Lambertianic acid amides, possessing analgesic activity and stimulating action

FIELD: chemistry.

SUBSTANCE: invention relates to lambertianic acid amides of formula (Ia, b), which have expressed analgesic activity and stimulating action, manifested in increase of motor and investigation activity of animals, absence of anxiety, etc. In formula I ; (Ib).

EFFECT: improvement of compound properties.

6 tbl, 7 ex

 

sabreena relates to organic chemistry, specifically to new Amida lambertianic acid, of formula (Ia, b)

where;

possessing analgesic activity and stimulating effect.

These properties suggest the possibility of using the compounds in medicine as a pharmaceutical drug.

In recent years, with the creation of painkillers attention is paid to the search of the Central analgesics not peptide structure. These compounds interact with different types of opioid receptors in the Central nervous system, causing changes of the pain signal. Itself the pain signal when it persists and continues to be transmitted through the local pain receptors in the CNS, but the patient's feeling of alienation from the pain. Opioid agonists are used in the clinic to reduce pain reaction, cancer, chronic pain, and colds [J. V. Aldrich, Vigil-Cruz S. C., in Burger''s Medicinal Chemistry and Drug Discovery. 6-th ed.; Abraham D. A., Ed., John Wiley: New York, 2003. Vol.6. P. 329-415]. Preclinical studies have established that opioid agonists can find application in the treatment of CNS stimulants [Prisinzano I.e., Tidgewell, K., Harding W. W. AAPS J. 2005, V. 7. E592]. Opioid agonists have diverse chemical structure and their analg the optical potential depends on various factors, including affinity to a specific receptor sites.

Selective agonists of the Kappa-opioid receptors found in several plant diterpenoids. This salvinorin A and B (IIa, b) - metabolites psychoactive plant Salvia divinorum [Ortega A., Blount, J. F., P. S. Manchand, J. Chem. Soc., Perkin Trans. 1. 1982. P. 2505-2515]. Salvinorin A (IIa) is analogous to the properties of synthesized derivatives of labdanoids (Ia, b). The compound (IIa) implements analgesic effect in mice, which is blocked by antagonists of the Kappa-opioid receptor [John T. F., French L. G., J. S. Erlichman Eur. J. Pharmacol; 2006, 545, p.129]. Animal studies revealed that the compound (IIa) is an agonist of the Kappa-opioid receptor in vivo [W. A. Carlezon Jr., Beguin S., Dinieri J. A., Baumann, M. H., Richards, M. R., Todtenkopf, M. S., Rothman R. B., Ma, Z., Lee D. Y., Cohen B. M. J. Pharmacol. Exp. Ther. 2006. V. 316. P. 440-448]. The compound (IIa) has other effects characteristic of Kappa-opioidnykh agonists, in particular, stimulates locomotor activity of animals [Zhang y, Butelman, E. R., Schlussman S. D., But A., Kreek M. J. Psychopharmacology (Berlin). 2005. V. 179. P. 551-560]. Synthesized a large number of derivatives of salvinorin (IIa), modified according to the provisions of the C(2), C(4) C(17) and furan fragment. Found that the introduction of the amide function in the position C(2) leads to an increase in analgesic activity and selectivity of binding to Kappa-opioid receptors [Prisinzano I.e., Rothman R. B. Chem. Rev. 2008. V. 108. P. 1732-1743].

Promising analge what IKI is labdane - marrubiin (IIIa) and marrubiin acid (IIIB), isolated from plants of the genus Shandra Marrubiin vulgare used in folk medicine Lebanon and China as a means to relieve pain and spasm of smooth muscles. Compounds (IIIa, b) possess significant analgesic activity in the test acetic cramps in vivo [S. E. Bardai, N. Morel, M. Wibo, N. Fabre, G. Llabres, B. Lyoussi, J. Quetin-Leclercq. Phytomedicine. 2000. V. 7. No 1. P. 111-115].

Listed plants - Salvia divinorum and Marrubiin vulgare on the territory of the Russian Federation does not grow, respectively, compounds (IIa, b, IIIa, b) are inaccessible metabolites, however, due to the selectivity of pharmacological effect (analgesic activity) receiving their structural analogues is of considerable interest to create a pharmacologically valuable agents.

Available plant metabolite is forentering lambertianic acid (IV). The compound (IV) is easily distinguished from pine needles, resin and shoots drinkwine Siberian pine, Pinus sibirica R. Mayr. [Tolstikova, So, Sorokina, I. C., Long, M. P.; Kharitonov, S. C., A. C. C., Schulz, E. E., Tolstikov, A. Chemical and pharmaceutical journal. 2004. So 38. No. 10. S. 13-15; RF Patent №2436781. Popov, S. A., Kozlov, L. P., Feldspar, A. C., Schulz, E. E., Tolstikov, A.]. Known neurotropic activity [Tolstikova T., Long, M. P., Tolstikov, A. reports of the Academy of Sciences, 2000. So 374 S. 268-270; Tolstikova, So, Commander T. C., Long, M. P., Forty is on I. C. The experimental. the clinically. Pharmacol. 2002. So 65. S. 86-88], antiplasmodial action [Chinou I. Current Med. Chem. 2005. So 12. 1295-1297)], and anti-allergic activity of lambrianou acid (IV) [Chae H.-S., Chin Y.-W. Immunopharmacol. & Immunotoxicol. 2012. V. 34. No 2. P. 250-255]. It is established that the compound (IV) inhibits the production of interleukin-6 (IL-6), prostaglandin D2(PGD2), leukotriene C4(LTC4), the expression of COX-2 and degranulation of β-hexosaminidase in PMA.

Identified analgesic activity of some forinteraction Larionova series and their derivatives. Derived lambertianic acid - flaminica acid (V) possesses analgesic activity test acetic cramps" (chemical irritation of the peritoneum) [Morozov, E. A., Tolstikova T. G., Schulz, E. E., Chernov, S. C., Y. Kharitonov Century, Mironov, M. E., Tolstikov, A. Chemistry in sustainable development. 2010. So 18. No. 4. S. 489-494].

Compounds (IIIa, b, V) are similar in structure and properties of the claimed compounds.

The objective of the invention is the creation of new agents with analgesic activity and has a stimulating effect on the behavior of animals.

The problem is solved with new chemical compounds - inorganic salts lambertianic acid, of formula (Ia, b), oblad the who analgesic activity and stimulating effect in tests of locomotor and exploratory activity of animals.

where;

The method of obtaining the compounds (Ia, b) lambertianic acid (IV) is implemented according to the scheme 1. Processing solution lambertianic acid (IV) in chloroform by the action of chloride of tonila in the presence of pyridine (0-5°C) gives the acid chloride lambertianic acid, the reaction of which (without allocation) with the aqueous ammonia is formed corresponding amide lambertianic acid (Ia) (yield 91%). When vzaimodeistvie lambertianic acid (IV) with N-methylpiperazine in chloroform in the presence of chloride tiomila formed piperazinone lambertianic acid (IB) (yield 88%).

