Adrenergic compounds

FIELD: chemistry.

SUBSTANCE: invention relates to compounds, which represent (4,5-dihydrooxazol-2-yl)-(5,6,7,8-tetrahydroquinoxylan-5-yl)-amino and (4,5-dihydrooxazol-2-yl(-(5,6,7,8-tetrahydroquinolin-5-yl)-amino or their pharmaceutically acceptable salt. Said compounds are applied in methods of intraocular pressure reduction and treatment of pain in mammals who require it.

EFFECT: obtaining compounds, which are alpha-adrenergic agonists.

3 cl, 1 tbl

 

Cross-reference

[1] this patent application claims the priority of provisional patent application U.S. 60/955960, filed August 15, 2007, incorporated herein by reference.

PRIOR art

[2] There is a continuing need in the alpha-adrenergic compounds for the treatment of pain, glaucoma and other conditions.

Description of the INVENTION

[3] Proposed here, the compound has the structure

where X represents O, S or NH; and

A represents a fused bicyclic ring system containing:

With3-5alkyl ring functional group condensed with a six-membered heteroaromatic ring having in the composition of the ring 1 or 2 heteroatoms independently selected from N, O or S;

where alkyl ring functional group forms a link identified in the structure as A-N, and the specified alkyl ring functional group is 0 or 1 C1-4alkyl substituent; and

where the heteroaromatic ring has from 0 to 3 substituents independently consisting of: from 0 to 4 carbon atoms, from 0 to 10 hydrogen atoms, from 0 to 2 oxygen atoms, from 0 to 1 sulfur atom, from 0 to 1 nitrogen atom, 0 to 3 fluorine atoms, from 0 to 1 chlorine atom and from 0 to 1 bromine atom.

[4] These compounds are suitable for treatment of pain, CH is okomi and reduce intraocular pressure. Connection include in dosage form or a drug, and is administered to a mammal in need of such introduction. For example, the liquid composition can be introduced in the form of eye drops for treating glaucoma or reducing intraocular pressure. Solid dosage form can be administered orally in any of these States. In this technology is well known and other types of dosage forms and drugs, and they can also be used here.

[5] For the problems of the present description, the terms "treat," "treating" or "treatment" refers to the use of compounds, compositions, a therapeutically active ingredient or drug in the diagnosis, treatment, mitigation, treatment or prevention of disease or other undesirable condition.

[6] Unless otherwise stated, a reference to that connection should be interpreted widely so as to include pharmaceutically acceptable salts, prodrugs, tautomers, alternate solid forms, and also non-covalent complexes of chemical compounds with the structure or chemical name.

[7] the Pharmaceutically acceptable salt is any salt of the parent compound, which is suitable for administration to an animal or person. Pharmaceutically acceptable salt also applies to any who nd salt, which can be formed in vivo by injection of acid, any salt or prodrug, which is converted to the acid or salt. Salt contains one or more than one ionic form of connection, such as a conjugate acid or base associated with one or more than one appropriate counterion. Salts can be formed from or include one or more than one deprotonirovannoi acid group (e.g. carboxylic acids), one or more than one protonated primary group (e.g., amines), or both (for example, zwitter-ions).

[8] the Prodrug is a compound that turns into a therapeutically active compound after administration. Although this does not limit the amount of isoberlinia, the transformation can be accomplished by hydrolysis of the ester group or any other biologically labile functional groups. Getting prodrugs is well known in the art. For example, "Prodrugs and Drug Delivery Systems," which is a Chapter in Richard C. Silverman, the Organic Chemistry of Drug Design and Drug Action, 2d Ed., Elsevier Academic Press: Amsterdam, 2004, pp.496-557, is more detailed information on the topic.

[9] the Tautomers are isomers that are in dynamic equilibrium with each other. For example, the tautomers can be formed by proton transfer, atom ogorodili hydride ion. Examples of tautomers as shown below.

[10] If the stereochemistry is not indicated precisely, it is assumed that the structure includes any possible stereoisomer, pure or as part of any possible mixture.

[11] Alternative solid forms are solid forms, different from those that may result from the procedures described here. For example, alternative solid forms may include polymorphs, various kinds of amorphous solid forms, glass, etc.

[12] Non-covalent complexes are complexes that can be formed between the compound and one or more additional chemical substance that does not occur covalent interaction between the compound and the additional chemical compounds. They may or may not have a specific ratio between the compound and the additional chemical substances. Examples may include solvate, hydrates, complexes with charge transfer etc.

[13] X represents O, S or NH. Thus, the included compound according to any of structural formulae given below.

[14] And represents Szul the ring functional group, condensed with a six-membered heteroaromatic ring having in the composition of the ring 1 or 2 heteroatoms independently selected from N, O or S. Thus, the basic ring structure of a is given below.

[15] the Alkyl ring functional group shown in the circle on the right. It is a part of the system, which should form cycloalkyl ring if both atom that circle the ring, i.e, the carbon atoms marked "a" and "b" represent-CH2-. Unsubstituted alkyl ring functional group consists of -(CH2)n-where n is from 3 to 5. Six-membered heteroaromatic ring shown in the rectangle on the left, where one or two of the numbers X1X2X3and X4independently represent S, N or O, and the remainder are CH or C-Y, where Y is described here by the Deputy.

[16] Examples of suitable heteroaromatic rings include substituted or unsubstituted pyridine, pyrazin, pyrimidine, etc.

[17] the Alkyl ring functional group forms a link shown in the General structure A-N. in Other words, forming a bridge connection of the nitrogen is attached directly to one of the non-aromatic hydrocarbons alkyl ring functional group.

[18 in Other words, included patterns shown below.

[19] the Alkyl ring functional group may be unsubstituted, but it may also have 1 C1-4alkyl substituent.

