6-methyl-5-morpholynomethyl-1-(thiethan-3-yl)pyrimidine-2,4(1h,3h)-dione, demonstrating antioxidant activity

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compound - 6-methyl-5-morpholynomethyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-dione of formula 6-methyl-5-morpholynomethyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-dione of formula: .

EFFECT: novel compound, possessing antioxidant activity, is obtained.

2 cl, 6 tbl, 7 ex

 

The present invention relates to organic chemistry and medicine, in particular to a new connection - 6-methyl-5-morpholinomethyl-1-(tietan-3-yl)pyrimidine-2,4(1H,3H)-dione with antioxidant activity.

Known complex compounds 6-methyluracil with succinic acid [patent RU 2259357, 2003], 1,3-bis(2-hydroxyethyl)-5-hydroxy-6-methyluracil with fumaric acid [patent RU 2330025, 2006], with antihypoxic activity.

Known Mannich bases in a series of uracil (pyrimidine-2,4(1H,3H)-dione): 6-methyl-5-morpholinomethyl and 6-methyl-5-piperidinomethyl with antioxidant activity [Chernyshenko Y. N., Mustafin A. G., Gimadieva A. R., Abdrakhmanov, I. B., Gerchikov A. J., I. Safarov Century // the Synthesis and antioxidant activity of manniche 6-methyluracil. Chem.-Pharm. journal, 2010. - So 44, No. 3, - n-14-16]; 6-methyl-5-morpholinomethyl adopted as the closest analogue of the invention.

The objective of the invention is to expand the Arsenal of biologically active compounds, including potent antioxidant.

The technical result - obtaining biologically active substances with antioxidant activity.

The inventive 6-methyl-5-morpholinomethyl-1-(tietan-3-yl)pyrimidine-2,4(1H,3H)-dione of the formula (I):

,

with antioxidantacaiacaibossajui.

The specified connection and its properties are not described in literature.

The claimed connection synthesize aminomethylpropanol 6-methyl-1-(tietan-3-yl)pyrimidine-2,4(1H,3H)-dione by reaction of manniche using formaldehyde and a secondary cyclic amine - research. 6-Methyl-1-(tietan-3-yl)pyrimidine-2,4(1H,3H)-dione obtained according to the method described in [Kataev C. A., Meshcheryakova S. A., Lazarev centuries, Kuznetsov Century. Century. // Synthesis diethanolamine pyrimidine-2,4(1H,3H)-diones. - Zhur.org.chem.. - 2013. - So 49. Vol.5. - S. 760-762; patent RU 2485118, 2013]

Example 1. The synthesis of the claimed compounds.

To the solution was 1.58 g (8 mmol) of 6-methyl-1-(tietan-3-yl)pyrimidine-2,4(1H,3H)-dione in 50 ml of ethanol with stirring, add 0.8 ml 33,7% (8,8 mmol) of a solution of formaldehyde, 0,76 g (8,8 mmol) of the research and 0.88 ml of 1M hydrochloric acid. The reaction mixture is boiled for 5 hours, cooled, precipitated precipitate is filtered off, washed with ethanol and dried. Yield 1.54 g (65%). Purify by crystallization from ethanol. So pl.=188-190°C.

Example 2. The synthesis of the claimed compounds.

To a suspension of 1.8 g (9 mmol) of 6-methyl-1-(tietan-3-yl)pyrimidine-2,4(1H,3H)-dione in 60 ml of acetone add to 8.1 ml 33,7% (90 mmol) of a solution of formaldehyde, 2.35 g (27 mmol) of the research. The reaction mixture is boiled for 3 h, cooled, precipitated precipitate is filtered off, washed with water and dried. The output of 1.95 g (73%). Purify by crystallization from ethanol. So pl.=188-190°C

IR spectrum, ν, cm-1: 3097 (N-H), 1717 (C2=O), 1646 (C4=O, C=C), 1423 (CH2-C5=C6).

An NMR spectrum1H (500 MHz, CDCl3) δ, M. D.: 2.32 (3H, 6-CH3), 2.46 t [4H, N(CH2)2, J 4.1 Hz], 3.18-3.22 m [2H, S(CH)2], 3.31 (2H, 5-CH2), 3.68 t [4H, O(CH2)2, J 4.5 Hz], 4.33-4.37 m [2H, S(CH)2], 6.23-6.30 m (1H, NCH), 10.37 ush. (1H, N3H).

An NMR spectrum13C (500 MHz, CDCl3) δ, M. D.: 17.04 (6-CH3), at 32.03 [S(CH2)Tiet.], at 47.58 (NCHtiet.), 52.39 (5-CH2), 53.51(Cmaboutpf2',6'), 67.11(Cmaboutpf3',5'), 107.34 (C5), 149.90 (C6), 152.76 (C2), 163.46 (C4).

Elemental analysis.

Found, %: C, 52.63; H, 6.21; N, 14.29 - C13H19N3O3S.

Calculated, %: C, 52.51; H, 6.44; N, 14.13.

The inventive compound is a white crystalline powder, insoluble in water, ethanol, soluble in chloroform, dimethylformamide, dimethyl sulfoxide.

Example 3. The influence of the proposed connection on the behavioral responses of experimental animals.

As the reference product is taken of the reference antioxidant oximetery (immoral), used in medical practice [the State register of medicines. // M, 2004, II, S. 417], antioxidant activity which is described in [Munchkin C. A., A. B. Bakirov // Oximetery. Essays in experimental pharmacology, Ufa, 2001. S. 136-137; Lazarev, A. N., Alekhin E. K., Places Century. Century. // Immure (Immureg). Bgmu, NGO "Babied", 2004].

