5-amino-3-(2-aminopropyl)-[1,2,4]thiadiazole derivatives, possessing anti-cancer activity

FIELD: chemistry.

SUBSTANCE: invention relates to application of 5-amino-3-(2-aminopropyl)-[1,2,4]thiadiazole derivatives of general formula (I) as cytostatic preparations for fighting oncologic process in form of bases or pharmacologically acceptable salts. In formula (I) R1, R2 can be similar or different and independently represent hydrogen, halogen, alkyl, R3 represents alkyl, aralkyl, heteroalkyl, cycloalkyl.

EFFECT: increased efficiency of composition application.

2 tbl

 

The invention relates to the field of synthesis of physiologically active compounds and may find application in the manufacture of pharmaceutical preparations for the treatment of cancer.

Malignant neoplasms steadily occupy the second place in the structure of morbidity and mortality of man. Considerable effort and money go around the world to develop new approaches to therapy of tumors and the search for effective drugs. However, the problem of creating adequate pharmacological tools for the fight against cancer is far from its solution. Annually coming to market drugs for therapy of this disease are either too specific to any one type of cancer, and only at a certain stage, either too toxic for the body of the patient. The development of highly effective drugs is hindered by the high heterogeneity of cancer structures and the abundance of mutations in those parts of the cells, which could be potential targets of therapy.

There are two fundamentally different approaches to the search for new anticancer agents: synthesis of compounds aimed at a specific target in cancer cells are able to suppress their growth, and the search for new cytostatic and cytotoxic agents among the bib is of iotek organic compounds. With the second approach, the mechanism of anticancer action of substances most commonly investigated after the evidence of its effectiveness in clinical studies. Given the heterogeneity of cancer cells, new connections must be multifunctional, which will affect different targets, which can be available in various cancer cells.

Derivatives thiadiazolo have a strong aromaticity cyclic system, which leads to their high stability in vitro. These compounds, as a rule, no toxicity to higher vertebrates, including humans. Join thiadiazoline the core of various functional groups able to react with various receptors, allows to obtain physiologically active compounds with superior pharmacological properties. These substances exhibit fungicidal, bactericidal, insecticidal, herbicide, anti-inflammatory, neurostimulatory and anticonvulsive activity [N. Siddiqui, P. Ahuja, W. Ahsan, S. N. Pandeya, M. S. Alam // "Thiadiazoles: Progress Report on Biological Activities", Journal of Chemical and Pharmaceutical Research 2009, 1(1): 19-30]. Some derivatives of 1,2,4-thiadiazole can be the basis of drugs to fight Alzheimer's disease, diseases of the cardiovascular system [Gupta, A., Mishra, P., Pandeya S. N. et al. // Eur. J. Med. Chem. 2009. V. 44. P. 1100-1105]. These compounds possess ways the ability to communicate with a number of G-beloxepin receptors (opioid, dopamine, adenosine) and can act as anti-inflammatory agents [A. Castro, T. Castano, A. Encinas. W. Porcal, P. Gil. Bioorg. Med. Chem. 2006, 14, 1644].

The authors of the present invention was able to detect new, previously unknown physiologically active properties for derivatives of 5-amino-3-(2-aminopropyl)-[1,2,4]thiadiazole, namely high anticancer activity.

The invention is directed to solving the problem of expanding Arsenal of tools that can be used as a new and effective drugs for the treatment of cancer.

The problem is solved by the use of derivatives of 5-amino-3-(2-aminopropyl)-[1,2,4]thiadiazole of the General formula:

where

R1, R2may be the same or different and independently denote hydrogen, halogen, alkyl;

R3means alkyl, aralkyl, heteroalkyl, cycloalkyl;

in the form of bases or pharmacologically acceptable salts.

The term "halogen" means chlorine, fluorine, bromine or iodine.

The term "alkyl" means unsubstituted or substituted alkyl group with straight or branched chain, containing from 1 to 12 carbon atoms. Substituents in the alkyl group may be halogen, hydroxy and alkoxygroup (for example, methoxy, ethoxy and the like), cyano, nitro, trihalomethyl (for example, trifluoromethyl, similar to the s), optionally substituted amino (e.g. amino, dimethylamino, acetylamino, N-piperidino, N-morpholino and the like), acyl groups (e.g. formyl, acetyl, benzoyl and the like), carboxamide (for example, N,N-diethylnitrosamine and similar), carboxypropyl, carbalkoxy and similar.