[20] the Substituents on the heteroaromatic ring are stable functional groups independently containing from 0 to 4 carbon atoms, from 0 to 10 hydrogen atoms, from 0 to 2 oxygen atoms, from 0 to 1 sulfur atom, from 0 to 1 nitrogen atom, 0 to 3 fluorine atoms, from 0 to 1 chlorine atoms, and from 0 to 1 bromine atom.

[21] In accordance with the limitations described here (for example, limits the number of atoms) examples of these substituents include:

[22] Hydrocarbon, indicating a functional group containing only carbon and hydrogen, including, but not limited to:

A. alkyl denoting hydrocarbon having no double or triple links, including:

linear alkyl, for example methyl, ethyl, n-propyl, n-butyl, etc.,

branched alkyl, such as isopropyl, tert-butyl and other branched butyl isomers, etc,

- cycloalkyl, for example, cyclopropyl, cyclobutyl etc.,

- combination of linear alkyl,branched alkyl and/or cycloalkyl;

B. alkenyl, for example, hydrocarbon having one or more than one double bond, including linear alkenyl, branched alkenyl or cycloalkenyl,

century quinil, for example hydrocarbon having one or more than one triple bond, including linear quinil, branched quinil or cycloalkenyl;

, combination of alkyl, alkenyl and/or quinil

[23] alkyl-CN, such as-CH2-CN, -(CH2)2-CN; -(CH2)3-CN, etc.;

[24] hydroxyalkyl, i.e. alkyl-OH, such as hydroxymethyl, hydroxyethyl and the like;

[25] the Vice - ethers, including-O-alkyl, alkyl-O-alkyl and the like;

[26] thioester deputies, including-S-alkyl, alkyl-S-alkyl and the like;

[27] amine substituents, including-NH2, -NH-alkyl-N-alkyl1alkyl2(i.e. alkyl1and alkyl2are the same or different, and both are associated with nitrogen)alkyl-NH2, alkyl-NH-alkyl, alkyl-N-alkyl1alkyl2etc.;

[28] aminoalkyl indicating alkylamine, such as aminomethyl (-CH2-Amin), aminoethyl etc.;

[29] the Vice - esters, including-CO2-alkyl, -CO2-phenyl, etc.;

[30] other carbonyl substituents, including aldehydes, ketones, such as acyl (i.e.and the like; in particular, acetylene, propionyloxy and benzene substituents;

[31] fluorocarbons or getopt ROPERTY, such as-CF3; CH2CF3and so on; and

[32] -CN;

[33] the possible combinations of the above compounds, taking into account the identified constraints;

[34] alternatively, a Deputy can be a-F, -Cl, -Br, or-I.

[35] In particular enabled alkyl having from 1 to 4 carbon atoms;

[36] the Substituents on the heteroaromatic ring are stable, i.e. they must be sufficiently stable to be stored in the vial at room temperature in a normal atmosphere for at least 12 hours, or stable enough to be used on any of the disclosed here assignments.

[37] If the Deputy is a salt, for example, carboxylic acid or amine, the counterion of the specified salt, i.e. ion, which ecovalence associated with the remainder of the molecule, is not taken into account when calculating kolejnictwa atoms of the functional group. Thus, for example Sol-CC2-Na+consists of one atom of carbon and two atoms of oxygen, i.e. sodium is not considered. In another example, salt-NH(Me)2+Cl-consists of two carbon atoms, one nitrogen atom and seven hydrogen atoms, i.e. chlorine is ignored.

[38] In another embodiment the substituents independently are-H, alkyl containing from 1 to 4 atoms in the of Lerida, -F, -Cl, -Br, -CH2HE, amine, containing from 0 to 4 carbon atoms, -CH2CN, -CF3or acyl containing from 1 to 4 carbon atoms.

[39] In another embodiment the substituents independently are-H, -F, -Cl, -Br, -CH3, -NHCH3or-CF3.

[40] Deputy alkyl ring functional group represents H or C1-4alkyl, i.e. methyl, ethyl, n-propyl, isopropyl, and butyl isomers. Thus, the included compound, having any of the structures shown below, where the Deputy alkyl ring depicted as Re.

[41] Some hypothetical examples of compounds used

shown below.

The synthesis methods

[42] the Method of obtaining (4,5-dihydro-oxazol-2-yl)-5,6,7,8-tetrahydroquinoxalin-5-yl)-amine, 772:

[43] 5,6,7,8-tetrahydroquinoxalin-5-amine (Intermediate compound 14) (3.0 mmol) in dichloromethane (10 ml) was added charaterization (3.3 mmol). The solution was stirred at room temperature for 1.5 hours. The solvents were removed under vacuum to obtain the crude substances Prohm is filling connection 15.

[44] the Intermediate compound 15 was boiled under reflux in N2O (60 ml) for 1 hour. After cooling to room temperature the reaction mixture was podslushivaet using NaOH (pH 14), extracted in ethyl acetate (3×50 ml). The combined organic layers were washed with brine and dried over magnesium sulfate to obtain 772.

1H NMR (nuclear magnetic resonance) (CDCl3, 300 MHz): δ=8.42 (d, J=6 Hz, 1H), 7.42 (d, J=6 Hz, 1H), 7.13 (dd, J=6, 9 Hz, 1H), 4.88-4.69 (m, 3H), 3.99-3.85 (m, 2H), 2.95-2.87 (t, 1H), 2.80-2.71 (m, 1H), 2.30-2.23 (m, 1H), 2.08-2.01 (m, 2H), 1.89-1.77 (m, 1H).

[45] the Method of obtaining (4,5-dihydrooxazolo-2-yli-tetrahydroquinolin-8-yl)-amine. 747:

[46] 5,6,7,8-tetrahydroquinolin-8-amine (Intermediate compound 17) (3.0 mmol) in dichloromethane (10 ml) was added charaterization (3.3 mmol). The solution was stirred at room temperature for 1.5 hours. The solvent was removed under vacuum to obtain raw material, which is boiled under reflux in H2O (60 ml) for 1 hour. After cooling to room temperature the reaction mixture was podslushivaet using NaOH (pH 14), were extracted in ethyl acetate (3×50 ml). The combined organic layers were washed with brine and dried over magnesium sulfate to obtain 747. (4,5-Dihydrooxazolo-2-yl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine, 747 in the form of solids

1H NMR (CDCl3, 300 MHz): δ=6.89-7.34 (m, 4H), 5.21 (s, J=4.5 Hz, 1H), 4.01-4.07 (m, 2H), 3.34-3.39 (m, 2H), 2.82-2.96 (m, 2H), 2.59-2.67 (m, 1H), 1.91-1.99 (m, 1H).

