2h-chromen derivatives as analgesic means

FIELD: medicine.

SUBSTANCE: application of a compound of the general formula 1 or its spatial isomers as analgesic means is claimed.

EFFECT: compounds have high efficiency, low toxicity, can be applied in medicine.

4 tbl 8 ex

 

The invention relates to the field of medicine, namely to medicines, analgesic effect.

Known painkillers, which the pharmacological action narcotic analgesics, such as acetylsalicylic acid, dipyrone and others [1]. Activity on the model of acetic cramps" (ED50) and acute toxicity (LD50) well-known medicines are given in [2] and is shown in table 1.

Table 1
Toxicity and analgesic effects of known drugs [2]
DrugED50mg/kgLD50mg/kg
Acetylsalicylic acid1551600
Analgin553300
Diclofenac sodium5370

The disadvantages of acetylsalicylic acid are low activity and gastrotoxicity; dipyrone is possible oppression by up to a full agranulocytosis.

�the ideal closest to the claimed means by pharmacological action the prototype - is diclofenac sodium [3].

The disadvantages of diclofenac sodium are gastrointestinal disorders and gastrotoxicity.

The problem to be solved by the invention is the search for new effective low-toxic drugs, analgesic activity.

The problem is solved by the use as painkillers compounds of the General formula 1, including its spatial isomers, including optically active,

where R1, R2, R3may be the same or different; and may be a hydrogen atom, an alkyl group, a nitro group, a halogen.

Compound 1A, where R1=R2=R3=N, was previously synthesized by the reaction isopulegol 2 with thiophene-2-carbaldehyde in the presence of a modified montmorillonite clay N-K10 in the conditions of microwave irradiation with the release of 50% [4].

Derivatives of compound 1A on the aromatic ring were not previously described in the literature.

We have shown that the compound 1A can be obtained with a yield of 78% interaction isopulegol 2 with thiophene-2-carbaldehyde in the presence of commercially available montmorillonite clay K10, without any preliminary chemical modificat�and, and in the absence of microwave irradiation simple keeping the reaction mixture without solvent for 1-2 hours

Derivatives of compound 1A on the aromatic ring can be synthesized by the reaction isopulegol 2 with substituted thiophene-2-carbaldehyde in the presence of K10 clay.

To obtain the compounds of General formula 1 in the form of various stereoisomers, including in optically active form, can be used as starting substances of different spatial isomers of compound 2, including possessing optical activity.

The analgesic activity of compounds of the General formula 1 have been studied in models of visceral pain "acetic cramps" and thermal irritation "hot plate" on white outbred mice weighing 20-22 g in groups of 8 animals at single doses of 1÷20 mg/kg.

"Acetic cramps" reproduced inside by peritoneal injection of 0.75% acetic acid at 0.1 ml per animal. Evaluation activity was carried out according to the number of writhing within 3 min.

Test "hot plate" describes thermal stimulation. Animals were placed on a copper plate, T=54°C. the Effect was assessed by the duration of the animal on the hot plate until the first "vocalizations".

Discovered that compounds of the General formula 1 in a dose of 10 mg/kg have a high�th analgesic activity in the test "acetic cramps", moreover, compound 1a (R1=R2=R3=H) and 1G (R1=N, R2=Br, R3=H) were more effective than diclofenac sodium, taken in the same dose (table 2).

Table 2
The analgesic activity of compounds of the General formula 1 in the test "acetic cramps" in a dose of 10 mg/kg
ConnectionAcetic cramps, amountPain reduction, %a
ControlAgent
1AR1=R2=R3=N9.6±0.94.3±1.15**
1BR1=R2=N, R3=Me10.9±0.57.0±0.636***
1BR1=Me, R2=R3=N10.9±0.56.6±0.539***
1GR1=N, R2=Br, R3=N/td> 9.6±0.93.6±1.563**
1DR1=Br, R2=R3=N9.6±0.96.3±1.234*
1ER1=NO2, R2=R3=N11.1±0.77.5±1.232*
Diclofenac sodium10.1±1.95.0±1.150***
a% reduction in pain = (tcontrol-texp)/tcontrol·100%
* P<0.05; ** P<0.01; *** P<0.001 compared with control

Data for the study of analgesic activity in the test "hot plate" is presented in Table 3. Significant analgesic activity in this test showed the compound 1A (R1=R2=R3=N).

Connection
Table 3
The analgesic activity of compounds of the General formula 1 in the test "hot plate" in a dose of 10 mg/kg
Hot plate, hProtection, %a
ControlAgent
1AR1=R2=R3=N9.8±0.813.1±1.234*
1BR1=R2=N, R3=Me18.4±2.112.8±1.7-
1BR1=Me, R2=R3=N18.4±2.117.4±2.4-
1GR1=N, R2=Br, R3=N9.8±0.813.6±1.739
1DR1=Br, R2=R3=N9.8±0.811.6±1.018
1ER1=NO2, R2=R3=N12.1±1.314.5±1.620
Diclofenac sodium9.6±1.615.6±2.462**
a% protection = (texp-tcontrol)/tcontrol·100%
* P<0,05;** P<0.01; *** P<0.001 compared with control

For compounds 1A, which showed high activity in both tests studied the dose-dependent effect (table 4). The data obtained show that the compound 1A retains a high analgesic activity in both tests at a dose of 1 mg/kg, not inferior in effectiveness the comparison drug diclofenac sodium taken in the dose of 10 mg/kg (Tables 2 and 3).

Table 4
Analgesic activity of compound 1A in tests "acetic cramps" and "hot plate" in different doses
Dose, mg/kgAcetic cramps, amountHot plate, h
ControlAgent (reducing pain, %)aControl Agent (protection, %)b
2011.0±0.78.3±0.5 (25)**10.7±1.416.0±2.6 (50)
109.6±0.94.3±1.1 (55)**9.8±0.813.1±1.2 (34)*
58.4±0.64.9±1.0 (42)**10.4±1.216.3±1.6 (57)*
18.4±0.62.4±0.8 (71)***10.4±1.216.5±1.9 (59)*
0.510.1±0.77.4±1.3 (27)15.8±1.620.3±2.2 (28)
a% reduction in pain = (tcontrol-texp)/tcontrol·100%
b% protection = (texp-tcontrol)/tcontrol·100%
* P<0.05; ** P<0.01; *** P<0.001 compared with control

Acute toxicity of compound 1A was determined on albino mice weighing 20-22 g at odnoga�nom intragastric introduction according to the method of Cerberus. It is shown that compound 1A is amerinational substance: LD50exceeds 1500 mg/kg, and therapeutic index (IS50) is more than 1500. Thus, compound 1A significantly less toxic than diclofenac sodium (LD50370 mg/kg [2]), and significantly greater latitude therapeutic index (IS50diclofenac sodium is equal to 74 [2]).

Based on the foregoing it can be concluded that compounds of the General formula 1 are high analgesic activity in the test of visceral pain "acetic cramps". Compound 1A combines high analgesic activity in tests "acetic cramps" and "hot plate" and low acute toxicity.