The term "aralkyl" means an alkyl group with limit optionally substituted aryl Deputy.

The term "heteroalkyl" means heteroaryl, attached to an alkyl group as described above. Examples of suitable substituents include optionally substituted ethylindole-3-yl, propyl-3-imidazol-1-yl.

The term "cycloalkyl" means saturated optionally substituted cyclic group with 3-8 ring carbon atoms, optionally containing heteroatoms N and O in an amount of from 1 to 2 (for example, cyclopropyl, cyclohexyl, piperazinil, morpholinyl).

The synthesis of these compounds previously described [Proshin, A. N., Bachurin, S. O. RF Patent №2449997, "5-Amino-3-(2-aminopropyl)-[1,2,4]thiadiazole", from 10.05.2012; Proshin, A. N., Serkov I. C., Bachurin, S. O. "New binary compounds based on the 1,2,4-thiadiazole DAN, 2012, 446, No. 1, S. 48-50; Proshin, A. N.; Serkov I. V.; Bachurm S. O., "5-Amino-[1,2,4]thiadiazole derivatives", WO 2012050484, Pub. 19.04.2012, EP 2628734, Pub 21.08.2013].

The ability of the investigated compounds to exert cytotoxic effect was confirmed in cultures of RA the new cells of rat C6 glioma cells and human osteosarcoma HOS. In all experiments, these compounds showed moderate or strong cytotoxic activity and caused the death of cancer cells at concentrations from 2 to 100 microns.

Thus, the use of derivatives of 5-amino-3-(2-aminopropyl)-[1,2,4] thiadiazole solves the problem of expanding the range of substances that are able to inhibit cancer cells, because previously anticancer properties of these compounds were not known.

The experimental technique

1. Cultivation of cells

Glioma C6 rat (cell Bank of the Russian cell culture collection. Institute of Cytology RAS, St. Petersburg) were cultured at 37°C in an atmosphere of 5% CO2in the DMEM (Paneco, Russia), containing 10% fetal calf serum (PAA Laboratories, USA), 2 mm glutamine, 25 mm HEPES [6], 100 units/ml penicillin, 0.1 mg/ml streptomycin and 0.25 μg/ml amphotericin b (Paneco, Russia).

Cells human osteosarcoma HOS (cell Bank of the Russian cell culture collection. Institute of Cytology RAS, St. Petersburg) were cultured at 37°C in an atmosphere of 5% CO2in the environment of the Needle MEM with salts Earl (Paneco, Russia), containing 10% fetal calf serum (PAA Laboratories, USA), 2 mm alanylhistidine, 1 mm sodium pyruvate, set of essential amino acids for medium MEM (Paneco, Russia), 100 units/ml penicillin, 0.1 mg/ml streptomycin and 0.25 μg/ml amtter is of CIN In (Paneco, Russia).

Attached cells were removed using a 0.25% solution of trypsin in 0.53 mm EDTA salts Hanks (Paneco, Russia). Counting of cells was performed using a camera Goryaeva.

2. Determination of inhibitory activity of substances

For analysis of cytotoxicity of the compounds under investigation cell culture dissipated in 96-well plates in the amount of 1.25×104 cells/cm2and raised within three days to a density of 105 cells/cm2(half the maximum density of cells). Serial dilution of the tested substances in the range of 0.1-100 μm (final concentration after addition to the cells) were prepared in DMSO and dissolved in the medium of cultivation, after which was added to the cell culture (three repetitions for each concentration) and incubated for 18 hours. The incubation time was chosen based on the criterion of the greatest differences between substances. The final concentration of DMSO was 0.5%. The control was added only DMSO at a final concentration of 0.5%. Separately was set control without DMSO (no differences with the control, 0.5% DMSO). To assess the viability of the cells under the action of the investigated substances used MTT-test (evaluation of the recovery of the dye MTT mitochondria of living cells) [Mosmann T. (1983) J. Immunol. Methods, 65, 55 to 63.]. After removal of the medium with the test substance, the cells were incubated for 1.5 h with 0.5 mg/ml solution of MTT (Paneco, Russia) in the solution is Hanks (Paneco, Russia). After that, the solution was removed, dissolved cells in DMSO and estimated the number of recovered dye photometrically at a wavelength of 574 and 620 nm using the apparatus Epos 9505 (MOH Sapphire, Russia). Additionally, before performing the MTT-test condition of the cells were evaluated microscopically. Each experiment was repeated three times. Curves to calculate LD50built using the program GraphPad Prism 5.0, it also conducted analysis of variance of the data using the test of Tukey (Tukey). Reliable considered differences with p<0.05.