Synthesis of amine 14 and 17.

[47] the Method of obtaining 5,6,7,8-tetrahydroquinoxalin-5-amine, 14:

To a solution of 5,6,7,8-tetrahydroquinoxaline (Intermediate 19) (is 3.08 g, 23,0 mmol, commercially available) in CCl4(200 ml) was added N-bromosuccinimide (4.09 g, 23,0 mmol) and a catalytic amount (56 mg) precisiontime. The reaction mixture was heated under reflux for 17 hours. The reaction mixture was cooled to room temperature and filtered through celite, and concentrated in vacuo to obtain 5-bromo-5,6,7,8-tetrahydroquinoxaline (Intermediate compound 20) (3.8 g, crude).

5-bromo-5,6,7,8-tetrahydroquinoxalin (Intermediate compound 20) (3.8 g, 17,92 mmol) and sodium azide (2.3 g, 35.8 mmol) was dissolved in dimethylformamide (DMF) (50 ml) under nitrogen atmosphere and the reaction mixture was heated to 60°C for 20 hours. The mixture was cooled to room temperature, poured water (200 ml)and was extracted with CH2Cl2(3×100 ml). The organic extracts were washed brine (2×100 ml), dried and concentrated in vacuum. The crude substance was purified using flash column-chromatography on silica gel using 1:1 EtOAc/hexane to obtain 5-azide-5,6,7,8-tetrahydro what enoxacin (Intermediate compound 21) (3.2 g, 84%).

A mixture of 5-azide-5,6,7,8-tetrahydroquinoxaline, (Intermediate compound 21) (3.2 g, 15,09 mmol) in Meon (40 ml) was treated with 10% Pd/C (300 mg) in an atmosphere of H2(balloon) for 16 h at room temperature. The mixture was filtered through celite and freed from solvent under reduced pressure. The residue was purified by chromatography on silica gel with 10% MeOH:CH2Cl2obtaining 5,6,7,8-tetrahydroquinoxalin-5-amine (Intermediate compound 21) (1.3 g).1H NMR (CD3OD, 500 MHz): δ=8.48 (s, 1H), 8.38 (s, 1H), 4.06 (dd, J=5.5, 9 Hz, 1H), 3.02-2.97 (m, 2H), 2.30-2.24 (t, 1H), 2.15-2.08 (m, 1 H), 1.96-1.73 (m, 1H).

[48] the Method of obtaining 5,6,7,8-tetrahydroquinolin-5-amine, 17:

To a solution of 7,8-dihydroquinoline-5(6N)-she (Intermediate 22) (1.06 g, 7.2 mmol, commercially available) in the Meon (20 ml) was added methoxylamine (1.2 g, 14.4 mmol) followed by the addition of triethylamine (2 ml, 14.4 mmol). The reaction mixture was heated under reflux for 16 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum. Then the residue was dissolved in CH2Cl2and extinguished with water (100 ml)and was extracted with CH2Cl2(3×100 ml). The organic extracts were dried and concentrated under vacuum. The crude substance was purified using flash column-chromatography on silica gel using MeOH:CH 2Cl2with the receipt of (Z/E)-7,8-dihydroquinoline-5(6N)-O-methyl of oxime, (Intermediate compound 23) (1,14 g, 90%).

To a mixture of (Z/E)-7,8-dihydroquinoline-5(6N)-Oh, it's of methyl oxime (Intermediate compound 23) (1,14 g, 6,47 mmol) in TFA (triperoxonane acid) (20 ml) was added 10% platinum on carbon (10 wt.% Pd/C; 0.15 g) in the atmosphere of argon in a flask Parra for shaker. The mixture was first made at 50 psi for 16 hours. The reaction mixture was flushed with nitrogen and filtered through a layer of Celite®and concentrated under vacuum. The crude substance was purified using flash column-chromatography on silica gel using NH3-MeOH:CH2Cl2obtaining 5,6,7,8-tetrahydroquinolin-5-amine (Intermediate 22), (0.74 g, 78%).1H NMR (CD3OD, 300 MHz): δ=8.41 (d, J=4.5 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.15-7.11 (m, 1H), 4.18 (m, 1H), 2.85-2.80 (m, 2H), 2.35-2.29 (m, 1H), 2.05-2.01 (m, 1H), 1.99-1.77 (m, 2H).

Biological data

[49] Analysis based on the selection of the receptor and amplificatio (RSAT)

[50] using RSAT test measure receptor-mediated loss of contact inhibition, which leads to selective proliferation of cells containing receptors, in a mixed population of confluent cells. The increase in the number of cells evaluated using a suitable transfitsirovannykh marker gene, such as p-galactosidase, the activity of which can easily measure concentration the ü in 96-well pad. Receptors that activate G protein, Gq, show this response. Alpha-2 receptors, which are normally merge with Gi, activate RSAT response co-expression with hybrid Gq protein that has the domain of Gi recognition receptor, named Gq/i5.