Compounds of the General formula 1, after conducting in-depth pharmacological studies, can be used both in pure form and as a component of new low-toxic highly effective analgesic dosage forms.

The invention is illustrated by the following examples.

Example 1. Synthesis of 4,7-dimethyl-2-(thiophene-2-yl)octahydro-2H-chromen-4-ol 1A.

To a suspension of 1.3 g of K10 clay in 5 ml of CH2Cl2added a solution of 0.29 g of thiophene-2-carboxaldehyde in 3 ml of CH2Cl2then added a solution of 0.400 g isopulegol 2 in 3 ml of CH2Cl2. The solvent drove away and left the reaction AGR�ü at room temperature for 60 minutes. Then added 10 ml of EtOAc, the catalyst was filtered and drove the solvent. The resulting mixture was divided into column with 13 g of silica gel, eluent a solution containing from 0 to 100% ethyl acetate in hexane. Got 0.543 g (78%) of compound 1A. The NMR spectrum1H compounds 1A corresponds to the range published in the literature [4].

Example 2. Synthesis of 4,7-dimethyl-2-(3-methylthiophene-2-yl)octahydro-2H-chromen-4-ol 1B.

Analogously to Example 1, the interaction 0.300 g isopulegol 2 with 0.25 g of 3-methylthiophene-2-carboxaldehyde in the presence of 1.1 g of K10 clay for 120 minutes was 0.381 g (70%) of compound 1B.

The NMR spectrum1H (CDCl3): 0.88-0.97 (m, 1H, Ha-8); 0.92 (d, J(16, 9a)=6.6 Hz, 3H, H-16); 1.03 (dddd, J(7a, 7e)=J(7a, 8a)=12.8 Hz, J(7a, 6a)=12.1 Hz, J(7a, 8e)=3.3 Hz, 1H, Ha-7); 1.11 (ddd, J(10a, 10e)=J(10a, 9a)=12.2 Hz, J(10a, 1a)=10.8 Hz, 1H, Ha-10); 1.28 (d, J(15, 4a)=0.7 Hz, 3H, H-15); 1.31 (ddd, J(6a, 7a)=12.1 Hz, J(6a, 1a)=10.2 Hz, J(6a, 7e)=3.3 Hz, 1H, Ha-6); 1.40-1.53 (m, 2H, Ha-9, OH); 1.72 (ddddd, J(8e, 8a)=12.9 Hz, J(8e, 7a)=J(8e, 9a)=J(8e, 7e)=3.3 Hz, J(8e, 10e)=2.0 Hz, 1H, He-8); 1.85 (ddq, J(4a, 4e)=12.7 Hz, J(4a, 3a)=11.7 Hz, J(4a, 15)=0.7 Hz, 1H, Ha-4); 1.91-1.97 (m, 1H, He-7); 1.95 (dd, J(4e, 4a)=12.7 Hz, J(4e, 3a)=2.4 Hz, 1H, He-4); 1.99 (dm, J(10e, 10a)=12.2 Hz, 1H, He-10); 2.19 (s, 3H, H-17); 3.26 (ddd, J(1a, 10a)=10.8 Hz, J(1a, 6a)=10.2 Hz, J(1a, 10e)=4.3 Hz, 1H, Ha-1); 4.71 (dd, J(3a, 4a)=11.7 Hz, J(3a, 4e)=2.4 Hz, 1H, Ha-3); 6.75 (d, J(13, 12)=5.0 Hz, 1H, H-13); 7.09 (d, J(12, 13)=5.0 Hz, 1H, H-12). The NMR spectrum13With (CDCl3): 77.63 (d, C-1); 71.09 (d, C-3); is at 49.70 (t, C-4); 70.64 (s, C-5); is at 51.91 (d, C-6); 22.94 (t, C-7); 34.26 (t, C-9); is at 41.32 (t, C-10); 138.34 (s, C-11); 122.92 (d, C-12); 129.72 (d, C-13); 133.29 (s, C-14); 21.09 (q, C-15); 22.03 (q, C-16); 13.63 (q, C-17). MC: Nai�eno 280.1488 (M +, (C16H24O2S)+; calc. 280.1492).

Example 3. Synthesis of 4,7-dimethyl-2-(5-methylthiophene-2-yl)octahydro-2H-chromen-4-ol 1B.

Analogously to Example 1, the interaction 0.300 g isopulegol 2 with 0.25 g of 5-methylthiophene-2-carboxaldehyde in the presence of 1.1 g of K10 clay for 120 minutes was 0.386 g (71%) of compound 1B.

The NMR spectrum1H (CDCl3): 0.87-0.96 (m, 1H, Ha-8); 0.92 (d, J(16, 9a)=6.6 Hz, 3H, H-16); 1.02 (dddd, J(7a, 7e)=J(7a, 8a)=12.8 Hz, J(7a, 6a)=12.2 Hz, J(7a, 8e)=3.3 Hz, 1H, Ha-7); 1.09 (ddd, J(10a, 10e)=J(10a, 9a)-12.3 Hz, J(10a, 1a)=10.8 Hz, 1H, Ha-10); 1.25 (d, J(15, 4a)=0.8 Hz, 3H, H-15); 1.28 (ddd, J(6a, 7a)=12.2 Hz, J(6a, 1a)=10.2 Hz, J(6a, 7e)=3.3 Hz, 1H, Ha-6); 1.39-1.52 (m, 2H, Ha-9, OH); 1.72 (ddddd, J(8e, 8a)=12.8 Hz, J(8e, 7a)=J(8e, 9a)-J(8e, 7e)=3.3 Hz, J(8e, 10e)=2.0 Hz, 1H, He-8); 1.86 (ddq, J(4a, 4e)=12.7 Hz, J(4a, 3a)=11.7 Hz, J(4a, 15)=0.8 Hz, 1H, Ha-4); 1.93 (dddd, J(7e, 7a)=12.8 Hz, J(7e, 6a)=J(7e, 8a)=J(7e, 8e)=3.3 Hz, 1H, He-7); 1.99 (dm, J(10e, 10a)=12.3 Hz, 1H, He-10); 2.01 (dd, J(4e, 4a)=12.7 Hz, J(4e, 3a)=2.2 Hz, 1H, He-4); 2.42 (d, J(17, 13)=1.1 Hz, 3H, H-17); 3.24 (ddd, J(1a, 10a)=10.8 Hz, J(1a, 6a)=10.2 Hz, J(1a, 10e)=4.3 Hz, 1H, Ha-1); 4.59 (dd, J(3a, 4a)=11.7 Hz, J(3a, 4e)=2.2 Hz, 1H, Ha-3); 6.56 (dq, J(13, 14)=3.4 Hz, J(13, 17)=1.1 Hz, 1H, H-13); 6.73 (d, J(14, 13)=3.4 Hz, 1H, H-14). The NMR spectrum13With (CDCl3): 77.43 (d, C-1); and 72.54 (d, C-3); 49.58 (t, C-4); 70.69 (s, C-5); is at 51.89 (d, C-6); 22.93 (t, C-7); 34.26 (t, C-8); 31.38 (d, C-9); is at 41.35 (t, C-10); 142.89 (s, C-11); 139.12 (s, C-12); 124.26 (d, C-13); 123.50 (d, C-14); 21.17 (q, C-15); 22.04 (q, C-16); 15.16 (q, C-17). MC: found 280.1491 (M+, (C16H24O2S)+; calc. 280.1492).