Below are the results of determination of the cytotoxic activity of derivatives of 5-amino-3-(2-aminopropyl)-[1,2,4]thiadiazole and their salts on C6 glioma cells in rats (table.1) and in cells of the human osteosarcoma HOS (PL.2), which illustrate, but do not exhaust the invention.

Table 1
The results of determination of the cytotoxic activity of derivatives of 5-amino-3-(2-aminopropyl)-[1,2,4]thiadiazole and their salts on C6 glioma cells in rats.
No.R1R2R3HClLD50, mcm
1ClCl-6±5
2ClCl-94±9
3FCl-11±1
4BrH-20±2
5MeH-79±9
6MeCl-15.9±0.3
7FCl -9±11
8ClCl-6±5
9MeClHCl18±8
10ClCl2HCl10±4
11HClHCl21±4
12HCl-14±4

13NClHCl 21±8
14ClClHCl2.9±0.6
15ClClMe-15.4±0.3
16CH(OH)MeH-14±2
17HCl2HCl10±4

As can be seen from this table, most of the compounds are active at concentrations from 2 to 20 microns.

Table 2
Cytotoxic activity of derivatives of 5-amino-3-(2-aminopropyl)-[1,2,4]thiadiazole and their salts in the cells of the human osteosarcoma HOS (cipher compounds corresponds to the structures in the table.1).
No.LD50that is km
120±6
751±3
826.5±0.7
1028±6
1720±7

This cell line, the activity of the compounds was in the range of 13-50 mm.

Use as a cytostatic funds to fight cancer process derivatives of 5-amino-3-(2-aminopropyl)-[1,2,4]thiadiazole of the General formula:
,
where R1, R2may be the same or different and independently denote hydrogen, halogen, alkyl;
R3means alkyl, aralkyl, heteroalkyl, cycloalkyl;
in the form of bases or pharmacologically acceptable salts.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compounds, represented by formula (I) , where X1 and X2 independently represent CH or N; ring U represents benzene ring, pyrazole ring, 1,2,4-oxadiazole ring, 1,2,4-thiadiazole ring, isothiazole ring, oxazole ring, pyridine ring, thiazole ring or thiophene ring, m represents integer number, which has values from 0 to 1; n represents integer number, which has values from 0 to 3; R1 represents hydroxygroup or C1-6 alkyl; R2 represents any of (1)-(3): (1) halogen atom; (2) hydroxygroup; (3) C1-6 alkyl or C1-6 alkoxy, each of which can independently contain any group, selected from group of substituents α; group of substituents α includes fluorine atom and hydroxygroup, or its pharmaceutically acceptable salt. Invention also relates to pharmaceutical composition, possessing inhibiting activity with respect to xanthenes oxidase, including formula (I) compound or its pharmaceutically acceptable salt as active ingredient.

EFFECT: derivative, which contains condensed ring structure, intended as means for prevention and treatment of disease, associated with abnormal level of uric acid in serum.

15 cl, 11 tbl, 126 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 5-amino-3-(2-aminopropyl)-[1,2,4]thiadiazole derivatives of general formula wherein R1, R2, R3 can be identical or different independently means hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, heteroaralkyl (wherein 5- or 6-member N-, O- or S-heteroaromatic cycle), cycloalkyl, 2,2,6,6-tetramethyl-piperidin-4-yl, and also R1+R2 can mean heterocycle specified in optionally substituted pyrrolidine, piperidine, azepane, piperazine, morpholine wherein optional substitutes can be hydroxyl, cyanogroup, halogens, alkyls, lower alkoxy groups, lower alkothio groups, trihalogen methyl, sulphamide, optionally substituted amino groups (amino, dimethyl amino, diethyl amino) provided R1=H, R2 is different from hydrogen or methyl.

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FIELD: medicine, pharmaceutics.

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FIELD: medicine.

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33 cl, 1499 ex

FIELD: medicine, pharmaceutics.

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FIELD: chemistry.

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Gsk-3 inhibitors // 2379300

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28 cl, 13 ex, 3 tbl

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1 cl, 1 tbl, 1 ex

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12 cl, 166 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

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EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

FIELD: chemistry.

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13 cl, 12 tbl, 9 ex

FIELD: medicine, pharmaceutics.

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11 cl, 1 ex, 2 dwg, 4 tbl

FIELD: medicine.