The technical result of the invention is to provide new derivatives of labdanoids (Ia, b), with analgesic activity and stimulating effect on the behavior of animals. The new compounds are obtained by chemical modification of available plant metabolite Pinus sibirica R. Mayr. - lambertianic acid (IV), which easily stands out from the timber product - resin or needles by drinkwine Siberian pine, Pinus sibirica (Siberian cedar) [Patent No. 2436781 of the Russian Federation. Priority from 10.06.2010, application No. 2010123753/04(033823). The method of obtaining lambertianic acid of the extractives of the wood green Siberian cedar. Popov, S. A., Kozlov, L. P., Feldspar, A. C., Schulz E. The., Tolstikov, A. the Decision to grant a patent of the Russian Federation from June 09, 2011; T. G. Tolstikova, I. C. Sorokina, M. P. Long., Y. C. Kharitonov, S. C. Chernov, E. E. Schultz, G. A. Tolstikov. Neurotropic activity of adducts lambertianic acid with N-substituted maleinimide. Chemical and pharmaceutical journal. 2004. So 38 (10). S. 13-15], which is the tonnage of the waste area. Physico-chemical constants of new, first obtained the compounds described in examples 1, 2.

Biological activity of compounds (Ia, b) was studied by determination of acute toxicity, analgesic activity, influence on the behavioral reactions of animals and widespread effects of chloral hydrate.

Acute toxicity (LD50) was determined after a single intragastric administration to mice. The toxicity parameters were determined by the method of Cerberus [Sanotski I. C. Methods for determining the toxicity and hazards of chemicals. M.: Medicine, 1970, 342 S.]. The data obtained (table 1) allow us to classify the compounds to the 3rd class is moderately toxic substances. The lowest toxicity has amide lambertianic acid (Ia). Its toxicity is more than 2 times lower than the comparison drug floridatoday acid (V). The toxicity of piperidylamine (IB) is comparable to the toxicity floridatoday acid (V).

Table 1.
Acute toxicity amides lambertianic acid and agent comparison
ConnectionIaIBV
LD50(mg/kg)>1500750633

It is known that the original connection lambertianic acid (IV) does not possess analgesic activity neither in the test for visceral pain ("acetic cramps"), nor in the test for thermal pain (hot plate") [Morozov, E. A., Tolstikova T. G., Schulz, E. E., Chernov, S. C., Y. Kharitonov Century, Mironov, M. E., Tolstikov, A. Chemistry in sustainable development. 2010. So 18. No. 4. S. 489-494]. For the analysis of the analgesic activity of synthetic derivatives lambertianic acid (Ia, b) used these tests chemical and thermal pain stimuli according to the recommendations [Manual on experimental (preclinical) study of new pharmacological substances. Edited Khabriev R. U. Moscow: Medicine. 2005. 832 C.]. "Acetic cramps reproduced by intraperitoneal administration animal 0.75% aqueous solution of acetic acid. Analgesic activity is represented as the average number of writhing in the group is for 3 min, as well as the percentage of inhibition of pain response (ABW). Thermal pain stimulation caused by placing the animal on a heated metal plate. Activity was assessed by the time spent by the animals on a hot plate.

The results of the study analgesic activity from both tests are shown in table 2. As you can see, the agent (Ia) exhibits a pronounced analgesic activity in the test "acetic cramps". This connection proved to be more effective inhibitor of painful reaction than used in medicine analgesic dipyrone and similar in structure flaminica acid (V). The compound (IB) has weak analgesic activity test acetic cramps".

Introduction animal agent (Ia), as well as the comparison drug dipyrone, does not affect the time spent by the animals on a hot plate. With the introduction of piperidylamine lambertianic acid (IB) increases significantly the time spent by the animals on a hot plate (in two times in comparison with control). Similar in structure flaminica acid (V) also does not possess analgesic activity test "hot plate".

Thus, the amide lambertianic acid (Ia) has a selective analgesic activity test acetic cramps, and N-metopimazine lambertianic acid (IB) has selection the th analgesic activity test "hot plate".

Table 2.
The impact of derivatives of labdanoids on the painful reaction, caused by thermal and chemical irritation.
Model
Agent
"Acetic cramps""Hot plate"
Qty cramps% ABWLatency time painful reaction
Control8.6±1.1-20.6±2.2
(Ia)4.2±0.7∗51.524.8±3.4
(IB)7.1±0.6∗17.640.0±2.9∗∗∗
(V)5.5±0.7∗35.925.5±2.5
Analgin5.7±0.4∗33.620.2±2.3
∗ p<0,05; ∗∗∗ p<0,001 compared to the control

Stimulating intercourse is the want to make agents (Ia, b) was established by studies of animal behavior in open-field test [Manual on experimental (preclinical) study of new pharmacological substances. Edited Khabriev R. U. Moscow: Medicine. 2005. 832 C.]. Registration of parameters of vertical and horizontal activity produced automatically set to "TRUSCAN" (COULBOURN INSTRUMENTS, USA). Locomotor activity was assessed by the parameter "distance" and "speed". Research activity - parameters "number of vertical racks, vertical racks" "number of zaglyadyvanie" and "time of zaglyadyvanie in the hole". The results are shown in table 3.

From table 3 it follows that the claimed compounds (Ia, b) have a significant impact on the behavior of animals in open-field test. At the dose of 5.0 mg/kg of these compounds showed a pronounced stimulating effect, increasing locomotor and exploratory activity of animals. While both agents significantly increased the speed of movement of animals and they traveled distance (locomotor activity), as well as the time spent by animals in the vertical posts and the number of vertical columns (in the last twice compared with the control group and the comparison drug) (research activity). In addition, the agent (IB) that is also significantly increased and the number of hops (in two times in comparison with control).

Table 3.
The influence of amides lambertianic acid (Ia, b) animal behavior in open-field test (dose 5.0 mg/kg)
Agents
Options
Control(Ia)(IB)(V)
Distance (cm)267.99±18.42328.31±21,63∗338.69±16.97∗270.50±8.48
Speed (cm/s)2.19±0.152.70±0.18∗2.80±0.14∗2.28±0.12
Qty VERTIC. racks7.00±1.8912.00±2.06∗12.88±1.68∗9.62±1.02
Time VERTIC. racks (C)10.13±3.0218.50±3.11(∗)22.00±2.73∗11.46±2.04
Qty Zagladin.4.13±1.096.00±0.983.63±096 5.66±0.96
Time Zagladin. (C)5.5±1.627.38±1.314.88±1.277.13±1.20
Number of jumps0.63±0.370.75±0.611.37±0.50(∗)1.07±0.58(∗)
The research. activity.11.13±2.6318.00±1.85(∗)19.52±1.65∗15.28±1.32(∗)
(∗) p<0,1; ∗ p<0,05 relative to the control

It is established that the influence of agents (Ia, b) animal behavior is dose-dependent nature. Table 4 shows data on locomotor activity of animals in open-field test at doses of 2.5 mg/kg and 10.0 mg/kg As can be seen, with the introduction of compounds (Ia, b) at a dose of 2.5 mg/kg behavioral responses of animals on the parameters of locomotor and exploratory activity remains insignificantly different from the control. With the introduction of agents at a dose of 10.0 mg/kg stimulating effect on the parameters of motor activity ("the distance" and "speed") is more pronounced than in the dose of 5.0 mg/kg (locomotor activity in trustet 1.2-1.3 times). Exploratory activity of animals treated with compounds (Ia, b), in the parameters "number of vertical racks" and "time in a vertical posts", and "number of hops" in the 1.7-2.0 times higher than the activity of animals in the control group, both at a dose of 5.0 and at a dose of 10.0 mg/kg of Total exploratory activity of animals with the introduction of compounds (Ia, b) at a dose of 10.0 mg/kg significantly increased twice compared to control.

