Radiopharmaceutical agent for diagnosing or treating (therapy) skeletal bone injuries and method of preparing said agent

FIELD: chemistry.

SUBSTANCE: invention relates to a radiopharmaceutical agent for diagnosing or treating (therapy) skeletal bone injury, containing a complex of zoledronic acid with 99mtechnetium or 188rhenium isotopes, zoledronic acid, tin halide or possibly an antioxidant - ascorbic or gentisic acid. The invention also relates to a method of preparing said radiopharmaceutical agent, involving mixing a lyophilisate, obtained by mixing a zoledronic acid solution and a solution of tin dichloride in hydrochloric acid in an inert gas atmosphere and adding a metal hydroxide, with a salt of a metal from the group of isotopes and a radionuclide solution.

EFFECT: more effective use of the compounds.

4 cl, 2 ex, 14 tbl

 

The invention relates to the field of chemistry and medicine, in particular radiopharmaceutical means on the basis of bisphosphonates and the way they are received, and can be used for diagnosis and treatment in Oncology, namely in the treatment of multiple myeloma, bone metastasis in breast cancer, lung, thyroid, colon, uterus, prostate and as a means of reducing hypercalcemia.

Complexes of radionuclides with di - and polyphosphonate have the ability to selective accumulation in the skeleton, especially in the areas of pathological osteoarthri. The main advantage of scintigraphy of the skeleton compared with the radiographic diagnosis is early detection of both the single and multiple foci of increased accumulation in malignant tumors of the skeleton and bone metastases.

Known phosphate complexes99mTC, in particular polyphosphate, triphosphate and pyrophosphate [G.Subramanian, J.G.Agfee // Radiology - 1971. - Vol.99, - p.192].

Also known diphosphonates99mTC with similar properties [Schmitt GH, R.A. Holmes, Isitman A.T. // Radiology - 1974. - Vol.112, - p.733].

Currently in the global radiological practice, the most widely used99mTC-methylenediphosphonate (99mTC-MDP) and99mTC-hydroxyethylidene-diphosphonic (99mTC-HEDP, in Russian the literature-eddc) [W.C.Eckelman, W.A.Volkert. // Int.J.Appl.Radiat.lsotopes-1982. - Vol.33, - p.945]. To obtain99mTC use pertechnetate,99mTC sodium derived from generator99Mo/99mThe TC. TC(VII) is chemically the most stable state of technetium, but pertinent-ions are not associated with chelating agents. To get a stable connection restored technetium requires the use of various reducing agents, such as ions of tin (II), sodium borohydride, concentrated hydrochloric acid, dithionite sodium, hydrazine [Nuclear Medicine. Diagnosis and Therapy // J.C. Harbert, W.C.Eckelman, R.D.Neumann Eds. - Thieme Medical Publishers, Inc., New York, 1990, p.218]. The most common reducing agent used douglaston tin, which is part of almost all drugs99mThe TC. Because douglaston tin is present in a large excess relative to the99mTC, it supports the technetium in the restored form and contributes to the formation of the restored complex of technetium with ligands.

All complexes of technetium with diphosphonates, Osteuropa, and therefore it is generally accepted the wording "99mTC-phosphonate complex.

Along with99mTC radionuclide therapy using isotopes of rhenium and Samaria, including153Sm-ethylenediaminetetramethylene (153Sm-EDTMP) [Resche l., Catal J.F., Peching A. // Eur. J / Cancer. - 1997. - Vol.33, p.1583], samarium-153-oxabiphor [Krylov V.V., Tsyb A.F, Drosdovsky B.Y. // Eur. J. Nucl. Med. and Molec. lmaging. - 2006. - Vol.33, Suppl. 2. - s. 335], rhenium-186 and rhenium-188-hydroxyethylidenediphosphonic (186Re-HEDP [Jak M.S.P., Han S.H. B.A. Zonnenberg, et al. // J. Nucl. Med. - 1996. - Vol.37. - p.1511],188Re-HEDP [Faintuch B.L., Faintuch, S., E. Muramoto // Radiochim. Asta - 2003. - Vol.91. - p.607],188-Re-methylenediphosphonate (188Re-MDP [Hashimoto K., Bagiawati S., lzumo M., Kobayashi K. Appl. Radiat. lsot. - 1996 - Vol.47, No.2, - p.195].

Rhenium-186 get in a nuclear reactor by the reaction185Re (n,γ)186Re or by the reaction186W (p, n)186Re cyclotron [Jak M.S.P., S.H. Han, B.A. Zonnenberg et al. // J. Nucl. Med. - 1996. - Vol.37. - p.1511]. These methods are quite expensive. Was developed by the generator rhenium-188, the parent isotope served W-188, derived from enriched in W-186 metallic tungsten or tungsten oxide [F.F. Knapp Mirzadeh, S., Zamora, P.,et al. // Nucl. Med. Commun. - 1996. - Vol.17, - p.268].

Rhenium and technetium, forms complexes with various ligands. We studied the processes of formation of rhenium-188 with three methylenephosphonate acids, namely Ethylenediamine-N,N,N',N'-tetrakis(methylenephosphonate acid, EDTMP (Ethylenediamine-N,N'-bis-(methylenephosphonate acid, EDBMP); (nitrilotri-(methylenephosphonate acid, NTMP). It was noted that in the presence of douglasthe tin all the ligands form complexes at pH<3 [Hashimoto K. The Second Japanese-German Seminar on technetium. Shizuoka, Japan, 1999, Abstracts, - p.40].

In addition diphosphonates often in medical practice, the use of bisphosphonates (BF) [Benevolen the Kai LI Bisphosphonates and osteoporosis. // A guide to osteoporosis / podrid Liebevolles), Binoche, Laboratory knowledge. - 2003, - GL, - s-216.]. Studies of acute, subacute and chronic toxicity BF show that they generally belong to the group of low-toxic substances with relatively low levels of acute and chronic toxicity. Not detected in them and teratogenic, mutagenic, and carcinogenic properties.

Zoledronicaa acid is bisphosphonates and has the property to inhibit bone resorption. Antiresorptive mechanism is not completely clear. In vitro, zoledronicaa acid inhibits the activity and induces apoptosis of osteoclasts. Blocks osteoclastic resorption of mineralized bone and cartilage.

