Substituted 4-imidazoles, method for preparing and using them

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new imidazole derivatives of formula I wherein R1 represents a hydrogen atom or C1-7alkyl; R2 represents C1-7alkyl; R3 represents C1-7alkyl, C1-7alkoxy, phenyloxy, benzyloxy, a halogen atom or C1-7alkyl substituted by a halogen atom; R4 represents a hydrogen atom or C1-7alkyl; X represents -CH2-, -CHR2 - or -O; Y represents -CH2-, -CH2CH2- or a bond; provided X represents -O-, Y represents -CH2-; Z represents -CH2- or -CHR2-; provided R2 is found twice, simultaneously for X and Z which are CHR2 , then R2 can be identical alkyls or different; n has the value 0, 1 or 2; provided n has the value 2, R3 can be identical or different; and its pharmaceutically acceptable acid addition salts, except for the following compounds: 1-(1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline and 1-(3H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indole. Also, the invention refers to a method for preparing the compounds of formula I, to a drug based on the compound of formula I and applying the compound of formula I in preparing the drug.

EFFECT: there are prepared new imidazole derivatives effective in treating such pathological conditions, as bipolar disorder, stress-induced disorder, psychotic disorders, schizophrenia, neurological conditions, Parkinson's disease, neurodegenerative disorders, Alzheimer's disease.

13 cl, 61 ex

 

The present invention relates to compounds of formula I,

where R1represents a hydrogen atom or lower alkyl;

R2represents a hydrogen atom or lower alkyl;

R3represents a hydrogen atom, lower alkyl, lower alkoxy, phenyloxy, benzyloxy, halogen atom, or

lower alkyl substituted by halogen atom;

R4represents a hydrogen atom or lower alkyl;

X represents-CH2-, -CH - or-O-;

Y represents-CH2-, -CH2CH2-, -CH -, or a bond; when X represents-O-, Y represents-CH2-;

Z represents-CH2- or-CH-;

m is 1 or 2; when m is set to 2, R2may be the same or different;

n is 1 or 2; when n is set to 2, R3may be the same or different;

and their pharmaceutically acceptable salts accession acids.

The invention includes all their racemic mixtures, all corresponding enantiomers and/or optical isomers.

In addition, all tautomeric forms of the compounds of formula I are also included within the scope of the present invention.

It is established that the compounds of formula I have a high affinity for receptors associated with trace amines (trace amine associated receptors, TAAR), especially the TAAR1.

These compounds can be used in the treatment of depression, anxiety disorders, bipolar disorder, attention deficit disorder and hyperactivity disorder (ADHD), a disorder caused by stress, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse, addictive, metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of consumption and assimilation of energy, and disorders of temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular-vascular diseases.

Classical biogenic amines (serotonin, norepinephrine, epinephrine, dopamine, histamine) as neurotransmitters play an important role in Central and peripheral nervous system [1]. Their synthesis and storage, as well as their degradation and reuptake after release is strictly regulated. It is known that an imbalance of the levels of biogenic amines is responsible for modifying the function of the brain in many pathological conditions [2-5]. Compounds that form the second class of endogenous amines, the so-called trace amines (trace amines, TA), very similar to the classic Biogen is passed amines in its structure, metabolism and subcellular localization. THAT include para-tyramine, β-phenylethylamine, tryptamine, octopamine, and their level in the nervous system of mammals is significantly below the level of the classical biogenic amines [6].

Violation of their regulation is associated with various mental illnesses such as schizophrenia and depression [7], and other conditions such as attention deficit disorder and hyperactivity, headache type migraine, Parkinson's disease, substance abuse, addictive, and eating disorders [8, 9].

