Thiazol derivatives as cannabinoid receptor modulators

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and pharmaceutically acceptable salts. Claimed compounds have modulation effect on CB cannabinoid receptor. In the general formula (I) , R and R1 are the same or different and are phenyl optionally substituted by 1-3 substitutes Y, where Y is substitute selected out of group including chlorine, iodine, bromine, fluorine, on condition that X is not a sub-group (ii); or one of R and R1 radicals is phenyl group, while the other radical is formed or linear C2-8-alkyl group or benzyl group; X is one of the sub-groups (i) or (ii). Also invention concerns application of the compounds in obtaining pharmaceutical composition, pharmaceutical composition with modulation effect on CB cannabinoid receptor, and compound of the general formula (IV) with radical values as indicated in the claim.

EFFECT: enhanced efficiency of composition and treatment method.

5 cl, 1 tbl, 25 ex

 

The present invention relates to a group of thiazole derivatives, to methods of producing these compounds, to pharmaceutical compositions containing at least one of these compounds as the active ingredient, as well as to the use of these compositions for the treatment of psychiatric and neurological disorders and other diseases caused by neurotransmission of cannabinoid ST. Derivatives of thiazole according to the invention are either antagonists of cannabinoid (CB) receptor agonists SV-receptor inverse agonists of CB-receptor or partial agonists of CB-receptor. Derivatives of thiazole according to the invention bind any ST.1-a receptor, or ST2the receptor or both SV1and ST2-receptors.

This invention relates to the use of the disclosed here are the links to obtain medications that provide beneficial effects. Beneficial effects revealed here or is obvious to the person skilled in the art from the description of the invention and prior art. This invention also relates to the use of compounds according to this invention to obtain a medicine for treating or preventing the disease or condition. More specifically, this invention relates to a new use for the treatment of the disease or what Oceania, unveiled here, or which is obvious to the person skilled in the art from the description of the invention and prior art. Disclosed here, a single connection in the embodiments of the present invention is used for receiving the medications.

Thiazole claimed in the patent WO0127094 as inhibitors of triglyceride. Patent WO0426863 discloses thiazole derivatives as inhibitors of the transforming growth factor (TgF). Derivatives of 4,5-varietease disclosed in patents EP 388909 and EP 377457 as inhibitors of 5-lipoxygenase for the treatment of thrombosis, hypertension, allergies and inflammation. All shows there patterns contain two phenyl rings that are substituted in the para-position by a methoxy group, fluorine, methylthiourea or methylsulfinyl group. Patent WO 9603392 reveals sulfonylurea-Aristotle for the treatment of inflammation and pain, arthritis, or fever as associated with inflammatory disorders. Patent JP 05345772 relates to 4,5-varietatem as acetylcholinesterase inhibitors and patent JP 04154773 discloses 4,5-directionally with analgesic, anti-inflammatory and antipyretic action.

At the moment unexpectedly found that the thiazole derivatives of formula (I), their prodrugs and their salts

where R and R1are the same or different and represent the Wallpaper phenyl or pyridinyl, optionally substituted by 1-3 substituents Y, where Y is a Deputy chosen from the group comprising methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, hydroxymethyl, hydroxyethyl, chlorine, iodine, bromine, fluorine, trifluoromethyl, triptoreline, methylsulphonyl, methylsulfanyl, trifloromethyl, phenyl or cyano, provided that X is not a subset of (ii);

or one of the radicals R and R1represents phenyl or pyridinyl group, optionally substituted by 1-3 substituents Y, where Y has the above meaning, and the other radical represents a hydrogen atom or a branched or linear C1-8is an alkyl group, branched or linear C3-8-heteroalkyl group containing one heteroatom from the group N, O, S)3-7-cycloalkyl group3-7-cycloalkyl-C1-3is an alkyl group, a C3-7-heteroseksualci-C1-3is an alkyl group, and these groups may be substituted by a hydroxyl group, methoxy group, methyl, triftormetilfullerenov or triptorelin group or fluorine atom, and3-7-heteroseksualci-C1-3is an alkyl group containing one or two heteroatoms from the group (O, N, S), or above the other radical is a benzyl group optionally substituted in the phenyl ring, 1-3 will replace the members of Y, where Y has the above meaning;

X represents one of the groups (i) or (ii):

where R2represents a branched or linear C1-8is an alkyl group, a C3-7-cycloalkyl group3-7-cycloalkyl-C1-2is an alkyl group, a C3-7-heteroseksualci-C1-2is an alkyl group, and these groups may be substituted by hydroxyl, methyl or triptorelin group or fluorine atom, and3-7-heteroseksualci-C1-2is an alkyl group containing one or two heteroatoms from the group (O, N, S)

or R2represents phenyl, benzyl, fenetylline or phenylpropyl group, which in its phenyl ring may be substituted by 1-3 substituents Y, where Y has the above meaning,

or R2represents pyridyloxy, thienyl or naftalina group, and naftalina group may be substituted by a halogen atom, methyl group or methoxy group or triptorelin group;

R3represents a hydrogen atom or a branched or linear C1-3is an alkyl group;

R4represents hydrogen, a branched or linear C1-10is an alkyl group or a C3-8-cycloalkyl-C1-2is an alkyl group, branched or linear C1-10-alkoxygroup is, With3-8-cycloalkyl group5-10-bicycloalkyl group5-10-bicycloalkyl-C1-2is an alkyl group, a C6-10-tricyclohexyl group6-10-tricyclohexyltin group, branched or linear C3-10-alkenylphenol group5-8-cycloalkenyl group, and these groups may contain one or more heteroatoms from the group (O, N, S) and can be substituted by hydroxyl, 1-3 methyl groups, ethyl group or 1 to 3 fluorine atoms,

or R4represents a phenyl group, phenylaminopropyl, fenoxaprop, benzyl, fenetylline or phenylpropyl group, optionally substituted in the phenyl ring, 1-3 substituents Y, where Y has the above meaning,

or R4represents pyridyloxy or thienyl group,

or R4represents a group NR5R6,

where

R5and R6together with the nitrogen atom to which they are attached, form a saturated or unsaturated, monocyclic or bicyclic, heterocyclic group having 4 to 10 atoms in the ring, and the heterocyclic group contains one or more heteroatoms from the group (O, N, S) and the said heterocyclic group may be substituted branched or linear C1-3-alkyl, phenyl, hydroxyl or triptorelin group or as the Ohm fluorine, or

R3and R4together with the nitrogen atom to which they are attached, form a saturated or unsaturated, monocyclic or bicyclic, heterocyclic group having 4 to 10 atoms in the ring, and the heterocyclic group contains one or more heteroatoms from the group (O, N, S) and the said heterocyclic group may be substituted branched or linear C1-3is an alkyl group, phenyl group, amino group, hydroxy-group, methoxy group, cyano or triptorelin group or fluorine atom or chlorine;

are modulators of cannabinoid (CB) receptor.

This invention includes all compounds having the formula (I), the racemates, mixtures of diastereomers and the individual stereoisomers. Thus, compounds in which the substituents at potentially asymmetric carbon atoms or are in the R-configuration or S-configuration, apply to this invention.

Also prodrugs, i.e. compounds that, when administered to humans by any known metabolized into compounds of formula (I), belong to this invention. Prodrugs are bioapatite derived molecules medicines used to overcome some of the barriers to achieving the usefulness of the original molecule drugs. These barriers VK is ucaut, but not limited to, solubility, permeability, stability, presystemic metabolism and limitations of targeting (J. Stella, "Prodrugs as therapeutics", Expert Opin. Ther. Patents, 14(3), 277-280, 2004). In particular, it relates to compounds with primary or secondary amino groups or hydroxyl groups. Such compounds can react with organic acids to form compounds having formula (I)where there is an additional group that is easily removed after the introduction (in the body) and representing, but not limited to, for example, amicin, enamine, the basis of manniche, hydroxymethylene derived derived O-(acyloxymethyl), carbamate, ester, amide or enamine. A prodrug is an inactive compound that becomes active when absorption (Medicinal Chemistry: Principles and Practice, 1994, ISBN 0-85186-494-5, ed.: F.D. King, S. 216).