The experiments were performed on 40 white weinbrenner rats weighing 200-220 g Animals within 21 days were injected drugs intragastrically at a dose of 50 mg/kg as a suspension in 2% starch mucus. The first group is the control (intact), the second group received daily drug comparison - oximetery and the third group - the claimed compound I (6-methyl-5-morpholinomethyl-1-(tietan-3-yl)pyrimidine-2,4(1H,3H)-dione).

On the background of the injection the animals were given physical load (LB) in the form swimming test, according to the method proposed Rylov are M. L. and R. Burgin [Rylov, M. L. // research Methods chronic action of harmful factors of the environment in the experiment. - M.: Medicine, 1964. - 230 S.; R. Burgin, R. Weizman, M. Gavish // Repeated swim stress and peripheral; benzodiazepines receptors. - Neuropsychobiology. - 1996. - Vol.33 - p.28-31], three times - at the beginning of the experiment, middle, and end. Swimming as violent in rats procedure causes nonspecific reaction to this TN and is used to create the animals in the experiment the state of strain and oxidative stress. As the pool used capacity of 1.7 m in diameter, the height of the edges - 50 cm, which was filled with water at 30 cm water Temperature was maintained at 25±1°C. In the pool rats were placed simultaneously on 3 individuals for 25 minutes.

The study of behavioral (approximate) reactions were carried out using the method of "open field" [Podshivalov VP // Experimental psychopharmacology aggressive behavior. - L., 1986. - 174 C.]. For this purpose, we used a round chamber (100 cm in diameter) with metal walls with a height of 40 cm, painted in white color. White floor of the chamber is lined with black paint on the 16 squares in the center of the camera drilled holes, holes with a diameter of 3 see the Chamber was illuminated by incandescent 60 W power located at a height of 100 cm above the center of the field. The rat was placed at the wall of the field, and then for 4 minutes (separately for each animal) were recorded parameters of free-riding behavior.

Integral criteria was calculated by the following formulas:

The OIA=Σ(O+P+N) ET=Σ(DNM+su+Su)

where Kpfactor mobility;

The OIA - orienting-investigative activity (s);

ET - emotional anxiety (sec);

P - pattern "progressive movement";

With - pattern "sits";

F - pattern "rising" (immobility);

H - pattern "looking Worku";

About - pattern "Obrucheva";

DNM - pattern movement on the spot";

Su - pattern "vertical stand on its hind legs, with a focus in front of the wall of the chamber";

Su - pattern "vertical stand on its hind legs".

The results of the study of animal behavior in the test are shown in tables 1-2.

Under the influence of FN in experimental animals of the first group went down "mink" reflex and decreased horizontal and vertical components of the spontaneous locomotor activity. Violated orienting-investigative activity. Animals of the second and third groups receiving the drugs, behavioral responses changed over time. With long-term use of the drug orienting-investigative activity in rats both before and after giving physical activity increased (in comparison with the same indicators at the beginning of the experiment). Animals were actively moving on the horizontal plane of the field. Increased the number of zaglyadyvanie in mink. To some extent, decreased emotional anxiety.

Thus, investigational drugs: oximetery and declare the connection I protect animals from inhibition of behavioral responses caused by a single physical exercise. The best results were revealed in the group of animals treated with the inventive compounds is their I.

Example 4. The influence of the proposed connection on the processes of free radical oxidation in the brain and liver of experimental animals in vivo.

Processes SRO in homogenates of brain and liver were studied by the method of registration of iron-induced chemiluminescence (CHL) [Farkhutdinov P. P., Lihovsky Century A. // Chemiluminescent methods for the study of free radical oxidation in biology and medicine. - Ufa, 1995. - 92 S.].

Preparation of homogenates of organs of experimental animals after FN: a portion of the fabric laundered chilled phosphate buffer, crushed and filled in phosphate buffer in the ratio 1:5 (weight : volume), homogenized in a mechanical homogenizer 5 minutes at a temperature of +4°C. the resulting homogenate was filtered through a nylon filter, protein content was determined by Lowry and brought up to 20 mg/ml For the study of PI was collected and 1 ml samples were dissolved in 20 ml of phosphate buffer. Chemiluminescence was initiated by addition of 1 ml of a solution of FeSO4·7H2O - 50 mm. Registration of luminescence was performed on the device "HL-003" (Russia).

Table 3 shows the average values of sutasoma and maximum light intensity in the homogenates of liver and brain of control animals and animals treated with the drugs: sutasoma glow (S) characterizes the ability of lipids to oxidation, the maximum luminescence intensity (I max) depends on the intensity of accumulation of lipid hydroperoxides. As can be seen from the table, the introduction of the claimed compound I resulted in a decrease of sutasoma and maximum luminance half-life, suggesting that compound I has a protective ability to neutralize lipid peroxide radicals in the brain tissue.

Example 5. The effect of the inventive compounds on the generation of reactive oxygen species (ROS) in blood of experimental animals.

The generation of ROS in the blood was estimated by the change of spontaneous and induced luminosisimo PI (LSHL) [Farkhutdinov P. P., Lihovsky Century A. // Chemiluminescent methods for the study of free radical oxidation in biology and medicine. - Ufa, 1995. - 92 S.]. For evaluation of spontaneous and induced LSHL blood using heparinised whole blood of experimental animals after LB (0.1 ml of blood was diluted in 2 ml of physiological solution pH to 7.2 with the addition of 0.1 ml of 10-5M solution lyuminola). To stimulate oxygen explosion" in the phagocytes of 0.1 ml of blood of experimental animals were incubated for 10 minutes at 37°C with 0.01 ml of 1% suspension of zymosan (zymosan - biopolymer isolated from the membranes of the yeast cells and consisting mainly of glucan in the form of a suspension in isotonic sodium chloride solution).