For a long time the existence of TA-specific receptors was just a hypothesis, based on the presence in the Central nervous system (CNS) of humans and other mammals anatomically discrete binding sites with high affinity to THE [10, 11]. Accordingly, it was believed that the pharmacological effect THAT is mediated by the same well-known mechanism, and that the action of the classical biogenic amines, that is, a signal that causes their release or inhibition of their reuptake or "cross-linking" with their receptor system [9, 12, 13]. Recently this view has undergone significant changes in connection with the identification of several members of a new family of GPCR (G-beloxepin receptors), Retz is Perov, associated with trace amines (trace amine associated receptors, TAAR) [7, 14]. Found 9 TAAR genes in the human genome (including the 3 pseudo) and 16 genes in the mouse genome (including 1 pseudogene). TAAR genes do not contain introns (with one exception, TAAR2 contains 1 intron) and are adjacent on the same chromosome segment. The phylogenetic relationship of the genes of these receptors, in accordance with a high degree of similarity with GPCR-pharmacophores and in accordance with the pharmacological data suggests that these receptors form three different subfamilies [7, 14]. TAAR1 refers to the first division, consisting of four genes (TAAR1-4), which are represented in the genomes of human and rodent highly conserved sequences. THE activate TAAR1 through Gα. It is shown that the violation of the regulation THAT is associated with the etiology of various diseases, such as depression, psychosis, attention deficit disorder and hyperactivity, substance abuse, addictive, Parkinson's disease, headache type migraine, eating disorders, metabolic disorders, and therefore, the use of TAAR1-ligands in the treatment of these diseases may be very promising.

Therefore, the acquisition of new knowledge about the receptors associated with the trace amines (trace amine associated receptors), is very important.

The literature dealing with the RA

1. Deutch, A.Y. and Roth, R.H. (1999) Neurotransmitters. In Fundamental Neuroscience (2ndedn) (Zigmond, M.J., Bloom, F.E., Landis, S.C., Roberts, J.L, and Squire, L.R., eds.), pp.193-234, Academic Press;

2. Wong, M.L. and Licinio, J. (2001) Research and treatment approaches to depression. Nat. Rev. Neurosci. 2, 343-351;

3. Carlsson, A. et al. (2001) Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence. Annu. Rev. Pharmacol. Toxicol. 41, 237-260;

4. Tuite, P. and Riss, J. (2003) Recent developments in the pharmacological treatment of PA's disease. Expert Opin. Investig. Drugs 12, 1335-1352;

5. Castellanos, F.X. and MP, R. (2002) Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nat. Rev. Neurosci. 3, 617-628;

6. Usdin, E. and Sandler, M. eds. (1984), Trace Amines and the brain, Dekker;

7. Lindemann, L. and Hoener, M. (2005) A renaissance in trace amines inspired by a novel GPCR family. Trends in Pharmacol. Sci. 26, 274-281;

8. Branchek, T.A. and Blackburn, T.P. (2003) Trace amine receptors as targets for novel therapeutics: legend, myth and fact. Curr. Opin. Pharmacol. 3, 90-97;

9. Premont, R.T. et al. (2001) Following the trace of elusive amines. Proc. Natl. Acad. Sci. U.S.A. 98, 9474-9475;

10. Mousseau, D.D. and Butterworth, R.F. (1995) A high-affinity [3H] tryptamine binding site in human brain. Prog. Brain Res. 106, 285-291;

11. McCormack, J.K. et al. (1986) Autoradiographic localization of tryptamine binding sites in the rat and dog central nervous system. J. Neurosci. 6, 94-101;

12. Dyck, LE (1989) Release of some endogenous trace amines from rat striatal slices in the presence and absence of a monoamine oxidase inhibitor. Life Sci. 44, 1149-1156;

13. Parker, E.M. and Cubeddu, L.X. (1988) Comparative effects of amphetamine, phenylethylamine and related drugs on dopamine efflux, dopamine uptake and mazindol binding. J. Pharmacol. Exp. Ther. 245, 199-210;

14. Lindemann, L. et al. (2005) Trace amine associated receptors form structurally and functionally distinct subfamilies of novel G protein-coupled receptors. Genomics 85, 372-385.

The aim of the present invention are new compounds forms the crystals I, receive them, the drugs based on the compounds according to the invention and their manufacture, as well as the use of compounds of formula I for the control of diseases such as depression, anxiety disorder, bipolar disorder, attention deficit disorder and hyperactivity disorder, stress-induced psychotic disorder, such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse, addictive, metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of consumption and assimilation of energy, disorders and disturbances of temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disease, or for the prevention of these diseases.

Preferred indications for the use of compounds of the present invention are depression, psychosis, Parkinson's disease, anxiety and attention deficit disorder and hyperactivity disorder (ADHD).

In the context of this description, the term "lower alkyl" means a group with a saturated normal or branched chain, containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopro the sludge, n-butyl, ISO-butyl, 2-butyl, tert-butyl and the like. Preferred alkyl groups are groups containing 1-4 carbon atoms.