Table 4.
The influence of agents (Ia, b) animal behavior in open-field test (dose 2.5 and 10.0 mg/kg)
Agents
Options
Control(Ia), dose(IB) dose
2.5 mg/kg10.0 mg/kg2.5 mg/kg10.0 mg/kg
Distance (cm)289.13±14.59264.60±19.33379.30±23.10∗∗280.96±to 20.88358.30±15.10∗
Speed (cm/s)2.38±0.12 2.20±0.163.10±0.19∗2.34±0.172.99±0.15∗
Qty VERTIC. racks7.43±0.986.38±1.4414.30±0.70∗8.25±2.0213.40±0.50 ∗
Time VERTIC. racks (C)10.93±1.489.50±2.1021.10±2.80∗∗13.13±3.4818.10±2.80∗
Number of zaglyadyvanie3.31±0.494.50±1.056.10±0.404.63±1.027.10±0.70
Time peeking (C)3.71±0.525.75±1.01(∗)5.80±0.605.00±1.15(∗)5.50±0.90
Number of jumps0.7±0.220.78±0.811.26±0.40(∗)0.86±0.40(∗)1.55±0.50(∗)
The research. activity10.75±1.1710.87±1.48 21.38±1.86∗∗12.87±2.1820.50±1.45(∗)
(∗) p<0,1; ∗ p<0,05; ∗∗ p<0,01 relative to the control

Table 5 shows data on anti-anxiety activity of animals in the test of "dark and light" camera. This test allows you to assess the state of anxiety in animals, since animals with a high level of anxiety prefer to be in a dark cell, while a low level of anxiety allows the animals to spend more time in the light compartment of the camera [Bourin M., Hascoët M. European Journal of Pharmacology. 2003. V. 463. No 1. P. 55-65]. As the comparison drug was used diazepam at a dose of 2.5 mg/kg, the introduction of which resulted in a significant increase in both indicators. From the data obtained it follows that the agents (Ia, b) not have a significant impact on the behavior of animals in the test of "dark and light" camera. The claimed compounds, in contrast to diazepam, affects neither the latency time of the first entry of the animal in a dark chamber, nor the time spent in dark chamber. According to the results of the test, we can conclude that the amides lambertianic acid (Ia, b) there is no increased level of anxiety and, therefore, identified the ability to increase exploratory activity of animals in the test "the open field", probably related to their ability to have a General stimulating effect.

Table 5.
The influence of amides lambertianic acid (Ia, b) on the behavior of animals in the test of "dark and light camera
Parameters
Agents
The latent time of entry into the dark compartment cameraThe time spent in dark chamber, with
Control58.28±9.1893.21±6.64
(Ia)48.72±6.12(∗)85.50±7.35(∗)
(IB)51.00±9.72(∗)90.50±4.08(∗)
Diazepam132.00±22.70∗159.87±11.48∗∗∗
(∗) p<0.5; ∗ p<0.05; ∗∗∗ p<0.001 compared to the control

It is known that the stimulating action of the agents is implemented through various neurotransmitter systems [Wezenberg e, Sabbe B. G., Hulstijn W., Ruigt, G. S., & Verkes, R. J. Journal of psychopharmacology (Oxford, England). 2007. V. 21. P. 579-587]. To study the effect of compounds on glutamate and GABA-ervices the second system uses a test chloralhydrate dream" [Guidance on experimental (preclinical) study of new pharmacological substances. Edited Khabriev R. U. Moscow: Medicine. 2005. 832 S.].

The interaction of agents (Ia, b) with hypnotic drugs studied for the effect on the hypnotic effect of chloral hydrate. Chloral hydrate in the amount of 350 mg/kg was administered intraperitoneally 1 h after injection of the agent. Estimated latent sleep time and sleep duration animals. The results are shown in table 6.

Table 6.
The effect of agents on the duration chloralhydrate sleep.
Parameters
Agents
Latency time falling asleep,The sleep duration, min
Control240.62±13.5786.77±8.74
(Ia)266.25±17.84(∗)105.76±10.38∗∗
(IB)233.12±19.9391.37±12.78(∗)
Diazepam192.50±18.02∗∗207.79±6.19∗∗∗
(∗) p<0,1; ∗∗ p<0,01; ∗∗∗ p<0,001 compared to the control

The study showed that Agay is you (Ia, b) in the dose of 5 mg/kg not change the latency time falling asleep animals, while diazepam significantly reduces it. Agents (Ia, b) is almost insensitive to the duration chloralhydrate sleep. Diazepam significantly increases the duration chloralhydrate sleep (≈ 2 times).

Thus, based on the study of behavioural responses of animals in tests open field, "dark and light" camera, as well as the effect on the hypnotic effect of chloral hydrate, found that amides lambertianic acid (Ia, b) have shared a strong stimulating effect.

The invention is illustrated by the following examples.

Example 1. Obtain (1S,4aR,5S,8aR)-5-[2-(furan-3-yl)ethyl]-1,4 a-dimethyl-6-methylentetrahydrofolate-1-carboxamide (amide lambertianic acid) (Ia).