[51] NIH-3T3 cells were seeded at a density of 2×106cells in 15 cm plates and supported on the modified Dulbecco environment, Needle, enriched with 10% bovine serum. After one day of cell transferout with deposition of calcium phosphate expression plasmids mammals, encoding the p-SV-β-galactosidase (5-10 µg), receptor (1-2 µg) and G protein (1-2 µg). In the mix for transfection can also include 40 µg DNA salmon sperm. The next day, add fresh medium, and after 1-2 days, the cells are harvested and freeze an aliquot for 50 tests. Cells are thawed, and 100 μl aliquots add 100 ál of drugs in different concentrations in three Parallels in 96-well plates. Incubation is carried out for 72-96 h at 37°C. After rinsing, phosphate buffered saline solution, the activity of the enzyme β-galactosidase activity was determined by adding 200 μl of chromogenic substrate (consisting of 3.5 mm o-nitrophenyl-β-D-galactopyranoside and 0.5% Nonidet P-40 in phosphate buffered saline), incubating overnight at 30°C and measuring the optical platnost is at 420 nm. The absorbance represented a measure of enzyme activity, which depends on the number of cells and affect cell proliferation, mediated by receptors. Efficiency or internal activity was calculated as the ratio of the maximum effect of the drug to maximum effect standard full agonists for each receptor subtype. Brimonidine, also called UK14304, the chemical structure of which is shown below, is used as the standard agonist for alpha, alphav and Alfas receptors. EU50(median effective concentration) is the concentration at which the efficacy of a drug is half of its maximum efficiency.

[52]

[53] the results of the test RSAT with several typical compounds according to the invention are presented in the above table 1, together with the chemical formulas of these typical compounds. Values EU50are nanomolar.: N.O. means "not determinable" at concentrations less than 10 micromol. IA stands for "internal activity."

Table 1
StructureAlpha 2BAlpha 2CAlfa-2A
545the concentration isthe concentration is
(67)(22)(3)
271the concentration isthe concentration is
(86)(27)(16)

[54] Methods of obtaining these compounds are well known in the art. For example, U.S. patent No. 7141597 (in particular, paragraph 10, line 27 to paragraph 14, line 47) contains information that can be used as the primary guide. Similar information is also available in many other sources. For more General guidance on the dosage depending on the particular application connection you can use the biological activity of the compounds privedennuyu here (for example, in table 1).

[55] the Preceding description describes in detail the specific methods and compositions that can be applied, by implementing the present invention and describes the best option. However, to a person skilled in the art it is obvious that other compounds possessing the e desired pharmacological properties, you can get a similar way, and that the proposed connection can also be obtained from different parent compounds by various chemical reactions.

Similarly, essentially the same result can be obtain and apply various pharmacological composition. Thus, as a detailed description of the no contained in the text, it should not be construed as limiting the scope of the invention, since the scope of the present invention is limited only by the claims.

1. The compound has a structure selected from
andor its pharmaceutically acceptable salt.

2. A method of reducing intraocular pressure comprising introducing the compound according to claim 1 to the needy in the mammal.

3. A method of treating pain, comprising introducing the compound according to claim 1 to the needy in the mammal.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described macrocyclic phenylcarbamates of formula (I), wherein A represents -C(=O)OR1 or -C(=O)-NH-SO2-R2, wherein R1 represents hydrogen or C1-C6alkyl; R2 represetns C3-7cycloalkyl, phenyl, thiazolyl or pyridyl each of which is optionally substituted by one or more substituted specified in C1-6alkyl, C1-6alkoxy, trifluoromethyl and halogen; X represents N or CH; E represents NR5; R5 represents hydrogen, C1-6alkyl, C1-6alkoxyC1-6alkyl or C3-7cycloalkyl; n is equal to 4 or 5; wherein a dash line -----, adjoining the fragment -(CH2)n-, represents a double bond; and wherein the dash line in a five-merous cycle including X, represents a single bond, and R7 represents hydrogen; R8 is such as specified in the patent claim, or N-oxide thereof, a pharmaceutically acceptable additive salt or a pharmaceutically acceptable solvate possessing antiviral activity, and used as HCV inhibitors; as well as pharmaceutical compositions containing the above compounds as an active ingredient.

EFFECT: preparing the pharmaceutically acceptable additive salt or pharmaceutically acceptable solvate possessing antiviral activity.

10 cl, 23 ex, 1 tbl

FIELD: biotechnologies.

SUBSTANCE: invention relates to derivatives of [1-(benzyl)piperydine-4-yl]-([1,3,4]thiadiazole- 2-yl)amine and [1-(benzyl)piperydine-4-yl]-(thiazole-2-yl)amine of the formula (I) or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts, where R means hydrogen; R1 means phenyl, substituted with 1, 2 or 3 substitutes, each of them is independently selected from a group containing halogen, cyano, C1-4alkyl, perfluoroC1-4alkyl and perfluoroC1-4alkoxy; R2 means hydrogen or C1-4alkyl; R3 means hydrogen, trifluoromethyl or cyano; X means N or CR4, where R4 is trifluoromethyl. Also the invention relates to a pharmaceutical composition containing compounds of the formula as an active ingredient. The following derivatives are presented: derivatives of [1-(benzyl)piperydine-4-yl]-([1,3,4]thiadiazole-2-yl)amine and [1-(benzyl)piperydine-4-yl]-(thiazole-2-yl)amine of the formula (I) representing quick-dissociating antagonists of dopamine 2 receptors and used as medicinal agents for treatment or prevention of central nervous system.

EFFECT: improved properties of compounds.

7 cl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to bicyclosubstituted pyrazolon azo derivatives of formula

or pharmaceutically acceptable salts thereof, intermediate compounds of formula ,

as well as methods for production thereof, a pharmaceutical composition containing a compound of formula (II), and use thereof as a therapeutic agent, which is a thrombopoietin (TPO) mimetic, as well as use thereof as agonists of the thrombopoietin receptor. Values of substitutes in formulae (I) and (IA) are given in the claim.

EFFECT: obtaining bicyclosubstituted pyrazolon azo derivatives.