In the context of this description, the term "lower alkoxy" means a group where the alkyl residue, such as defined above, attached via an oxygen atom.

In the context of this description, the term "lower alkyl substituted by halogen atom"means an alkyl group such as defined above, where at least one hydrogen atom replaced by a halogen atom, for example, CF3, CHF2CH2F, CH2CF3CH2CH2CF3CH2CF2CF3and the like.

The term "halogen atom" means a chlorine atom, iodine, fluorine and bromine.

The term "pharmaceutically acceptable salts join acid" includes salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, para-toluensulfonate acid and the like.

Preferred compounds of formula I are those compounds where X represents CH2and Y represents a bond.

These compounds include

(RS)-1-(1H-imidazol-4-ylmethyl)-2-IU the Il-2,3-dihydro-1H-indole,

1-(3H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indole,

5-bromo-1-(1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indole,

5-chloro-1-(1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indole,

(RS)-5-chloro-1-(1H-imidazol-4-ylmethyl)-2-methyl-2,3-dihydro-1H-indole,

7-ethyl-1-(1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indole,

4-chloro-1-(1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indole,

1-(1H-imidazol-4-ylmethyl)-5-methoxy-2,3-dihydro-1H-indole,

1-(1H-imidazol-4-ylmethyl)-6-methoxy-2,3-dihydro-1H-indole,

1-(1H-imidazol-4-ylmethyl)-7-methoxy-2,3-dihydro-1H-indole,

1-(1H-imidazol-4-ylmethyl)-5-methyl-2,3-dihydro-1H-indole,

1-(1H-imidazol-4-ylmethyl)-4-methoxy-2,3-dihydro-1H-indole,

7-chloro-1-(1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indole,

1-(1H-imidazol-4-ylmethyl)-6-methyl-2,3-dihydro-1H-indole,

(RS)-1-(1H-imidazol-4-ylmethyl)-3-methyl-2,3-dihydro-1H-indole,

5-fluoro-1-(1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indole,

6-fluoro-1-(1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indole,

5,6-debtor-1-(1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indole,

(RS)-5-fluoro-1-(1H-imidazol-4-ylmethyl)-2-methyl-2,3-dihydro-1H-indole,

1-(1H-imidazol-4-ylmethyl)-7-methyl-2,3-dihydro-1H-indole or

1-(1H-imidazol-4-ylmethyl)-4-methyl-2,3-dihydro-1H-indole.

Preferred compounds of formula I are those compounds where X represents CH2and Y is CH2.

These compounds include

(RS)-1-(1H-imidazol-4-ylmethyl)-2-methyl-1,2,3,4-Tetra the draw quinoline,

(RS)-6-fluoro-1-(1H-imidazol-4-ylmethyl)-2-methyl-1,2,3,4-tetrahydro-quinoline,

1-(3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline,

6-bromo-1-(1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline,

(-)-1-(1H-imidazol-4-ylmethyl)-2-methyl-1,2,3,4-tetrahydro-quinoline,

5-benzyloxy-1-(1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline,

7-benzyloxy-1-(1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline or

1-(1H-imidazol-4-ylmethyl)-5-phenoxy-1,2,3,4-tetrahydro-quinoline.

Preferred compounds of formula I are those compounds where X is a and Y is CH2.

These compounds include

4-(1H-imidazol-4-ylmethyl)-3,4-dihydro-2H-benzo[1,4]oxazin,

(RS)-4-(1H-imidazol-4-ylmethyl)-3-methyl-3,4-dihydro-2H-benzo[1,4]oxazin or

(-)-4-(1H-imidazol-4-ylmethyl)-3-methyl-3,4-dihydro-2H-benzo[1,4]oxazin.

Preferred compounds of formula I are those compounds where X represents CH2and Y is CH2CH2.

These compounds include

1-(3H-imidazol-4-ylmethyl)-7-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin or

1-(3H-imidazol-4-ylmethyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin.

Compounds of the present invention of the formula I and their pharmaceutically acceptable salts may be obtained using methods known in the art, for example using neuopsychological, which include

a) reductive amination, where the compound of the formula

interacts with the compound of the formula

obtaining the compounds of formula

where R1, R2, R3, R4, X, n and m are as defined above, or

b) reductive amination, where the compound of the formula

interacts with the compound of the formula

obtaining the compounds of formula

.

where R1, R2, R3, R4, m, and n are as defined above, or

b) reductive amination, where the compound of the formula

interacts with the compound of the formula

obtaining the compounds of formula

,

where R1, R2, R3, R4X, Y, m, and n are as defined above; and

if desired, the conversion of the compounds obtained into pharmaceutically acceptable salts accession acids.