Due to its activity against SV-receptor compounds according to this invention are suitable for use in the treatment of psychiatric disorders such as psychosis, anxiety, depression, attention deficit, memory impairment, cognitive impairment, impaired appetite, obesity, addiction, appetence, drug dependence and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle with stichnoth, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, Huntington's disease, Tourette's syndrome, cerebral ischaemia, cerebral apoplexy, craniocerebral trauma, spinal cord injury, neirolepticalkie disease, blaskovic sclerosis, viral encephalitis, a disease associated with demyelination, as well as for treatment of diseases associated with pain, including neuropathic disorders, and other diseases caused by the cannabinoid neurotransmission, including the treatment of septic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory diseases, gastro-intestinal disorders, sexual disorders, stomach ulcers, diarrhea and cardiovascular disorders.

PHARMACOLOGICAL METHODS

In vitro affinity (affinity) to the human cannabinoid receptors SV1

The affinity of the compounds according to the invention for cannabinoid receptors SV1can be determined using membrane preparations from cells of the Chinese hamster ovary (Cho), stable transfirieran human cannabinoid receptor SV1conjugated with [3H]CP-55,940 as radioligand. After incubation with freshly prepared cell membrane preparation with [3N]-what egendom, with addition or without addition of compounds according to this invention the separation of bound and free ligand is carried out by filtration through glass fiber filters. The radioactivity on the filter is measured by liquid scintillation counter.

In vitro affinity to human cannabinoid receptors SV2

The affinity of the compounds according to this invention for cannabinoid receptors SV2can be determined using membrane preparations from cells of the Chinese hamster ovary (Cho), stable transfirieran human cannabinoid receptor SV2conjugated with [3H]CP-55,940 as radioligand. After incubation with freshly prepared cell membrane preparation with [3N]-ligand, with addition or without addition of compounds according to this invention the separation of bound and free ligand is carried out by filtration through glass fiber filters. The radioactivity on the filter is measured by liquid scintillation counter.

In vitro antagonism towards human cannabinoid receptors SV1

In vitro antagonism to the ST1the receptor can be assessed using human SV1-receptor, cloned in the cells of the Chinese hamster ovary (Cho). SNO-cells to multiwire the t in nutrients, modified by Dulbecco environment Needle (DMEM)with the addition of 10% thermoinactivation fetal calf serum. The medium removed and replaced with DMEM without fetal calf serum but containing [3H]-arachidonic acid, and incubated overnight in a closet for cell culture (5% CO2/95% air; 37°; water-saturated atmosphere). During this period, [3H]-arachidonic acid is introduced into membrane phospholipids. On the day of the test medium is removed and cells are washed three times using 0.5 ml of DMEM containing 0.2% bovine serum albumin (BSA). Stimulation of ST.1-receptor with WIN 55,212-2 leads to activation of the PLA2with the subsequent release of [3H]-arachidonic acid in the environment. This WIN 55,212-2-induced release depending on the concentration of antagonists counteract ST1-receptor. Antagonistic activity against ST1test compounds is expressed as the RA2values.

In vivo antagonism towards human cannabinoid receptors SV1

In vivo SV1-antagonism can be estimated using test CP-55,940-induced hypotension in rats. Male rats with normal blood pressure (weighing 225-300 g; Harlan, Horst, the Netherlands) anaesthetize pentobarbital (80 mg/kg, intraperitoneally). Blood pressure is measured through the Yu cannula, inserted into the left carotid artery by the pressure sensor Spectramed DTX-plus (Spectramed B.V., Bilthoven, the Netherlands). After amplification through amplifier Nihon Kohden Carrier Amplifier (type AP-621G; Nihon Kohden B.V., Amsterdam, the Netherlands), the blood pressure signal recorded on a personal computer (Compaq Deskpro 386s) using a data collection program Po-Ne-Mah (Po-Ne-Mah Inc., Storrs, USA). Heart rate output from the pulse signal of the blood pressure. All compounds are administered orally in the form of microsuspension with 1% methylcellulose, 30 minutes before induction of anesthesia, which is carried out for 60 minutes prior to injection of the agonist ST1-receptor CP-55,940. The amount of injection of 10 ml·kg-1. After hemodynamic stabilization enter agonist ST1-receptor CP-55,940 (0.1 mg·kg-1intravenously) and install anti-hypertensive effect (Wagner J.A., and others, Hemodynamic effects of cannabinoids: coronary and cerebral vasodilation mediated by cannabinoid chemistry CB1 receptors. Eur. J. Pharmacol., 2001, 423, 203-210).

This hypotensive test can also be used to assess agonistic action of the compounds against ST1-receptor. Such SV1-agonistic action in relation to blood pressure can be counteracted by using a selective antagonist of ST1-receptor, such as rimonabant.

Agonistic or partial agonistic activity of the compounds according to wannamoisett towards cannabinoid receptor can be determined using published methods, such as evaluation of in vivo cannabimimetic effects (Wiley J.L. and others, J. Pharmacol. Exp. Ther., 2001, 296, 1013).

Compounds according to this invention can be converted to forms suitable for injection, using conventional methods, using excipients and/or liquid or solid media.

Compounds according to the present invention, usually administered in the form of pharmaceutical compositions, which are important and new embodiments according to this invention due to the presence of compounds, in particular the specific compounds disclosed in this context. Types of pharmaceutical compositions, which can be used include, but are not limited to, tablets, chewable tablets, capsules, solutions, parenteral solutions, suppositories, suspensions, and other types of disclosed here or obvious to the person skilled in the art from the description of the invention and prior art.

Embodiments according to this invention provide a pharmaceutical package or kit containing(s) one or more containers filled with one or more ingredients of the pharmaceutical compositions according to this invention. Associated with such container (containers) can be written informational materials, such as instructions for use and a notice in the form predicando the state Agency for regulation of production, use or sale of pharmaceutical products which reflects approval by the Agency of manufacture, use or sale for administration to humans or animals.

GENERAL ASPECTS of SYNTHESIS

Derivatives of thiazole can be obtained using known methods, for example:

a) Organic Reactions, volume VI, (1951), S. 367-409, ed. R. Adams, John Wiley and Sons Inc., New York;

b) J.S. Carter and others, Bioorg. Med. Chem. Lett. (1999), 9, 1167-1170;

(C) T. T. Sakai and others, Bioorg. Med. Chem. (1999), 7, 1559-1566;

d) A. Tanaka and others, J. Med. Chem. (1994), 37, 1189-1199;

e) J.J. Talley and others, patent WO 9603392: Chem. Abstr., 125, 33628;

f) V. Cecchetti and others, Bioorg. Med. Chem. (1994), 2, 799-806;

g) T. Eicher and others, The Chemistry of Heterocycles, (1995), S. 149-155, Georg Thieme Verlag, Stuttgart, 1995, ISBN 313-100511-4, and here links;

h) T.L. Gilchrist, Heterocyclic Chemistry, 3rd ed., 1997, S. 319-327, Longman, UK, ISBN 0-582-27843-0.

Alpha halogenation can be obtained by halogenation of the corresponding ketone. Reaction of alpha-halogenocarboxylic compounds and thioamide can lead to a large number of derivatives of thiazole. More specifically, as a result of condensation of alpha-bromoketones with ethylthioxanthone receive (2-etoxycarbonyl)thiazole General formula (II).

The compounds of formula (II) can be converted into the corresponding N-methoxy-N-methylamide (III) and then to enter into interaction with the reagent alkyllithium or abilities, receiving the compound of General formula (I), where x represents subgroup (i).

Compounds of General formula (II) can be lidirovat using an amine of General formula R3R4NH with obtaining compounds of General formula (I), where X represents subgroup (ii). Such amidation can be catalysed using (CH3)3Al. (For more information about indirect aluminum conversion of esters to amides, see J.I. Levin, E. Turos, S.M. Weinreb, Synth. Commun., (1982), 12, 989-993).

Alternatively, the compound having the formula (II)is converted into the corresponding carboxylic acid and then injected into the interaction with the so-called halogenation agent such as, for example, thionyl chloride (SOCl2). When this reaction receive the appropriate carbonylchloride, which is then injected into interaction with the compound having the formula R3R4NH, where R3andR4have the meanings as described above.