12 cl, 58 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel cyclic 5-nitropyridin-2-yl-thioalkenyl-4-dithiocarbamate derivatives of general formula (I) or pharmaceutically acceptable acid- or base addition salts thereof. The compounds have antifungal activity even in case of deep, subcutaneous and surface mycoses in humans, caused by strains (including those resistant to existing drugs) of mycosis causative agents. In general formula , R denotes nitro, cyano, halide-substituted C1-C6 alkyl group, n=1, 2 or 3. The invention also relates to use of compounds of formula (I), a method of producing said compounds, a pharmaceutical composition and a method for treatment using said compounds.

EFFECT: improved method.

12 cl, 2 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), stereoisomers, trans- and cis-isomers, racemates or pharmaceutically acceptable salts thereof, having modulating activity on histamine H3-receptors. In formula (I) m equals 0; one of R1 and R2 is selected from a group which includes hydrogen, C1-10alkoxycarbonyl, amido-, carboxy-, C3-8cycloalkyl, halogen, -NRARB, (NRARB)carbonyl, or a group of formula -L2-R6; the other of R1 and R2 is selected from a group which includes hydrogen, halogen; each of R3a and R3b is independently selected from a group which includes hydrogen; each of R4 and R5 is independently selected from a group which includes C1-10alkyl and C1-10hydroxyalkyl; or R4 and R5, taken together with a nitrogen atom to which each is bonded, form a heteroaromatic ring of the type (a) or (b), where Q1 is O or C; Q2 is -N(R20)-; R20 is selected from a group which includes hydrogen and C1-10alkoxycarbonyl; each of p1 and p2 is independently equal to 1, 2 or 3; each of q1, q2, q3, q4 and q5 are independently equal to 0, 1 or 2; and wherein each carbon atom in the ring is substituted with hydrogen or 0, 1 or 2 substitutes, independently selected from a group which includes hydrogen, hydroxy group, fluorine, C1-10alkyl, C1-10hydroxyalkyl and C1-10fluoroalkyl; R6 is a phenyl, heterocycle or heterocycloC1-4alkyl, wherein the heterocycle is a 4-6-member aromatic or non-aromatic ring which contains 1 or 2 heteroatoms independently selected from N, O and S, optionally condensed with a benzene ring, wherein the phenyl or heterocycle can be unsubstituted or optionally substituted with one or more substitutes independently selected from a group which includes C1-4alkoxy, C1-4alkyl, cyano, halogen and oxo-; L is a bond or C1-4alkylene; L2 is a bond, C1-4alkylene, -C(=O)-, -SO2N(R14a)-, -N(R14a)SO2-, -C(O)N(R14a)-, -N(Rl4a)C(O)- or -N(R15)-; R10 is selected from a group which includes hydrogen; R14a is selected from a group which includes hydrogen; R15 is selected from a group which includes hydrogen; and RA and RB are independently selected from a group which includes hydrogen, C1-10alkyl, C1-10acyl, C1-4halogenalkyl, C1-10alkoxycarbonyl, C3-8cycloalkyl and C3-8cycloalkylcarbonyl. The invention also relates to a pharmaceutical composition which contains compounds of formula (I), a method for selective modulation of effects of histamine H3-receptors, use of said compounds in producing a medicament for treating a condition or disorder modulated by histamine H3-receptors, as well as specific compounds of formula (I).

EFFECT: improved properties of compounds.

18 cl, 2 tbl, 154 ex

FIELD: chemistry.

SUBSTANCE: disclosed is a compound having chemical formula or a salt thereof, where: Ar is an optionally substituted heteroaryl; R1 in each case is independently selected from a group which includes halogen, lower alkyl, optionally substituted with one or more substitutes selected from fluorine, lower alkoxy, fluorine-substituted lower alkoxy, monoalkylamino, dialkylamino, -O-R5, -N(R5)-R6 and -N(R5)-C(X)-R7; m equals 0 or 1; n equals 0, 1 or 2; R2 is hydrogen or a halogen; L2 is -S(O)2-; R3 is a lower alkyl, optionally substituted with fluorine, C3-6 cycloalkyl, optionally substituted with a lower alkyl, a 5- or 6-member nitrogen-containing heterocycloalkyl, optionally substituted with one or more substitutes selected from fluorine, lower alkyl, fluorine-substituted lower alkyl, lower alkoxy, fluorine-substituted lower alkoxy, lower alkylthio or fluorine-substituted lower alkylthio, aryl, optionally substituted with a halogen, lower alkyl, optionally substituted with a halogen or lower alkoxy, optionally substituted with a halogen, or a heteroaryl, optionally substituted with a halogen or a lower alkyl; L1 is selected from a group which includes -O-, -C(R12R13)-X-, -X-C(R12R13)-, -C(R12R13)-N(R11)-, -(R11)-C(R12R13)-, -C(X)-N(R11)-, -N(R11)-C(X)-; X is O; R11 is hydrogen; R4 is hydrogen or a lower alkyl; R5 and R6 in each case are independently selected from a group which includes hydrogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, where each is optionally substituted with one or more substitutes selected from fluorine, lower alkoxy, fluorine-substituted lower alkoxy, lower alkylthio, fluorine-substituted lower alkylthio, monoalkylamino, dialkylamino; R7 in each case is independently selected from a group which includes lower alkyl; where the terms "lower alkyl", "lower alkoxy", "lower alkylthio", "monoalkylamino", "dialkylamino", "cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", are as described in the claim. The invention also discloses a pharmaceutical composition for treating Raf kinase mediated diseases which is based on a compound of formula I; use of the compound of formula I to produce a medicinal agent is also disclosed.

EFFECT: novel compound which can be useful in treating diseases and conditions associated with aberrant activity of protein kinases is obtained and described.

9 cl, 13 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: application describes prodrugs being 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)-4-[4-(2-hydroxyethoxy)-phenyl]pyridine-3,5-dicarbonitryl derivatives, and a method for preparing them.

EFFECT: invention can find application in treating and/or preventing cardiovascular diseases.