The compounds of formula I can be obtained using the above-described variants of the method in accordance with the following schemes 1-4. The source of the substance or are selling the e, or described in the chemical literature, or can be obtained using techniques well known in the art.

Method 1

Scheme 1

Scheme 1 describes the reductive amination using 1,2,3,4-tetrahydroquinoline (X=CH2) or 3,4-dihydro-2H-benzo[1,4]oxazine (X=O) of formula II, as the amine component, and imidazole-4-carboxaldehyde or (imidazol-4-yl)-alkyl-ketone of formula III, as the carbonyl component.

Method 2

Scheme 2

Scheme 2 describes the reductive amination using indolinone the compounds of formula IV, as the amine component, and imidazole-4-carboxaldehyde or (imidazol-4-yl)-alkyl-ketone of formula III, as the carbonyl component. Data indolinone compounds can be obtained by restoring the appropriate antolovich analogues of formula V.

Method 3

Scheme 3

Scheme 3 describes the reductive amination using indolinone connection (-X-Y=-CH2-), or 1,2,3,4-tetrahydroquinoline connection (-X-Y=-CH2-CH2-), or 3,4-dihydro-2H-benzo[1,4]oxazino connection (-X-Y-=-O-CH2-) the formula VI, as the amine component, and imidazole-4-carboxaldehyde or (imidazol-4-yl)-and the keel-ketone of the formula III, as the carbonyl component. These amino compounds may be obtained from the corresponding 1,3-dihydro-indol-2-about the connection (-X-Y=-CH2-), or 3,4-dihydro-2(1H)-hinolinovogo connection (-X-Y=-CH2-CH2-), or 2H-1,4-benzoxazin-3(4H)-about the connection (-X-Y-=-O-CH2-) the formula VII by adding a Grignard reagent and subsequent recovery.

Method 4

Scheme 4

PG = protective group for the nitrogen atom, stable to the conditions used for the conversion of FG1in R3such as tert-butoxycarbonyl (VOS)

In those cases, when the starting material contains a reactive functional group (for example, free hydroxyl group on the aryl ring, before performing the recovery stage amination can be performed in the transformation of functional groups. To perform the transformation of the desired functional groups, it is often useful to first protect the nitrogen atom that participates in the recovery aminating at the next stage. For example, the nitrogen atom may be protected by conversion to tert-BUTYLCARBAMATE grouping. Examples of transformations of functional groups include well-known transformations of functional groups already described in the chemical literature, such as prewash is the FG1 = hydroxy, R 3= alkilany ether by treatment with base such as sodium hydride, and an alkylating agent such as alkylhalogenide. Another possible transformation of the functional groups is a transformation FG1= hydroxy, R3= arrowy ether by treating arylboronic acid and copper acetate (II) in accordance with the method described by Evans et al. (Tetrahedron Lett. 1998, 39, 2937-2940).

Isolation and purification of compounds

Isolation and purification of the compounds and intermediates described in this invention can be performed, if desired, using any suitable methods of separation or purification, such as, for example, filtration, extraction, crystallization, column chromatography, thin layer chromatography, chromatography in a thick layer, preparative liquid chromatography low or high pressure, or using combinations of these techniques. Specific illustrations of suitable separation techniques or selection, you can reference the preparations and examples given in this description below. However, could be used and other equivalent methods of separation or discharge. Racemic mixtures of chiral compounds of formula I can be separated using chiral ghvd (liquid chromatography high pressure).

Salts of compounds Formula

The compounds of formula I are bases and can be converted into the corresponding salt accession acid. This conversion is carried out by processing at least a stoichiometric amount of a suitable acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like and such organic acids as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid, econsultancy acid, para-toluensulfonate acid, salicylic acid and the like. Usually the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and add acid in the same solvent. The temperature maintained within the range from 0°C to 50°C. the Resulting salt or spontaneously precipitates, or can be precipitated out of solution with a less polar solvent.

Salt accession acids the major compounds of formula 1 can be converted into the corresponding free OS is Finance by processing at least a stoichiometric equivalent of a suitable base, such as sodium hydroxide or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia and the like.