SUBSTANCE: using the human placental perfusate cells in preparing a therapeutic agent for suppressing tumour cells proliferation in an individual having the tumour cells, wherein the placental perfusate cells represent a collection of nuclear cells of the placental perfusate. Using natural killer cells of CD56+, CD16- recovered from the placenta for preparing the therapeutic agent for suppressing the tumour cells proliferation in the individual having the tumour cells. Using the combined natural killer cells in preparing the therapeutic agent for suppressing the tumour cells proliferation in the individual having the tumour cells, wherein the above combined natural killer cells comprise the natural killer cells recovered from the placental perfusate, and the natural killer cells recovered from the umbilical blood, and wherein the umbilical blood is recovered from the placenta, which is used to prepare the above placental perfusate. A method for suppressing the tumour cells proliferation in vitro, involving the tumour cells contact to the human placental perfusate cells, wherein the placental perfusate cells represent the collection of the nuclear cells from the placental perfusate. The method for suppressing the tumour cells proliferation in vitro, involving the tumour cell contact to the number of the natural killer cells prepared of placental CD56+, CD16-. The method for suppressing the tumour cells proliferation in vitro, involving the tumour cells contact to the combined natural killer cells, wherein the above combined natural killer cells involve the natural killer cells recovered from the placental perfusate, and the natural killer cells recovered from the umbilical blood, and wherein the umbilical blood is recovered from the placenta, which is used for prepare the above placental perfusate. A composition applicable in suppressing the tumour cells proliferation, containing the recovered natural killer cells of CD56+, CD16-, wherein the above natural killer cells are recovered from the placental perfusate, and wherein the above natural killer cells make at least 50% cells in the composition.

EFFECT: placental perfusate cells and methods for using them enable suppressing the tumour cells proliferation effectively.

40 cl, 13 tbl, 6 ex, 11 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compound of formula (I) or its racemate, enantiomer, diastereoisomer and their mixture, as well as to their pharmaceutically acceptable salt, where A is selected from the group, consisting of carbon atom or nitrogen atom; when A represents carbon atom, R1 represents C1-C6-alkoxyl; R2 represents cyano; when A represents nitrogen atom, R1 hydrogen atom or C1-C6-alkoxyl; where said C1-C6-alkoxyl is optionally additionally substituted with one C1-C6-alkoxyl group; R2 is absent; R3 represents radical, which has the formula given below: or , where D represents phenyl, where phenyl is optionally additionally substituted with one or two halogen atoms; T represents -O(CH2)r-; L represents pyridyl; R4 and R5 each represents hydrogen atom; R6 and R7 each is independently selected from hydrogen atom or hydroxyl; R8 represents hydrogen atom; R9 represents hydrogen atom or C1-C6-alkyl; r equals 1 and n equals 2 or 3. Invention also relates to intermediate compound of formula (IA), method of obtaining compound of formulae (I) and (IA), pharmaceutical composition based on formula (I) compound and method of its obtaining and to application of formula (I) compound.

EFFECT: novel heterocyclic compounds, inhibiting activity with respect to receptor tyrosine kinases EGFR or receptor tyrosine kinases HER-2 are obtained.

18 cl, 12 ex, 4 tbl

FIELD: medicine, pharmaceutics.

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EFFECT: invention provides the clinical improvement of T-cell redistribution and the enhanced safety profile.

17 cl, 8 tbl, 26 dwg, 26 ex

FIELD: biotechnology.

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EFFECT: enhancement of antitumor activity.

2 dwg, 5 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel fluorinated 1,4-naphthoquinone derivatives of general formula , where 1 R=C6H5, X=F; 2 R=2, 5-F2C6H3, X=F; 3 R=CH3, X=F; 4 R=C6H5, X, , possessing cytotoxic activity with respect to cancer cells, which can be applied in medicine.

EFFECT: claimed are novel compounds with anti-cancer activity for therapy of malignant neoplasms.

1 dwg, 3 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention relates to the field of biotechnology and cell technology. The claimed invention is aimed at the creation of pluripotent, multipotent and/or self-renewing cells, which are able to start differentiating in a culture into various types of cells and are capable of further differentiation in vivo. The claimed invention is also aimed at the creation of populations of the required differentiating cells, which can be transplanted to patients, genetic modification of endogenic cells and treatment of patients, suffering from diseases, intensity of which can be reduced by means of the said methods.

EFFECT: invention also claims methods of prevention, treatment or retardation of a disease, associated with an infection of immunodeficiency virus.