8 cl, 4 tbl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula III which possess the properties of JAK pathway inhibitors and JAK-kinase inhibitors. In formula III: X is specified in a group consisting of C1-C10alkyl, amino, halogen, carboxyl, carboxylic acid ester, C2alkynyl, substituted tri-C1-C6alkylsilyl; R represents hydrogen; the cycle A is specified in a group consisting of C6aryl, bicycloheptene, five-and sis-member mono- or 10-member bicyclic heteroaryl including 1 to 3 heteroatoms specified in a group of heteroatoms, including N, O or S, and five- or six-member mono- or 10-member bicyclic heterocycle, including 1 to 2 heteroatoms specified in a group of heteroatoms, including N or O; p means 0, 1, 2 or 3; each of R2 is independently specified in a group consisting of C1-C6alkyl, C1-C4alkyl substituted by 1 to 3 substitutes. The other substitute and radical values are specified in the patent claim.

EFFECT: compounds may be used in preparing a therapeutic agent for T-cell mediated autoimmune disease, for treating or preventing allograft rejection in a recipient, for treating or preventing a type IV hypersensitivity reactions, which includes administering the above agent containing the compound according to cl 1-11, in an amount effective to treat the autoimmune disease or the allograft rejection or the type IV hypersensitivity.

23 cl, 7 dwg, 12 tbl, 43 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely to new 1,2-dihydroquinoline derivatives of general formula , or to a pharmaceutically acceptable salt thereof, wherein R1 represents a lower alkyl group; R2 represents a hydrogen atom; each of R3 and R4 represents a lower alkyl group; R5 represents a lower alkyl group; R6 represents a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group; X represents -CO-, -C(O)NR8 - or -S(O)2-; each of R7 and/or R8 may be identical or different, and represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower cycloalkyl group, a phenyl or naphthyl group, a saturated or unsaturated monocyclic 5- or 6-member heterocyclyl with one or two heteroatoms specified in nitrogen, oxygen and sulphur atoms, and 3-5 carbon atoms in a cycle, a lower alkoxy group, a phenoxy group; provided R7 and/or R8 represent a lower alkyl group, a lower alkoxy group, the mentioned lower alkyl group and lower alkoxy group may contain one or three groups specified in a halogen atom, a phenyl group, an unsubstituted monocyclic 6-member heterocyclyl with one heteroatom specified in a nitrogen atom, and 5 carbon atoms in a cycle, a lower alkoxy group, and -NRaRb as a substitute (substitutes); provided R7 and/or R8 represent a phenyl group, a saturated or unsaturated monocyclic 5- or 6-member heterocyclyl with one or two heteroatoms specified in nitrogen, oxygen and sulphur atoms, and 3-5 carbon atoms in a cycle, a phenoxy group, the mentioned phenyl group, saturated or unsaturated monocyclic 5- or 6-member heterocyclyl with one or two heteroatoms specified in nitrogen, oxygen and sulphur atoms, and 3-5 carbon atoms in a cycle, phenoxy group may contain one or two groups specified in a halogen atom, a lower alkyl group, a halogen-substituted lower alkyl group, a phenyl group, a hydroxyl group, a lower alkoxy group, a halogen-substituted lower alkoxy group, a lower alkylthio group, a lower alkylcarbonyl group, a lower alkoxycarbonyl group, a lower alkylcarbonyloxy group, -NRaRb, a nitro group and a cyano group as a substitute (substitutes); Ra and Rb may be identical or different, and each of them represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group; Y represents a lower alkylene group; Z represents an oxygen atom; p is equal to 2, provided p is equal to 2, R6 may be identical or different. The invention also relates to a pharmaceutical composition and a glucocorticoid receptor modulator of the compound of formula (1).

EFFECT: there are produced new 1,2-dihydroquinoline derivatives possessing glucocorticoid receptor binding activity.

7 cl, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyrrol derivatives of formula (1): or a pharmaceutically acceptable salt thereof wherein the values A, R1-R3, n are specified in clause 1 of the patent claim.

EFFECT: compounds (1) inhibit activity against the interleukin IL-6 production that allows using them both in pharmaceutical compositions, and in a prophylactic drug for ocular inflammatory disease.

23 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an amide derivative of formula (I), where A is benzene or pyridine, where the benzene or pyridine optionally contain 1 or 2 or 3 identical or different substitutes selected from an alkyl containing 1-6 carbon atoms, a cycloalkyl containing 3-6 carbon atoms, an alkoxy containing 1-6 carbon atoms, a halogen atom, nitro, cyano, alkylsulphonyl containing1-6 carbon atoms, amino, cyclic amine selected from 1,1-di-oxoisothiazolidinyl, 2-oxooxazolidinyl, oxopyrrolidinyl, 1,1-dioxothiazinyl and 2-oxoimidazolidinyl optionally having a substitute selected from an alkyl containing 1-6 carbon atoms and an alkylcarbonyl containing a total of 2-7 carbon atoms, acylamino containing a total of 2-7 carbon atoms, and an alkylsulphonyl amino containing 1-6 carbon atoms, wherein the right-side bond is linked to the carbonyl and the left-side bond is linked to the nitrogen atom, R1 and R2 are identical or different and each is a hydrogen, an alkyl containing 1-6 carbon atoms and optionally containing 3 halogen atoms as substitutes, a cycloalkyl containing 3-6 carbon atoms, a phenyl, a halogen atom or a cyano group and R1 and R2 are not a hydrogen atom at the same time, R3 is a hydrogen atom, an alkyl containing 1-6 carbon atoms, an alkenyl containing 2-6 carbon atoms, a cycloalkyl containing 3-6 carbon atoms, or a halogen, R4a, R4b and R4c are each independently a hydrogen atom, an alkyl containing 1-6 carbon atoms, or an oxo, R5a, R5b and R5c are identical or different and each is a hydrogen atom, an alkyl containing 1-6 carbon atoms and optionally containing substitute(s) selected from phenyl, an alkoxy group containing 1-6 carbon atoms, optionally substituted with an alkoxy group containing 1-6 carbon atoms, a phyenylcarbonyloxy group and a hydroxy group, or a phenyl, X is a carbon atom (any of R4a, R4b and R4c can be bonded to a carbon atom, but the carbon atom is not substituted with oxo) or a nitrogen atom (if Y is a single bond, the nitrogen atom can be oxidised to form an N oxide), Y is a single bond, a carbonyl or an oxygen atom, Z1 and Z2 are each independently a carbon atom (substitute R3 is optionally bonded to a carbon atom) or a nitrogen atom, and m equals 1 or 2, a pharmacologically acceptable salt thereof. The amide derivative is used as a preventive/therapeutic drug for treating autoimmune diseases, inflammatory bowel diseases or osteoarthritis.