Alternatively, hard-ester group in the compound (II) can be converted into the corresponding carboxylic acid. This carboxylic acid can enter into interaction with the compound having the formula R3R4NH, where R3andR4have the meanings as described here above, through the activation methods and linking, such as the formation of the active complex ether, or in the presence of the so-called binding reagent, such as, for example, DCC, HBTU, HOAT (N-hydroxy-7-azabenzo eazol), The THIEF, CIP (2-chloro-1,3-dimethylimidazolidine), PyAOP (7-sabastiano-1-yloxytris(pyrrolidino)fosfodiesterasa) and the like. (For more information about how to activate and bind, see (a) M. Bodanszky, A. Bodanszky: The Practice of Peptide Synthesis, Springer-Verlag, new York, 1994; ISBN: 0-387-57505-7; (b) K. Akaji, etc., Tetrahedron Lett. (1994), 35, 3315-3318; c) F. Albericio and others, Tetrahedron Lett. (1997), 38, 4853-4856).

The following compounds can be obtained in accordance with these methods. They are intended to further, more detailed illustration of this invention and is therefore not considered to be limiting the scope of protection of the invention in any way.

The SYNTHESES ACCORDING to INDIVIDUAL EXAMPLES

1H-NMR spectra were recorded on a Varian instrument UN400 (400 MHz) with tetramethylsilane was as an internal standard. Chemical shifts get in ppm (d-scale) in the weak field from tetramethylsilane. Constant interaction (J) are expressed in Hz. Thin-layer chromatography carried out on pre-coated F25460 plates Merck and zone visualize ultraviolet radiation. Flash chromatography carried out using silica gel 60 (0,040-0,063 mm, Merck). Column chromatography is carried out using silica gel 60 (0,063-0,200 mm, Merck). The melting temperature recorded on the device for determining the melting temperature of Büchi B-545 and not correct.

Example 1

Example 1

Part a: To a solution of 1-(2,4-dichlorophenyl)-2-phenylethanone (54,35 g, 0,205 mol) in benzene (220 ml) was slowly added bromine (10,6 ml, 0,205 mol) and the resulting solution was stirred at room temperature for 1 hour. Slowly add water 5%solution of NaHCO3. Separate the organic layer, dried over MgSO4, filtered and evaporated in vacuo to obtain crude 2-bromo-1-(2,4-dichlorophenyl)-2-phenylethanone (69,4 g, yield 98%) as oil.

1H-NMR (400 MHz, CDCl3): δ of 6.20 (s, 1H), 7,26 (DD, J=8 and 2 Hz, 1H), 7,31-to 7.50 (m, 7H).

Part b: 2-Bromo-1-(2,4-dichlorophenyl)-2-phenylethanone (25,83 g of 0.075 mol) and atitikimas (15.0 g, 0,112 mol) is dissolved in absolute ethanol (200 ml). The resulting mixture is heated at boiling temperature under reflux for 16 hours. After evaporation in vacuo the crude substance was dissolved in a mixture of water and dichloromethane. Separate the dichloromethane layer and the aqueous layer was extracted three times with dichloromethane. The collected organic layers are dried (MgSO4), filtered and concentrated. The resulting material purified by column chromatography (silica gel/dichloromethane) to give 4-(2,4-dichlorophenyl)-5-phenylthiazol-2-carboxylate (10.5 g, yield 37%).

1H-NMR (400 MHz, CDCl3): δ T,46 (t, J=7 Hz, 3H), 4,53 (kV, J=7 Hz, 2H), 7.24 to 7,38 (m, 7H), the 7.43 (d, J=2 is C, 1H).

The part With: To a solution of ethyl-4-(2,4-dichlorophenyl)-5-phenylthiazol-2-carboxylate (10.5 g, 0,028 mol) in methanol (170 ml) is added slowly a solution of KOH (8,9 g, 0,0896 mol) in water (170 ml). The resulting solution was heated at 90°C for 2 hours and cooled to room temperature. Add a mixture of concentrated HCl and ice. The precipitate is collected, washed with water and diethyl ether and dried to obtain 4-(2,4-dichlorophenyl)-5-phenylthiazol-2-carboxylic acid (8,99 g, yield 92%). Melting point: 105aboutC.

Part D: To stir with a magnetic stirrer suspension of 4-(2,4-dichlorophenyl)-5-phenylthiazol-2-carboxylic acid (4,2 g, 0.012 mol) in anhydrous dichloromethane (170 ml) was successively added 7-Aza-1-hydroxybenzotriazole (HOAT) (4,083 g, being 0.030 mol), 7-sabastiano-1-yloxytris(pyrrolidino)phosphonium-hexaphosphate (PyAOP) (15,64 g, 0.03 mol), diisopropylethylamine (6,26 ml, being 0.036 mol) and N-methoxy-N-methylamine·HCl (2,925 g, being 0.030 mol) and the resulting solution was stirred for 16 hours at room temperature. Slowly add water 5%solution of NaHCO3and the resulting mixture was extracted (3 times) with dichloromethane. The collected organic layers are dried (MgSO4), filtered and concentrated to obtain a crude oil (18,9 g). Purify using flash chromatography (silica gel; ethyl acetate/petroleum ether = 1/1)to give N-m is l-N-methoxy-4-(2,4-dichlorophenyl)-5-phenylthiazol-2-carboxamide (4.0 g, yield 85%).

1H-NMR (400 MHz, CDCl3): δ 3,60 (Sirs, 3H), 3,90 (s, 3H), 7,21-7,33 (m, 7H), was 7.45 (d, J=2 Hz, 1H).

Similarly receive N-methyl-N-methoxy-4-(2-chlorophenyl)-5-phenylthiazol-2-carboxamide.

1H-NMR (400 MHz, CDCl3): δ 3,62 (Sirs, 3H), 3,90 (s, 3H), 7,22 was 7.45 (m, 9H).

Part E: To a cooled (-70° (C) and stirred solution of N-methyl-N-methoxy-4-(2,4-dichlorophenyl)-5-phenylthiazol-2-carboxamide (2.0 g, of 0.005 mol) in THF (20 ml) in an atmosphere of N2add n-BuLi (3,13 ml, 1.6 M solution in hexane, of 0.005 mol). After stirring for 30 minutes the solution is held until it reaches room temperature and stirred for 16 hours. Add an aqueous solution of HCl (20 ml, 1 n) and the resulting mixture extracted with diethyl ether. Layers of diethyl ether, washed with water (2 times), dried (MgSO4), filtered and concentrated to obtain a crude oil (2,03 g). Purify using flash chromatography (silica gel/dichloromethane)to give 1-[4-(2,4-dichlorophenyl)-5-phenylthiazol-2-yl]pentane-1-she (0.6 g, yield 31%).

1H-NMR (400 MHz, CDCl3): δ of 0.95 (t, J=7 Hz, 3H), of 1.38 to 1.48 (m, 2H), 1,72 and 1.80 (m, 2H), and 3.16 (t, J=7 Hz, 2H), 7,20-7,35 (m, 7H), 7,46 (d, J=2 Hz, 1H).

Similarly receive

Example 2

Example 2

1H-NMR (400 MHz, CDCl3): δ of 0.93 (t, J=7 Hz, 3H), 1.26 in-the 1.44 (m, 6H), 1,73-to 1.82 (m, 2H), 3.15 in (t, J=7 Hz, 2H), 7,21-7,34 (m, 7H), 7,47 (d, J=2 Hz, 1H).

Example 3

Example 3

Melting point 78-80°C.

Example 4

Example 4

1H-NMR (400 MHz, CDCl3): δ of 0.93 (t, J=7 Hz, 3H), 1,25-of 1.44 (m, 6H), 1,73-to 1.82 (m, 2H), 3,17 (t, J=7 Hz, 2H), 7,22-7,40 (m, 8H), 7,47 (DD, J=8 and 2 Hz, 1H).

Example 5

Example 5

Melting point 131-132°C.