17 cl, 1 dwg, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

wherein A1 represents N or C (A2); A2 represents H, F, Cl or CN; B1 represents H, OR1, SO2R1, NHR1, NHC(O)R1, F or Cl; D1 and E1 represents H or Cl; Y1 represents H, CN, NO2, F, Cl, Br, CF3, R17, OR17, SO2R17 or C(O)NH2; or Y1 and B1 together with atoms to which they are attached, represent 5- or 6-merous heteroarene having 2-3 nitrogen atoms, wherein heteroarene rings are unsubstituted or substituted by (O); G1 represents H; Z1 represents uncondensed phenylene substituted by OR41; R41 represents 6-merous heteroaryl having 1 N atom, wherein heteroaryl is condensed with R43A, R43A represents 5-merous heteroarene having 1 N atom; Z2 represents monocyclic 6-merous heterocycloalkylene having 1-2 N atoms and 0 double bonds; Z1A and Z2A are both absent; L1 represents -CH2-; Z3 represents R38 or R40; R38 represents uncondensed phenyl; R40 represents cycloalkyl, wherein cycloalkyl represents a monocyclic ring system having 3 to10 C atoms and 0 double bonds, cycloalkenyl, wherein cycloalkenyl represents monocyclic 6-merous ring having 1 heteroatom specified in a group consisting of O and N, and 1 double bond, wherein cycloalkenyl is uncondensed or condensed with R40A; R40A represents cycloalkane, wherein cycloalkane represents a monocyclic ring having 3-10 C atoms and 0 double bonds, or heterocycloalkane, wherein heterocycloalkane represents monocyclic 6-merous ring having 1 N atom and 0 double bonds (the rest substitutes are those as specified in cl. 1 of the patent claim). The invention also refers to compounds of formula

and a pharmaceutical composition containing an effective amount of the compound of formula (I) or (II) or its pharmaceutically acceptable salt.

EFFECT: compounds of formula (I) or (II) inhibiting the activity of anti-apoptotic Bcl-2 proteins.

6 cl, 5 tbl, 378 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to traumatology and orthopaedics, and can be used for treating patients with epicondylitis. That is ensured by applying a complex of measures, in particular a restraint of motions in the involved segment, physiotherapy and drug treatment. A pain syndrome is pre-evaluated by a visual analogue scale (VAS). A proximal forearm is immobilised with an epicondylic bandage in the daytime for 7-10 days in sportsmen, and for 2-3 weeks in common patients. Therapeutic exercises (TE) are prescribed from the first day of treatment. The first part of TE consisting of isometric and static exercises aiming at strengthening arm muscles is done before noon. The second part of TE comprising relaxing exercises is performed in the late afternoon or after any physical loads. The patient continues with the therapeutic exercises after the bandage is removed and to be used for professional or sports loads only. Electric stimulation is conducted daily for 7-10 days with using TENS apparatus or its analogues generating electrical signals covering the enthesis and the involved forearm muscles. Arthrofoon is administered with underlying electric stimulation. If the pain syndrome value according to the VAS is less than 4 points, the preparation is administered as a monotherapy in a dose of 4 weeks a day for three months. If the pain syndrome according to the VAS is more than 4 points, Arthrofoon is administered in a dose of 8 tablets a day in a combination with a selective non-steroid anti-inflammatory preparation in a therapeutic dose for no more than 10 days. The therapeutic regimen also contains Sirdalud 2-4 mg one hour before bedtime for 2 weeks. There are also administered vasodilators improving microcirculation of the involved segment, intramuscularly for 10 days. The therapeutic complex is also added with Milgamma B 2 ml, 5 injections, and another 5 injections triduan. Wobenzyme is administered for 3-4 weeks. Calcemine or Calcemine-advance, the preparations of calcium are administered for six months. The therapeutic course according to the presented regimen is repeated half a year later. The physical exercising for the arm muscles strengthening are to be further done two or three times a week on the average for min. 30 minutes for the life term if suffering high loads or doing any top-class sports for the purpose of maintaining the forearm tonus. The segment of interest is fixed with an orthesis when suffering a load. The therapy with the TENS or similar apparatus of the forearm muscles of interest and the enthesis follow a pronounced load 2-3 hours before bedtime and shall be accompanied with a session of relaxing exercises.

EFFECT: method provides the evident and stable clinical effect characterised by the complete recurrence-free recovery by the physical restoration of the tissue structure within the inflammation with the high quality of life and a surgical intervention avoided.

1 dwg, 2 ex

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