To a solution of 3.1 g (10 mmol) lambertianic acid (IV) and 1 ml of pyridine in 20 ml of chloroform under good stirring and cooling to 0-5°C is added dropwise 0.8 ml chloride tiomila. The mixture is stirred for 1 h at +5°C and added with stirring to 10 ml conc. ammonia solution, cooled to +5°C. the Reaction mass is stirred for 1 h, then add 20 ml of chloroform, the organic layer was separated, washed with water, dried with magnesium sulfate. The solvent is evaporated in vacuo, the residue chromatographic on a column of silica gel (eluent-ethyl acetate). Allocate 2.8 g(91%) of compound (Ia) in the form of oil, [α]D20+102.5°(c 0.64, CHCl3). IR spectrum, ν, cm-1: 3410, 3360, 3141, 2952, 1690, 1680, 1660, 1612, 1515, 1500, 1480, 1440, 1380, 1360, 1235, 1220, 1190, 1160, 1145, 1090, 1045, 972, 890, 820, 795, 750. An NMR spectrum1H CDCl3, δ, M. D. (J, Hz): 0.64 (3H, C20H3), 1.01 D. D. D. (1H, H3, J13.5, 4.6, 1.8). 1.12 D. D. D. (1H, H1, J 13.8, 4.5, 2.2), 1.18 (3H, C19H3), 1.28 D. D. (1H, H5, J 12.6, 2.0), 1.51-1.62 (m, 3H, H2, 9, 11), 1.71 m (1H, H6), 1.79-1.91 (m 4H, H1,2,6,7), 2.19-2.25 m (2H, H3, 6), 2.23 m (1H, H12), 2.42 m (1H, H7), 2.53 m (1H, H12), 4.56 (1H, H17), 4.87 (1H, H17), 5.53 ush.s (1H, NH, Jpolyserena4.1), 5.88 ush.s (1H, NH, Jpolyserena4.1), 6.23 D. D. (1H, H14, J 2.5 and 1.8), 7.16 (1H, H15, J 1.8), 7.31 (1H, H16, J 2.5). An NMR spectrum13C, δ, M. D.: 12.75 (C20), 20.03 (C2), at 23.43 (C12), 24.13 (C11), 26.56 (C6), 30.01 (C19), 38.44 (C3), 38.71 (C7), at 39.23 (C1), 40.22 (C10), 44.01 (C4), at 55.10 (C9), 56.29 (C5), 106.58 (C17), 110.81 (C14), 125.28 (C13), 138.57 (C15), 142.52 (C16), 147.47 (C8), 179.71 (C18). Mass spectrum, m/z. (IRel., %): 398 (0.6), 358 (0.3), 339 (0.9), 283 (0.6), 265 (0.8), 249 (7), 189 (26), 150 (100), 133 (13), 108 (30), 83 (24), 59 (24). Found: m/z 315.2444 [M]+. C20H29NO2. Calculated: M 315.2452.

Example 2. Obtaining {(1S,4aR,5S,8aR)-5-[2-(furan-3-yl)ethyl]-1,4 a-dimethyl-6-methyland Kugitangtau-1-yl}(4-methylpiperazin-1-yl)methanone [(4-methylpiperazine)amide lambertianic acid] (IB). To a solution of 3.1 g (10 mmol) lambertianic acid (IV) and 1 ml of pyridine in 20 ml of chloroform under good stirring and cooling to 0-5°C is added dropwise 0.8 ml chloride tiomila. The mixture is stirred for 1 h at +5°C, then added dropwise 3.0 ml of N-methylpiperazine. The reaction mass is stirred for 1 h, then add 20 ml of chloroform, the organic layer was separated, washed with water, dried with magnesium sulfate. The solvent is evaporated in vacuo, the residue chromatographic on a column of silica gel (eluent - petroleum ether - ethyl acetate). The fraction containing the product precipitated as oxalate from the solution in a solution of petroleum ether - ethyl acetate, 2:1 when adding a saturated solution of oxalic acid in ethyl acetate. Allocate 3.0 g (88%) of compound (IB). MP. 162-164°C.[α]D20+54.18(0.27, CHCl3). The infrared spectrum, cm-1: 3420, 2957, 2928, 2874, 1690, 1660, 1625, 1590, 1570, 1500, 1460, 1375, 1330, 1254, 1240, 1210,1170, 1150, 1140, 1090, 960, 945, 890, 870, 750, 680. An NMR spectrum1H CDCl3+CD3OD, δ, M. D. (J, Hz): 0.68 (3H, C20H3), 0.96 D. D. D. (1H, H3, J 13.6, 4.6, 1.8), 1.18 D. D. D. (1H, H1, J 13.8, 4.8, 2.0), 1.22 D. D. (1H, H5, J 12.8, 2.0), 1.29 (3H, C19H3). 1.53-1.72 m (4H, H2, 6, 9, 11), 1.78-1.98 m (4H, H1, 2, 6, 7), 2.12-2.32 (m, 3H, H3, 6, 12), 2.40-2.68 m (10H, 2H-H7, 12and 8H, H 2', 3', 5', 6'), 2.89 (3H, NCH3when C4'), 4.61 (1H, H17), 4.91 (1H, H17). 6.31 D. D. (1H, H14, J 2.6 and 1.8), 7.20 (1H, H15, J 2.6), 7.41 (1H, H16, J 1.8). An NMR spectrum13C, δ, M. D.: 15.40 (C20), 20.69 (C2), 23.46 (C12), at 24.23 (C11), 26.01 (C6), 27.31 (C19), 38.89 (C3), 39.08 (C7), 39.25 (C1), 40.74 (C10), 42.38 (NCH3when C4'), 42.89 (C4), 46.05 (C3', 5'), 52.76 (C2', 6'), 55.16 (C9), 58.07 (C5), 106.28 (C17), 111.39 (C14), 125.38 (C13), 139.05 (C15), 143.21 (C16), 148.27 (C8), 175.68 (C18). Mass spectrum, m/z (IRel., %): 516.3 (14.58), 57.0 (100), 42.9 (80.84), 55.0 (70.68), 71.0 (66.62). Found: m/z 399.2505 [M]+. C25H38N2O2. Calculated: M 399.2506.

Example 3. Study of analgesic activity of the compounds (Ia, b) in the test "acetic cramps". The experiment is carried out on outbred mice-males weighing 22-25, Experimental form a group of 8 animals each. "MC" reproduce by intraperitoneal injection of 0.75% acetic acid at 0.1 ml per animal. Investigational agents (Ia, b, V) and drug compare aspirin at a dose of 10 mg/kg administered intragastrically once per hour to play model. Control animals are, which entered acetic acid. Assessment activity is carried out in 5 min after injection of acetic acid. R is histeroidea number cramps for 3 minutes Analgesic activity is represented as the average number of writhing in the group, as well as the percentage of inhibition of pain response (UBR), which is calculated by the formula

%ABW=100%∗(Tcontrol-Texperience)/Tcontrolwhere T is the average number of writhing in the group.

The results are presented in table 2. It is established that the compound (Ia) exerts its analgesic effect on the model "MC", significantly reducing the number of writhing in 2 times in comparison with control. The effect of the agent (Ia) is 18% larger than the effect of analgesic dipyrone and 15% activity floridatoday acid (V). Thus, the amide lambertianic acid (Ia) significantly blocks the development of painful effect caused by the introduction of acetic acid shows high and selective analgesic activity in the test "acetic cramps". Amide (IB) has weak analgesic activity in the test for visceral pain ("UK").

Example 4. Study of analgesic activity on the model of thermal pain stimulation. The experiment was carried out on outbred mice-males weighing 22-25, Experimental groups were formed in 8 animals each. Investigational agents is administered in a dose of 5 mg/kg intragastrically once for 1 h to play model. To play model "hot plate" animals are placed on a metal square is the Steen, heated to 54±0,5°, limited by a cylinder of org. glass (15×15 cm). Register latency time of painful reaction, i.e. the time before jumping or licking his hind legs. Analgesic activity is represented as the average latency time of painful reaction. The results are presented in table 2. The compound (Ia) has weak analgesic activity test "hot plate". The compound (IB) shows a pronounced analgesic effect on the model of thermal pain, significantly increasing the time spent on the hot plastic to 40 s, which is twice the analgesic effect of dipyrone and agent comparison floridatoday acid (V). Thus, N-methylpiperidine lambertianic acid (16) blocks the development of painful effect and shows high selective analgesic activity in the test of thermal pain stimulation.