In article Storto, G., G. Paone, Ibello F., et al. // Eur.J. Nucl. Med. And Molec. Imaging. - 2004. - Vol.31, - s. 291 the authors used a combination therapy Sr-89 + zoledronicaa acid to reduce bone pain associated with metastases caused by breast cancer and prostate cancer, and compared the results with therapy using a single Sr-89.

Now for scintigraphy of the skeleton (diagnostics) use basically the simplest diphosphonates, technetium -99 m in the General formula

,

where R1and R2mean hydrogen, hydroxy, carboxy, a hydrocarbon radical, e.g. methylenediphosphonate (MDP), oxyethylidenediphosphonic (HEDP) or decarboxylation (DPD) [W.C.Eckelman, W.A.Volkert. // lnt. J. Appl. Radiat. lsotopes - 1982. - Vol.33. - p.945] and diphosphonates labeled with rhenium-186 or rhenium-188, mainly oxyethylidenediphosphonic [Jak M.S.P., Han S.H. Zonnenberg B.A, et al. // J. Nucl. Med. - 1996. - Vol.37 - p.1511],188Re-HEDP [Faintuch B.L., Faintuch, S., E. Muramoto // Radiochim. Asta - 2003. - Vol.91,- p.607].

However, they have not sufficiently high specificity and sensitivity in the diagnosis and effectiveness of treatment.

The present invention is to eliminate the above drawbacks.

The problem is solved by the invention related to compositions based on the latest generation bisphosphonates, in particular zoledronate acid, radiopharmaceutical agents on their basis, as well as how the radiopharmaceutical receipt of such funds.

The first object of the claimed invention is a radiopharmaceutical agent for diagnosis and treatment (therapy) of bone lesions in the skeleton, including complex zoledronate acid by isotope99mTechnetium or188Rhenium obtained in the presence of a reducing agent and possible antioxidant.

This set of common essential features is the essence of the claimed device. It is necessary and sufficient for all purposes of its implementation.

Furthermore, with respect to zavlin the th object the applicant considers necessary to identify the following development and/or refinement of the totality of its essential features, related to personal performance or use.

According to the invention as a reducing agent, you can use the tin halide (for example, dichloride or differed tin), or sodium borohydride, or ditioned sodium. At the same time as the halide of tin can be applied, for example, dichloride or differed tin.

As an antioxidant it is possible to use ascorbic acid or entityname acid.

The second object of the claimed invention is a method for radiopharmaceutical tools for the diagnosis and treatment (therapy) of bone lesions in the skeleton, which consists in the fact that they are freeze-dried by mixing an aqueous solution by zoledronate acid and halide of tin in hydrochloric acid and possible antioxidant in a stream of inert gas when adding alkali metal hydroxide, the resulting lyophilisate is mixed with the salt of a metal from the group of isotopes selected from the group99mTechnetium or188Rhenium, obtaining a complex and then adding a solution of the radionuclide.

The following examples illustrate the obtaining of the proposed systems and tools radiopharmaceutical.

Example 1

Example of synthesis of the drug with technetium-99m:

1. Preparation of lyophilized reagent

0.15 g of zoledronate acid was dissolved in 92 ml in the s in a stream of inert gas. This and subsequent operations were performed in a stream of inert gas. To the resulting solution was added 5 ml of a solution of tin dichloride in 1 M hydrochloric acid (6-7 mg/ml) and 3 ml of 1.5 M NaOH solution. The resulting reagent solution was filtered through a 0.22 μm filter and packaged in portions of 1 ml vials for pharmaceuticals. The contents of the vials liofilizirovanny.

2. The freeze-dried composition in the vial:

zoledronate acid1,53 mg
douglasthe tin, anhydrous0.3 mg
pH4-6,5

3. Preparation

In a bottle with liofilizirovannam reagent was added to 5 ml of isotonic sodium pertechnitat,99mTC (740-1480 MBq/ml) of the generator, and was kept for 20 min at room temperature.

4. The composition of the drug:

Technetium-99m in the form of a complex

td align="right"> 4-6
with zoledronate acid740-1480 MBq/ml
zoledronate acid0,31 mg/ml
douglasthe tin, anhydrous0.06 mg/ml
pH
Radiochemical purity≥ 95%

(for definitions used methods HPLC and TLC)

Example 2.

The synthesis of the drug with rhenium-188

1. Preparation of lyophilized reagent

0,42 g hentaimovi acid was dissolved in 60 ml of water. This and subsequent operations were performed in a stream of inert gas. To the resulting solution was added 8 ml of a solution of tin dichloride in 1 M hydrochloric acid (18 mg/ml) and 40 ml of an aqueous solution by zoledronate acid (6 mg/ml). The resulting reagent solution was filtered through a 0.22 μm filter and packaged in portions of 1 ml vials for pharmaceuticals. The contents of the vials liofilizirovanny.

2. The composition of lyophilized reagent in the vial:

zoledronate acid2.2 mg
douglasthe tinof 1.33 mg
hentaimovi acid3.9 mg
pH2,4

3. Preparation:

a) Into the vial containing 40 μl of perrenate sodium concentration of 0.8 mg/ml for rhenium was added 1.5 ml of a solution of sodium perrenate,188Re generator. The solution was stirred (the bottle is 2).

b) Into the vial with liofilizirovannam reagent (vial No. 1) syringe made all the contents of the vial No. 2 and stirred.

b) the Preparation is kept at room temperature for 2 hours Before use the solution was filtered through a 0.22 μm filter.

4. The composition of the drug:

rhenium-188 in the form of a complex
with zoledronate acid740-7400 MBq/ml
zoledronate acidof 1.45 mg/ml
douglasthe tin0,89 mg/ml
hentaimovi acid2,59 mg/ml
rhenium0.02 mg/ml
pH2-4
Radiochemical purity≥90%

(for definitions used methods HPLC and TLC)

Other metal complexes get analogously to examples 1 and 2.

Biological testing of the proposed complexes

Experiments were performed on intact outbred white rats and rats with a model of bone pathology. Bone pathology was simulated per the scrap hips.

For making funds in a bottle with lyophilisate was introduced in 5.0 ml of a solution of sodium pertechnitat99mTC from a technetium generator (Fund 42-0225-4528-03, the Fund 42-0018-2694-02) by puncture needle of the syringe rubber tube, after which the vial was shaken and kept for 20 minutes. The tool in the volume of 0.2 ml was injected into the tail vein. After 1, 3, 5, 24 hours after injection the animals were killed by decapitation and selected samples of blood, liver, kidneys, stomach, right and left hip, bladder content. The radionuclide content in organs and tissues was determined by direct counting.