Example 6

Example 6

Part a: To stir with a magnetic stirrer a solution of 1-phenylheptane-1-he (23.7 g, 0.125 mol) in benzene (160 ml) was slowly added bromine (7,0 ml, 0.125 mol) and the resulting solution is kept for interaction at room temperature for 1 hour. Slowly add water 5%solution of NaHCO3with the subsequent addition of dichloromethane. Separate the organic layer, dried over MgSO4, filtered and evaporated in vacuo to obtain crude 2-bromo-1-phenylheptane-1-it (41.8 g, quantitative yield) as oil.

1H-NMR (400 MHz, CDCl3): δ of 0.90 (t, J=7 Hz, 3H), 1,28-of 1.78 (m, 6H), 2,04 was 2.25 (m, 2H), 5,11-5,16 (m, 1 H), 7,42 to 7.62 (m, 3H), 8,00-of 8.04 (m, 2H).

Part b: 2-Bromo-1-phenylheptane-1-he (20,17 g of 0.075 mol) and atitikimas (15.0 g, 0,112 mol) is dissolved in absolute ethanol (200 ml). The resulting mixture is heated at boiling temperature under reflux for 16 hours. After evaporation in vacuum is iroe substance dissolved in a mixture of water and dichloromethane. Separate the dichloromethane layer and the aqueous layer was extracted three times with dichloromethane. The collected organic layers are dried (MgSO4), filtered and concentrated. The resulting material purified by column chromatography (silica gel; dichloromethane/petroleum ether = 1/1) to obtain ethyl 5-(n-pentyl)-4-phenylthiazol-2-carboxylate (12,09 g, yield 53%) as a slowly curing oil. Melting point 51-52°C.

The part With: To stir with a magnetic stirrer a solution of ethyl-5-(n-pentyl)-4-phenylthiazol-2-carboxylate (12,09 g 0,039 mol) in methanol (240 ml) is added slowly a solution of KOH (8,9 g) in water (240 ml). The resulting solution was heated at boiling temperature under reflux for 2 hours and then cooled to room temperature. Add a mixture of concentrated HCl and ice. The precipitate is collected, sequentially washed with water and cold diethyl ether and dried to obtain 5-(n-pentyl)-4-phenylthiazol-2-carboxylic acid (3,54 g, yield 32%).

1H-NMR (400 MHz, CDCl3): δ of 0.87 (t, J=7 Hz, 3H), 1,28-of 1.40 (m, 4H), from 1.66 to 1.76 (m, 2H), 2.93 which is 3.00 (m, 2H), 4.00 points (Sirs, 1H), 7,35-7,46 (m, 3H), 7,58-to 7.64 (m, 2H).

Part D: To stir with a magnetic stirrer suspension of 5-(n-pentyl)-4-phenylthiazol-2-carboxylic acid (1.18 g, 0,0043 mol) in anhydrous dichloromethane (35 ml) was successively added 7-Aza-1-hydroxybenzyl eazol (HOAT) (1,46 g, 0,0107 mol), 7-sabastiano-1-yloxytris - and CIS-mertaniemi (CAS (pyrrolidino)phosphodiesterase (Roar) (5,59 g, 0,0107 mol), diisopropylethylamine (2,24 ml, 0,0129 mol) and aniline (0,98 ml, 0,0107 mol) and the resulting solution was stirred for 16 hours at room temperature. The resulting mixture was concentrated and purified using flash chromatography (silica gel/dichloromethane) to give N-phenyl-5-(n-pentyl)-4-phenylthiazol-2-carboxamide (0,89 g, yield 59%).

1H-NMR (400 MHz, CDCl3): δ and 0.98 (t, J=7 Hz, 3H), 1,26-of 1.41 (m, 4H), 1,68-of 1.78 (m, 2H), 2,97 (t, J=7 Hz, 2H), 7,12-to 7.18 (m, 1H), 7,34-7,52 (m, 5H), 7,60-to 7.64 (m, 2H), 7,69-7,74 (m, 2H), 9,10 (Sirs 1H).

Similarly receive

Example 7

Obtained from 5-(n-pentyl)-4-phenylthiazol-2-carboxylic acid and 1-aminoadamantana.

Melting point 90-92°C.

Example 8

Obtained from 5-(n-pentyl)-4-phenylthiazol-2-carboxylic acid 38235-68-6).

1H-NMR (400 MHz, CDCl3): δ to 0.89 (t, J=7 Hz, 3H), of 1.08 (s, 3H), of 1.20 (s, 3H), 1,26-to 1.38 (m, 4H), 1,50-of 1.62 (m, 1H), 1,66-of 1.74 (m, 2H), 1,82-2,04 (m, 5H), 2,28-to 2.40 (m, 2H), equal to 2.94 (t, J=7 Hz, 2H), 3,39-to 3.50 (m, 2H), 7,29 (shirt, J=7 Hz, 1H), 7,37-of 7.60 (m, 5H).

Example 9

Example 9

Part a: 1-Bromo-1-phenylheptane-2-he (19,98 g 0,074 mol) and atitikimas (15.0 g, 0,112 mol) is dissolved in absolute ethanol (200 ml). The resulting mixture is heated under those is the boiling temperature under reflux for 2 hours. After evaporation in vacuo the crude substance was dissolved in a mixture of water and dichloromethane. Separate the dichloromethane layer and the aqueous layer was extracted three times with dichloromethane. The collected organic layers are dried (MgSO4), filtered and concentrated. The resulting material purified by column chromatography (silica gel; dichloromethane/petroleum ether = 1/1) to obtain ethyl-4-(n-pentyl)-5-phenylthiazol-2-carboxylate (5,24 g, yield 23%) as oil.

1H-NMR (400 MHz, CDCl3): δ to 0.89 (t, J=7 Hz, 3H), 1,24-of 1.32 (m, 4H), of 1.44 (t, J=7 Hz, 3H), 1.70 to of 1.78 (m, 2H), 2,81-2,87 (m, 2H), 4,48 (kV, J=7 Hz, 2H), 7,40-of 7.48 (m, 5H).

Similarly receive

Ethyl-4-benzyl-5-phenylthiazol-2-carboxylate in the form of oil.

Ethyl-5-(n-pentyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylate.

Melting point 92-93°C.

Part b: To stir with a magnetic stirrer a solution of 1-aminoadamantana (1,607 g, 0,0086 mol) in anhydrous dichloromethane (10 ml) was added Al(CH3)3(4.3 ml, 2 M solution in hexane, 0,0086 mol) and the resulting solution is kept for interaction at room temperature for 10 minutes. Slowly add water 5%solution of NaHCO3. Extracted with dichloromethane, dried over MgSO4, filtered and concentrated in vacuo and subsequent column chromatography (silica gel; dichloromethane)to give N-(adamant-1-yl)-4-(n-pentyl)-5-phenylthiazol-2-carbox the ID (1,17 g, yield 72%).

1H-NMR (400 MHz, CDCl3): δ to 0.88 (t, J=7 Hz, 3H), of 1.26 to 1.34 (m, 4H), 1,68-of 1.78 (m, 8H), 2,08-to 2.18 (m, N), 2,71 was 2.76 (m, 2H), 7,02 (Sirs, 1H), of 7.36 was 7.45 (m, 5H).

Similarly receive

Example 10

Derived from ethyl-4-(n-pentyl)-5-phenylthiazol-2-carboxylate and CIS-mertaniemi (CAS 38235-68-6).

1H-NMR (400 MHz, CDCl3): δ to 0.89 (t, J=7 Hz, 3H), 1,10 (s, 3H), 1,22 (s, 3H), of 1.25 to 1.34 (m, 4H), 1,54-of 1.78 (m, 3H), 1,84-to 2.06 (m, 5H), 2,31-to 2.42 (m, 2H), 2,72-2,78 (m, 2H), 3,44-to 3.50 (m, 2H), 7.24 to 7,28 (m, 1H), 7,37-7,46 (m, 5H).

Example 11

Example 11

Derived from ethyl-4-(n-pentyl)-5-phenylthiazol-2-carboxylate and cyclohexylamine.

The melting point of 84-85°C.

Example 12

Example 12 Exo

Derived from ethyl-5-(n-pentyl)-4-phenylthiazol-2-carboxylate and Exo-2-aminobutyl[2.2.1]heptane.

Melting point 64-65°C.