Example 4. Synthesis of 4,7-dimethyl-2-(4-bromothiophene-2-yl)octahydro-2H-chromen-4-ol 1G.

Analogously to Example 1, in�aimogasta 0.300 g isopulegol 2 with 0.37 g of 4-bromothiophene-2-carboxaldehyde in the presence of 1.4 g of K10 clay for 120 minutes was 0.499 g (74%) of compound 1G.

The NMR spectrum1H (CDCl3): 0.87-0.96 (m, 1H,-8); 0.93 (d, J(16, -9)=6.6 Hz, 3H, H-16); 1.02 (dddd, J(7a, 7e)=J(7a, 8a)=12.8 Hz, J(7a, 6a)=12.1 Hz, J(7a, 8e)=3.2 Hz, 1H, Ha-7); 1.10 (ddd, J(10a, 10e)=J(10a, 9a)=12.2 Hz, J(10a, 1a)=11.1 Hz, 1H, Ha-10); 1.26 (d, J(15, 4a)=0.7 Hz, 3H, H-15); 1.29 (ddd, J(6a, 7a)=12.1 Hz, J(6a, 1a)=10.1 Hz, J(6a, 7e)=3.2 Hz, 1H, Ha-6); 1.39-1.50 (m, 1H, Ha-9); 1.56 (br. s, OH); 1.72 (dm, J(8e, 8a)=12.8 Hz, other J<3.5 Hz, 1H, He-8); 1.82 (ddq, J(4a, 4e)=12.7 Hz, J(4a, 3a)=l 1.7 Hz, J(4a, 15)=0.7 Hz, 1H, Ha-4); 1.93 (dddd, J(7e, 7a)=12.8 Hz, J(7e, 6a)=J(7e, 8a)=J(7e, 8e)=3.2 Hz, 1H, He-7); 1.99 (dddd, J(10e, 10a)=12.8 Hz, J(10e, 1a)=4.3 Hz, J(10e, 9a)=3.7 Hz, J(10e, 8e)=2.0 Hz, 1H, He-10); 2.01 (dd, J(4e, 4a)=12.7 Hz, J(4e, 3a)=2.2 Hz, 1H, He-4); 3.26 (ddd, J(1a, 10a)=11.1 Hz, J(1a, 6a)=10.1 Hz, J(1a, 10e)=4.3 Hz, 1H, Ha-1); 4.62 (ddd, J(3a, 4a)=11.7 Hz, J(3a, 4e)=2.2 Hz, J(3a, 14)=0.8 Hz, 1H, Ha-3); 6.86 (dd, J(14, 12)=1.5 Hz, J(14, 3a)=0.8 Hz, 1H, H-14); 7.11 (d, J(12, 14)=1.5 Hz, 1H, H-12). The NMR spectrum13With (CDCl3): 77.65 (d, C-1); 72.07 (d, C-3); at 49.54 (t, C-4); 70.52 (s, C-5); 51.82 (d, C-6); is at 22.89 (t, C-7); 34.20 (t, C-8); 31.36 (d, C-9); 41.22 (t, C-10); 146.74 (s, C-11); 121.72 (d, C-12); 108.88 (s, C-13); 126.11 (d, C-14); 21.16 (q, C-15); 22.02 (q, C-16). MC: found 344.0442 (M+, (C15H21O2SBr)+; calc. 344.0440).

Example 5. Synthesis of 4.7-dimethyl-2-(5-bromothiophene-2-yl)octahydro-2H-chromen-4-ol 1D.

Analogously to Example 1, the interaction 0.300 g isopulegol 2 with 0.37 g of 5-bromothiophene-2-carboxaldehyde in the presence of 1.4 g of K10 clay for 120 minutes was 0.512 g (76%) of compound 1D.

The NMR spectrum1H (CDCl3): 0.87-0.96 (m, 1H,-8); 0.92 (d, J(16, -9)=6.6 Hz, 3H, H-16); 1.02 (dddd, J(7a, 7e)=J(7a, 8a)=12.8 Hz, J(7a, 6a)=12.2 Hz, J(7a, 8e)=3.3 Hz, 1H, Ha-7); 1.09 (ddd, J(10a, 10e)=J(10a, 9a)=12.2 Hz, J(10a, 1a)=10.8 Hz, 1H, Ha-10); 1.25 (d, J(15, 4a)=0.8 Hz, 3H, H-15); 1.28 (ddd, J6a, 7a)=12.2 Hz, J(6a, 1a)=10.2 Hz, J(6a, 7e)=3.3 Hz, 1H, Ha-6); 1.37-1.50 (m, 2H, Ha-9, OH); 1.72 (dm, J(8e, 8a)=12.8 Hz, other J<3.5 Hz, 1H, He-8); 1.81 (ddq, J(4a, 4e)=12.7 Hz, J(4a, 3a)=11.8 Hz, J(4a, 15)=0.8 Hz, 1H, Ha-4); 1.92 (dddd, J(7e, 7a)=12.8 Hz, J(7e, 6a)=J(7e, 8a)=J(7e, 8e)=3.3 Hz, 1H, He-7); 1.98 (dddd, J(10e, 10a)=12.2 Hz, J(10e, 1a)=4.3 Hz, J(10e, 9a)=3.7 Hz, J(10e, 8e)=2.0 Hz, 1H, He-10); 2.01 (dd, J(4e, 4a)=12.7 Hz, J(4e, 3a)=2.2 Hz, 1H, He-4); 3.24 (ddd, J(1a, 10a)=10.8 Hz, J(1a, 6a)=10.2 Hz, J(1a, 10e)=4.3 Hz, 1H, Ha-1); 4.59 (ddd, J(3a, 4a)=11.8 Hz, J(3a, 4e)=2.2 Hz, J(3a, 14)=0.8 Hz, 1H, Ha-3); 6.68 (dd, J(14, 13)=3.8 Hz, J(14, 3a)=0.8 Hz, 1H, H-14); 6.86 (d, J(13, 14)=3.8 Hz, 1H, H-13). The NMR spectrum13With (CDCl3): 77.58 (d, C-1); 72.53 (d, C-3); 49.42 (t, C-4); 70.54 (s, C-5); 51.84 (d, C-6); is at 22.89 (t, C-7); 34.20 (t, C-8); 31.35 (d, C-9); 41.23 (t, C-10); 147.17 (s, C-11); 111.45 (s, C-12); 129.01 (d, C-13); 123.55 (d, C-14); 21.16 (q, C-15); 22.02 (q, C-16). MC: found 344.0442 (M+,(C15H21O2SBr)+; calc. 344.0440).

Example 6. Synthesis of 4,7-dimethyl-2-(5-nitrothiophen-2-yl)octahydro-2H-chromen-4-ol 1E.