The results of average values of sutasoma and maximum light intensity is shown in table 4. The table shows, is then under the influence of auximetilurazil and compound I increased the values of integral parameters LSHL blood: spontaneous 1.8 times induced - 1.2-1.5 times, indicating that the suppression of ROS generation.

Example 6. The influence of the proposed connection on the content of TBA-active products in homogenates of brain, liver and blood plasma of experimental animals.

The results of the study SRO in homogenates of brain and liver, obtained by the method of registration of CHL was confirmed by evaluating the content of TBA-active products, which characterize the state of processes of lipid peroxidation (LPO). The content of TBA-active products was assessed by color reaction with 2-thiobarbituric acid in the presence THU. The maximum absorption of a colored complex has at 532 nm, the molar absorption coefficient is of 1.56·105cm-1[Farkhutdinov P. P., Tevdoradze S. I. // methods of research gemologically biological material on chemiluminometer CHL-003. - Methods of evaluation of antioxidant activity of biologically active substances of therapeutic and prophylactic purposes: collection of reports. nauch.-the practical. of the workshop. - M., 2005. - S. 147-154].

Table 5 shows the average values of the concentration of TBA-active products in the brain, liver and blood plasma of experimental animals. The levels of malondialdehyde in the brain and liver in animals, which were introduced oximetery and the connection I was somewhat lower than the control Zn the values, which indicates the inhibition of the FLOOR.

Example 7. The influence of the proposed connection on status total antioxidant status in homogenates of brain, liver and blood plasma of experimental animals.

Status total antioxidant status were investigated independent spectrophotometric method (TAS) in the brain, liver and blood plasma of experimental animals after TN. The method is based on: the presence of antioxidants in the sample inhibits the blue-green radical cation ABTS with detection at 600 nm, and the degree of inhibition of the color is proportional to the concentration of antioxidant in the test substance.

The results of the study status total antioxidant status independent spectrophotometric method (TAS) in the brain, liver and blood plasma of experimental animals in norm and the infusion of drugs confirmed minor changes CPO in the organism of experimental animals: the presence of the desired antioxidants in the samples weakly inhibited blue-green radical cation ABTS with detection at 600 nm.

Table 6 shows the average values of the concentration of the antioxidant in the brain, liver and blood plasma of experimental animals. It may be noted that in samples of liver and brain obtained from a group of animals treated with the inventive compound I showed the largest increase in concentration is AI antioxidant. In plasma detected another trend - the highest concentration of antioxidant identified in the group of animals treated with the drug compared oximetery.

Presents a chemical compound through the study of its influence on the physiological and metabolic processes in the organism of experimental animals on the background of TN, accompanied by oxidative stress, antioxidant activity, some indicators exceeding the product comparison - oximetery, and protects experimental animals from the inhibition of behavioral responses induced FN. Also found the greatest increase in the concentration of the inventive compound I in the liver (1.5 times) and the brain (1.35 times) experimental animals compared with oxyethylation.

Table 1
Characteristics of behavioral reactions in experimental animals on the background of the introduction of the claimed compounds before and after the swimming test at the beginning of the experiment (on day 4 of the infusion)
ConnectionKPThe OIAET
(n±M)(n±M)(n±M)
toaftertoaftertoafter
Control100100100100100100
Oximetery281,8±1,4*160,0±0,4*130,7±1,8*to 82.9±7,8*55,1±7,4*71,4±1,6*
I263,6±0,7*160,0±0,9*103,6±1,7*113,8±3,3*66,9±3,3*to 139.3±3,0*

Table 2
Characteristics of behavioral reactions in experimental animals on the background of the introduction of the claimed compounds before and after the swimming test at the end of e is speriment (21-day injection)
ConnectionKPThe OIAET
(n±M)(n±M)(n±M)
toaftertoaftertoafter
Control100100100100100100
Oximetery128,2±0,8*29,0±0,3*of 111.9±7,8*149,4±2,7*82,7±2,7*27,9±1,1*
I189,7±3,5*48,4±0,4*139,4±10,2*132,1±2,2*194,2±2,7*to 132.6±2,2*

Table 3
The influence of the proposed connection on the performance chemiluminescence in homogenates of brain and liver of experimental animals (% of control)
ConnectionHoldem homogenate of liverHoldem brain homogenate
SI maxSI max
Control100100100100
Oximetery50,65*56,6*57,6*62,5*
I89,7*85,5*90,1*77,3*

Table 4
The influence of the proposed connection on the performance chemiluminescence of whole blood of experimental animals (% of control)
Connection Chemiluminescence of whole blood
spontaneousinduced
SI maxSI max
Control100100100100
Oximetery179,2*186,6*125,7*to 140.5*
I175,0*240,0*157,0*135,4*

Table 5
The influence of the proposed connection on the content of TBA-active products in homogenates of brain, liver and blood plasma of experimental animals (% of control)
ConnectionTBA-active products in the liverTBA-active products in the brainTBA-active products in plasma
Control of the ü 100100100
Oximetery76,5*75,0*94,1*
I82,3*95,0*91,0*

Table 6
The overall antioxidant status of the claimed compounds in homogenates of brain, liver and blood plasma of experimental animals
ConnectionThe concentration of antioxidants in the liver (mmol/l)The concentration of antioxidants in the brain (mmol/l)The concentration of antioxidants in plasma (mmol/l)
Control100100100
Oximetery106,5*96,9*191,3*
I161,5*130, 8mm*to 120.3*
Note: * - differences are reliable with the control group animals (p<0,5).