The differential accumulation (DVS) was determined as the quotient of the division values the concentration of funds in the femur model bone pathology and healthy femur.

Statistical processing of data was performed by the method of t-test.

The results are presented in Tables 1 and 2.

Table 1
Pharmacokinetics "Zoledronate acid99mTS in organs and tissues of intact female rats after intravenous (% dose/organ)
The organ/tissue1 h3 hours5 hBlood1,7±0,270,9±0,380,4±0,03traces
Liver0,8±0,121,0±0,270,6±0,110,2±0,13
Kidney1,3±0,170,9±0,211,2±0,130,6±0,32
Stomach0,1±0,030,1±0,010,1±0,040,3±0,05
Bladder (1, 3 h);45,4±4,0330,1±to 4.41
Excretion (5, 24 h)52,4±2,8039,1±5,00
Hip1,8±0,161,9±0,351,6±0,111,8±0,06
Skeleton48,1±4,3647,3±2,89 42,9±2,9349,6±1,77

Table 2
Pharmacokinetics means "Zoledronicaa acid,99mTS in organs and tissues of rats with a model of bone pathology after intravenous (% dose/ organ)
The organ/tissue1 h3 hours5 h24 hours
Blood1,7±0,712,0±0,810,5±0,010,7±0,01
Liver1,7±0,581,1±0,421,0±0,050,5±0,09
Kidney1,8±0,831,4±0,680,9±0,060,5±0,08
Stomach0,4±0,030,2±0,090,4±0,05traces
The bladder (1,3 h); Development (5, 24 h)35,1±10,53 44,8±3,8943,4±of 5.0552,5±10,86
Hip, Norma2,1±0,201,9±0,421,9±0,201,4±0,40
Hip fracture4,2±1,044,0±1,343,1±0,702,5±0,05
Skeleton57,7±5,5446,6±7,81to 49.9±5,4438,0±11,02
KDN2,02,11,71,9

Investigation of the pharmacokinetics of the means showed that the distribution of the analyzed tools are characterized by a strong osteotropic. After intravenous injection of funds intact animals after 1 hour to 48% of the injected activity is localized in the skeleton and 45% is excreted in the urine. After 3 hours after the introduction of the accumulation in the skeleton is 47%, the elimination of 30%. The activity level in the blood decreases rapidly and after 5 hours after the beginning of the study is practically trace.

The values of the coefficients of differential accumulation Pat the logic bone/Norma tool provides the possibility of osteointegration. This confirms the functional suitability of the tools as tools radiopharmaceutical for the diagnosis of pathological processes in the bone tissue, accompanied osteopaticheskii processes.

In scientific research Institute of Urology was conducted in an open comparative study of the efficacy and safety of drug zoledronate acid, technetium, the detection of pathological changes of the skeleton in patients with prostate cancer by the method of osteointegration. We studied the frequency of agreement and disagreement between the results of osteointegration when using drugs, claimed as the invention of this application and known Technifor. The safety of a new drug was assessed on the basis of the analysis of the frequency of adverse events and side effects. The results obtained prove equally effective diagnostic significance of the study drug for the claimed invention (1 hour after injection) and known drug Technifor,99mTc (3 hours after injection). Not registered significant differences in the minimum values KDA 1,48±0,29 vs 1,41±0,52 (p=0,668), and maximum values KDA 2,22±1,19 vs 1,88±0,82 (p=0,381). In the clinical studies of the drug for the claimed invention was shown its high efficiency, security, the economic feasibility for osteointegration in patients with a pathological process in the bone skeleton. The drug helped to visualize how osteoclastic and osteolytic metastases, to carry out differential diagnostics of pathological processes in the bones, contributed to the definition of treatment and control outcomes. Osteointegrated with the drug for the claimed invention allows for a 67 percent reduction in the time study and get a higher quality image. A new drug can be recommended for widespread use in clinical practice of medical institutions on the territory of the Russian Federation.

Investigation of the pharmacokinetics of the radiopharmaceutical99mTc according to the claimed invention have shown that the physiological distribution of the investigational radiopharmaceuticals are characterized by a strong osteotropic. After intravenous injection of intact animals after 1 h to 52.5% of the injected activity is localized in the skeleton and 40% is excreted in the urine. After 3 h after injection accumulation in the skeleton is 48,9%, excretion - 40%. The level of activity in the blood not higher than 1.9% after 1 h after injection, decreasing by 24 h after the start of the study to the background level. In other organs also occurs a significant accumulation of the drug.

According to the "Manual on experimental (preclinical) study of new radiopharmaceuticals" the drug stated on the Lenna invention with 99mTc can be attributed to the RN on the basis of chemical compounds with known pharmacological properties, because one of the main substances is zoledronicaa acid, which belongs to the pharmacological group 8.8 (Corrector metabolism of bone and cartilage). At the same time the radiopharmaceutical composition according to the invention with99mTc is not identical to the known dosage forms based on zoledronate acid.

The studied samples of the preparation according to the invention with99mTc were sterile, apyrogenic and never had a single animal adverse reactions when administered intravenously. Experimental study demonstrated the safety of using this drug.

From the above it can be concluded that the preparation according to the invention with99mTc - the first in the world commercial radiopharmaceutical preparation (RFP) based on zoledronate acid, intended to detect pathological changes of the skeletal system by the methods of nuclear medicine.

The main difference from the existing radiopharmaceuticals of this type is used as the primary substance (target media) bisphosphonates last generation - zoledronate acid, which has the highest affinity (compared to other used bisphosphonates) to areas of pathologically increased resorption to the things of cloth, including the foci of metastatic origin for tumors of different localization and origin.

To assess the efficacy and safety of the drug according to the invention with99mTc pathological changes of the skeleton in patients with prostate cancer, we have taken an open, multicenter comparative study of the results of osteointegration with the preparations according to the invention with99mTc, Technifor,99mTc (known).

Materials and methods.