Example 13

Example 13 endo

Derived from ethyl-5-(n-pentyl)-4-phenylthiazol-2-carboxylate and endo-2-aminobutyl[2.2.1]heptane.

The melting point of 80-82°C.

Example 14

Example 14

Derived from ethyl-5-(n-pentyl)-4-phenylthiazol-2-carboxylate and 4-isopropylpiperazine.

The melting point of 84-85°C.

Example 15

Example 15

Derived from ethyl-5-(n-pentyl)-4-phenylthiazol-2-carboxylate and indan-2-ylamine.

1H-NMR (400 MHz, CDCl3): δ of 0.85 (t, J=7 Hz, 3H), 1,26-to 1.38 (m, 4H), of 1.65 and 1.75 (m, 2H), 2,90-a 3.01 (m, 4H), 3,36-3,44 (m, 2H), 4,86-4,96 (m, 1H), 7,15-7,27 (m, 4H), 7,35-7,47 (m, 4H), 7,52-7,56 (m, 2H).

Example 16

Example 16

Derived from ethyl-5-(n-pentyl)-4-phenylthiazol-2-carboxylate and 3-amino-3-azabicyclo[3.3.0]octane.

Melting point 86-87°C.

Example 17

Example 17

Derived from ethyl-5-(n-pentyl)-4-phenylthiazol-2-carboxylate and 1,2,3,4-tetrahydroisoquinoline.

Melting point 50-51°C.

Example 18

Example 18

Derived from ethyl-5-(n-pentyl)-4-phenylthiazol-2-carboxylate and R-(+)-Binyamina (CAS 32511-34-5).

1H-NMR (400 MHz, CDCl3): δ 0,90-1,02 (m, 13H), to 1.22 to 1.47 (m, 6H), 1.60-to of 1.84 (m, 5H), 2,36 at 2.45 (m, 1H), equal to 2.94 (t, J=7 Hz, 2H), 4,36-of 4.44 (m, 1H), 7,32 (sird, J=7 Hz, 1H), 7,38-to 7.50 (m, 3H), 7,58-7,63 (m, 2H).

Example 19

Example 19

Derived from ethyl-4-benzyl-5-phenylthiazol-2-carboxylate and cyclohexylamine.

Melting point 104-106°C.

Example 20

Example 20

Derived from ethyl-5-(n-pentyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylate and cyclohexylamine.

1NAMR (400 MHz, CDCl3): δ of 0.85 (t, J=7 Hz, 3H), 1,13-of 1.46 (m, 8H), 1,55 by 1.68 (m, 4H), 1,71 and 1.80 (m, 2H), 1,96-to 2.06 (m, 2H), to 2.67 (t, J=7 Hz, 2H), 3,86-3,98 (m, 1H), 7,05 (sird, J=7 Hz, 1H), 7,26-7,37 (m, 2H), 7,53 (d, J=2 Hz, 1H).

Example 21

Example 21

Derived from ethyl-5-(n-pentyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylate and cyclopentylamine.

1H-NMR (400 MHz, CDCl3): δ of 0.85 (t, J=7 Hz, 3H), 1,20-1,30 (m, 4H), 1,48-1,77 (m, 8H), 2,01 is 2.10 (m, 2H), to 2.67 (t, J=7 Hz, 2H), or 4.31-to 4.41 (m, 1H), 7,09 (sird, J=7 Hz, 1H), 7,25-7,37 (m, 2H), 7,53 (d, J=2 Hz, 1H).

Example 22

Example 22

Derived from ethyl-4-benzyl-5-phenylthiazol-2-carboxylate and n-pentylamine.

1H-NMR (400 MHz, CDCl3): δ to 0.89 (t, J=7 Hz, 3H), 1,33-of 1.40 (m, 4H), 1,59-to 1.67 (m, 2H), 3,40-3,47 (m, 2H), 4.16 the (s, 2H), 7,15-to 7.32 (m, 6H), 7,39-7,42 (m, 5H).

Example 23

Example 23

Derived from ethyl-5-(n-pentyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylate and 1-aminopiperidine.

1H-NMR (400 MHz, CDCl3): δ of 0.85 (t, J=7 Hz, 3H), 1,20 of 1.28 (m, 4H), 1,39 of 1.46 (m, 2H), 1.56 to of 1.64 (m, 2H), 1,71-to 1.79 (m, 4H), to 2.66 (t, J=7 Hz, 2H), 2,82-is 2.88 (m, 4H), 7,29 (d, J=8 Hz, 1H), 7,35 (DD, J=8 and 2 Hz, 1H), 7,53 (d, J=2 Hz, 1H), 7,88 (Sirs, 1H).

Example 24

Example 24

Derived from ethyl-5-(n-pentyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylate and 4-aminomorpholine.

1H-NMR (400 MHz, CDCl3): δ of 0.85 (t, J=7 Hz, 3H), 1,21-of 1.29 (m, 4H), 1,57-of 1.66 (m, 2H), to 2.67 (t, J=7 Hz, H), 2,93 are 2.98 (m, 4H), 3,82-3,88 (m, 4H), 7,29 (d, J=8 Hz, 1H), 7,35 (DD, J=8 and 2 Hz, 1H), 7,54 (d, J=2 Hz, 1H), 7,95 (Sirs, 1H).

Example 25

Example 25

Derived from ethyl-5-(n-pentyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylate and N-methylaniline.

1H-NMR (400 MHz, CDCl3): δ 0,80 (shirt, J=7 Hz, 3H), 1,14 of 1.28 (m, 4H), 1,50-of 1.62 (m, 2H), 2,56-of 2.66 (m, 2H), 3,56 (Sirs, 3H), 6,80 was 7.45 (m, 8H).

The RESULTS of PHARMACOLOGICAL TESTS

Data on the affinity in relation to the cannabinoid receptor, obtained in accordance with the above protocols are listed in the table below.

The affinity to the receptor
human SV1human SV2
ConnectionPKivaluePKivalue
Example 16,6
Example 46,8
Example 77,3
Example 86,8
Example 97,88,1
Example 106,98,1
Example 116,67,7

1. With the unification of the formula (I)

where R and R1are the same or different and represent phenyl, optionally substituted by 1-3 substituents Y, where Y is a Deputy chosen from the group comprising chlorine, iodine, bromine, fluorine, provided that X is not a subset of (ii);

or one of the radicals R and R1represents a phenyl group and the other radical is a branched or linear C2-8is an alkyl group or a benzyl group;

X represents one of the groups (i) or (ii)

where R2represents a branched or linear C3-8is an alkyl group or phenyl group, provided that when R2represents a phenyl group, R is not phenyl or 4-chlorophenyl,

R3represents hydrogen, a branched or linear C1-3is an alkyl group;

R4represents a branched or linear C1-10is an alkyl group, a C3-8-cycloalkyl group5-10-bicycloalkyl group5-10-bicycloalkyl-C1-2is an alkyl group, a C6-10-tricyclohexyl group6-10-tricyclohexyltin group, and groups can be substituted by 1-3 is utilname groups,

or R4represents a phenyl group, a group NR5R6,

where R5and R6together with the nitrogen atom to which they are attached, form a saturated or unsaturated, monocyclic or bicyclic, heterocyclic group having 4 to 10 atoms in the ring, and the heterocyclic group contains one or two heteroatoms from the group (O and N) and the said heterocyclic group may be substituted branched or linear C1-3is an alkyl group, or

R3and R4together with the nitrogen atom to which they are attached, form a saturated or unsaturated, monocyclic or bicyclic, heterocyclic group having 4 to 10 atoms in the ring, and the heterocyclic group contains one or two N heteroatoms;

and its pharmacologically acceptable salts.

2. The compound according to claim 1 or its pharmacologically acceptable salt as modulators of cannabinoid CB-receptor.

3. The use of the compounds of formula (I)

and its pharmacologically acceptable salts, where

R, R1and X are defined in claim 1, to obtain a pharmaceutical composition having properties antagonist of cannabinoid CB-receptor.

4. The pharmaceutical composition active modulator of cannabi odnogo SV-receptor, containing as active ingredient at least one compound according to claim 1.