1. 6-Methyl-5-morpholinomethyl-1-(tietan-3-yl)pyrimidine-2,4(1H,3H)-dione of the formula:

2. Connection on p. 1, a potent antioxidant.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrimidine compounds of general formula (I) or their pharmaceutically acceptable salts, which can be used in treating the diseases related to mTOR kinase or PI3K kinase, such as cancer, immune diseases, viral infections, inflammations, neurological and other disorders. In general formula (I) , R1 means a group (A), wherein P represents C6aryl optionally substituted by a halogen, -OH, -NH2, -OC1-C6alkyl, unsubstituted 6-merous heteroaryl containing 1-2 heteroatoms N, unsubstituted indolyl, unsubstituted indazolyl, Q is specified in -H, -OR, -SR, -halo, -NR3R4, -OS(O)mR, -OC(O)NHR, -S(O)mNR3R4, -NRC(O)R, -NRS(O)mR, -NRC(O)NR3R4 and -NRC(S)NR3R4, wherein each R, R3 and R4 are independently specified in H, C1-C6 alkyl optionally substituted by a halogen, -N(C1-C3alkyl)2, 5-, 6-merous heterocyclic group containing 1-2 heteroatoms specified in N and O, 6-merous heterocyclic group containing 1-2 heteroatoms specified in N and O, optionally substituted by C1-C6alkyl, C6aryl group optionally substituted by one or two substitutes specified in a halogen, -OC1-C3alkyl, -CF3, -NH2, -C(O)NH2, -NHC(O)C1-C3alkyl, -N(C1-C3alkyl)2, -COOH, -SO2NH2, -SO2C1-C3alkyl, -NHSO2C1-C3alkyl, -CO2C1-C6alkyl, dioximethylene group, -NHC(O)CF3, -C(O)NH(CH2)2÷3N(C1-C3alkyl)2, -O(CH2)2N(C1-C3alkyl)2, 6-merous heterocyclyl containing 1-2 heteroatoms specified in N, O and S optionally substituted by oxo, C1-C3alkyl, -SO2C1-C3alkyl, -C(O)-6-merous heterocyclyl optionally substituted by C1-C3alkyl, 6-merous heteroaryl containing 1-2 heteroatoms N optionally substituted by one or two substitutes presenting a 6-merous heterocyclyl or -SC1-C3alkyl, or a 5-, 6-merous heteroaryl group containing 1-2 heteroatoms specified in N, O and S, optionally condensed with a benzene ring and optionally substituted by a halogen, -CO2C1-C3alkyl, oxo, -NHC(O)C1-C3alkyl, C1-C3alkyl, 6-merous heterocyclyl containing 2 heteroatoms specified in N and O optionally substituted by C1-C3alkyl, m means 1 or 2, or R3 and R4 together with a nitrogen atom to which they are attached, form a saturated 5-, 6-merous N-containing heterocyclic group, which is unsubstituted or substituted by C1-C3alkyl, -SO2C1-C3alkyl, oxo, Y is specified in -O-(CH2)n-, -S-(CH2)n- and -S(O)m(CH2)n-, wherein m means 1, n means 0 or an integer from 1 to 2, R2 is specified in H or a group -NR3R4, wherein R3 and R4 are those as specified above, Z is specified in halo, -(CH2)s-COOR, -(CH2)sCONR3R4, -(CH2)sCH2NR3R4, wherein s means 0 or an integer from 1 to 2 and wherein R, R3 and R4 are those as specified above, unsubstituted 6-merous heteroaryl containing one heteroatom N, substituted or unsubstituted heterocyclyl containing two heteroatoms specified in N and O; the substitute is specified in C1-C3alkyl and C1-C3alkylsulphonyl, and W is specified in a morpholine cycle and pyridine cycle. The invention also refers to a method for preparing the compounds of formula (I).

EFFECT: preparing the new pyrimidine compounds.

12 cl, 5 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

,

where R2 is a heteroaryl group and where said monocyclic heteroaryl group is unsubstituted or substituted with one or more groups selected from F, Cl, Br, I, -NR10R11 and C1-C12 alkyl; and groups selected from F, -NH2, -NHCH3, -N(CH3)2, -OH, -OCH3, -C(O)CH3, -NHC(O)CH3, -N(C(O)CH3)2, -NHC(O)NH2, -CO2H, -CHO, -CH2OH, -C(=O)NHCH3, -C(=O)NH2, and -CH3; R3x, R3y, R3z and R3p is hydrogen; R4x, R4y, R4z and R4p are independently selected from a group consisting of: hydrogen, F, Cl, Br, I, and -C(C1-C6 alkyl)2NR10R11; and R10 and R11 are hydrogen, which are phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitors.

EFFECT: high effectiveness of compounds.

7 cl, 7 tbl, 50 ex

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

Amide derivative // 2536409

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where R1 is a hydrogen atom or a C1-C6-alkyl group, substituted with one or two substitutes selected from C1-C6-alkoxy group, hydroxyl group, which can be substituted with a C1-C6-alkylcarbonyl group (substituted with one or two substitutes γ), and a 4-6-member saturated monocyclic heterocyclic carbonyl group containing a N atom; γ is a hydroxyl group, amino group, di(C1-C6-alkyl)amino group and carbamoyl group; R2 is a H atom or a C1-C6alkyl group, which can be substituted with a hydroxyl group; or R1 and R2, together with the nitrogen atom with which they are bonded, can be combined to form an azetidine group, a pyrrolidine group or morpholine group, which can be substituted with one hydroxyl group or a hydroxy-C1-C6-alkyl group; R3 and R4 is a C1-C6-alkyl group; R5 is a halogen atom or a C1-C6-alkyl group; R6 is a halogen atom; m and n denote an integer from 0 to 1; V and W are CH; X, Y and Z each independently can be CH or N. The invention also relates to a pharmaceutical composition containing a compound of formula (I), use of the compound of formula (I) and a method of treating sugar diabetes a disease associated with diabetes.

EFFECT: compounds of formula (I), having hypoglycemic activity.