Analogously to Example 1, the interaction 0.400 g isopulegol 2 0.407 g of 5-nitrothiophen-2-carboxaldehyde in the presence of 1.6 g of K10 clay for 60 minutes got 0.400 g (50%) of compound 1E.

The NMR spectrum1H (CDCl3): 0.86-0.95 (m, 1H, Ha-8); 0.93 (d, J(16, -9)=6.6 Hz, 3H, H-16); 1.01 (dddd, J(7a, 7e)=J(7a, 8a)=12.8 Hz, J(7a, 6a)=12.1 Hz, J(7a, 8e)=3.4 Hz, 1H, Ha-7); 1.09 (ddd, J(10a, 10e)=J(10a, 9a)=12.2 Hz, J(10a, 1a)=10.9 Hz, 1H, Ha-10); 1.26 (d, J(15, 4a)-0.7 Hz, 3H, H-15); 1.29 (ddd, J(6a, 7a)=12.1 Hz, J(6a, 1a)=10.2 Hz, J(6a, 7e)=3.2 Hz, 1H, Ha-6); 1.39-1.50 (m, 1H, Ha-9); 1.72 (dm, J(8e, 8a)=12.8 Hz, other J<3.5 Hz, 1H, He-8); 1.75 (ddq, J(4a, 4e)=12.8 Hz, J(4a, 3a)=11.9 Hz, J(4a, 15)=0.7 Hz, 1H, Ha-4); 1.92 (dddd, J(7e, 7a)=12.8 Hz, J(7e, 6a)=J(7e, 8a)=J(7e, 8e)=3.2 Hz, 1H, He-7); 1.99 (dddd, J(10e, 10a)=12.2 Hz, J(1e, 1a)=4.3 Hz, J(10e, 9a)=3.7 Hz, J(10e, 8e)=1.9 Hz, 1H, He-10); 2.04 (dd, J(4e, 4a)=12.8 Hz, J(4e, 3a)=2.2 Hz, 1H, He-4); 3.27 (ddd, J(1a, l0a)=10.9 Hz, J(1a, 6a)=10.2 Hz, J(1a, 10e)=4.3 Hz, 1H, Ha-1); 4.65 (ddd, J(3a, 4a)=11.9 Hz, J(3a, 4e)=2.2 Hz, J(3a, 14)=0.9 Hz, 1H, Ha-3); 6.82 (dd, J(14, 13)=4.2 Hz, J(14, 3a)=0.9 Hz, 1H, H-14); 7.75 (d, J(13, 14)=4.2 Hz, 1H, H-13). The NMR spectrum13C (CDCl3): 77.81 (d, C-1); 72.38 (d, C-3); 49.42 (t, C-4); 70.25 (s, C-5); 51.68 (d, C-6); 22.78 (t, C-7); 34.09 (t, C-8); 31.25 (d, C-9); 41.04 (t, C-10); 154.79 (s, C-11); 150.56 (s, C-12); 128.17 (d, C-13); 121.75 (d, C-14); 21.01 (q, C-15); 21.95 (q, C-16). MC: found 311.1185 (M+, (C15H21O4NS)+; calc. 311.1186).

Example 7. Study of analgesic activity of the compounds of the General formula 1 in the test "acetic cramps".

The experiment was carried out on outbred mice-males weighing 22-25 g. Experimental groups were formed based on 8 animals in each. "Acetic cramps" was reproduced by intraperitoneal injection of 0.75% acetic acid at 0.1 ml per animal. Investigational agents was administered intragastrically once per hour to play model. Control animals were only with the introduction of acetic acid. Evaluation activity was carried out according to the number of writhing within 3 min.

The results are shown in tables 2 and 4.

Found that compounds of the General formula 1 possess high analgesic activity in the test "acetic cramps".

Example 8. Study of analgesic activity of compound 1 in the test "hot plate".

The experiments were performed �and outbred mice-males weighing 22-25 g. Experimental groups were formed based on 8 animals in each. Animals were placed on a copper plate T=54°C. the Effect was assessed by the duration of the animal on the hot plate until the first "vocalization", in seconds.

The study agents were administered intraperitoneally one hour before play model. Control animals received an appropriate solvent. The results are presented in tables 3 and 4.

Found that compound 1A has high analgesic activity in the test "hot plate".

Sources of information

1. Mashkovsky M. D. Medicines. Vol. 1. M.: Medicine. 2007.

2. Subev R. D. Mashkovsky M. D., Schwartz G. J., V. I. Pokryshkin Comparative pharmacological activity of modern non-steroidal anti-inflammatory drugs. Chem.-Pharm. Phys. 1986. T. 20. No. 1. P. 33-39.

3. On The Main Page. Drugs in Russia: a Handbook. M.: Attraversare. 2002. W-90.

4. Baishya, G., Sarmah B., Hazarika N. Synlett 2013, Vol. 24, P. 1137-1141.

Use of a compound of the General formula 1, including its spatial isomers, including optically active,

where R1, R2, R3may be the same or different and may be a hydrogen atom, an alkyl group, a nitro group, a halogen, as painkillers.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

possessing properties of binding with delta opioid receptors. In formula I R1 is selected from the group, consisting of phenyl, pyridinyl and thiazolyl, with R1 being optionally substituted with one or two substituents, independently selected from the group, consisting of C1-4alkoxy, fluorine atom, chlorine atom, bromine atom and cyanogroup; in addition, R1 is optionally substituted with di(C1-4alkyl)aminocarbonyl; Y represents O, S, H3, vinyl, ethinyl or S(O); R2 represents a substituent, selected from the group, consisting of hydrogen, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluorine atom, chlorine atom, bromine atom and hydroxy; Ra represents hydrogen or methyl; R3 is selected from the group, consisting of pyrrolidin-2-ylmethyl; pyrrolidin-3-ylmethyl; piperidin-2-ylmethyl, piperidin-3-ylmethyl, piperidin-4-ylmethyl, piperidin-2-ylethyl, piperidin-3-ylethyl, piperidin-4-ylethyl, pyridine-4-yl-(C1-2)alkyl, azetidin-3-ylmethyl; morpholin-2-ylmethyl, morpholin-3-ylmethyl, imidazolylmethyl, thiazolylmethyl, (amino)-C3-6cycloalkyl, 3-hydroxy-2-aminopropyl, 8-azabicyclo[3.2.1]octanyl, 1-azabicyclo[2.2.2]octanyl, guanidinylethyl, 4-(imidazol-1-yl)phenylmethyl, 2-(methylamino)ethyl, 2-diethylaminoethyl, 4-diethylaminobut-2-yl, piperidin-3-yl, piperidin-4-yl and pyrrolidin-3-yl; with piperidin-3-yl being optionally substituted on a carbon atom with phenyl; with pyrrolidin-2-yl in pyrrolidin-2-yl-methyl, pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl being optionally substituted on a nitrogen atom with methyl, phenylmethyl, phenethyl or methylcarbonyl.