To assess the sensitivity and safety of the drug according to the invention with99mTc the study included 20 patients with a diagnosis of common prostate cancer" after its initial detection methods ultrasound, CT and morphological confirmation. The study selected patients with clinical and/or radiological signs of pathological changes of the skeletal system. We studied the frequency of coincidence of the results of osteointegration carried out with the preparations according to the invention with99mTc, Technifor,99mTc. The safety of the drugs were assessed on the basis of the analysis of the frequency of adverse events and side effects.

All patients studied groups at different times before inclusion in the study was established prostate cancer. The rank values of PSA levels in serum shelter who was 110-2150 ng/ml Patients were identified or anticipated defeat skeletal metastatic process according to clinical data, as well as in the x-ray and radioisotope studies. Patients received specific therapy according to established the stage and form of the underlying disease.

All patients gave written informed consent to participate in the study and comply with the instructions of the doctor. From the Protocol were excluded patients with established hypersensitivity to preparations containing99mTc; past radiological study with 111In or 67Ga within 10 days before inclusion in the study, and patients who, in the opinion of the investigator, for any reason, are not fit to participate in it.

The preparation according to the invention with99mTc was administered intravenously, based on 5 MBq kg-1 body mass. In this study scintigraphy in all patients was performed 1 hour after injection. Technifor,99mVehicle was administered intravenously in an amount of 5 MBq per 1 kg of body weight of the patient, the scan was performed 3 hours after injection. The study was conducted using a gamma camera. The interval between scintigraphy with the use of the preparation according to the invention with99mTc and Tehrefore,99mTc was not less than 72 hours.

Images etc is osteointegration with these drugs, analyzed by the doctor-radiologist, were evaluated for the presence or absence seizure99mTc in the bones of the skeleton. Images obtained with the use of these drugs was considered positive if defined foci accumulation in the bones of the skeleton with a difference of isotope accumulation in the symmetric region more than 40% (DVS≥140%). The image was negative in the absence of foci of hyperfixation radionuclide.

1. Getting lyophilised compositions of different composition by isotope of rhenium

For recovery of rhenium (188Re), it is necessary to use more douglasthe tin than for restore99mTc, and therefore, it is necessary to increase the concentration of zoledronate acid reagent. Due to the limited solubility of zoledronate acid in acidic solutions and sludge formation we were faced with the task of choosing the conditions for obtaining a clear solution of the reagent. For this purpose we have developed lyophilized composition with a molar ratio of zoledronicaa acid (HCC): SnCl2from 1 to 3.

Preparation of reagent solution (volume 50 ml) was mixed in a stream of inert gas pre-prepared solutions hentaimovi acid, zoledronate acid and douglasthe tin in 1 M HCl. The obtained solutions of the reagents, if they were murky is whether opalestiruet, before packing filtered through a Millipore filter 0.22 μm. After filtration of the reagent solution was packaged in 1 ml glass vials and placed in a freeze drying. Upon completion of the lyophilization process chamber lyophilic drying filled with argon, the vials were closed with rubber stoppers and cavalcaselle. Summary data on the composition of the reagents and liofilizatow presented in tables 3, 4, 5, 10.

Table 3
The quantitative ratio of the components liofilizatow based on zoledronate acid
The composition of the reagent in the vial mgThe molar ratio of [sq]/[Sn]Appearance of solution
LCSnCl2Gent. thethe solution pH
2,181,333,892,41,1Very muddy
1,921,321,41,41 Slightly opalestiruet
4,11,52,31,32Transparent.*
6,271,53,32,53Transparent.*
*before packing does not filter.

2. Preparation of lyophilised preparations of compositions

In the vial containing lyophilized composition has introduced the acidified eluate (solution of Na188ReO4in 0.9%NaCl) to ensure that the recovery was 30 min After 30 min after recovery in a vial was added 2 ml of a solution of NaHCO3(~10 mg/ml). the pH of the preparation is 2.0 to 2.5. Before the introduction of the animal preparation was filtered through a Millipore filter 0.22 μm, in order to reduce the content of hydrolyzed recovered rhenium. Radiochemical purity of the preparation was determined by the chromatographic method by using two systems immediately after recovery, after adding NaHCO3and after filtering. In tables with data for the study of the biological behavior of drugs will be presented data only on RHC drug after filtering (that is the drug who was directly injected animals). Data RHC presents the results of the scan chromatograms.

3. The study of the biological behavior of drugs prepared from lyophilized reagents

In the tables presents data biological behavior of drugs. For standard taken the sum of all the bodies.

3.1. The molar ratio of [sq]/[Sn]=1

When this molar ratio were developed lyophilized composition of the following composition:

Table 4
The quantitative composition of liofilizatow based on zoledronate acid at the [WC]/[Sn]=1
No.The composition of the reagent in the vial mgthe pH of the reagent solution
LCSnCl2Gent. theRe
12,181,333,8902,4
22,181,333,89 05
-2,181,333,8902,9
41,921,321,401,4
51,921,321,40,031,4

Table 5
The biological behavior of the drug prepared from the dried composition with [WC]/[Sn]=1
(If you are receiving this drug is used in the freeze-dried composition No. 1, the restoration was carried out for 2 h, and medium was added to the eluate)
The composition of the drug (mg/mlBodiesAfter 1 hAfter 3 h
LC1,45Blood, %/g 0,80,6
SnCl20,89Liver2,01,5
GK2,59Kidney11,39,5
Re0,02Stomach1,91,7
pH2,4Much. The HSS.of 57.565,4
RHC, %92,6Hip norms.0,60.6
ReO4, %6,2Hip fracture1,41,0
GWR %1,2Skeleton17,2the 17.3
The amount of impurities, %7,4KDN2,2,8

3.2. The molar ratio of [3K]/[Sn]=2

When this molar ratio were prepared lyophilized compositions of four different structures:

Table 6
The quantitative composition of the components of liofilizatow based on zoledronate acid at [3K]/[Sn]=2
No.The composition of the reagent in the Vial mgthe pH of the reagent solution
LCSnCl2Gents-TARe
14,11,5001,3
24D1,500,031,3
34,11,52,301,4
44,1 1,52,30,031,4

Table 7
The biological behavior of the drug prepared from the dried composition in which the molar ratio of [sq]/[Sn]=2. (The composition of the lyophilized reagent not included gentisic acid and perrenate sodium}
The composition of the drug (mg/mlBodiesAfter 1 hAfter 3 h
LC2,73Blood. %/g1,40,7
SnCl21,0Liver5,52,2
GKKidney17,114,2
Re-Stomach6,53,4
pH 2,4Much. The HSS.35,261,2
RHC, %89,6Hip norms.0,50,3
ReO4, %6,6Hip1,00,6
GWR %1,2Skeleton15,37,5
The amount of impurities, %10,4KDN1,82,4