21 cl, 6 tbl, 72 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of general formula [1] or their pharmaceutically acceptable salts, which possess properties of an inhibitor of the JAK2 thyrokinase activity. In general formula radicals are selected from group (I) or (II). In group (I) X represents CH or N; R1 represents a halogen atom and R2 represents H, a halogen atom, CN, or is selected from the groups of formulas

,

or a group -ORP or 5-6-membered heteroaryl, containing 1-4 nitrogen atoms and optionally additionally containing an oxygen or sulphur atom or containing an oxygen atom as a heteroatom, optionally substituted; or (II) X represents -CRA; and RA represents a group of formula , RB represents (a) amino, optionally substituted with one or two groups, selected from the group, consisting of C1-6alkyl, C3-6cycloalkyl, (C3-6cycloalkyl)C1-6alkyl and C1-3alcoxyC1-3alkyl, (b) C1-3alcoxy, (c) hydroxy or (d) a 5-6-membered saturated cyclic amino group, which additionally can contain a heteroatom, selected from an oxygen atom; R1 represents a halogen atom and R2 represents H; R3 -R5 have values given above. Other values of the radicals are given in the invention formula.

EFFECT: compounds can be applied for the prevention or treatment of cancer, for instance hematologic cancer disease or a solid form of cancer, inflammatory disorder, for instance, rheumatoid arthritis, inflammatory intestinal disease, osteoporosis or multiple sclerosis and angiopathy, for instance, pulmonary hypertension, arteriosclerosis, aneurism or varicose veins.

14 cl, 19 tbl, 234 ex

FIELD: medicine, pharmaceitics.

SUBSTANCE: invention relates to particular derivatives of N-(phenylsulphonyl)benzamide, given in i.1 of the invention formula. The invention also relates to a pharmaceutical composition, possessing an inhibiting activity with respect to anti-apoptotic proteins Bcl-2, containing an effective quantity of one of the said compounds or a therapeutically acceptable salt of such a compound.

EFFECT: N-(phenylsulphonyl)benzamide derivatives as inhibitors of the anti-apoptotic proteins Bcl-2.

2 cl, 2 tbl, 458 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to a heterocyclic compound of formula I and its pharmaceutically acceptable salt, wherein if a chemical valency permits, i represents 1 or 2, R1 represents H; a linear (C1-C4) alkyl group, R2 represents H, Cl or F, X represents either N, or CR3, R3 represents H; halogen; a linear (C1-C4) alkyl or (C1-C4) alkoxyl group, Y represents Z represents O or NRx, Rx represents H or a linear or branched (C1-C4) alkyl, k is equal to 2, 3 or 4, n and p independently represents 2, and a sum of n+p cannot exceed 4, T represents H or a linear (C1-C4) alkyl group; T′ represents a linear C1-C3 alkyl chain substituted by either (C1-C6)-dialkylaminogroup, or a 5-6-merous saturated heterocycle containing one nitrogen atom and optionally containing the second heteroatom specified in O, such a heterocyclic ring is optionally substituted by a (C1-C4) alkyl chain at nitrogen atoms; or a 5-merous saturated heterocycle containing one nitrogen atom, such a heterocyclic ring is optionally substituted by a (C1-C4) alkyl chain at nitrogen atoms; r represents zero, 1; R′ represents di(C1-C4)alkylamino, (C1-C4)alkoxy; except for the compounds specified in the clause. The invention also refers to a pharmaceutical composition based on the compound of formula (I), using the compound of formula (I) and to a method of treating diseases, in which the hedgehog signalling pathway modulation is effective.

EFFECT: there are prepared new heterocyclic compounds possessing t effective biological properties.

20 cl, 193 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to a new compound of formula or its pharmaceutically acceptable salt, wherein R1 represents (C1-C6)alkyl; an oxodihydropyridyl ring in the formula is optionally substituted by 1-3 groups optionally specified in fluorine, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, halo(C1-C6)alkyl and (C1-C6)alkoxy(C1-C6)alkoxy; R2 represents (C1-C6)alkyl, phenyl, or tetrahydropyranyl optionally substituted by a group in the number of up to 1 independently specified in fluorine, hydroxy(C1-C6)alkyl and (C3-C6)cycloalkyl; R3 is specified in (C1-C6)alkyl optionally substituted by groups in the number of up to 3 independently specified in fluorine, cyano, R4, R4O-, (R4)2N-, R4C(=O)NR4-, (R4)2NC(=O)-, R4OC(=O)NR4-, R4S(=O)2NR4- and oxadiazolyl optionally substituted by (C1-C6)alkyl; R4 independently represents H or (C1-C6)alkyl. Also, the invention refers to a method of treating an individual by using the above compound, a method of inhibiting 11β-HSD1, and a compound-based pharmaceutical composition.

EFFECT: there are prepared new compounds effective in treating the diseases related to 11β-HSD1 activity or expression.

15 cl, 6 tbl, 101 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where R1 and R2 have the following values: (i) R1 and R2 together form =O; (ii) R1 and R2 together with carbon atom, which they are bound with, form duoxacycloalkyl; R1 represents hydrogen or halogen; and R2 represents halogen; (iv) R1 represents C1-6alkyl, where alkyl is optionally substituted with cyano, -RxS(O)qRv or -RxNRyRz; and R2 represents hydrogen; (v) R1 represents -OR12 or -NR13R14; and R2 represents hydrogen, deutero or phenyl, which is optionally substituted with halogen; R3 represents hydrogen, halogen, C1-6alkyl, cyano, halogen C1-6alkyl, C3-10cycloalkyl or C1-6alkoxy; R4 and R5 represent hydrogen; R6 is independently selected from halogen, C1-6alkyl, halogenC1-6alkyl, -RxOR18 and -RxS(O)qRv; R7 independently represents halogen or -RxORw; R12 is selected from hydrogen and C1-6alkyl, R13 represents hydrogen; R14 is selected from hydrogen, C3-10cycloalkyl, -C(O)Rv and -C(O)ORw; R18 represents hydrogen, C1-6alkyl, or pyperidinyl, where R18 is optionally substituted with 1-3 Q1 groups, each Q1 is independenly selected from hydroxyl, C1-6alkoxy, C1-6alkoxycarbonyl, carboxyl and morpholinyl; Rx independently represents C1-6alkylene or simple bond; Rv and Rw represent hydrogen or C1-6alkyl; Ry and Rz represent hydrogen; n has value 0-4; p has value 0-5; and each q independently has value 0, 1 or 2. Invention also relates to compounds of formula (II) , where substituents have values, given in the invention formula, to pharmaceutical composition, possessing inhibiting activity with respect to JAK kinases, containing compounds of formula (I) or (II), methods of treating JAK-modulated disease, and application of compounds of formula (I) or (II).