Example 5. The study of the influence of agents on locomotor and emotional activity of animals in open-field test. Studies carried out on outbred mice weighing 20-25, Registration of motor acts performed automatically set to "TRUSCAN" (COULBOURN INSTRUMENTS, USA). Compounds (Ia, b, V) is mixed with tween-80, dissolved in water and injected once intragastrically at a dose of 2.5, 5.0 and 10.0 mg/kg (0.1, 0.2 or 0.4 ml / 10 g weight of the animal). Animal control is the group receives an equivalent volume of solvent. Testing of motor activity performed within 1 hour after administration of the agents. Animals are placed in the center of the installation and TruScan for 2 min for each animal record the performance of vertical and horizontal activity. The results of the study are shown in tables 3 and 4.

Introduction compounds (Ia, b) at doses of 5.0 and 10.0 mg/kg leads to a significant increase stimulating agents on locomotor activity parameters "distance" and "speed". At the dose of 5 and 10 mg/kg distance traversed animals are 328 and 379 cm (Ia) and 338 and 358 cm (IB), 1.2-1.3 times longer than the distance traveled by the animals of the control group. Increases the movement speed [from 2.2-2.4 cm/s (rear group) to 2.7-2.8 (dose 5.0) and 3.1-3.0 cm/s (dose 10 mg/kg)].

Introduction compounds (Ia, b) at doses of 5.0 and 10.0 mg/kg leads to a significant increase stimulating agents on exploratory activity of animals. According to the parameters "number of vertical racks" [12.0 (Ia), 12.9 (IB) - 5.0 mg/kg and 14.3 (Ia), 13.4 (IB) - 10.0 mg/kg], "time in vertical racks" [18.5 (Ia), 22.0 (for IB) - 5.0 mg/kg and 21.1 (Ia), with 18.1 (IB) - 10.0 mg/kg], and the "number of hops" [0.8 (Ia), 1.4 (IB) - 5.0 mg/kg and 1.3 (Ia), 1.6 (IB) - 10.0 mg/kg], the locomotor activity of animals increases of 1.7-2.0 times in comparison with the control the group. General exploratory activity of animals with the introduction of compounds (Ia, b) reliably increased in two times: from 11 to 18 (5.0 mg/kg) and 21 (10.0 mg/kg) or from 11 to 20 (5.0 mg/kg) and 21 (10.0 mg/kg).

Example 6. The study of the influence of agents on locomotor and emotional activity of animals in the test of "dark and light" camera. Animals are placed in a chamber consisting of two compartments - dark and light, the passage between them is always open. The mouse was placed in the bright compartment, tail to the entrance to the dark part of the camera and record the latency time of entry into the dark compartment, and also the total time finding an animal in the dark and light compartments. Introduction compounds at a dose of 5 mg/kg has no effect on the latency time of the first entry of the animal into the dark compartment of the chamber [48 with agent (Ia) and 51 for (IB)] neither the time he was in a dark cell [86 with agent (Ia) and 90 s - (IB)], in contrast to the comparison drug diazepam, which significantly increases as time passes in the dark compartment of the chamber (132) and the time spent in dark chamber (160).

Example 7. The influence of agents on the hypnotic effect of chloral hydrate study in the test "chloralhydrate dream." Chloral hydrate administered to the animals intraperitoneally in a dose of 350 mg/kg over 1 h after injection of the agent. Assess the duration of sleep of animals, as well as the latent time of loss of reflex-turn. As you can see from the data is the GLA.6, latency time falling asleep animals under the action of agents (Ia, b) is greater than the effect of the drug comparison diazepam (266 and 233, for diazepam 192). The introduction of agents (Ia, b) significantly reduces sleep time (106 and 91 min for diazepam - 208 min.)

Statistical analysis all experiments were performed using Statistica 8.0, the confidence level was determined by t-criterion of student.

Thus, the claimed invention has the following advantages, namely:

- new amides lambertianic acid of formula (Ia, b) are of low toxicity, significant selective analgesic activity in tests of chemical (compound Ia) or thermal (compound IB) pain stimulation. The inventive agents have expressed a General stimulating effect, manifested in the increase of locomotor and exploratory activity of animals in the open field test, in the absence of anxiety in the test of "dark and light" camera, and no effect on the latency time of the sleep of animals and duration of sleep with the introduction of chloral hydrate,

- the claimed compounds (Ia, b) are synthesized from available plant materials - pine needles or resin Siberian pine (Pinus sibirica.

Amides lambertianic acid, of formula (Ia, b)
,
g is e ;
possessing analgesic activity and stimulating effect.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for preparing a compound of general formula VIII of enantiomeric purity min. 80% by a reaction of the compound according to general formula IV with enantiomeric pure 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid to produce a compound of general formula II to be reduced to prepare a compound for general formula I to be oxidated to form an aldehyde which then reacts with an aromatic amine of formula H2N-Ar to produce a respective imine which is then reduced to prepare a compound described by formula VIII in the enantiomeric pure form. Also, it refers to methods for preparing the compound of formula I, as well as to the compounds of formula I. In general formulas

, ,

, , X1, X2, X3 is specified in fluorine, chlorine, bromine, hydroxy, methoxy, ethoxy, trifluoromethyl, amino whereas the other groups X1, X2, X3 represent a hydrogen atom.

EFFECT: preparing the non-steroid anti-inflammatory drugs.

12 cl, 5 ex

FIELD: medicine.

SUBSTANCE: invention is related to new heterocyclic compounds of common formula (I), and also their pharmaceutically acceptable salts, hydrates and/or solvates, possessing properties of human neutrophil elastase. In common formula (I) , A means phenyl or pyridyl cycle, R1 and R3 each means atom of hydrogen, R2 means atom of fluorine, chlorine, bromine, nitro group or cyano group, R4 means cyano group, alkyl carbonyl group with number of carbon atoms in alkyl residue from one to four, or alkoxycarbonyl group with number of carbon atoms in alkoxyl residue from one to four, besides alkoxycarbonyk group with number of carbon items in alkoxyl residue from one to four, may be substituted with substituent, which is selected from the group that includes hydroxyl group, alkoxygroup with number of carbon atoms from one to four, alkoxycarbonyl group with number of carbon atoms in alkoxyl residue from one to four, mono- or dialkylaminogroup, with number of carbon atoms in each of alkyl residues from one to four, 5-6-member heteroaryl group, which contains from 1 to 4 heteroatoms in heteroaryl ring, selected from nitrogen, oxygen or sulfur, possibly susbstituted with alkyl group, which contains from 1 to 4 atoms of carbon and possibly condensed with benzene ring, and 5-8 member heterocyclyl group, which contains from 1 to 3 heteroatoms from group of nitrogen, oxygen or sulfur, or SO, SO2 possibly substituted with ketogroup, R5 means methyl group, R6 means atom of hydrogen, alkyl group with number of carbon atoms from one to four, mono- or dialkylaminocarbonyl group with number of carbon atoms in each of alkyl residues from one to four, etc., Y1, Y2, Y3, Y4 and Y5 each means CH-group. Invention is also related to pharmaceutical composition.