Table 8
The biological behavior of the drug prepared from the dried composition in which the molar ratio of [sq]/[Sn]=2. (The composition of the lyophilized reagent not included gentisic acid)
The composition of the drug (mg/mlBodiesAfter 1 hAfter 3 h
LC 2,73Blood, %/g1,00,7
SnCl21,0Liver2,92,1
GK-Kidneythe 15.615,4
Re0,02Stomach2,62,2
pH2,4Much. The HSS.48,053,2
RHC, %91,0Hip norms.0,40,8
ReO4, %5,0Hip fracture2,01,7
GWR %4,0Skeleton13,116,2
The amount of impurities, %9,0 KDN1,82,1

Table 9
The biological behavior of the drug prepared from the dried composition in which the molar ratio of [sq]/[Sn]=2. (The composition of the lyophilized reagent not included perrenate sodium)
The composition of the drug (mg/mlBodiesAfter 1 hAfter 3 h
LC2,73Blood, %/g2,01,0
SnCl21,0Liver8,13,5
GK1,53Kidney16,613,2
Re-Stomach3,22,0
pH2,4Much. The HSS. 35,954,5
RHC, %89,4Hip norms.0,50,3
ReO4, %7,5Hip fracture0,90,8
GWR %3,1Skeleton12,28,6
The amount of impurities, %10,6KDN2,23,0

Table 10
The biological behavior of the drug prepared from the dried composition in which the molar ratio of [sq]/[Sn]=2. (The composition of the lyophilized reagent includes all components)
The composition of the drug (mg/mlBodiesAfter 1 hAfter 3 h
LC2,73Blood, %/g 0,90,6
SnCl21,0Liver4,41,5
GK1,53Kidney17,213,5
Re0,02Stomach1,71,6
pH2,4Much. The HSS.47,347,7
RHC, %91,0Hip norms.0,40,3
ReO4, %6,5Hip fracture1,00,4
GWR %2,5Skeleton11,87,3
The amount of impurities, %9,0KDN2,220

3.3. The molar ratio of [sq]/[Sn]=3

When this molar ratio were prepared lyophilized compositions of four different structures:

Table 11
The quantitative composition of the components of liofilizatow based on zoledronate acid at the [WC]/[Sn]=3
No.The composition of the reagent in the vial mgthe pH of the reagent solution
LCSnCl2Gents-TARe
16,271,5002,5
26,271,500,032,5
36,271,53,301,7
46,27 1,53,30,031,7

Table 12
The biological behavior of the drug prepared from the dried composition in which the molar ratio of [sq]/[Sn]=3. (The composition of the lyophilized reagent not included gentisic acid and perrenate sodium)
The composition of the drug (mg/mlBodiesAfter 1 hAfter 3 h
LC4,18Blood, %/g1,70,7
SnCl21,0Liver7,81,5
GK-Kidney22,113,2
Re-Stomach4,41,7
pH 2,1Much. The HSS.37,372,1
RHC, %86,7Hip norms.0,40,2
ReO4, %13,2Hip fracture1,10,3
GWR %0,1Skeleton12,15,6
The amount of impurities, %13,3KDN2,41,8

4,18
Table 13
The biological behavior of the drug prepared from the dried composition in which the molar ratio of [sq]/[Sn]=3. (The composition of the lyophilized reagent not included gentisic acid)
The composition of the drug (mg/mlBodiesAfter 1 hAfter 3 h
LCBlood, %/g1,21,3
SnCl21,0Liver4,24,2
GK-Kidney22,413,8
Re0,02Stomach0,60,9
pH2,1Much. The HSS.53,964,0
RHC, %90,3Hip norms.0,50,4
ReO4, %6,7Hip fracture1,70,4
GWR %3,0Skeleton16,813,3
The amount of impurities, %the 9.7 KDN2,61,1

Table 14
The biological behavior of the drug prepared from the dried composition in which the molar ratio of [sq]/[Sn]=3. (The composition of the lyophilized reagent not included perrenate sodium)
The composition of the drug (mg/mlBodiesAfter 1 hAfter 3 h
LC4,18Blood, %/g2,11,8
SnCl21,0Liver10,94,2
GK2,2Kidney15,214,9
Re-Stomach2,73,4
pH2,5MOUs. 35,950,3
RHC, %83,3Hip norms.0,70,7
ReO4, %14,8Hip fracture1,01,1
GWR %1,9Skeleton19,619,6
The amount of impurities, %16,7KDN1,71,5

1. Radiopharmaceutical agent for diagnosis and treatment (therapy) of bone lesions in the skeleton, including complex zoledronate acid with isotopes99mTechnetium or188Rhenium, zoledronic acid, a halide of tin and possible antioxidant, obtained by the interaction of liofilizirovannogo reagent consisting of zoledronate acid halide of tin as a reducing agent and a possible antioxidant, salt of the corresponding isotope.

2. Radiopharmaceutical tool according to claim 1, characterized in that as a reducing agent halide tin it contains dichloride is whether differed tin.

3. Radiopharmaceutical tool according to claim 1, characterized in that as an antioxidant it contains ascorbic acid or entityname acid.

4. A method of obtaining a radiopharmaceutical tools for the diagnosis and treatment (therapy) of bone lesions in the skeleton, which consists in the fact that they are freeze-dried by mixing an aqueous solution by zoledronate acid and halide of tin in hydrochloric acid and possible antioxidant in a stream of inert gas when adding alkali metal hydroxide, the resulting lyophilisate is mixed with the salt of a metal from the group of isotopes selected from the group99mTechnetium or188Rhenium, obtaining a complex and then adding a solution of the radionuclide.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to derivatives of 13(l)-N-{2-N-(closo-monocarbadodecaboran-1-yl)-methyl]aminoethyl}amide-15(2), 17(3)-dimethyl ether of chlorine e6 of general formula

, where M=Cs, Na, manifesting properties of photosensitiser.

EFFECT: compounds can be used in medicine as agents for boron neutron capture therapy (BNCT) and photodynamic therapy (FDT) of malignant neoplasms.

2 ex, 1 tbl, 2 dwg

FIELD: medicine.