EFFECT: amide derivative which suppresses production of inductive type MMP-9.

14 cl, 4 tbl, 581 ex

FIELD: chemistry.

SUBSTANCE: disclosed is a compound having chemical formula or a salt thereof, where: Ar is an optionally substituted heteroaryl; R1 in each case is independently selected from a group which includes halogen, lower alkyl, optionally substituted with one or more substitutes selected from fluorine, lower alkoxy, fluorine-substituted lower alkoxy, monoalkylamino, dialkylamino, -O-R5, -N(R5)-R6 and -N(R5)-C(X)-R7; m equals 0 or 1; n equals 0, 1 or 2; R2 is hydrogen or a halogen; L2 is -S(O)2-; R3 is a lower alkyl, optionally substituted with fluorine, C3-6 cycloalkyl, optionally substituted with a lower alkyl, a 5- or 6-member nitrogen-containing heterocycloalkyl, optionally substituted with one or more substitutes selected from fluorine, lower alkyl, fluorine-substituted lower alkyl, lower alkoxy, fluorine-substituted lower alkoxy, lower alkylthio or fluorine-substituted lower alkylthio, aryl, optionally substituted with a halogen, lower alkyl, optionally substituted with a halogen or lower alkoxy, optionally substituted with a halogen, or a heteroaryl, optionally substituted with a halogen or a lower alkyl; L1 is selected from a group which includes -O-, -C(R12R13)-X-, -X-C(R12R13)-, -C(R12R13)-N(R11)-, -(R11)-C(R12R13)-, -C(X)-N(R11)-, -N(R11)-C(X)-; X is O; R11 is hydrogen; R4 is hydrogen or a lower alkyl; R5 and R6 in each case are independently selected from a group which includes hydrogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, where each is optionally substituted with one or more substitutes selected from fluorine, lower alkoxy, fluorine-substituted lower alkoxy, lower alkylthio, fluorine-substituted lower alkylthio, monoalkylamino, dialkylamino; R7 in each case is independently selected from a group which includes lower alkyl; where the terms "lower alkyl", "lower alkoxy", "lower alkylthio", "monoalkylamino", "dialkylamino", "cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", are as described in the claim. The invention also discloses a pharmaceutical composition for treating Raf kinase mediated diseases which is based on a compound of formula I; use of the compound of formula I to produce a medicinal agent is also disclosed.

EFFECT: novel compound which can be useful in treating diseases and conditions associated with aberrant activity of protein kinases is obtained and described.

9 cl, 13 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, specifically to novel 3-(trinitromethyl-ONN-azoxy)-4-nitraminofurazans of general formula I . In formula I, R is Me, or . The invention also relates to methods of producing compounds of formula I.

EFFECT: obtaining compounds which can be used as oxidants for rocket fuel and explosive compositions.

3 cl, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula III which possess the properties of JAK pathway inhibitors and JAK-kinase inhibitors. In formula III: X is specified in a group consisting of C1-C10alkyl, amino, halogen, carboxyl, carboxylic acid ester, C2alkynyl, substituted tri-C1-C6alkylsilyl; R represents hydrogen; the cycle A is specified in a group consisting of C6aryl, bicycloheptene, five-and sis-member mono- or 10-member bicyclic heteroaryl including 1 to 3 heteroatoms specified in a group of heteroatoms, including N, O or S, and five- or six-member mono- or 10-member bicyclic heterocycle, including 1 to 2 heteroatoms specified in a group of heteroatoms, including N or O; p means 0, 1, 2 or 3; each of R2 is independently specified in a group consisting of C1-C6alkyl, C1-C4alkyl substituted by 1 to 3 substitutes. The other substitute and radical values are specified in the patent claim.

EFFECT: compounds may be used in preparing a therapeutic agent for T-cell mediated autoimmune disease, for treating or preventing allograft rejection in a recipient, for treating or preventing a type IV hypersensitivity reactions, which includes administering the above agent containing the compound according to cl 1-11, in an amount effective to treat the autoimmune disease or the allograft rejection or the type IV hypersensitivity.

23 cl, 7 dwg, 12 tbl, 43 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely to new 1,2-dihydroquinoline derivatives of general formula , or to a pharmaceutically acceptable salt thereof, wherein R1 represents a lower alkyl group; R2 represents a hydrogen atom; each of R3 and R4 represents a lower alkyl group; R5 represents a lower alkyl group; R6 represents a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group; X represents -CO-, -C(O)NR8 - or -S(O)2-; each of R7 and/or R8 may be identical or different, and represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower cycloalkyl group, a phenyl or naphthyl group, a saturated or unsaturated monocyclic 5- or 6-member heterocyclyl with one or two heteroatoms specified in nitrogen, oxygen and sulphur atoms, and 3-5 carbon atoms in a cycle, a lower alkoxy group, a phenoxy group; provided R7 and/or R8 represent a lower alkyl group, a lower alkoxy group, the mentioned lower alkyl group and lower alkoxy group may contain one or three groups specified in a halogen atom, a phenyl group, an unsubstituted monocyclic 6-member heterocyclyl with one heteroatom specified in a nitrogen atom, and 5 carbon atoms in a cycle, a lower alkoxy group, and -NRaRb as a substitute (substitutes); provided R7 and/or R8 represent a phenyl group, a saturated or unsaturated monocyclic 5- or 6-member heterocyclyl with one or two heteroatoms specified in nitrogen, oxygen and sulphur atoms, and 3-5 carbon atoms in a cycle, a phenoxy group, the mentioned phenyl group, saturated or unsaturated monocyclic 5- or 6-member heterocyclyl with one or two heteroatoms specified in nitrogen, oxygen and sulphur atoms, and 3-5 carbon atoms in a cycle, phenoxy group may contain one or two groups specified in a halogen atom, a lower alkyl group, a halogen-substituted lower alkyl group, a phenyl group, a hydroxyl group, a lower alkoxy group, a halogen-substituted lower alkoxy group, a lower alkylthio group, a lower alkylcarbonyl group, a lower alkoxycarbonyl group, a lower alkylcarbonyloxy group, -NRaRb, a nitro group and a cyano group as a substitute (substitutes); Ra and Rb may be identical or different, and each of them represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group; Y represents a lower alkylene group; Z represents an oxygen atom; p is equal to 2, provided p is equal to 2, R6 may be identical or different. The invention also relates to a pharmaceutical composition and a glucocorticoid receptor modulator of the compound of formula (1).