5. The compound of General formula (IV)

where one of the radicals R and R1represents a phenyl group, optionally substituted by 1-3 substituents Y, where Y has the above meaning, and the other radical is a branched or linear C2-8is an alkyl group, and R7represents a hydroxyl group, a branched or linear C1-4-alkoxygroup.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention concerns method of treatment, alleviation and/or prevention of neurological state, particularly neurodegenerative disorders, involving administration of effective quantity of compound with formula I: . Also invention concerns application of compound of the formula I as neurotherapeutical, neuroprotective or antimyloid agent, pharmaceutical or veterinary composition for treatment, alleviation and/or prevention of neurological states, and compounds of the formula I on the following additional terms: (b) if R3, R and R' are H, and R2 is (CH2)2NR9R10, then both R9 and R10 are not ethyl or methyl; (c) if R3, R and R' are H, and R2 is (CH2)2NR9R10, then both R9 and R10 are not hydrogen or ethyl; (d) if R3, R and R' are H, and R2 is NR11R12, then both R11 and R12 are not hydrogen; (e) if R3, R and R' are H, and R2 is COR6, then R6 is not H, OH or CH2Cl; (f) if R3, R and R' are H, and R2 is not CH3 or CH2Cl; (g) if R3, R and R' are H, and R2 is HCNN R9R10, then both R9 and R10 are not H.

EFFECT: efficient treatment, alleviation and prevention of neurological state.

24 cl, 14 tbl, 21 ex, 14 dwg

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) , where R1 is phenyl optionally substituted by halogen, cyano, C1-4alkyl or C1-4haloalkyl; R2 is hydrogen, C1-6alkyl or C3-6cycloalkyl; and R3 is a group with NH or OH and calculated or measured pKa from 1.0 to 8.0, selected out of: 2-oxo-thiazol-5-yl with C1-4fluoroalkyl, optionally substituted phenyl group, optionally substituted heterocyclyl group or CH2S(O)2(C1-4alkyl) group in position 4; 2-oxo-oxazol-5-yl with C1-4fluoroalkyl or CH2S(O)2(C1-4alkyl) in position 4; 1H-1,2,3-triazol-4-yl with C1-4alkyl, C3-6cycloalkyl, C1-4fluoroalkyl, S-R4 (where R4 is C1-4alkyl, C1-4fluoroalkyl or C3-6cycloalkyl), NHS(O)2(C1-4alkyl), N(C1-4alkyl)S(O)2(C1-4alkyl), phenyl group, heterocyclyl group or CH2S(O)2C1-4alkyl) group in position 5; 4-oxo-1H-1,4-dihydropyridine-3-yl with C1-4fluoroalkyl in position 2; 2,6-dioxo-1H-1,2,3,6-tetrahydropyrimidine-4-yl with C1-4alkyl, C3-6cycloalkyl or CH2(C1-3fluoroalkyl) in position 3 and optionally substituted in one or more other ring positions; 6-oxo-1H-1,6-dihydropyridine-3-yl with C1-4fluoroalkyl, cyano or phenyl in position 2 and/or in position 5 and optionally substituted in one or more other ring positions; 6-oxo-1H-1,6-dihydropyridine-3-yl with CH2CO2H at ring nitrogen atom and optionally substituted in one or more other ring positions; 2H-tetrazol-5-yl; CO2H, CH2CO2H or OCH2CO2H group at optionally substituted phenyl, optionally substituted CH2O phenyl or optionally substituted naphtyl ring or optionally substituted acylated dihydroisoquinolinyl ring; or group NHS(O)2(C1-4alkyl) at optionally substituted aromatic heterocyclic ring; or their tautomer where possible; in indicated positions where heterocyclyl ring in R3 can be optionally substituted, it can be optionally substituted by fluoro, chloro, bromo, C1-4alkyl, C3-6cycloalkyl, C1-4fluoroalkyl, S-R4 (where R4 is C1-4alkyl, C1-4fluoroalkyl or C3-6cycloalkyl), cyano, S(O)2(C1-4alkyl); in indicated positions where phenyl or naphtyl ring in R3 can be optionally substituted, it can be optionally substituted by halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4fluoroalkyl, OCF3, SCF3, nitro, S(C1-4alkyl), S(O)(C1-4alkyl), S(O)2(C1-4alkyl), S(O)2NH(C1-4alkyl), S(O)2N(C1-4alkyl)2, NHC(O)(C1-4alkyl) or NHS(O)2(C1-4alkyl); or its pharmaceutically acceptable salts. Also invention concerns compounds of formula (I), method of obtaining compounds of any of claims 1-12, as well as pharmaceutical composition.

EFFECT: obtaining novel bioactive compounds with chemokine receptor activity modulation effect.

16 cl, 51 ex

FIELD: chemistry.

SUBSTANCE: invention claims derivatives of pyridazin-3(2H)-one of formula (I), where R1, R2 and R4 are organic radicals described in the claim 1, R3 is cyclic group described in the claim, and R5 is phenyl or heteroaryl group described in the claim. Compounds of formula (I) inhibit phosphodiesterase 4 (PDE-4) and can be applied in treatment of various diseases or pathological states alleviated by PDE-4 inhibition, and in medicine production for treatment of aforesaid diseases. Also invention claims method of obtaining these compounds and intermediate compounds for their obtainment.

EFFECT: obtaining compounds which can be used in treatment of various diseases or pathological states and in medicine production for treatment of aforesaid diseases.

25 cl, 28 tbl, 243 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with formula I: , where L represents radical , in which R1 represents H, C1-4alkyl; n represents 0 or 1; or L represents radical , in which R1 represents H, C1-4alkyl; m equals 1; R represents H, halogen, C1-C4alkyl or C1-C4-alkoxy; Z represents a bond, -C(O)NH-, O or S; p is an integer from 1 to 5; Q represents a bond with the condition that, Z is not a bond, when p equals 1; or represents O, S or -C(O)NR6-, where R6 represents H, C1-4alkyl or C3-6cycloalkyl; or W and R6 together with a nitrogen atom, to which they are bonded, form or or Q represents -NR6-, or in the condition that, p is not equal to 1; W represents , , , , ,

, , ,

, , ,

, , , ,

, , , ,

, , , ,

, , , , ,

, , , , , and

.

EFFECT: obtaining compounds with agonistic activity towards PPAR receptors, which enables them to be used in pharmaceutical compositions and methods of treating conditions, mediated by these receptors.

12 cl, 7 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula 1 and their pharmaceutically acceptable salts as inhibitors of post-proline aminopepdidases, as well as to pharmaceutical composition based on them and application for manufacturing such composition, and to method of inhibition with their application. Compounds can be applied for treatment of diseases mediated by activity of post-proline aminopeptidases, such as type II diabetes and disturbed tolerance to glucose. In general formula 1 ,

either G1 represents -CH2-X2-(CH2)a-G3, and G2 represents H, or G2 represents -CH2-(CH2)a-G3, and G1 represents H; G3 is selected from group according to general formula 2 ,

group according to general formula 3

and group according to general formula 4 ;

a is 0, 1 or 2; b is 1 or 2; X1 is selected from CH2, S, CF2, CHF and O; X2 is selected from CH2; X3, X4 and X5 are selected from N; X6 is selected from NH; X7 is selected from NH; R1 is selected from H and CN; R2 represents H; R3 is selected from H, Cl, OH, NH2, NH-C1-C10alkyl and N(C1-C10alkyl)2; R4, R5, R6, R7 and R8 are independently selected from H, Br, Cl, F, OH, NO2; R9 represents H; R10, R11, R12, R13 and R14 are independently selected from H, Cl and CF3; R15 and R16 are independently selected from H, C1-C10alkyl, C1-C10alkenyl, C3-C10cycloalkyl, C3-C10cycloalkenyl, quinoline, naphtyl and -CH2-L-R17; R17 is selected from C1-C10alkyl, phenyl, naphtyl, quinolinyl and indolyl; L is selected from covalent bond, CH=CH and -C6H4-; on condition that when R15 and R16 both represent H, and b is 1, then X1 does not represent S or CH2.

EFFECT: obtaining compounds that can be applied for treatment of diseases mediated by activity of post-proline aminopeptidases, such as type II diabetes and disturbed tolerance to glucose.