SUBSTANCE: invention refers to nanocrystalline compounds of formula (I) AOx-(L-Men+)i where AOx represents metal oxide where A it specified from Ti or Zr, x=2; Men+ represents metal ion exhibiting antibacterial activity, specified from Ag+ and Cu++, where n=1 or 2; L represents a bifunctional molecule, or a organic or metal-organic molecule able to get bound with metal oxide and ion metal Men+ simultaneously; where the organic molecule is specified from pyridine, dipyridyl, tripyridyl, functionalized with carboxylic groups (-COOH), boronic groups (-B(OH)2), or phosphonic groups (-PO3H2), or 4-mercaptophenylboronic acids; where the metal-organic molecule represents a metal-organic complex containing organic ligand coordinated with central metal atom and containing boronic (-B(OH)2), phosphonic (-PO3H2) or carboxylic (-COOH) functional group, and the groups are coordinated with central metal atom and able to get bound with metal ions with antibacterial activity; where specified organic ligand coordinated with central metal atom is specified from pyridine, dipyridyl, tripyridyl functionalized with carboxylic groups (-COOH), boronic groups (-B(OH)2), or phosphonic groups (-PO3H2), or 4-mercaptophenylboronic acids; i represents a number of groups L-Men+ bound with nanoparticle AOx. Also, there are offered a composition exhibiting antibacterial and/or antiviral activity, dermatological compositions, application of nanocrystalline compounds, a method of nanocrystalline compounds regeneration.

EFFECT: nanocrystalline compounds show effective antibacterial action.

27 cl, 4 tbl, 4 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of exo-pentacyclo[5.4.0.02.9.03.6.08.10]undecane-4-spiro-1'-(3'-ethyl-3'-aluminium)-cyclopentane of general formula . The method involves reaction of 4-methylene-exo-pentacyclo[5.4.0.02.9.03.6.08.10]undecane with triethylaluminium (Et3Al) in the presence of a zirconocene dichloride (Cp2ZrCl2) catalyst in molar ratio 4-methylene-exo-pentacyclo[5.4.0.02.9.03.6.08.10]undecane: Et3Al:Cp2ZrC2=10:(10-14):(0.6-1.0) in an argon atmosphere at normal pressure in hexane for 5-7 hours.

EFFECT: invention enables to obtain said compound which can be used as a component a catalyst system in oligo- and polymerisation of olefin, diene and acetylene hydrocarbons.

1 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel carboranyl derivative of fluorinated porphyrins of general formula I , where Ia: M=2H, R=o-CB10H10C-, Ib: M=2M, R=o-C6H5-CB10H10C-, Ic: M=2H, R=-CB11H11-Cs+, Id: M=Cu, R=-CB11H11-Cs+, Ie: M=Pd, R=-CB11H11-Cs+, If: M=2H, R=-CB11H11-Na+, Ig: M=Cu, R=-CB11H11-Na+, Ih: M=Pd, R=-CB11H11-Na+,having photosensitiser properties. The invention also discloses methods for synthesis of said compounds.

EFFECT: compounds which exhibit photosensitiser properties can be used in boron neutron capture therapy (BNCT) and photodynamic therapy (PDT) of oncological diseases.

6 cl, 8 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: compounds contain a boroxine ring in which boron atoms of the said ring have a substitute which contains an oxy-function bonded to (1) a boron atom and to (2) a saturated, non-aromatic part which contains a triple carbon-carbon bond. The invention also discloses a method for synthesis of said compound, use of said compound, a fire-proof composition of a polymer resin and an article.

EFFECT: invention enables to obtain compounds with low inflammability with retention of mechanical and thermal properties.

13 cl, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are structure and manufacturing of antibiotics which include borinic acid complexes, in particular derivatives of hydroxyquinoline, imidazole and picolinic acid, together with compositions of said antibiotics and methods of application of antibiotics and compositions as bactericidal and fungicidal preparations as well as therapeutic medications for treatment of diseases caused by bacteria and fungi.

EFFECT: obtaining antibiotics which include borinic acid complexes.

51 cl, 1 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are structure and manufacturing of antibiotics which include borinic acid complexes, in particular derivatives of hydroxyquinoline, imidazole and picolinic acid, together with compositions of said antibiotics and methods of application of antibiotics and compositions as bactericidal and fungicidal preparations as well as therapeutic medications for treatment of diseases caused by bacteria and fungi.

EFFECT: obtaining antibiotics which include borinic acid complexes.

51 cl, 1 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: method involves reaction of an aliphatic alcohol containing 2-4 carbon atoms with activated aluminium with purity not lower than 99.97% and subsequent purification of the obtained product. The reaction takes place in a tube reactor in which excess aluminium is loaded, where the said aluminium is activated with tin in amount of 0.0025-0.04 wt % of the initial aluminium in the presence of ammonium halides in amount of at least 0.01 wt % of the initial aluminium. The reaction takes place with dosed supply of alcohol into the top part of the reactor. The bottom part of the reactor is heated to temperature which corresponds to melting point of the aluminium alkoxide.

EFFECT: design of an efficient method of producing highly pure aluminium alkoxides which can be widely used, eg as catalysts in various processes in organic chemistry.

13 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention describes a lubricant material and/or hydrocarbon fuel additive which is a product of reacting an acidic organic compound and a boron compound, where the acidic organic compound is selected from a group consisting of alkyl-substituted salicylic acids and di-substituted salicylic acids. The additive has the following structure: , where R1 is a C1-50 alkyl group; a equals 1 or 2, when a equals 2, R1 groups are selected independently; R2 is a C1-50 alkyl group; and R3 is hydrogen or C1-6.

EFFECT: higher detergent and oxidation power.

7 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing hydride complexes [(CpMe)2Zr(µH)]2(µH)2(AlR3)2 having general formula (1a-c) , where R=Me(a), Et(b), Bui(c). The method involves reacting substituted bis-methylcyclopentadienyl zirconium dihydride (CpMe)2ZrH2 with organoaluminium compounds (AlMe3, AIEt3, AlBui3), taken in molar ratio 1:1, in toluene in an argon atmosphere at temperature of approximately 10°C and normal pressure.

EFFECT: invention enables to obtain compounds with higher hydro-aluminising capacity with respect to olefins.