The compounds of formula 1 and their pharmaceutically acceptable salts accession possess useful pharmacological properties. Specifically, it was found that the compounds of the present invention have a high affinity for receptors associated with trace amines (trace amine associated receptors, TAAR), especially for TAAR1.

These compounds have been investigated in accordance with the test described in this description below.

Materials and methods

Design TAAR-expressing plasmids and stably transfected cell lines

To construct expressing plasmids amplified coding sequences TAAR1 from human genomic DNA, rats and mice essentially as described by Lindemann et al. [14]. Used the Expand High Fidelity PCR System (Roche Diagnostics) with 1.5 mm Mg2+and purified PCR products were cloned into the cloning vector pCR2.1-TOPO (Invitrogen) according to the manufacturer's instructions. PCR products were subcloned into the vector plRESneo2 (BD Clontech, Palo Alto, California), and prior to introduction into the cell line sequences obtained expressing plasmids was confirmed by sequencing.

Cells HEK293 (ATS (American type culture collection) # CRL-1573) were cultured essentially as described by Lindemann et al.(2005). To obtain stably transfected cell lines HEK293 cells were transfusional expressing plasmids plRESneo2 containing coding sequences TAAR (described above) using a reagent for transfection with Lipofectamine 2000 (Invitrogen) according to the manufacturer's instructions, and 24 hours after transfection in culture medium was added G418 (Sigma, Buchs, Switzerland) at a concentration of 1 mg/ml After cultivation for about 10 days, clones were isolated, subcultured, and explored their atachement on trace amines (all connections acquired Sigma) using the cAMP Biotrak Enzyme immunoassay (EIA) System (Amersham) in accordance with the Protocol EIA (enzyme immunoassay) without acetylation provided by the manufacturer. For all subsequent studies used a monoclonal cell line, which showed stable EU50(the concentration required to achieve 50% effect) during the cultivation period of 15 passages.

Preparation of membranes and binding radioligand

Cells from monolayer cell cultures were washed cooled to 0°C phosphate-salt buffer without CA2+and Mg2+containing 10 mm EDTA (ethylenediaminetetraacetate), and precipitated by centrifugation at 1000 rpm for 5 min at 4°C. Then the precipitate was twice washed cooled to 0°C phosphate-olivem buffer, and the cell sediment was immediately frozen by immersion in liquid nitrogen and stored until use at -80°C. Then the cell residue suspended in 20 ml buffer HEPES-NaOH (20 mm), pH 7.4, containing 10 mm EDTA, and homogenized at a transmitter station (PT 3000, Kinematica) at 10,000 rpm for 10 C. the homogenate was centrifuged at 48000 × g for 30 min at 4°C, and the precipitate resuspendable in 20 ml of buffer HEPES-NaOH (20 mm), pH 7.4, containing 0.1 mm EDTA(buffer A) and homogenized at a transmitter station at 10,000 rpm for 10 statem the homogenate was centrifuged at 48000 x g for 30 min at 4°C, and the precipitate resuspendable in 20 ml of buffer a and homogenized at a transmitter station at 10,000 rpm for 10 C. the protein Concentration was determined according to the methodology Pierce (Rockford, IL). Then the homogenate was centrifuged at 48000 × g for 10 min at 4°C, the precipitate resuspendable in the buffer HEPES-NaOH (20 mm), pH 7.0, containing MgCl2(10 mm) and CaCl2(2 mm), (buffer) to a protein concentration of 200 ml and homogenized at a transmitter station at 10,000 rpm for 10 sec.

The analysis of binding was performed at 4°C in a final volume of 1 ml, the incubation time was 30 min Radioligand [3H]-rat-2-(1,2,3,4-tetrahydro-1-naphthyl)-2-imidazolin used in concentrations equal to the calculated value of Kd60 nm, at which binds approximately 0.1% of the total added radioligand, and specific the binding is approximately 70-80% of the total binding. Nonspecific binding was defined as the amount of [3H]-rat-2-(1,2,3,4-tetrahydro-1-naphthyl)-2-imidazoline, linked in the presence of the corresponding unlabeled ligand (10 μm). Competing ligands investigated in a wide range of concentrations (10 PM - 30 μm). The final concentration of dimethylsulfoxide in the samples was 2%, and it had no effect on the binding of radioligand. Each experiment was performed with a double repetition. The incubation was stopped by rapid filtration through tablets UniFilter-96 (Packard Instrument Company) and a glass filter GF/C, which was pre-soaked for at least 2 h in 0.3% polyethylenimine, using a Filtermate harvester 96 Cell Harvester (Packard Instrument Company). The tubes and filters 3 times washed with aliquot of cold buffer In a volume of 1 ml. Filters without pre-drying soaked in Ultima gold (45 μl/well, Packard Instrument Company), and bound radioactivity was counted on the counter TopCount Microplate Scintillation Counter (Packard Instrument Company).