EFFECT: possibility of application for treatment of chronic obstructive lung diseases, acute coronary syndrome, acute myocardial infarction and progressing cardiac decompensation.

8 cl, 1 dwg, 111 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound represented by the structural formula: or its pharmaceutically acceptable salt wherein Z represents -(CH2)n-; double dotted line represents a double bond; n = 0-2; R1 and R2 are chosen independently from the group comprising hydrogen atom (H), alkyl with 1-6 carbon atoms; R3 means H, hydroxy-, alkoxy-group with 1-6 carbon atoms, -C(O)OR17 or alkyl with 1-6 carbon atoms; Het means monocyclic heteroaromatic group consisting of 6 atoms and comprising 5 carbon atoms and one heteroatom chosen from nitrogen atom (N) and wherein Het is bound through ring carbon atom and wherein Het-group has one substitute W chosen independently from the group comprising bromine atom (Br), heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N; heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N substituted with OH-substituted alkyl with 1-6 carbon atoms or =O; R21 -aryl-NH-; -C(=NOR17)R18; R21-aryl; R41-heteroaryl representing group consisting of 5-6 atoms comprising 3-5 carbon atoms and 1-4 heteroatoms chosen independently from the group: N, S and O; R8 and R10 are chosen independently from group comprising R1; R9 means H; R11 is chosen from group comprising R1 and -CH2OBn wherein Bn means benzyl; B means -(CH2)n4CR12=CR12a(CH2)n5; n4 and n5 mean independently 0; R12 and R12a are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; X means -O-; Y means =O; R15 is absent as far as double dotted line mean a simple bond; R16 means lower alkyl with 1-6 carbon atoms; R17 and R18 are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; R21 means 1-3 substituted chosen independently from group comprising hydrogen atom, -CN, -CF3, halogen atom, alkyl with 1-6 carbon atoms and so on; R22 is chosen independently from group comprising hydrogen atom; R24-alkyl with 1-10 carbon atoms; R25-aryl and so on; R23 is chosen independently from group comprising hydrogen atom, R24-alkyl with 1-10 carbon atoms, R25-aryl and -CH2OBn; R24 means 1-3 substitutes chosen independently from group comprising hydrogen atom, halogen atom, -OH, alkoxy-group with 1-6 carbon atoms; R25 means hydrogen atom; R41 means 1-4 substitutes chosen independently from group comprising hydrogen atom, alkyl with 1-6 carbon atoms and so on. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to receptors activated by protease and comprising the effective dose of derivative of nor-seco-chimbacine of the formula (I) and a pharmaceutically acceptable excipient. Also, invention relates to methods for inhibition of thrombin and cannabinoid receptors comprising administration in mammal derivative of nor-seco-chimbacine of the formula (I) in the effective dose as active substance. Invention provides derivatives of nor-seco-chimbacine as antagonists of thrombin receptors.

EFFECT: valuable medicinal and biological properties of compounds and pharmaceutical composition.

8 cl, 1 tbl, 18 ex

The invention relates to new cycloalkenes and cycloalkanes, suitable as pharmaceutically active substances, more particularly to derivatives of 1,3-substituted of cycloalkene and cycloalkane formula (I)

Z-CH2-Y (I)

where Z stands for a group

< / BR>
where

where R is aryl, 2-, 3 - or 4-pyridinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2-, 4 - or 5-pyrimidinyl, unsubstituted or substituted lower alkyl, lower alkoxide, hydroxyl or halogen, 2-pyrazinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2 - or 3-thienyl, unsubstituted go substituted lower alkyl or halogen, 2 - or 3-furanyl, unsubstituted or substituted lower alkyl or halogen, 2-, 4 - and 5-thiazolyl, unsubstituted or substituted lower alkyl or halogen, 3-indolyl, 2-, 3 - or 4-chinoline, and m is the number 1, 2, or 3, or group

< / BR>
in which R and m have the above meanings;

Y - group

< / BR>
where R is the specified value,

mixtures of their isomers or the individual is

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing bis(5-alkyl-2-furyl)(2-azidophenyl)methane derivatives of general formula I, which can be used as starting compounds in synthesis of indoles, promising biologically active substances. A mixture of readily available 2-azidobenzaldehydes and 2-alkylfurans is treated with acids in different solvents:

EFFECT: method enables to obtain a compound of formula I with high output.

2 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel compounds of formula (V), compounds of formula (IX), compounds of formula (XIII) or their tautomers or pharmaceutically acceptable salts, which are capable of inducing Hsp70, as well as to pharmaceutical composition, which contains claimed compounds.

Value of substituents in formulas (V), (IX) and (XIII) are such, as claimed in invention formula.

EFFECT: obtaining pharmaceutically acceptable salts, which have possibility of inducing Hsp70.

12 cl, 12 ex, 36 dwg, 2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to a compound which represents a biphenyl derivative of formula . What is also described is a pharmaceutical composition for treating or relieving HCV on the basis of said compound.

EFFECT: higher efficacy of the composition.

3 cl, 265 ex

FIELD: chemistry.

SUBSTANCE: method involves extraction of green Siberian cedar wood with a hydrocarbon solvent (petroleum ether), followed by treatment of the extract with aqueous solutions of a weak inorganic base and a strong organic base to obtain salts of weak carboxylic acids, acidification of the solution of salts of weak carboxylic acids with mineral acid and extraction of weak acids with petroleum ether, followed by cooling down the extract in order to separate coloured and polar impurities from the lambertian acid concentrate. The lambertian acid is purified through crystallisation of diethylammonium salt, followed by acidification.

EFFECT: obtaining a product of better quality.