EFFECT: compounds of formula (I) or (II) as inhibitors of JAK kinases.

32 cl, 6 dwg, 2 tbl, 84 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein A means morpholinyl, 1,4-oxazepamyl, piperidinyl, pyrrolidinyl or azetidinyl which is bound to N; R1 means C1-C6-alkyl group; R2 means bicyclic aryl group specified in 1H-indolyl, 1H-pyrrolo[3,2-b]pyridyl, quinolyl, naphthyl, 1H-pyrrolo[2,3-b]pyridyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, benzo[b]thiophenyl, imidazo[1,2-a]pyridyl, benzo[b]thiazolyl, 5H-pyrrolol[2,3-b]pyrazinyl and quinoxalinyl which can be substituted by R4; R3 means hydrogen or halogen atom; R4 means C1-C6-alkyl group, C1-C6-halogenalkyl group, OR1A, halogen, -(CH2)aOH, CN, NHCOR1A, SO2R1A or NHSO2R1A; R5 means C1-C6-alkyl group, -(CH2)aOH, -(CH2)aOR1B, halogen or CONH2; provided p is a plural number, R5 can be identical or different, or R5 can be combined with another R5; each of R1A and R1B independently means C1-C6-alkyl group; a is equal to 0, 1 or 2; n is equal to 1 or 2; p is equal to 0, 1, 2, 3, 4 or 5. Besides, the invention refers to intermediate compounds of formulas (IA) and (IB) for preparing the compounds of formula (I), to a preventive or therapeutic agent containing the compounds of formula (I), pharmaceutical compositions, using the compounds of formula (I) and to a method for preventing or treating diseases.

EFFECT: compounds of formula (I) as selective 5-HT2B receptor antagonists.

11 cl, 1 dwg, 18 tbl, 88 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula

,

where values A, R1-R6 are given in i.1 of the invention formula. Methods of obtaining the formula (I) compound are described.

EFFECT: compounds demonstrate an inhibiting activity of the cathepsin enzyme, which makes it possible to use them for the preparation of a pharmaceutical composition and for the preparation of a medication.

38 cl, 12 dwg, 495 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formulas I, II, III, IV, V, VIII or to their pharmaceutically acceptable salts, wherein: Z represents , or phenyl; D represents or ; X represents N(R9), O, S, S(=O) or S(O)2; each Y independently represents O or S; G represents or ; the other radical values are described in the patent claim. The invention also refers to pharmaceutical compositions based on the above compounds.

EFFECT: there are prepared new compounds and based compositions which can find application for treating malaria or eliminating or inhibiting the growth of Plasmodium species.

30 cl, 3 tbl, 23 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula or to its therapeutically acceptable salt, where A1 represents N or C(A2); A2 represents H; B1 represents H, OR1 or NHR1; D1 represents H; E1 represents H; Y1 represents CN, NO2, F, Cl, Br, I, R17 or SO2R17; R1 represents R4 or R5; Z1 represents R26 or R27; Z2 represents R30; Z1A and Z2A both are absent; L1 represents R37; R26 represents phenylene; R27 represents indolyl; R30 represents piperasinyl; R37 represents R37A; R37A represents C2-C4 alkylene; Z3 represents R38, R39 or R40; R38 represents phenyl; R39 represents benzodioxilyl; R40 represents C4-C7cycloalkenyl, heterocycloalkyl, which represents monocyclic six- or seven-member ring, containing one heteroatom, selected from O, and zero of double bonds, or azaspiro[5.5]undec-8-ene; the remaining values of radicals are given in i.1 of invention formula. Invention also relates to pharmaceutical composition, based on claimed compound.

EFFECT: novel compounds, which can be applied in medicine for treatment of diseases, in the process of which anti-apoptotic Bcl-2 protein is expressed, are obtained.

8 cl, 2 tbl, 411 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula 1.0:

,

where Q represents tetrahydropyridinyl ring substituted. R5, R1 are selected from: (1) pyridyl, substituted with substituent, selected from group, consisting of: -O-CH3, -O-C2H5, -O-CH(CH3)2, and -O-(CH2)2-O-CH3, R2 is selected from group, consisting of: -OCH3 and -SCH3; and R5 is selected from (a) substituted triazolylphenyl-, where triazolyl is substituted with one or two alkyl groups, selected from group, consisting of: -C1-C4alkyl, (b) substituted triazolylpheenyl-, wheretriazolyl is substituted on nitrogen atom with -C1-C4alkyl, (c) substituted triazolylphenyl-, where triazolyl is substituted on nitrogen atom with -C2alkylene-O-C1-C2alkyl, (d) substituted triazolylphenyl-, where triazolyl is substituted on nitrogen atom with -C2-C4alkylene-O-CH3, and (e) substituted triazolylphenyl-, where triazolyl is substituted on nitrogen atom with hydroxy-substituted -C1-C4alkyl, and where phenyl is optionally substituted with from 1 to 3 substituents, independently selected from group, consisting of halogen; and their pharmaceutically acceptable salts and solvates, which are claimed as ERK inhibitors.