EFFECT: compounds can be used in the treatment of pain, induced by diseases or conditions, such as osteoarthritis, rheumatoid arthritis, migraine, burn, fibromyalgia, cystitis, rhinitis, neuropathic pain, idiopathic neuralgia, toothache, etc.

24 cl, 3 tbl, 19 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to pharmaceutical industry, namely to composition for treating skin ageing. Composition for treating signs of skin ageing, increase of cytikin IL-1α secretion, contains: NF-kB inhibitor, selected from the group, consisting of substituted resorcinols, (E)-3-(4-methylphenylsulphonyl)-2-propenenitrile, tetrahydrokurkuminoids, extracts of Paulownia tomentosa wood, as well as their combinations, and anti-inflammatory compound, which is not NF-kB inhibitor. Composition for treating signs of skin ageing, increase of cytokine IL-1α, containing NF-kB inhibitor, selected from the group, consisting of substituted resorcinols, and anti-inflammatory compound (versions).

EFFECT: compositions are effective for treating signs of skin ageing.

4 cl, 9 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention aims at pharmaceutical compositions containing a number of microparticles with taste masking, containing high-/low-dose therapeutic agents, at dosage forms containing the above pharmaceutical compositions (such as orally dispersible tablets), and at methods for producing these pharmaceutical compositions and dosage forms.

EFFECT: dosage forms containing the pharmaceutical compositions according to the invention represent the improved homogenous mixtures of the high-dose and low-dose therapeutic agents, which enable controlling the release rate of the therapeutic agent from particles by various ways, as well as flexible correction of dosages when administering the combinations of the therapeutic agents, eg in pain management.

31 cl, 4 dwg, 12 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of the general formula

,

wherein R1/R2 independently represent hydrogen, (CR2)o-C3-7 cycloalkyl optionally substituted by a lower alkyl or hydroxy, or represent a lower alkyl or tetrahydropyranyl, and o represents 0 or 1; and R can be identical or different, and represent hydrogen or a lower alkyl; or R1 and R2 can form together with a N atom to which they are attached, a heterocycloalkyl group specified in a group consisting of pyrrolidinyl, piperidinyl, 3-aza-bicyclo[3.1.0]hex-3-yl or 2-aza-bicyclo[3.1.0]hex-2-yl which are optionally substituted by hydroxy; R3 represents an S-lower alkyl, lower alkyl, lower alkoxy or C3-7 cycloalkyl; R3′ represents hydrogen, a lower alkyl substituted by a halogen, lower alkyl or lower alkoxy; R4 represents a lower alkyl substituted by a halogen; X represents -O- or -CH2-; X' represents -O- or -CH2-; provided one of X or X' always represent -O- and the other represents -CH2-; or a pharmaceutically acceptable acid-additive mixture, a racemic mixture, or a respective enantiomer and/or an optical isomer.

EFFECT: compounds of the general formula (I) are good inhibitors of glycine transporter 1 (GlyT-1) and hence can be used for treating schizophrenia and other neurological conditions, including pain.

13 cl, 1 tbl, 63 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel N-containing heteroaryl derivatives of formula I or II or their pharmaceutically acceptable salts, which possess properties of JAK kinase, in particular JAK3, and can be applied for treating such diseases as asthma and chronic obstructive pulmonary disease (COPD). In formulae A represents carbon and B represents nitrogen or A represents nitrogen and B represents carbon; W represents CH or N; R1 and R2, independently represent hydrogen, C1-4alkyl, halogenC1-4alkyl, -CN; R3 represents C1-4alkyl, R9-C1-4alkyl, Cy1, where Cy1 is optionally substituted with one or several substituents R10; R4 represents hydrogen, C1-4alkyl, R12R7N-C0alkyl, where one of R7 and R12 represents hydrogen, and the other represents C1-4alkyl or group R13, which is selected from C1-5alkyl, Cy2-C0alkyl; R5 represents hydrogen; R6 represents hydrogen, C1-4alkyl, C1-4alkoxyC1-4alkyl, hydroxyC1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0alkyl, Cy1; R7 represents hydrogen or C1-4alkyl; R9 represents halogen, -CN, -CONR7R12, -COR13, CO2R12, -OR12, -SO2R13, -SO2NR7R12, -NR7R12, -NR7COR12; R10 represents C1-4alkyl or R9-C0-4alkyl; R11 represents C1-4alkyl, halogen, -CN, -NR7R14; R12 represents hydrogen or R13; R13 represents C1-5alkyl, hydroxyC1-4alkyl, cyanoC1-4alkyl, Cy2-C0alkyl or R14R7N-C1-4alkyl; where Cy2 is optionally substituted with one or several constituents R11; R14 represents hydrogen or C1-4alkyl; R16 represents C1-4alkyl, halogenC1-4alkyl, C1-4alkoxyC1-4alkyl, hydroxyC1-4alkyl or cyanoC1-4alkyl; Cy1 represents monocyclic carbocyclic unsaturated or saturated ring, selected from C3-C6cycloalkyl, phenyl, or saturated monocyclic 4-6-membered heterocyclic ring, containing from 1 to 2 heteroatoms, selected from N and S, or partially unsaturated 10-membered bicyclic heterocyclic ring, containing oxygen atom as heteroatom, which can be substituted with group R11, where said ring is bound with the remaining part of molecule via any available C atom, and where one or several ring C or S atoms are optionally oxidised with formation of CO or SO2; and Cy2 represents monocyclic carbocyclic unsaturated ring, selected from C3-C6cycloalkyl, or aromatic monocyclic 4-6-membered heterocyclic ring, containing from 1 to 2 heteroatoms, selected from N and S, or unsaturated 10-membered bicyclic heterocyclic ring, containing oxygen atom as heteroatom, which can be substituted with group R11, where said ring is bound with the remaining part of molecule via any available atom C or N.

EFFECT: obtaining novel heteroaryl derivatives.

27 cl, 41 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula I, possessing ability of binding with delta-opioid receptors. In formula R1 is selected from the group, consisting of i) phenyl, optionally substituted with one-two substituents, independently selected from the group, consisting of C1-4alkyl, C1-4alcoxy, C1-4alkylthio, hydroxyl, di(C1-4alkyl), aminocarbonyl, chlorine and fluorine, in such a way that only one di(C1-4alkyl)aminocarbonyl is present; ii) naphthyl; iii) pyridinyl, optionally substituted with one substituent, selected from the group, consisting of C1-4alkyl, C1-4alcoxy, C1-4alkylthio, hydroxy, fluorine, chlorine and cyano; iv) pyrimidin-5-yl; v) furanyl; vi) thienyl; vii) 5-oxo-4,5-dihydro-[1,2,4]oxodiazol-3-yl; and viii) di(C1-2alkyl)aminocarbonyl; Y represents ethyl, vinyl or bond; or Y represents O, when R1 represents optionally substituted phenyl, where substituent represents C1-4alcoxy; R2 represents phenyl, optionally substituted with one-two substituents, independently selected from the group, consisting of C1-4alkyl, C1-4alcoxy, fluorine, chlorine and cyano, trifluoromethoxy and hydroxy; or R2 represents phenyl, substituted with one aminocarbonyl, di(C1-4alkyl)aminocarbonyl, C1-4alcoxycarbonyl or carboxysubstituent; R3 is selected from the group, consisting of i) 3-aminocyclohexyl; ii) 4-aminocyclohexyl; iii) piperidin-3-yl; iv) piperidin-4-yl; v) pyrrolodin-2-yl-methyl, in which pyrrolodin-2-yl is optionally substituted by 3-rd or 4-th position with one or two fluorine-substituents; vi) azetidin-3-yl; vii) 2-(N-methylamino)ethyl; viii) 3-hydroxy-2-aminopropyl; ix) piperidin-3-yl-methyl; x) 1-azabicyclo[2.2.2]octan-3-yl; and xi) 8-azabicyclo[3.2.1]octan-3-yl; or R3 together with Ra and nitrogen atom, which they both are bound to, form piperazinyl, optionally substituted with 4-C1-4alkyl; Ra represents hydrogen, 2-(N-methylamino)ethyl or C1-2alkyl, optionally substituted with azetidin-3-yl.