58 cl, 10 tbl, 1705 ex

FIELD: chemistry.

SUBSTANCE: this invention refers to compounds of formula where one of R6, R7 or R8 means , and X, Y, substitutes of R1-R13 and n are as it is defined in item 1 of formula of invention, and to all their enantiomers, to pharmaceutically acceptable salts and/or esters.

EFFECT: production of compounds for treatment and/or prevention of diseases modulated by PPARδ and/or PPARα agonists.

26 cl, 1 tbl, 35 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to methods of obtaining rosiglytasone, rosiglytasone, obtained by said methods, and its pharmacological compositions and methods of treatment using it.

EFFECT: obtaining of new crystalline modifications of rosiglytasone, which have useful biological properties.

58 cl, 4 dwg, 2 tbl, 9 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to novel compounds of formula (I), its pharmaceutically acceptable salts, possessing qualities of chemokine receptor modulators. Compounds can be applied for asthma, allergic rhinitis, COLD, inflammatory intestinal disease, irritated intestine syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis, psoriasis or cancer. In compound of formula (I) , R1 represents group selected from C1-8alkyl, said group is possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4 , -NR5R6 , phenyl, phenyl is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4,-NR5R6,-SR10,C1-6alkyl and trifluoromethyl; R2 represents group selected from C1-8alkyl, said group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-(C1-6alkyl)-N-(phenyl)amino; R3 represents hydrogen, R4 represents hydrogen or group selected from C1-6alkyl and phenyl, R5 and R6, independently, represent hydrogen or group selected from C1-6alkyl and phenyl, said group being probably substituted with 1, 2 or 3 substituents, independently selected from -OR14, -NR15R16, -COOR14,-CONR15R16, or R5 and R6 together with nitrogen atom, to which they are bound, form 4-7-member saturated heterocyclic ring system, possibly containing additional heteroatom, selected from oxygen and nitrogen atoms, ring possibly being substituted with 1, 2 or 3 substituents, independently selected from -OR14, -COOR14,-NR15R16,CONR15R16 and C1-6alkyl; R10 represents hydrogen or group selected from C1-6alkyl or phenyl; and each from R7, R8, R9, R14, R15, R16 independently represents hydrogen, C1-6alkyl or phenyl; X represents hydrogen, halogeno; Rx represents trifluoromethyl, -NR5 R6 , phenyl, naphtyl, heteroaryl, heteroring can be partly or fully saturated, and one or more ring carbon atoms can form carbonyl group, each phenyl or heteroaryl group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR4, -NR5R6, -CONR5R6, -COR7, -COOR7, -NR8COR9, -SR10, -SO2R10, -SO2NR5R6, -NR8SO2R9, C1-6alkyl or trifluoromethyl; or Rx represents group selected from C1-6alkyl, said group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6, phenyl or heteroaryl, where heteroaryl represents monocyclic or bicyclic aryl ring, containing from 5 to 10 ring atoms, from which 1, 2 or 3 ring atoms are selected from nitrogen, sulfur or oxygen. Invention also relates to methods of obtaining compounds, versions, pharmaceutical composition and application for manufacturing medications using compounds of invention.

EFFECT: obtaining novel compounds of formula (I), its pharmaceutically acceptable salts, possessing properties of chemokine receptor moduators.

25 cl, 138 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula (I) HetAr represents pyrimidinyl or thiadiasolyl; R1 and R2 represent H; A represents C1-C2-alkyl; B represents aryl(CH2)0-3-O-C(O)-or arylcyclopropyl-C(O)-, in which aryl can be substituted with 1-5 substituents, each substituent represents C1-C4-alkyl. Invention also relates to pharmaceutical composition and to application of compounds of item 1. Obtaining novel compounds, as well as pharmaceutical composition possessing NMDA/NR2B antagonist activity.

EFFECT: increase of composition efficiency.

13 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new compounds with general formula: , where R is -(CH2)n-A, where A: where each of B and C independently represent phenyl or phenyl substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl) and -NO2; or n equals an integer from 0 to 3; n1 equals an integer from 1 to 3; n2 equals an integer from 0 to 4; n3 equals an integer from 0 to 3; n4 equals an integer from 0 to 2; X1 is chosen from a chemical bond -S-, -S(O)2-, -NH-, -NHC(O)- and -C=C-, R1 is chosen from C1-C6alkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, tetrahydropyranyl, CN, -N(C1-C6alkyl)2, phenyl, pyridinyl, pyrimidinyl, furyl, thienyl, naphtyl, morpholinyl, triazolyl, pyrazolyl, piperidinyl, pyrrolidinyl, imidazolyl, piperizinyl, thiazolydinyl, thiomopholinyl, tetrazolyl, benzoxazolyl, imidazolidine-2-thionyl, 7,7-dimethylbicyclo[2.2.1]heptane-2-onyl, benzo[1.2.5]oxadiazolyl, 2-oxa-5-azabicyclo[2.2.1]heptyl and pyrrolyl, each of which can be optionally substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NO2, -SO2(C1-C3alkyl), -SO2NH2, -SO2N(C1-C3alkyl)2, -COOH, -CH2-COOH, pyridyl, 2-methylazolyl, morpholino, 1-chloro-2-methylpropyl, phenyl, (optionally substituted with one or more halogens), benzyloxy, and , X2 selected from -O-, -CH2-, -S-, -SO-, -SO2-, -NH- and , R2 represents a ring group, chosen from a phenyl or thienyl group. Each ring group is substituted with a group with formula -(CH2)n4-CO2H; and besides that, the ring group can optionally be substituted with 1 or 2 extra substitutes, independently chosen from halogen, - C1-C6alkyl and -C1-C6alkoxy; R3 is chosen from H, halogen and -NO2; R4 is chosen from H, halogen and morpholino; or its salt form, used in pharmaceuticals. The invention also relates to pharmaceutical compositions, to methods of treatment, and to compounds with formula (A).

EFFECT: obtaining new biologically active compounds and pharmaceutical compositions based on them, which have inhibiting effect on cytosolic phospholipase A2.

45 cl, 300 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds with inhibition effect on thrombocyte aggregation, their pharmaceutically acceptable salts, particularly compounds of general formula (I) (where R1 is C1-C6 alkyl etc., R2 is hydrogen, C2-C7 alkanoyl, C7-C11 arylcarbonyl, group of formula R4-(CH2)1- etc., R3 is C6-C10 aryl etc., X1, X2, X3, X4 and X5 are independently hydrogen, halogen etc., and n is an integer from 0 to 2), its pharmaceutically acceptable salts. Invention claims pharmaceutical compositions inhibiting thrombocyte activation and containing claimed compounds as agent.

EFFECT: obtaining compounds applicable as media of prevention and treatment of diseases related to thrombo- or embologenesis.

26 cl, 272 ex, 8 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: compounds of this invention possess properties of protein kinase inhibitors. In the general formula p means integer within 0 to 2; R and R1 mean O; A1 and A2 mean single bond, (C1-C6)alkyl; B2 means monocyclic or bicyclic, saturated or unsaturated heterocyclic radical including 1 to several identical or different heteroatoms, chosen among O, S, N and NR7, probably substituted with one or several identical or different substitutes.

EFFECT: inhibiting effect on protein kinase, effective application of compounds of formula for medical products.

49 cl, 1 tbl, 6 dwg, 334 ex

FIELD: chemistry.

SUBSTANCE: described are 2,6-substituted pyridine-3-carbonyl derivatives of formula (I) , in which A stands for alkandiyl, is necessary disrupted by oxygen; X stands for halogen, alkylsulfonyl with 1-6 carbon atoms; Y stands for heterocycle and, if necessary, heterocycle can contain SO2-group or oxo-group (C=O), possibly substituted by alkyl, alkoxy, alkylthio with 1-6 carbon atoms in alkyl groups; Z stands for group of formula: or . Also described are intermediate derivatives of formulas (II) and (IV) .

EFFECT: extension of range of substituted pyridylketones with herbicidal activity.