1 cl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of C-cyclohexylmethylamine of the general formula (I): in their free form or physiologically compatible salts possessing analgesic effect. In the general formula (I) A means hydrogen atom (H) or unsubstituted phenyl; R1 means saturated or unsaturated, branched or linear mono- or multisubstituted or unsubstituted (C1-C10)-alkyl or (C3-C10)-cycloalkyl, phenyl, naphthyl, furyl, thiophenyl or naphthyl added through unsaturated (C2-C3)-alkyl either through (C1-C3)-alkylene or ethynyl, (C3-C10)-cycloalkyl added through unsaturated (C2-C3)-alkyl or through (C1-C3)-alkylene or ethynyl, or thiophenyl added through unsaturated (C2-C3)-alkyl, either through (C1-C3)-alkylene or ethynyl, respectively, unsubstituted or mono- either multi-substituted with residues chosen independently of one another from a group comprising fluorine (F), chlorine (Cl), bromine (Br), iodine (J) atom, -OR18, -SR18, silyl, unsubstituted or mono- either multi-substituted alkyl wherein substituted of substitutes of (C1-C10)-alkyl are similar or different and are chosen from the group comprising F, Cl, and Br and wherein R18 represents H or saturated or unsaturated, branched or linear, unsubstituted (C1-C10)-alkyl; R2 and R3 mean independently of one another branches or linear saturated unsubstituted (C1-C10)-alkyl, or R2 and R3 form in common the group -CH2CH2NR6CH2CH2 wherein R6 means branched or linear (C1-C10)-alkyl; X in the formula (I) in correspondence with the subformula (1a): of the formula (I) represents or wherein B represents -OH, -OR7, H, F or Cl wherein R7 means mono- or multi-substituted phenyl added through (C1-C3)-alkylene wherein substitutes of phenyl are chosen from F and Cl and others. Also, invention relates to a pharmaceutical composition based on compounds of the invention and to using these compounds. Proposed compounds can be used in treatment of pain being firstly in case of nephropathic or chronic pains.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 421 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): wherein R1 represents alkyl; R2 represents halogen atom, formyl, substituted or unsubstituted alkyl, hydroxyl, (C1-C6)-alkoxy-group, halogenalkyl; or R and R2 in common with atom to which they are bound form unsubstituted 5-7-membered structure of the formula: -CH2-(CH2)nS- wherein n = 1 or 2; R3 represents hydrogen atom, halogen atom or alkyl; R4 represents alkoxy-group or unsubstituted aryl or aryl substituted with halogen atom, (C1-C6)-alkyl, halogenated (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkylsulfonyl; R5 represents hydrogen atom, hydroxyl, alkyl, alkenyl or alkoxy-group; R6 represents hydrogen atom or alkyl; or R5 and R6 represent in common =O; X represents oxygen atom or -NR8 wherein R8 represents aryl substituted with halogen atom; m means a whole number in the range from 0 to 2, and its pharmaceutically acceptable salts. Also, invention relates to pharmaceutical compositions based on these compounds, method for treatment of diseases mediated by cyclooxygenase and to a method for inhibition of cyclooxygenase activity in cells. Invention provides preparing novel compounds possessing valuable biological effect.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical compositions.

11 cl, 98 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to novel retinoid compounds of the structural formula (I) or their pharmaceutically acceptable salts and pharmaceutical compositions possessing agonistic activity with respect to retinoid receptors and comprising indicated compounds wherein n = 1; d = 0 or 1; B means -CR7=CR8-, -CH2O- wherein R7 and R8 each means independently hydrogen atom; X means phenyl optionally substituted with halogen atom, or 5-membered heteroaryl comprising sulfur atom (S) as a heteroatom; R1 means -C(=O)-R9 wherein R9 means alkyl, hydroxyl, amino-, heteroaryloxy-group comprising oxygen atom (O) or 6-membered heterocyclyl comprising nitrogen atom (N) as a heteroatom; R2 means: (a) -(CR10R11)m-Yp-R12; m means a whole number from 1 to 10; p means 0 or 1; R10 and R11 mean hydrogen atom; Y means -O-, -S- or -NR13-; R13 means hydrogen atom; R12 means hydrogen atom, alkyl, cycloalkyl, phenyl, 5- or 6-membered heteroaryl comprising atoms N, S, O as a heteroatom, 5- or 6-membered heteroarylalkyl comprising atoms N, S, O as a heteroatom, heteroalkyl comprising atoms N, S, O as a heteroatom, 5- or 6-membered heterocyclyl comprising atoms N, S, O as a heteroatom, or 5- or 6-membered heterocyclylalkyl comprising atoms N, S, O as a heteroatom under condition that when p means 0 then R12 doesn't mean hydrogen atom or alkyl; (b) 5- or 6-membered heteroaryl comprising atoms N, S, O as a heteroatom; (c) -Z-L wherein Z means -CR14=CR15-, -C≡C-, -C(=O) or -S-; R14 and R15 mean hydrogen atom; L means 5- or 6-membered heteroaryl comprising atoms N, S, O as a heteroatom; (d) -CR14=CR15-L1 wherein L1 means -S(O)2R17 or -SO2NR18R19 wherein R17 means alkyl; R18 and R19 mean hydrogen atom; each R3 means independently hydrogen atom, hydroxyl or oxo-group; t means 1 or 2.

EFFECT: valuable medicinal properties of compounds and compositions.

59 cl, 10 tbl, 54 ex

FIELD: organic chemistry, medicine, endocrinology, pharmacy.

SUBSTANCE: invention relates to new derivatives of acylphenylurea of the formula (I) and to their physiologically acceptable salts possessing property of glycogen phosphorylase inhibitors. In compound of the formula (I) A means phenyl and phenyl residue can be substituted three times with fluorine (F), chlorine (Cl), bromine (Br) atoms, -CF3, -NO2, -O-(C1-C6)-alkyl, -SO2-(C1-C6)-alkyl, (C1-C6)-alkyl, -COOH; R1 means hydrogen atom (H), (C1-C6)-alkyl; R2 means H, (C1-C6(-alkyl, -CO-(C1-C6)-alkyl; 3, R4, R5 and R6 mean independently of one another H, F, Cl, Br, -O(C1-C6)-alkyl, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, -COOH, -COO-(C1-C6)-alkyl; X means oxygen (O), sulfur (S) atom; R7 means (C1-C10)-alkylene-COOH, (C1-C10)-alkylene-COO-(C1-C6)-alkyl, (C1-C10)-alkylene-NH2, (C1-C10)-alkylene-NH-(C1-C6)-alkyl, (C1-C10)-alkylene-N-[(C1-C6)-alkyl]2, (C1-C10)-alkylene-B wherein B means piperidinyl or furyl. Also, invention relates to a pharmaceutical composition and a method for preparing the pharmaceutical composition. Proposed compounds can be used for preparing pharmaceutical composition useful for declining level of blood glucose and for treatment of diabetes mellitus type II.

EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.

7 cl, 2 sch, 2 tbl, 1 ex

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to compounds of formula I ,

where R(1), R(2), R(3), R(4), R(5), R(6), R(7), R(8), R(30), and R(31) are disclosed in claims. Compound of present invention are particularly useful as new antiarrythmia bioactive substances, in particular for treatment and prophylaxis of atrial arrhythmia (e.g., atrial fibrillation or auricular flutter).

EFFECT: higher efficiency.