1 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: method involves reacting triethanol ammonium salts of o-cresoxyacetic and p-chloro-o-cresoxyacetic acid with the corresponding metal salt in alcohol or aqueous medium preferably at room temperature for 1-48 hours. The three-component complexes are extracted through solvent distillation with subsequent washing of the formed powder with ether and drying in a vacuum. The said complexes can be used as a base for making medicinal drugs.

EFFECT: design of a method of preparing complexes of o-cresoxy- and p-chloro-o-cresoxyacetic acid, triethanolamine and metals having formula n[R(o-CH3)-C6H3-OCH2COO-•N+H(CH2CH2OH)3]•MXm, where R = H, p-Cl; M = Mg, Ca, Mn, Co, Ni, Cu, Zn, Rh, Ag; X = CI, NO3, CH3COO; n = 1, 2; m = 1-3.

2 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of producing manganese (II) alcoholates which can be used in different syntheses, in purification of complex multicomponent mixtures from alcohols, in analytical control and in scientific research. The method involves direct reaction of metal with alcohol in a vertical bead mill. The liquid phase used is the corresponding alcohol taken in mass ratio to glass beads of 1:1.5. Manganese is taken in amount of 5.81-43.3 % of the mass of the liquid phase. The process is initiated at room temperature and is carried out while controlling by taking samples and determination of content of manganese (II) compounds until all the loaded metal is virtually exhausted, after which stirring in the glass bead is stopped. The suspension of the reaction mixture is separated from the glass beads and taken for filtering. The alcoholate residue is washed with a liquid phase solvent and taken for purification by recrystallisation, and the filtrate and washing liquid phase with traces of dissolved alcoholate are returned for a repeated process. As a rule, the alcohol used is C1-C5-alcohol with normal and isomeric structure, cyclohexanol, ethyl cellosolve and ethylene glycol.

EFFECT: method allows for reaction of manganese with alcohol in conditions where the reaction could have been quantitatively insufficient with respect to the reagent, could have taken place at technically acceptable rates and led to accumulation the main mass of the product in solid phase, which can be easily separated by simple filtering.

2 cl, 2 tbl, 18 ex

FIELD: medicine.

SUBSTANCE: new pure syn-aminoacids of formulas I and II have ability of specific binding in biological system and may be used to produce image of tumor. II and I. In formulae I and II Y and Z are independently selected from group made of CH2 and (CR4R5)n, n=1, 2; R1-R3 are independently selected from group made of H and alkyl C1-C4; R4, R5 = H and R7 = 18F. Invention is related to method of synthesis of syn-aminoacids with formula II, which includes stages of ketone transformation into trans-spirit of formula I and transformation of produced trans-spirit into syn-aminoacid of formula II, and also to pharmaceutical composition for production of tumor image and method for production of tumor image.

EFFECT: improved efficiency of compounds and method of treatment.

12 cl, 1 tbl, 3 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: method of synthesis of manganese (II) fumarate through direct reaction of metal with acid is presented. The process is carried out in a vertical type bead mill with mass ratio of beads to the reaction mixture equal to 1:1, and the liquid phase is a solution of fumaric acid in an organic solvent with content of acid of 0.70-1.80 mol/kg. Manganese is taken in stoichiometric amount with acid or in deficiency of up to 5%. The process is started by loading the liquid phase solvent and acid and preparation of the acid solution in a bead mill, after which metal is loaded and the process is carried out at temperature ranging from 25 to 35°C while preventing spontaneous increase of temperature through forced cooling and controlling through sample taking and determination of manganese salt in the samples and residual amount of acid until attaining values close to calculated values during quantitative conversion of the reagent in deficiency. After that stirring and cooling are stopped. The suspension of the reaction mixture is separated from the glass beads, cooled to temperature between 5.2 and 6.2°C and filtered. The filtering residue is washed with the liquid phase solvent, cooled to approximately the same temperature, and taken for purification by recrystallisation. The filtrate and the washing solvent are returned to the repeated process.

EFFECT: method is easy to implement, the end product can be easily separated and there are no auxiliary materials which contaminate the obtained product.

2 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing manganese (II) fumarate from manganese metal and its oxide (III) through direct reaction of the metal and its oxide Mn2O3 with an acid in the presence of a liquid phase and a stimulating iodine additive in a vertical type bead mill with glass beads as grinding agent. The metal and its oxide are loaded in molar ratio (2±0.1):1 in total amount of 7.87 to 10.93% of the mass of the load. Acid is added with 15 to 25% excess of the calculated value, equal to the number of moles of metal and twice the number of moles of metal oxide in the load. The base of the liquid phase is isoamyl alcohol, in which the iodine stimulating additive is dissolved in amount of 0.02 to 0.05 mol/kg. Glass beads are loaded first, in mass ratio to the reaction mixture of 1.35:1, and then later the liquid phase solvent, acid and stimulating additive, and after brief stirring, metal oxide and metal, stirring all the while. Taking this moment as the beginning of the process, forced cooling is introduced right away. Operating temperature is stabilised in the range 33 to 45°C and in this mode, the process is carried out until virtually quantitative conversion of metal and its oxide to the target salt, after which stirring and forced cooling are stopped. The reaction mixture is separated from the glass beads, cooled to temperature 5 to 6°C and kept at that temperature for 1 to 2 hours. The solid phase of the target salt is filtered off and washed with isoamyl on a filter cooled to approximately the same temperature, after which it is taken for purification by recrystallisation. The filtrate and the cleaning solvent, containing excess acid, the bulk of the stimulating additive and a certain amount of dissolved target salt, are returned for loading in the repeated process. The process is carried out in light temperature conditions. The target substance can be easily separated.

EFFECT: design of a low-waste method, which allows for obtaining target product from available manganese oxide with an easy to implement process.

9 ex

FIELD: medicine.

SUBSTANCE: invention refers to chelating agents and their technetium complexes to be used as radiopharmaceuticals and characterised by formula I where X is -NR-, -CO2-, -CO-, -NR(C=S)-, -NR(C=O)-, -CONR- or Q; Y represents amino acid, -CH2-, -CH2OCH2-, -OCH2CH2O- or X; Z is an aggregation from peptides, their analogues, substrata, antagonists or enzyme inhibitors, receptor-bonding compounds, oligonucleotides, oligo-DNA- or oligo-RNA-fragments; n is a number 1 to 8; m is a number 0 to 30; R represents H, C1-4alkyl, C2-4alkoxyalkyl, C1-4hydroxyalkyl or C1-4fluoroalkyl; Q represents remains of succinimide , A is a pharmaceutically acceptable anion.