EFFECT: compounds can be used in treatment of pain in the range from medium to strong, caused by diseases or conditions, such as osteoarthritis, migraine, burn, fibromyalgia, cystitis, rhenite, neuropathic pain, idiopathic neuralgia, toothache, etc.

21 cl, 4 tbl, 26 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to substituted phenylureas and phenylamides of formula in which X stands for CR3 or N, where R3 stands for H; C1-10alkyl, saturated or unsaturated, branched or non-branched, non-substituted; or CF3; A stands for N or CR5b; R1 stands for substructure , which has the formula, given below. The other radicals and symbols have the values, given in the invention formula. The invention also relates to methods of obtaining formula (If) compounds, to pharmaceutical compositions, containing the said compounds, as well as to the application of the said compositions for the preparation of the pharmaceutical compositions.

EFFECT: formula (If) compounds possess activity with respect to the vanilloid receptor of I subtype (receptor VR1/TRPV1).

7 cl, 1 tbl, 147 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a novel compound of formula

(I)

or its pharmaceutically acceptable salt, possessing properties of the IKKβ and TNFα inhibitor. The compound can be used with an additional therapeutic agent, selected from vincristine, camptothecin hydrochloride (CPT-11), lefunomid, dexamethasone and TNFα. Preferable are compounds of formula (I), corresponding to 2-{5-chloro-2-[(1R,2R)-2-hydroxycyclopentylamino]pyrimidin-4-yl}-N-cyclopropyl-1H-indole-4-carboxamide and 2-{5-chloro-2-[(1R,2S)-2-hydroxycyclopentylamino]pyrimidin-4-yl}-N-cyclopropyl-1H-indole-4-carboxamide.

EFFECT: compound can be applied in the treatment of inflammatory diseases such as rheumatoid arthritis, chronic obstructive lung disease, bronchial asthma, multiple sclerosis and intestinal inflammatory diseases, or cancer diseases, such as multiple myeloma, colon cancer, pancreas cancer and ovary cancer, by IKKβ inhibition.

30 cl, 4 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: method includes treating crushed Echinacea purpurea (L.) Moench roots and rhizome with steam, extraction with ethyl alcohol, then steeping, stirring, steeping, draining a portion of the extract which is equal to the amount of the loaded Echinacea purpurea (L.) Moench roots and rhizome, after draining a portion of the extract, adding ethyl alcohol to the treated material, draining the whole extract; extracting crushed Echinacea purpurea (L.) Moench herbs with ethyl alcohol, steeping, then stirring, steeping, draining a portion of the extract which is equal to the amount of the loaded Echinacea purpurea (L.) Moench herbs, after draining a portion of the extract, adding ethyl alcohol to the treated herbs, draining the whole extract; all obtained extracts are mixed, cooled and filtered under certain conditions. An Echinacea purpurea (L.) Moench tincture. Use of the method to obtain an Echinacea purpurea (L.) Moench tincture.

EFFECT: method preserves the biological activity of components of the tincture and medicinal properties.

3 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I), their pharmaceutically acceptable salts, tautomers or stereoisomers. In formula R1 represents benzimidazolyl optionally substituted by C1-4alkyl, C1-4alkoxyC1-4alkyl, hydroxyC1-4alkyl, dimethylaminoC1-4alkyl or oxo group; benzioxazolyl optionally substituted by C1-4alkyl or amino group; benzotriazolyl optionally substituted by C1-4alkyl; dihydrobenzisothiazol-1,1-dionyl; pyrimidyl; dihydroisoquinolinonyl optionally substituted by oxo group; imidazopyridyl; indazolyl optionally substituted by C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, tetrahydropyranylamino, piperidinylamino, halogen, trifluoromethyl or amino group; indolinyl optionally substituted by C1-4alkyl, hydroxyC1-4alkyl, carboxylate or oxo group; isoindolinyl optionally substituted by C1-4alkyl, aminoC1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl or oxo group; phenyl optionally substituted by C1-4alkyl, C1-4alkoxy, halogen, cyano, trifluoromethyl, carbamoyl, methylcarbamoyl, piperidinylcarbamoyl, methylpiperidinylcarbamoyl, aminoC1-4alkyl, carboxyl, amino, dialkylamino, imidazolyl, pyrrolidin-2-one, triazolyl, morpholinyl, C1-4alkylcarbonylamino, C1-4alkoxyC1-4alkoxy or hydroxyC1-4alkyl; pyrazolopyridyl optionally substituted by C1-4alkyl; pyridyl optionally substituted by C1-4alkyl, C1-4alkoxy, halogen, cyano, hydroxy, amino, morpholinyl, carbamoyl, monoC1-4alkylamino, diC1-4alkylamino, aminoC1-4alkoxy, aminoC1-4alkylamino, hydroxypiperidinyl, hydroxyC1-4alkyl, hydroxyC1-4alkoxy, pyrrolidinylC1-4alkylamino, pyrrolidinylC1-4alkoxy; pyrrolopyridinyl optionally substituted by oxo group; quinolinyl optionally substituted by amino or hydroxy group; or triazolopyridyl substituted by C1-4alkyl. The other radical values are presented in the patent claim. The invention also refers to individual compounds, to a pharmaceutical composition, possessing kinase inhibitory activity and containing an effective amount of the compound of the invention, to a method for kinase inhibition in a cell, to a method of treating or preventing inflammatory conditions, immunological conditions, allergic conditions, rheumatic conditions, cancer, and neuroinflammatory diseases.

EFFECT: there are prepared new compounds possessing Syk, FLT3, JAK1, JAK2 inhibitory activity.