EFFECT: obtaining pharmaceutically acceptable salts and solvates, claimed as ERK inhibitors.

15 cl, 2 tbl, 32 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula (I) or pharmaceutically acceptable salts thereof, where Alk is an C1-C6alkyl group; G is C=O and Q is CR51R52 or NR51, where R51 and R52, being identical or different, independently denote H, C1-C6alkyl, optionally substituted with a substitute selected from a group comprising carboxy, phenoxy, benzyloxy, C1-C6alkoxy or hydroxy; C3-C6cycloalkylC1-C6alkyl; phenylC1-C6alkyl, optionally substituted with a halogen; phenylamidoC1-C6alkyl; phenylC1-C6alkylamidoC1-C6alkyl, optionally substituted with a C1-C6alkoxy group; or R51 and R52, together with a carbon atom with which they are bonded form a C=O or C2-C6alkenyl group, optionally substituted with a phenyl; M1 is CR49, where R49 is H; M2 is CR50, where R50 is H; R38 is H, C1-C6alkyl, substituted with a phenoxy group; C3-C6cycloalkylC1-C6alkyl; arylC1-C6alkyl, optionally substituted with 1 or 2 substitutes selected from a group comprising C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxycarbonyl, carboxyl, N-methylamido, hydroxy, C1-C6alkoxyC1-C6alkoxy, C1-C6alkylthio, C1-C6alkylsulphanyl, cyano, halogen, perfluoroC1-C6alkyl, nitro, formyl, hydroxyC1-C6alkyl and amino, wherein the aryl moiety is a phenyl or naphthyl; and heteroarylC1-C6alkyl, where the heteroaryl moiety is pyridinyl, optionally substituted with 1 or 2 groups selected from C1-C6alkoxy or hydroxyC1-C6alkyl, pyrazolyl or isoxazolyl, substitute with 1 or 2 C1-C6alkyl groups; R47 and R48 is C1-C6alkyl. The invention also relates to specific compounds, a method of reducing or weakening bitter taste, a composition of a food/non-food product or beverage or drug for reducing or lightening bitter taste and a method of producing a compound of formula (I).

EFFECT: obtaining novel compounds which are useful as bitter taste inhibitors or taste modulators.

37 cl, 6 dwg, 12 tbl, 186 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 5-membered heterocyclic compounds of general formula (I), their prodrugs or pharmaceutically acceptable salts, which possess xanthine oxidase inhibiting activity. In formula (I) T represents nitro, cyano or trifluoromethyl; J represents phenyl or heteroaryl ring, where heteroaryl represents 6-membered aromatic heterocyclic group, which has one heteroatom, selected from nitrogen, or 5-membered aromatic heterocyclic group, which has one heteroatom, selected from oxygen; Q represents carboxy, lower alkoxycarbonyl, carbomoyl or 5-tetrasolyl; X1 and X2 independently represent CR2 or N, on condition that both of X1 and X2 do not simultaneously represent N and, when two R2 are present, these R2 are not obligatorily similar or different from each other; R2 represents hydrogen atom or lower alkyl; Y represents hydrogen atom, hydroxy, amino, halogen atom, perfluoro(lower alkyl), lower alkyl, lower alkoxy, optionally substituted with lower alkoxy; nitro, (lower alkyl)carbonylamino or (lower alkyl) sulfonylamino; R1 represents perfluoro(lower alkyl), -AA, -A-D-L-M or -A-D-E-G-L-M (values AA, A, D, E, G, L, M are given in i.1 of the invention formula).

EFFECT: invention relates to xanthine oxidase inhibitor and pharmaceutical composition, which contain formula (I) compound.

27 cl, 94 tbl, 553 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where A is a 6-member heteroaryl, having 1 nitrogen atom as a heteroatom, substituted with 2-3 substitutes such as indicated in the claim, R5 is a halogen atom, cyano or C1-C6alkyl, optionally substituted with a halogen atom; R6 is C1-C6 alkyl, optionally substituted with OH; C1-C3 alkenyl; a 5-member heteroaryl, having 2-4 heteroatoms, each independently selected from N, O or S, substituted with 0-2 substitutes such as indicated in the claim, R10 is a 5-member heteroaryl, having 2-3 heteroatoms, each selected from N, O or S, substituted with 0-2 substitutes, which are C1-C3 alkyl; R7, R8, R17 denote a hydrogen or halogen atom. The invention also relates to a pharmaceutical composition, having BK B2 receptor inhibiting activity, which contains compounds of formula (I), a method of inhibiting, a method of localising or detecting the BK B2 receptor in tissue, use of the compounds of compositions to produce a medicinal agent and methods for treatment.

EFFECT: compounds of formula (I) as BK B2 receptor inhibitors.

22 cl, 1 tbl, 54 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyranyl aryl methylbenzoquinazolinone compounds of formula (I), which are positive allosteric modulators of the M1 receptor and which can be used to treat diseases associated with the M1 receptor, such as Alzheimer's disease, schizophrenia, pain disorders or sleep disturbance. In formula (I) X-Y are selected from a group comprising (1) -O-CRARB-, (2) -CRARB-O-, (3) -CRARB-SRC-, (4) -CRARB-NRC- and (5) -NRC-CRARB-, where each RA and RB is a hydrogen atom, and RC is selected from a group comprising (a) hydrogen, (b) -C(=O)-C1-6alkyl, (c) -C1-6alkyl, (d) -C(=O)-CH2-C6H5, (e) -S(=O)2-C1-6 alkyl, R1 is a hydroxy group, R2 is selected from a group comprising (1) -phenyl, (2) - heteroaryl, where the phenyl or heteroaryl group R2 is optionally substituted; the rest of the values of the radicals are given in the claim.