The table below shows the preferred connection, which in the analysis using mouse TAAR1 showed a Ki value in the range of 0.001-0,100 mm.

ExampleKi (µM) murine receptorsExampleKi ExampleKi
10,0688270,0389400,0405
20,0104280,0409410,0104
30,0258290,0115430,0538
40,0091310,0243440,0151
60,0598320,0403450,017
70,0264330,003470,0872
140,0102340,0133490,057
160,0345350,0323550,0046
180,0578360,0277570,0702
230,0042370,0106610,0027
250,0016380,0144
260,0834390,0493

The compounds of formula I and pharmaceutically acceptable salts of compounds of formula I can be used as medicaments, for example in the form of pharmaceutical preparations. Data pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. They may, however, be maintained that the same rectal, for example in the form of suppositories, parenterally, e.g. in the form of injection solutions.

To obtain pharmaceutical preparations of the compounds of formula I can be prepared together pharmaceutically inert, inorganic or organic carriers. For example, as such carriers for tablets, coated tablets, dragées and hard gelatin capsules can be used lactose, corn starch or its derivatives, talc, stearic acid or their salts and the like. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. In the case of soft gelatin capsules carriers usually are not required, but it depends on the nature of the active substance. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyol, glycerin, vegetable oil, and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

Furthermore, these pharmaceutical preparations can contain preservatives, soljubilizatory, stabilizers, moistening agents, emulsifiers, sweeteners, colorants, corrigentov, salts for regulating osmotic pressure, b is the atmospheric agents, masking agents or antioxidants. They can also contain other therapeutically useful substances.

Drugs, containing a compound of formula I or its pharmaceutically acceptable salt and a therapeutically inert carrier are also an object of the present invention, as the method of their manufacture, which includes the use of one or more than one compounds of formula I and/or pharmaceutically acceptable salts accession acids and, optionally, one or more than one other therapeutically useful substances in the form Galanova drug together with one or more than one therapeutically inert carrier.

The most preferred indications in accordance with the present invention are indications, which include disorders of the Central nervous system, for example the treatment or prevention of depression, psychosis, Parkinson's disease, anxiety, and attention deficit disorder and hyperactivity disorder (ADHD).

Of course, the dosage can vary within wide limits and is generally in each case it should be selected in accordance with individual needs. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day for compounds of General formula I or the corresponding the adequate range for its pharmaceutically acceptable salt. The daily dose can be administered as a single dose or in the form of fractional doses, and, in addition, can also be exceeded when indicated.

The method of cooking

1. Mix the substances 1, 2, 3 and 4 and granularit with purified water.

2. Dry the granules at 50°C.

3. Pass the granules through a suitable milling equipment.

4. Add substance 5 and stirred for three minutes; pressed on a suitable press.

Drug capsules
ItemIngredientsmg tablet
5 mg25 mg100 mg500 mg
1.The compound of the formula I525100500
2.Lactose water159123148-
3.Corn starch25354070
4.Talc10151025
5.Magnesium stearate1225
6.Only200200300600

The method of cooking

1. Mix the substances 1, 2 and 3 in a suitable mixer for 30 minutes.

2. Add substances 4 and 5 and mix for 3 minutes.

3. Fill a suitable capsule.

Experiments

The following examples illustrate the invention, but it is assumed that they do not limit its scope.