3 cl, 3 tbl, 49 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: compound of formula [I]: is described, where the ring A represents halogen substituted benzene ring; the ring B represents benzene ring substituted with two lower, 1 to 4 carbon atoms, alcoxy-groups; the ring C represents benzene ring or five-member aromatic heterocyclic ring, that may be optionally substituted with substitute as follows: carboxyl group, C1-4-alkyl group, C2-7-alkanoiloxy-C1-6-alkyl group, phenyl-C1-4-alkyl group, phenyl group, optionally substituted with carboxyl group, or oxo-group; R1 represents C1-6-alkyl group, optionally substituted with hydroxyl group, that optionally substituted with C2-20-alkanoil or C1-7-alkyl group; X1a represents bound or C1-6-alkylen, optionally substituted with hydroxyl or oxo-group; X1b represents bound or C1-6-alkylen, optionally substituted with hydroxyl or oxo-group; X2 represents bound, -O- or -S- ; X3 represents bound or group, formed by one hydrogen atom elimination from either straight or branched chain C1-7-alkyl, or C2-6-alkenyl group, that optionally substituted with hydroxyl or oxo-group; and Y represents optionally etherified carboxyl group; or its salt. Benzoxazepin derivatives production method, medicine based on them, and their application are also described.

EFFECT: novel compounds have high lipids-decreasing effect and are helpful as hyperlipidemia prevention and treatment medicine.

20 cl, 168 ex

FIELD: chemistry; medicine.

SUBSTANCE: invention concerns aryl- or heteroarylcarbonylpiperazine compound of the general formula (I) , where R1 is selected out of the group including fluorene-9-on, isoxazole, cinnoline, isothiazole, isoquinoline, 9H-fluorene, 9H-xanthene and 1H-pyrazole, where linkage is implemented by any desired and possible end atom of heteroaryl or aryl radical, so that they can optionally be unsubstituted or mono- or disubstituted by substitutes: halogen, SO2-alkyl, saturated alkyl, non-saturated alkyl with one double link, halogenalkyl where alkyl part contains 1 to 20 carbon atoms, phenyl optionally mono- or disubstituted by substitutes: NO2, -OH, -NH2, halogen; R2 is O; R3 is H; R4 is phenyl substituted by one or two substitutes selected out of group: OH, halogen, alkyl, alkoxy, where alkyl part contains 1 to 20 carbon atoms; or 5, 6 or 7-atom cyclic aromatic radical including N heteroatom and substituted by alkyl containing 1 to 20 carbon atoms; m and n are 1; or its physiologically acceptable salt. The invention also concerns method of obtaining compound of the formula (I), application of compounds of the formula (I) as therapeutically effective compounds for obtaining medication for human and animal tumour treatment, medical preparations based on compound of the formula (I), method of obtaining medications and method of benignant and malignant tumour treatment. The compounds inhibit tubulin polymerisation, thus enabling their application for indicated purpose.

EFFECT: improved efficiency.

15 cl, 2 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: description is given of the substituted pyridine with formula in which the substituting groups have values given in paragraph 1 of the formula of invention. Description is also given of the herbicide compound on its base and the derived pyridine of formula , in which the substituting groups have values given in paragraph 4 of the formula of invention, which is an intermediate product.

EFFECT: compounds have an herbicide action.

5 cl, 24 tbl, ex

FIELD: chemistry.

SUBSTANCE: invention pertains to compounds with formula I or to its pharmaceutically accepted salts: where R1 is chosen from phenyl, thienyl, furanyl and thyazolyl; and R2, R3, R4 and R5 are independently chosen from hydrogen and C1-6alkyl. The invention also relates to the use and methods of obtaining compounds of formula I, as well as to compounds of formula III.

EFFECT: obtaining new biologically active compounds.

12 cl, 5 ex, 2 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: invention relates to the novel compounds with formula (I) and their pharmaceutically acceptable salts. The compounds of this invention has the properties of the NPY receptor antagonists and can be used fortreatment of such diseases as arthritis, diabetes, malnutrition, obesity. In general formula (I) , R1 means phenyl or 6-term nitrogen-containing heteroaryl, where in at least one of two meta-positions each phenyl group or 6-term nitrogen-containing heteroaryl group is substituted by group R5; R2 means hydrogen; R3 means C3-C6cycloalkyl, naphthyl, phenyl or 5-6-term heteroaryl, containing N or S as heteroatoms, where in at least one of two ortho-positions each group of C3-C6 cycloalkyl, naphthyl, phenyl or 5-6-term heteroaryl, containing N or S as heteroatoms, substituted by group R6; R4 means hydrogen, C1-C6alkyl; R5 means hydrogen, cyano, trifluoromethyl, C1-C6alkyl-SO2-, amino-SO2-, halogen, C1-C6alcoxy, C1-C6alkylcarbonil or aminocarbonil; R6 means hydrogen, halogen, cyano, nitro, trifluoromethyl, C1-C6 alkyl, C1-C6 alcoxy or hydroxy, provided, one R5 group, and R6 doesn't mean hydrogen.

EFFECT: described compounds and based on them pharmaceutical agents are efficient in treatment and prevention of above listed diseases.

19 cl, 2 tbl, 2 dwg, 130 ex

FIELD: chemistry.

SUBSTANCE: invention covers new compounds of formula I or its salts suitable for pharmacology: , where R1 is selected from phenyl, pyridyl, thienyl, difurylglyoxal, imidazolyl, pyrrolyl and thiazolyl; R2, R3 and R4 independently are d-zalkyl or halogenated C1-zalkyl; and R5 is hydrogen. And also new intermediate compounds formula III: , where R2, R3 and R4 independently are C1-3alkyl or halogenated C1-6alkyl; and R5 is hydrogen. Invention also covers method of production of compound formula I and their applications.

EFFECT: production of new biologically active compounds.

12 cl, 9 ex, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 3-hydrozy-2-pyridone represented by the formula (I): wherein R1 means aryl optionally substituted with one or more alkyl group; R2 means hydrogen atom; each R3 and R4 is taken independently of one another from hydrogen atom, alkyl, alkylheteroaryl and aralkyl group; or R3 and R4 in common with nitrogen atom bound with them form heteroaryl or heterocycloaryl substitute optionally substituted with one halogen atom, alkoxy group, aryl, heteroaryl and heterocycloalkyl; R5 and R6 mean hydrogen atom. Also, invention relates to using the compound by any claims among 1-7 for preparing pharmaceutical compositions showing antibacterial properties, and to above said pharmaceutical compositions. Invention provides synthesis of novel compounds possessing useful biological properties, and a pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

9 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula I R1 represents phenyl, possibly substituted with phenyl or heterocyclic group, or heterocyclic group, possibly substituted with phenyl, where said heterocyclic group represents mono- or bicyclic ring, containing 4-12 atoms, of which at least one atom is selected from nitrogen, sulfur or oxygen, each phenyl or heterocyclic group possibly being substituted with one or more than one of the following groups: C1-6alkyl group; phenylC1-6alkyl, alkyl, phenyl or alkylphenyl group is possibly substituted with one or more than one from Rb; halogen; -ORa; -OSO2Rd; -SO2Rd; -SORd; -SO2ORa; where Ra represents H, C1-6alkyl group, phenyl or phenylC1-6alkyl group; where R represents halogeno, -OH, -OC1-4alkyl, Ophenyl, -OC1-4alkylphenyl, and Rd represents C1-4alkyl; group -(CH2)m-T-(CH2)n-U-(CH2)p- is bound either in third, or in fourth position in phenyl ring, as shown with figures in formula I, and represents group selected from one or more than one of the following: O(CH2)2, O(CH2)3, NC(O)NR4(CH2)2, CH2S(O2)NR5(CH2)2, CH2N(R6)C(O)CH2, (CH2)2N(R6)C(O)(CH2)2, C(O)NR7CH2, C(O)NR7(CH2)2 and CH2N(R6)C(O)CH2O; V represents O, NR8 or single bond; q represents 1, 2 or 3; W represents O, S or single bond; R2 represents halogeno or C1-4alkoxyl group; r represents 0, 1, 2 or 3; s represents 0; and R6 independently represent H or C1-10alkyl group; R4, R5, R7 and R8 represent hydrogen atom; and to their pharmaceutically acceptable salts.

EFFECT: increase of composition efficiency.

12 cl, 31 ex

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