21 cl, 1 tbl, 133 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new aminotetraline derivatives of formula (I) and their physiologically tolerable salts. In formula

,

A means a benzene ring or a ring specified in a group consisting of a 5-merous ring

,

R means the group R1-W-A1-Q-Y-A2-X1-; R1 means hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl-C1-C4-alkyl, halogenated C1-C6-alkyl, tri-(C1-C4-alkyl)-silyl-C1-C4-alkyl, C1-C6-alkoxy-C1-C4-alkyl, amino-C1-C4-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, an optionally substituted phenyl, C1-C6-alkoxy, di-C1-C6-alkylamino, an optionally substituted 5 or 6-merous heterocyclyl containing 1-3 heteroatoms specified in nitrogen and/or oxygen or sulphur; W means a bond; A1 means a bond; Q means -S(O)2- or -C(O)-; Y means -NR9- or a bond; A2 means C1-C4-alkylene, or a bond; X1 means -O-, C1-C4-alkylene, C2-C4-alkynylene; R2 means hydrogen, halogen, or two radicals R2 together with the ring atom to which they are attached form a benzene ring; R3 means hydrogen. The other radical values are specified in the patent claim. The invention also refers to intermediate products for preparing the compounds of formula (I).

EFFECT: compounds possess the properties of glycine transporter inhibitors, particularly GlyT1 and can find application in treating neurological and psychiatric disorders, such as dementia, bipolar disorder, schizophrenia, etc or for managing pain related to glycerinergic or glutamatergic neurotransmission dysfunction.

20 cl, 2 tbl, 326 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula or its therapeutically acceptable salts, wherein A1 represents furyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, piperidinyl, morpholinyl, dihydro-1,3,4-thiadiazol-2-yl, benzothien-2-yl, banzothiazol-2-yl, tetrahydrothien-3-yl, [1,2,4]triazolo[1,5-a]pyrimidin-2-yl or imidazo[2,1-b][1,3]-thiazol-5-yl; wherein A1 is unsubstituted or substituted by one, or two, or three, or four, or five substitutes independently specified in R1, OR1, C(O)OR1, NHR1, N(R1)2, C(N)C(O)R1, C(O)NHR1, NHC(O)R1, NR1C(O)R1, (O), NO2, F, Cl, Br and CF3; R1 represents R2, R3, R4 or R5; R2 represents phenyl; R3 represents pyrazolyl or isoxazolyl; R4 represents piperidinyl; R5 represents C1-C10alkyl or C2-C10alkenyl each of which is not specified or specified by substitutes specified in R7, SR7, N(R7)2, NHC(O)R7, F and Cl; R7 represents R8, R9, R10 or R11; R8 represents phenyl; R9 represents oxadiazolyl; R10 represents morpholinyl, pyrrolidinyl or tetrahydropyranyl; R11 represents C1-C10alkyl; Z1 represents phenylene; Z2 represents piperidine unsubstituted or substituted by OCH3, or piperazine; both Z1A and Z2A are absent; L1 represents C1-C10alkyl or C2-C10alkenyl each of which is unsubstituted or substituted by R37B; R37B represents phenyl; Z3 represents R38 or R40; R38 represents phenyl; R40 represents cyclohexyl or cyclohexenyl; wherein phenylene presented by Z1 is unsubstituted or substituted by the group OR41; R41 represents R42 or R43; R42 represents phenyl, which is uncondensed or condensed with pyrrolyl, imidazolyl or pyrazole; R43 represents pyridinyl, which is uncondensed or condensed with pyrrolyl; wherein each cyclic fragment presented by R2, R3, R4, R8, R9, R10, R38, R40, R42 and R43 is independently unsubstituted or substituted by one or more substitutes independently specified in R57, OR57, C(O)OR57, F, Cl CF3 and Br; R57 represents R58 or R61; R58 represents phenyl; R61 represents C1-C10alkyl; and wherein phenyl presented by the group R58 is unsubstituted or substituted by one or more substitutes independently specified in F and Cl.

EFFECT: invention refers to a pharmaceutical composition containing the above compounds, and to a method of treating diseases involving the expression of anti-apoptotic Bcl-2 proteins.

7 cl, 2 tbl, 48 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: chemistry.

SUBSTANCE: invention relates to linear heterocyclic anthracenedione derivatives containing guanidino(alkylamino) groups in positions 2, 4 and 11 and having the formula: as well as pharmacologically acceptable salts, where X independently denotes a heteroatom selected from O, S or an NH group which forms a five-member heteroarene condensed with an anthracenedione nucleus at bonds 2-3; n independently denotes a number from 2 to 4, which is equal to the number of spacer CH2 groups which link amino groups in peri-positions of heteroarene anthracenedione with nitrogen atoms of guanidine group residues located in side chains; m independently denotes a number from 2 to 4, which is equal to the number of spacer CH2 groups which link the nitrogen atom of a carboxamide group located at position 2 of the heterocyclic nucleus of heteroarene anthracenedione with the nitrogen atom of the guanidine group residue located in the side chain.

EFFECT: obtaining novel compounds which can be used in medicine for therapy of cancerous diseases.

2 tbl, 2 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of linear tetracyclic heteroarene anthracehediones, which contain in side chains residues of halogen acetamidines and correspond to formula: as well as to their pharmacologically acceptable salts, where X, Y, Z independently stand for CH- or Nh-groups or heteroatoms, selected from O, N and S, forming five-member heteroarene, optionally substituted with alkyl; Hal independently stands for fluorine, chlorine, bromine or iodine atom; m and n independently stand for number from 2 to 4 and equal quantity of spacer CH2-groups, connecting aminogroups in peri-positions of heteroarene anthracenedione with nitrogen atoms of residues of halogenacylamidines, located in side chain; W stands for substituents, independently selected from the group: amino, hydroxy, alkoxy, fluorine; k stands for number of substituents W in anthracenedione fragment, independently equal from 0.

EFFECT: novel compounds, which can be applied in medicine for therapy of oncological diseases, have been obtained.

3 tbl, 4 dwg, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound presented by formula

,

wherein A1 means benzene or heterocycle specified in a group consisting of pyridine, pyrazine, imidazole, thiazole, pyrimidine, thiophen, pyridazine, benzoxazine and oxobenzoxazine; A2 means benzene, if needed substituted by fluorine, or thiophen; B1 means hydrogen, lower alkyl, if needed substituted by piperazinyl or morpholino, halogen-substituted lower alkyl, lower alkoxy substituted by carbamoyl, acylamino, carbamoyl or lower alkylcarbonyloxy (provided A1 means thiazole, B1 does not mean acylamino); B2 means hydrogen or a functional group containing at least one nitrogen atom specified in a group consisting of acylamino, pyrrolidinyl, morpholino, piperidinyl, if needed substituted by acyl, piperazinyl, if needed substituted by lower alkyl or acyl, pyrazolyl, diazabicyclo[2.2.1]heptyl, if needed substituted by acyl, and di-(lower alkyl)amino, if needed substituted by amino or acylamino (provided A1 means thiazole, B2 does not mean acylamino); Y means a group presented by formula

,

wherein J means ethylene or lower alkynylene; L means a bond; M means a bond; X means -(CH2)m-, -(CH2)m-O- or -(CH2)m-NR2- (wherein m is an integer of 0 to 3, and R2 means hydrogen); D means -NR3-, wherein R3 means hydrogen; and E means amino, or its pharmaceutically acceptable salt. The compounds of formula (I) are used for preparing a pharmaceutical agent or a pharmaceutical composition for treating or preventing the VAP-1 related diseases.