EFFECT: production of new chelating agents applicable for making the technetium complexes.

22 cl, 12 ex, 3 dwg, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention is related to improved method for preparation of manganese oxalate (II) by means of direct interaction of metal with acid in bead mill in presence of liquid phase, in which manganese and oxalic acid are loaded into bead mill in stoichiometric ratio in amount of 0.75-2.4 mole/kg of load at mass ratio of load and glass beads of 1:1.2, liquid phase dissolvent used is water or organic substance, or mixture of organic substances; loading is carried out in the following sequence: liquid phase dissolvent, acid, then metal; process is started at room temperature and is carried out under conditions of forced cooling in the temperature range of 18-39°C with control over procedure by sampling method to practically complete spend of loaded reagents for product making, afterwards mixing and cooling are terminated, suspension of reaction mixture is separated from glass beads and filtered, salt deposit is sent for product cleaning from traces of non-reacted metal, and filtrate is returned into repeated process.

EFFECT: method makes it possible to produce target product in absence of manganese dioxide and stimulating additive at temperatures close to room temperature.

2 cl, 13 ex, 2 tbl

FIELD: chemical industry; methods of production of the manganese salts with the organic acids.

SUBSTANCE: the invention is pertaining to production of the manganese salts with the organic acids in particular, to the salt of the divalent manganese and formic acid. The method is exercised by interaction of manganese, its oxides in the state of the highest valence with the formic acid solution in the organic solvent in the presence of iodine as the stimulating additive. The production process is conducted in the bead grinder of the vertical type having the revertive cooler-condenser, the high-speed paddle stirrer and the glass beads of in the capacity of the grinding agent loaded in the mass ratio to the loading of the liquid phase as (1÷2): 1. The liquid phase consists of the formic acid solution in the organic solvent. The concentration of the acid is taken within the range of 3.5÷10.8 mole/kg. In the loaded liquid phase they dissolve the stimulating additive of iodine in the amount of 0.025-0.100 mole/kg of the liquid phase. The ratio of the masses of the liquid phase and the total of the metallic manganese and the manganese oxide are as(4.9÷11):1. The molar ratio of the metal and the oxide in the loading is as (1.8÷2.,2):1. The metal and the oxide are loaded the last. It is preferable in the capacity of the dissolvent to use the butyl alcohol, ethyl acetate, ethylene glycol, 1.4-dioxane, dimethyl formamide. The production process is started and conducted at the indoor temperature up to practically complete(consumption of the whole loaded manganese oxide. Then the stirring is stopped, the suspension of the salt is separated from the beads and the nonreacted manganese and after that conduct filtration. The filtrate and the nonreacted manganese are returned into the repeated production process, and the filtered out settling of the manganese salt is exposed to purification by recrystallization. The technical result of the invention is - simplification of the method at usage of accessible reactants.

EFFECT: the invention ensures simplification of the method at usage of accessible reactants.

16 ex, 2 tbl

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved solid-phase method for synthesis of radioisotope indicators, in particular, for synthesis of compounds labeled with 18F that can be used as radioactive indicators for positron- emission tomography (PET). In particular, invention relates to a method for synthesis of indicator labeled with 18F that involves treatment of a precursor fixed on resin if the formula (I): SOLID CARRIER-LINKER-X-INDICATOR wherein X means a group promoting to nucleophilic substitution by a definite center of a fixed INDICATOR with 18F- ion for preparing a labeled indicator of the formula (II): 18F-INDICATOR; to compound of the formula (Ib):

and compound of the formula (Ih): ;

to radiopharmaceutical set of reagents for preparing indicator labeled with 18F for using in PET; to a cartridge for radiopharmaceutical set of reagents for preparing indicator labeled with 18F for using in positron-emission tomography.

EFFECT: improved method of synthesis.

13 cl, 1 sch, 3 ex

FIELD: chemical industry; methods of production of the bromine derivatives of fullerene С60.

SUBSTANCE: the invention is pertaining to the method of production of the bromine derivatives of fullerene С60. The process consists in the interaction of the bromoform and the tetra bromomethane with fullerene С60 at presence of the rhodium-containing catalyst - Wilkinson's complex [RhCl(PPh3)3] at the temperature of 100°С within 10-20 hours, at the molar ratio of [Rh]:[C60]:[CHBr3 or CBr4]= 1:100:100-500. The technical result of the invention is the increased output of the product, the reduced amount of the wastes, the insignificant consumption of the catalyst.

EFFECT: the invention ensures the increased output of the product, the reduced amount of the wastes, the insignificant consumption of the catalyst.

3 ex, 1 tbl

FIELD: organic chemistry, medicine, physiology.

SUBSTANCE: invention relates to agents for regulation (maintaining or suppression) of physical working ability and/or adaptation to different variants represented by solvated complex compounds of the general formula (I): Katm+[L1qEL2]Ann- x p.Solv (I) wherein L1 means aminothiols of the formula: R1NHCH(R2)(CH2)1-2SR3 wherein R1 means hydrogen atom (H), (C1-C20)-alkyl or RCO; R means (C1-C19)-alkyl; R2 means H or carboxyl; R3 means H, (C1-C20)-alkyl, (C2-C20)-alkenyl or benzyl; q = 1, 2 or 3; L2 means halogen atom, water and/or organic ligand. For example, bis-(N-acetyl-L-cysteinato)aquozinc (II) diheptahydrate suppresses physical working ability and in the dose 50 mg/kg increases reviving time of mice by 6 times and cats - by 2.8fold under conditions of acute hypoxia with hypercapnia, and increases reviving time of mice by 4 times under conditions of acute hypobaric hypoxia. Under the same conditions the known antihypoxic agents amtizol, acizol or mexidol are inactive or less active significantly by their activity. Bis-(N-acetyl-L-cysteinato)-ferrous (II) pentahydrate is more active as compared with the known antihypoxic agents and protects experimental animals in 4 variants of hypoxia. Bis-(N-acetyl-L-cysteinato)zinc (II) sulfate octahydrate is similar to enumerated compounds by its antihypoxic activity.

EFFECT: valuable medicinal properties of compounds.

4 cl, 1 dwg, 11 tbl, 33 ex

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