EFFECT: there are produced new 1,2-dihydroquinoline derivatives possessing glucocorticoid receptor binding activity.

7 cl, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyrrol derivatives of formula (1): or a pharmaceutically acceptable salt thereof wherein the values A, R1-R3, n are specified in clause 1 of the patent claim.

EFFECT: compounds (1) inhibit activity against the interleukin IL-6 production that allows using them both in pharmaceutical compositions, and in a prophylactic drug for ocular inflammatory disease.

23 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-hydroxylsulphonamide derivatives of formula or , where R1 is H; R2 is H; n is 0; b is an integer in the range of 1-4; R3, R4, R5, R6 and R7 are independently selected from H, halogen, carboxyl, carboxyl ester selected from a group including -C(O)O-morpholino, -C(O)O-C1-C8alkyl and -C(O)O-substituted C1-C8alkyl, where the substitute is morpholino; acylamino, which is a -C(O)NRaRb group, where Ra and Rb are independently C1-C8alkyl, or Ra and Rb together with a nitrogen atom to which they are bonded form morpholino; and sulphonylamino, which is a SO2NR2 group, where two groups R, together with a nitrogen atom to which they are bonded, form morpholino; R8 is selected from halogen and carbonylamino, selected from a -CONH-substituted C1-C8alkyl, where the substitute is morpholino; and -CONR2, where two groups R, together with a nitrogen atom to which they are bonded, form morpholino; C is a heteroaromatic ring which contains cyclic fragments Q9, Q10, Q11, Q12, Q13 and Q14, which are independently selected from C, CH and S, under the condition that at least one of the fragments Q9, Q10, Q11, Q12, Q13 and Q14 is S. The invention also relates to a method of modulating nitroxyl levels, a method of treating diseases which respond to treatment with nitroxyl, a treatment set and a pharmaceutical composition containing compounds of formula (I) or (III).

EFFECT: compounds of formula (I) or (III) for treating diseases which respond to treatment with nitroxyl.

20 cl, 5 ex, 4 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing substituted pyrimidin-5-yl carboxylic acids of formula I and can be used in organic chemistry. The method is realised by reacting N-substituted guanidines and hetarylamidines with ethoxymethylene derivatives of 1,3-ketoesters according to a scheme given below (where the substitutes are as defined in the claim).

EFFECT: improved method of producing substituted pyrimidin-5-yl carboxylic acids of formula I.

2 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to isoxazole-pyridine derivatives of formula , where X; R1; R2, R3, R4, R5 and R6 are as described in claim 1 of the invention and a pharmaceutically acceptable salt thereof. The invention also relates to a medicinal agent for treating diseases associated with the binding site of the GABA A α5 receptor based on compounds of formula I and use of said compounds in preparing a medicinal agent.

EFFECT: novel compounds are active towards the binding site of said receptor and are useful in treating cognitive disorders such as Alzheimer's disease.

22 cl, 372 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I), wherein A represents a pyrrole group or a pyrazole group, and X represents a carbon atom or a nitrogen atom; R1 represents a carboxy group; R2 independently represents a group specified in a substitute group α; R3 independently represents phenyl(C1-C6alkyl)group substituted by, phenyl(C1-C6alkyl)group (wherein the substitute(s) represents (represent) 1-4 groups independently specified in the substitute group α); m is equal to 0, 1, 2 or 3, n is equal to 0 or 1; each of R4, R5, R6 and R7 independently represents a hydrogen atom, C1-C6alkyl group or a halogen atom; B represents a substituted naphthyl group (wherein the substitute(s) represents (represent) 1-4 groups independently specified in the substitute group α), or the group represented by formula (II), wherein B1, B2 and α are those as specified in the patent claim. Also, the invention refers to a pharmaceutical composition possessing lipolysis inhibiting activity, to the use of the compounds of formula (I) in preparing a drug preparation for treating hyperlipidemia, dislipidemia, abnormal lipid metabolism, arteriosclerosis or type II diabetes mellitus and to a method of treating or preventing the mentioned diseases.

EFFECT: preparing the compounds of formula (I) possessing lipolysis inhibiting activity.

36 cl, 1 dwg, 1 tbl, 69 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula (1a) possessing the properties of Syk-kinase inhibitors, pharmaceutically acceptable salts thereof, as well as to a based pharmaceutical composition. In general formula (1a), R4 represents or , R2 is specified in a group consisting of phenyl which can be substituted by one or more identical or different groups R8, (C1-C6) alkyl, and pyridyl can be substituted by one or more identical or different groups R8. R5 represents fluorine; each R6 represents hydrogen. The other radical values are specified in the patent claim.

EFFECT: compounds may be used for treating or preventing the autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematous, as well as multiple sclerosis.

12 cl, 11 ex, 16 dwg, 11 tbl

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