EFFECT: benzene or thiophen derivative as a VAP-1 inhibitor.

13 cl, 25 tbl, 125 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is a group of inventions, which includes a method of treating a hyperproliferative disorder by introduction to a mammal of a therapeutic combination in the form of a combined composition or by alternation, and the therapeutic combination contains a therapeutically effective quantity of formula compound 4-(2-(1H-indasol-4-yl)-6-((4-(methylsulphonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine, or formula (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one, or their stereoisomers, geometrical isomers, tautomers, or their salts and a therapeutically effective quantity of a chemiotherapeutic agent, selected from erlotinib, docetaxel, 5-FU, gemcitabine, PD-0325901, cisplatin, carboplatin, paclitaxel, bevacizumab, trastuzumab, pertuzumab, temozolomide, tamoxifen, doxorubicin, Akti-1/2, HPPD, rapamycin and lapatinib; a pharmaceutical composition of the same purpose and composition, application of the said therapeutic combination for manufacturing of medication for treatment of cancer, selected from breast cancer, cervical cancer, cancer of large intestine, endometrium, glioma, lung cancer, melanoma, ovarian cancer, cancer of pancreas and prostate, a product for treatment of a hyperproliferative disorder, including the said composition and an instruction and the product, containing the said combination for separate, simultaneous or successive application in treatment of a hyperproliferative disorder.

EFFECT: synergism of suppression of cell proliferation and regression of forms of cancer mentioned above.

45 cl, 52 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (1), having affinity to the µ-opioid receptor and the to the ORL1 receptor, a medicinal agent containing said compounds and use thereof to obtain a medicinal agent for treating pain and other diseases. In general formula (1), Y1, Y1', Y2, Y2', Y3, Y3', Y4 and Y4' denote -H; R1 and R2 independently denote -CH3; R3 denotes R0, where R0 denotes C1-8-alkyl; aryl, selected from phenyl which is unsubstituted or mono-substituted with -F, -Cl, -Br, -I, -CN or -OR0, where R0 denotes -C1-3-alkyl; unsubstituted heteroaryl, selected from a 5-member heteroaryl with one S atom as a heteroatom; R4 denotes R0, where R0 denotes aryl, selected from phenyl which is unsubstituted or mono-substituted with -F, -Cl, -Br, -I, -CN or -OR0, where R0 denotes -C1-3-alkyl; 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolyl, mono-substituted with -S(O)2-phenyl; unsubstituted -dihydroisoindolyl or unsubstituted -indolyl; or R4 denotes -OR0 or -SR0, where R0 denotes a cycloaliphatic group selected from -C5-6-cycloalkyl; aryl, selected from unsubstituted phenyl; C1-2-alkylaryl, where aryl denotes phenyl, which is unsubstituted or mono-substituted with -OR0, where R0 denotes -C1-3-alkyl; and R5 denotes -H or -CH3.

EFFECT: obtaining a medicinal agent for treating pain and other diseases.

7 cl, 3 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel quinazoline derivatives of formula , where each of R1, R2 and R5, independently, represents H; one of R3 and R4 represents where n - 1 or 2; each Ra represents H, C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkoxy, C1-10alkansulfonyl carboxy-group, 5-6-membered monocyclic heterocycloalkyl, which has one or several heteroatoms, selected from O and N, where N atom can be substituted with C1-10alkyl, phenyl, optionally substituted with halogen, 5-6-membered monocyclic heteroaryl, which has one or several heteroatoms, selected from N and S, 7-membered bicyclic heterocycloalkyl, which has 2 N atoms; C2-10alkenyl; C2-10alkinyl; cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms; each of Rb and Rc, independently, represents H or C1-10alkyl, optionally substituted C1-10alkoxy, or Rb and Rc, together with atom of nitrogen, with which they are bound, form bicyclic ring of the following formula: , where each of m1, m2, m3, and m4 is 0, 1 or 2; A is CH; B is NR, where R is H or C1-10alkyl; and each of Ri, Rii, Riii, RiV, Rv, Rvi, Rvii and Rviii is H; or 6-7-membered monocyclic heterocycloalkyl, containing 1-2 N atoms, optionally substituted with substituent, selected from group, including hydroxy, C1-10alkyl, optionally substituted C1-10alkoxy, C1-10alkyl, optionally substituted with C3-6cycloalkyl; and each of Rd, Re, independently represents H, C2-10alkenyl; C2-10alkinyl; or C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkyloxy, hydroxy, CN, 5-6-membered monocyclic heterocycloalkyl, which has 1 or 2 N atoms, optionally substituted with C1-10alkyl, halogen or 5-6-membered heterocycloalkyl, which has 1 N atom, phenyl, optionally substituted with halogen, cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms, 5-6-membered monocyclic heteroaryl, which has one or 2 N atoms; or Rd and Re, together with nitrogen atom, with which they are bound, form 5-6-membered saturated heterocycloalkyl, which has 1-2 heteroatoms, selected from N and O, optionally substituted with substituent, selected from group, including C1-10alkyl (which is optionally substituted with C3-6cicloalkyl, C1-10alkoxy, halogen), 5-membered heterocycloalkyl, which has one N atom, halogen, C1-10alkansulfonyl, C1-10alkylcarbonyl, optionally substituted with halogen, or Rd and Re, together with nitrogen, with which they are bound, form 7-10-membered, saturated, bicyclic heterocycloalkyl, containing 1-2 heteroatoms, selected from N and O, optionally substituted with C1-10alkyl; and the other of R3 and R4 represents H, halogen or C1-10alkoxy; X represents NRf, where Rf represents phenyl, substituted with C2-4 alkinyl; and Z represents N. Invention also relates to particular quinazoline derivatives, based on it pharmaceutical composition, and to method of cancer treatment.

EFFECT: novel quinazoline derivatives, inhibiting EGFR activity are obtained.

11 cl, 171 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to biologically active substances which are (Z)-2-[(3-carbamoyl-4,5,6,7-tetrahydrobenzo [b]thien-2-yl)amino]-4-(4-R-phenyl)-4-oxobut-2-enoic acids of general formula (1-3) . The acids (1-3) are obtained by reacting 4-(4-R-phenyl)-2,4-dioxobutanoic acid with an amide of 2-amino-4,5,6,7-tetrahydro[b]thiophene-3-carboxylic acid in a medium of ethyl alcohol at 60°C, followed by extraction of the end product using existing methods.

EFFECT: obtaining novel compounds with high output, having marked analgesic activity and low toxicity.

1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and describes a combination of tetrahydrocannabinol (THC) and cannabidiole (CBD) cannabinoids in ratio 1:5 for preparing a drug applicable in treating glioma, wherein the cannabinoid concentration falls within the range of 5 to 100 mg of the total cannabinoid concentration, wherein treating glioma involves reducing the cell survival rate, suppressing the cell growth and reducing the tumour volume.

EFFECT: invention provides increasing the efficacy of cannabinoids in a combination of THC and CBD in treating glioma.

5 cl, 5 ex, 2 tbl, 6 dwg

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