13 cl, 18 ex, 1 tbl

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new biphenylsulfonylcyanamides of the formula (I): wherein R1 means: 1. (C1-C8)-alkyl; 4. -CnH2n-nn-Y wherein nn = 0 or 2 and n = 0-4, and n is not 0 or 1 if nn = 2; 5. CnH2n-nn-Y wherein nn = 0 or 2 and n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with amino-group or NR(22)R(23); R2 means: 2. (C1-C)-alkyl; 4. (C2-C12)-alkenyl; 5. (C2-C8)-alkynyl; 6. -CnH2n-nn-Z wherein nn = 0 or 2; n = 0-4, and n is not or 1 if nn = 2; 7. -CnH2n-nn-Z wherein nn = 0 or 2; n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with a residue taken among a series: 1. phenyl; 3. NR(22)R(23); 5. COOR(16); R3 and R4 mean hydrogen atom; R5, R6 and R7 mean independently of one another hydrogen atom (H), (C1-C8)-alkyl; SO2-(C1-C4)-alkyl, F, Cl, Br, J, OR(10) wherein R(10) means hydrogen atom, (C1-C4)-alkyl that is substituted if necessary with methoxy- or ethoxy-group; R(9) means OR(13) wherein R(13) means hydrogen atom, H,(C1-C8)-alkyl;X means carbonyl group, -CO-CO- or sulfonyl group; Y and Z mean independently of one another: 1. phenyl, 1-naphthyl, 2-naphthyl; 2. one of residues determined in cl. 1 substituted with 1-5 similar or different residues taken among a series: phenyl, F, Cl, Br, J, CF3, SOqR(18), OR(16), NR(19)R(20), -CN, NO2, COR(9), or two residues form methylenedioxy-group; 3. furyl, thienyl, pyridyl, benzimidazolyl, indolyl, benzothiophenyl, dihydroquinazolinyl; 5. (C3-C10)-cycloalkyl wherein cyclopropyl, cyclopentyl, cyclohexyl and indalyl are preferable; 6. one of residues determined in cl. 5 substituted with phenyl; R(16) means: 1. hydrogen atom; 2. (C1-C4)-alkyl; 3. (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; R(19) and R(20) mean independently: hydrogen atom (H), (C1-C4)-alkyl; R(22) and R(23) mean independently of one another hydrogen atom (H) or CO-OR(24) wherein R924) means -CnH2n-phenyl wherein n = 1-4; q = 2; and their physiologically acceptable salts. Compound of the formula (I) inhibit sodium-dependent chloride-bicarbonate exchange "NCBE".

EFFECT: improved preparing method, valuable medicinal properties of compounds.

4 cl, 2 tbl, 568 ex

FIELD: chemistry.

SUBSTANCE: in general formula

A represents optionally substituted aminocarbonyl group -N-C(O)-, in which amino group can be substituted and substituents can be selected from hydrogen, C1-C5alkyl, possibly substituted with C1-C3alkoxy, C3-C6cycloalkyl, 5-6-membered heteroaryl, in which heteroatoms are selected from oxygen or nitrogen; aryl, selected from phenyl, possibly substituted with hydroxy, C1-C5alkyl, C1-C5alkoxy, halogen, C1-C5acylamino group, or naphthyl; or amino group is selected from C3-C7heterocyclyl, containing 1-2 heteroatoms in cycle, selected from nitrogen, oxygen or sulphur, possibly substituted with hydroxy, C1-C3alkyl, benzyl, phenyl, which can be substituted with halogen, and said heterocyclyl can be condensed with benzene ring; acylamino group, in which acyl is selected from C1-C6alkylcarbonyl, where alkyl can be substituted with phenyl, substituted with phenyl, in which substituents are selected from C1-C5alkoxy; 5-membered heteroaryl with heteroatom, selected from atom of oxygen or sulphur; benzoyl, possibly substituted with C1-C5alkyl, C1-C5alkoxy, C1-C5alkylthio or halogen, methylenedioxy; heterocyclylcarbonyl, in which heterocyclyl is selected from 5-6-membered heterocyclyl, with 1-2 heteroatoms, selected from nitrogen, oxygen or sulphur, possibly condensed with benzene ring and possibly substituted with C1-C5alkyl, halogen; or ureido group, in which one of substituents of terminal amido group represents hydrogen, and the second substituent is selected from: C1-C3alkyl, substituted with phenyl, 5-membered saturated or aromatic heterocyclyl, in which heteroatoms are selected from oxygen or sulphur; C2-C6alkenyl; aryl, selected from phenyl, substituted with C1-C5alkyl, C1-C5alkoxy, ethylenedioxy, methylenedioxy, halogen, C1-C3alkylcarbonyl; 5-membered heterocyclyl, in which heteroatoms are selected from sulphur or oxygen atom, and possibly substituted with alkyloxycarbonyl group; B represents non-aromatic cyclic substituent, selected from C4-C6cycloalkyl; and has other values, given in the invention formula. Values R1a R1b R1c are given in the invention formula.

EFFECT: increased efficiency of application of compounds.

12 cl, 8 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new crystalline forms of acid addition salts of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, wherein the acid is specified in methanesulphonic, maleic, fumaric, citric, orotic, 10-camphor sulphonic acids and fencifose. The salts possess the agonist properties of neuronal nicotine receptor (NNR) and can be used for managing or preventing pain, an inflammation or a CNS disorder. Each of the crystalline salts is characterised by an X-ray powder diffraction diagram. The invention also involves an amorphous form of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine monocitrate and polymorphic forms of the above crystalline salts.

EFFECT: invention refers to a pharmaceutical composition containing an effective amount of the presented salts.

19 cl, 8 dwg, 33 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new compounds of formula I or their pharmaceutically acceptable salts, wherein R1 means phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen or 5-6-merous heteroaryl; R2 is phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen, halogen-C1-6alkyl, halogen-C1-6alkoxy, C1-6 alkylsulphonyl, nitrile, etc. R3 means H or C1-6 alkyl; X - -O-, -NRa-,-S(O)m- or CRbRc, wherein Ra - H, C1-6 alkyl or C1-6 alkylcarbonyl; Rb and Rc mean H or together with the atom to which they are attached, form 5-merous cycle additionally containing 2 oxygen atoms; m is equal to 0-2; Y means -NRc-, wherein Rc - H or C1-6 alkyl.

EFFECT: compounds can find application in medicine for treating autoimmune and inflammatory diseases related to P2X7 purinoceptor.

15 cl, 1 tbl, 10 ex

FIELD: biotechnology.

SUBSTANCE: humanised antibody against human IFN-α is proposed, obtained based on the murine antibodies ASO-1. Also the therapeutic composition and method of prevention, treatment or diminution of intensity of the symptoms of an autoimmune or inflammatory disease or disorder is considered.

EFFECT: invention may find further application in treatment of IFN-α-related diseases.

13 cl, 13 dwg, 18 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: in formula (I) each of A1, A2 and A3 is independently selected from the group, consisting of O and S, R1 represents an alkyl chain with the length of 2-28 carbon atoms, R2 is selected from the group, consisting of (3-carboxy)propyl and (20carboxy)ethyl, and R3 is selected from the group, consisting of H, C1-20acyl, phosphate, phosphocholine, phosphoethanolamine, phosphoethanolamine-N-glutaric acid and phosphoserine. The invention also relates to a pharmaceutical composition, containing the said compounds, and to the application of the compounds for manufacturing a medication, intended for treatment or prevention of diseases or disorders, associated with inflammation, or for the reduction of the level of cytokine, selected from the group, consisting of interleukin-12 and interleukin-23.

EFFECT: increase of the treatment efficiency.

60 cl, 39 dwg, 18 ex

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