EFFECT: obtaining novel pyranyl aryl methylbenzoquinazolinone compounds.

28 cl, 12 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1) or a salt thereof, where D1 is a single bond, -N(R11)- or -O-, where R11 is a hydrogen atom or C1-C3 alkyl; A1 is C2-C4 alkylene, or any of divalent groups selected from the following formulae , and ,

where n1 equals 0 or 1; n2 equals 2 or 3; n3 equals 1 or 2; R12 and R13 are each independently a hydrogen atom or C1 -C3 alkyl; v is a bond with D1; and w is a bond with D2; D2 is a single bond, C1-C3 alkylene, -C(O)-, S(O)2-, -C(O)-N(R15)-, or -E-C(O)-, where E is C1-C3 alkylene, and R15 is a hydrogen atom; R1 is a hydrogen atom, C1-C6 alkyl, a saturated heterocyclic group which can be substituted with C1-C6 alkyl groups, an aromatic hydrocarbon ring which can be substituted with C1-C3 alkyl groups, C1-C4 alkoxy groups, halogen atoms, cyano groups, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or the following formula ,

where n1 equals 0, 1 or 2; m2 equals 1 or 2; D12 is a single bond, -C(O)- or -S(O)2-; R18 and R19 denote a hydrogen atom; R17 is a hydrogen atom or C1-C3 alkyl; and x is a bond with D2; under the condition that when R17 denotes a hydrogen atom, D12 denotes a single bond; under the condition that when D1 denotes a single bond, A1 denotes a divalent group of said formula (1a-5) or (1a-6); when D1 denotes -N(R11)-, -O-, or -S(O)2-, A1 denotes a single bond, C2-C4 alkylene, or any of divalent groups selected from formulae (1a-1)-(1a-3), where, when A1 denotes a single bond, D2 denotes -E-C(O)-; and D3 is a single bond, -N(R21)-, -N(R21)-C(O) - or -S-, where R21 is a hydrogen atom; and R2 denotes a group of formula ,

where Q denotes an aromatic hydrocarbon ring, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, a condensed polycyclic aromatic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or a partially unsaturated monocyclic or a condensed bicyclic carbon ring and a heterocyclic ring; and y denotes a bond with D3; and R23, R24 and R25 each independently denotes a hydrogen atom, a halogen atom, a cyano group, C1-C3 alkyl, which can be substituted with hydroxyl groups, halogen atoms or cyano groups, C1-C4 alkoxy group, which can be substituted with halogen atoms, alkylamino group, dialkylamino group, acylamino group, or the formula ,

where D21 denotes a single bond or C1-C3 alkylene; D22 denotes a single bond or -C(O)-; R26 and R27 each independently denotes a hydrogen atom or C1-C3 alkyl; and z denotes a bond with Q; under the condition that when D22 denotes a single bond, R27 is a hydrogen atom. The invention also relates to specific compounds, a pharmaceutical composition based on the compound of formula , a IKKβ inhibitor, a method of inhibiting IKKβ, a method of preventing and/or treating an NF-kB-associated or IKKβ-associated disease, and intermediate compounds of formulae and .

EFFECT: obtaining novel isoquinoline derivatives, having useful biological properties.

46 cl, 3 dwg, 38 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: described are racemic- or enantiomer-rich 3-substituted piperidine compounds of formula (I) or pharmaceutically acceptable salts thereof, where A denotes phenyl, naphthyl, optionally substituted, or benzothiophenyl; B denotes an azole selected from a group consisting of triazole, benzotriazole, 5-methyl- or 5-phenyltetrazole; Y-CH2 and X- N-R, where R denotes hydrogen or C1-4alkyl, pharmaceutical compositions containing said compounds, and methods of treating depression, anxiety or pain disorder in mammals.

EFFECT: high efficiency of using compounds.

11 cl, 4 tbl, 126 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compounds of general formula I

or to pharmaceutically acceptable salts or solvates or stereoisomers thereof, where R and R* are each independently -CR1R2R3, C1-4alkylamino, benzylamino, C6-10arylamino, heteroC4-7cycloalkyl containing 1 heteroatom selected from O; where R1 is selected from C1-4alkyl; phenyl, optionally substituted with 1, 2 or 3 substitutes independently selected from halogen, C1-4alkyl, C1-4alkoxy, trifluoromethoxy or 2 substitutes at neighbouring ring atoms, which form a 1,3-dixolane group; benzyl, optionally substituted with a halogen or methoxy; phenylsulphonylmethyl; C3-5heteroaryl containing 1 to 2 heteroatoms independently selected from N and O; C3-5heteroarylmethyl containing 1 to 2 heteroatoms selected from N and C3-6cycloalkyl; R2 is selected from hydrogen, hydroxyl, di-C1-4alkylamino, C1-4alkylcarbonylamino, C1-4alkyloxycarbonylamino, C1-4alkylaminocarbonylamino, piperidin-1-yl or imidazol-1-yl; R3 is hydrogen or, alternatively, R2 and R3 together form an oxo group; or R1 and R3 together form cyclopropyl; under the condition that if one of R and R* is -CH(C6H5)N(CH3)2, the other cannot be -CH(C6H5)NHC(=O)OCH3; and if R and R* are identical, R1 is not phenyl, when R2 is hydroxyl, acetylamino, methoxycarbonylamino or tert-butoxycarbonylamino, and R3 is hydrogen; and R1 is not C1-4alkyl, when R2 is C1-4alkyloxycarbonylamino, and R3 is hydrogen. The invention also relates to a pharmaceutical composition based a compound of formula I and use thereof.

EFFECT: obtaining novel compounds which are useful in preventing or treating HCV infection.

9 cl, 2 tbl, 3 ex

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