ingredient.

4. The modulation method of the level of des-γ-carboxyprothrombin in the blood of the patient, including the introduction of a specified patient an effective dose of a medicinal product containing menatetrenone as the active ingredient.



 

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FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyridylcyanoguanidines of the general formula (I):

or their pharmaceutically acceptable salts wherein 1 means hydrogen atom; X means hydrocarbon (C1-C12)-biradical; Y means a bond or oxygen atom (O); Z means 5-10-membered aromatic heterocyclic radical optionally substituted with hydroxy-group under condition that R1 is not bound to nitrogen atom in pyridyl ring. Compounds of the formula (I) and their salts possess antiproliferative activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

9 cl, 1 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

Kahalalide f // 2292216

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to novel compositions and using kahalalide F, to a set containing the kahalalide F composition and to a reduced solution prepared from the kahalalide F composition. Combination of non-ionic surface-active substance and organic acid is suitable for using with a filling agent for preparing lyophilized formulation of kahalalide F.

EFFECT: improved preparing method.

10 cl, 7 ex

FIELD: pharmaceuticals, organic chemistry.

SUBSTANCE: invention relates to method for production of sterilized microcrystalline cis-dichlorodiamineplatinum (II). Claimed method includes heat treatment of microcrystalline cis-dichlorodiamineplatinum (II) salt of high purity (not less than 99.5 mol %) at 160°C for 6 hours.

EFFECT: new method for production of sterilized microcrystalline cis-dichlorodiamineplatinum (II).

2 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: preparation belongs to gestagen class as 17α-acetoxy-3β-butanoyloxy-6-methyl-pregna-4,6-dien-20-on allowing peroral application. The compound shows no toxic activity and has no androgenic side effect. It is found to be better than Depo-Provera gestagen used in clinical practice and possesses chemosensitizing activity. The preparation is obtained by megestrol acetate reduction with sodium borohydride with following product etherification with butyric acid anhydride. The reaction mixture is treated with ammonia solution after etherification with butyric acid excess being removed to increase output and target product separation.

EFFECT: enhanced effectiveness of treatment.

3 cl, 3dwg, 1 tbl

FIELD: medicine.

SUBSTANCE: method involves applying chlorocholine chloride as antitumor means.

EFFECT: enhanced effectiveness of treatment; reduced risk of adverse side effects manifestation; low toxicity.

FIELD: medicine.

SUBSTANCE: method involves preparing composition comprising epotilone analogs by dissolving said epotilone analog in aqueous butanol. The produced solution is dried in two stages to produce lyophilized product being lyophilized epotilone analog and pharmacological means for treating cancer diseases containing lyophilized epotilone analog.

EFFECT: high solubility of obtained product.

20 cl,1 tbl

FIELD: chemistry of metalloorganic compounds, medicine, oncology.

SUBSTANCE: invention relates to novel chemical compounds, namely, to complexes of palladium with heterocyclic ligands of the general formula (I): wherein R1 means-NH, oxygen atom (O), -CH2; R2 means two hydrogen atoms (2H), O; R3 means hydrogen atom H, CH3, CH2-CH2-NH2,-(CO)-CH3; X means chlorine (Cl), bromine (Br) atom; n = 1; m = 1 if R1 means -NH, O; R2 means 2H; R3 means H, CH3, CH2-CH2-NH2, -(CO)-CH3; n = 2; m = 1 if R1 means O, -CH2; R2 means O, 2H; R3 means H, CH3, -(CO)-CH3; n = 2; m = 3 if R1 means -NH; R2 means 2H; R3 means CH2-CH2-NH2 eliciting pharmacological, in particular, anti-tumor activity. Proposed compounds possess high activity and characterized by reduced toxicity as compared with anti-tumor preparations with platinum complexes.

EFFECT: valuable medicinal properties of complexes.

4 cl, 2 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of quinazoline of the formula (I): m means a whole number from 1 to 3; R1 represents halogen atom or (C1-C3)-alkyl; X1 represents -O-; R2 represents (C1-C5)-alkyl-R3 wherein R3 represents piperidine-4-yl that can comprise one or two substitutes chosen from (C1-C4)-alkyl and to their salts. Also, invention relates to methods for synthesis of these compounds and pharmaceutical compositions comprising compound of the formula (I) or its pharmaceutically acceptable salts as an active component. Compounds of the formula (I) and their pharmaceutically acceptable salts inhibit effect of VEGF that is a valuable property in treatment of different pathological states including cancer and rheumatic arthritis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

28 cl, 14 ex

FIELD: pharmaceutical industry.

SUBSTANCE: claimed adsorbent contains spherical active carbon, obtained from thermosetting resin as carbon source, having particle size of 0.001-1 mm, specific surface determined by Langmuir adsorption equation of 1000 m2/g or more and pore volume of 7.5-15000 nm in diameter less than 0.25 ml/g. Also disclosed is adsorbent being similar to abovementioned one, wherein total content of acidic groups is 0.40-1.00 meq/g; total content of basic groups is 0.4-1.1 meq/g. Pharmaceutical compositions contain said adsorbents and pharmaceutically acceptable carriers and recipients. Agents of present invention are useful in treatment of kidney or liver diseases or disorders associated with uremic substance by administration of said adsorbents.

EFFECT: products of increased selectivity.

21 cl, 5 ex, 2 tbl, 11 dwg

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