Example 1

(RS)-1-(1H-Imidazol-4-ylmethyl)-2-methyl-2,3-dihydro-1H-indol

To a solution of 2-methylindoline (0.50 g, 5,20 mmol) in 1,2-dichloroethane (12 ml) was sequentially added imidazole-4-carboxaldehyde (0.75 g, 7,81 mmol), triacetoxyborohydride the three is (of 3.31 g, 15.6 mmol) and acetic acid (0.06 ml, 1.04 mmol). This reaction mixture was shaken at 40°C for 16 hours, then was added triethylamine (0.5 ml) and the mixture was further shaken for 5 minutes the resulting suspension was filtered, and the filtrate was concentrated under vacuum. The residue was purified by chromatography on silica gel (eluent: gradient of methanol/dichloromethane) to obtain the specified title compound as a white solid (0.28 g, 25%); MS (ISP) (mass spectrometry with ionization by monoraphidium): 214,1 ([M+H+]).

The following compounds were obtained analogously to the compound of Example 1.

Example 2

1-(3H-Imidazol-4-ylmethyl)-2,3-dihydro-1H-indol

Received from indoline, imidazol-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 200,1 ([M+H]+).

Example 3

(RS)-1-(1H-Imidazol-4-ylmethyl)-2-methyl-1,2,3,4-tetrahydro-quinoline

Received from 1,2,3,4-tetrahydroquinoline, imidazol-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 228,4 ([M+H]+).

Example 4

5-Bromo-1-(1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indol

Was obtained from 5-bromoindoline, imidazol-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-DIH is oratane. MS (ISP): 280,1 ([{81Br}M+H]+), 278,1 ([{79Br}M+H]+).

Example 5

1-(1H-Imidazol-4-ylmethyl)-6-trifluoromethyl-2,3-dihydro-1H-indol

Was obtained from 6-(trifluoromethyl)indoline, imidazol-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 268,3 ([M+H]+).

Example 6

(RS)-6-Fluoro-1-(1H-imidazol-4-ylmethyl)-2-methyl-1,2,3,4-tetrahydro-quinoline

Was obtained from 6-fluoro-2-methyl-1,2,3,4-tetrahydro-quinoline, imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 246,3 ([M+H]+).

Example 7

1-(3H-Imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline

Received from 1,2,3,4-tetrahydro-quinoline, imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 214,4 ([M+H]+).

Example 8

(RS)-2-Methyl-1-(2-methyl-1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indol

Was obtained from 2-methylindoline, 2-methyl-imidazol-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 228,4 ([M+H]+).

Example 9

2-Methyl-1-(2-methyl-1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline

Received from 1,2,3,4-tetrahydroquinoline, 2-methyl-imidazole-4-Carbo is zaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 242,3 ([M+H]+).

Example 10

5-Bromo-1-(2-methyl-1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indol

Was obtained from 5-bromoindoline, 2-methyl-imidazol-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 294,0 ([{81Br}M+H]+), 292,0 ([{79In}M+H]+).

Example 11

1-(2-Methyl-1H-imidazol-4-ylmethyl)-6-trifluoromethyl-2,3-dihydro-1H-indol

Was obtained from 6-(trifluoromethyl)indoline, 2-methyl-imidazol-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): of 282.3 ([M+H]+).

Example 12

(RS)-6-fluoro-2-methyl-1-(2-methyl-1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline

Was obtained from 6-fluoro-2-methyl-1,2,3,4-tetrahydro-quinoline, 2-methyl-imidazol-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 260,3 ([M+H]+).

Example 13

1-(2-methyl-1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline

Received from 1,2,3,4-tetrahydroquinoline, 2-methyl-imidazol-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 228,6 ([M+H]+).

Example 14

5-Chloro-1-(1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indol

Was obtained from 5-floridain, imidazol-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 236,2 ([{37Cl}M+H]+), of 234.2 ([{35Cl}M+H]+).

Example 15

5-Chloro-1-(2-methyl-1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indol

Was obtained from 5-floridain, 2-methyl-imidazol-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 250,1 ([{37Cl}M+H]+), 248,2 ([{35Cl}M+H]+).

Example 16

(RS)-5-Chloro-1-(1H-imidazol-4-ylmethyl)-2-methyl-2,3-dihydro-1H-indol

a) (RS)-5-Chloro-2-methyl-2,3-dihydro-1H-indol

To a solution of 5-chloro-2-methylindole (1,00 g, 6,04 mmol) in acetic acid (7 ml) was added in portions cyanoborohydride sodium (0,76 g, 12.1 mmol)and this reaction mixture was stirred at room temperature for 16 hours. The resulting solution was diluted with ethyl acetate and then washed with water and 5 N. aqueous sodium hydroxide solution. The organic phase was dried over sodium sulfate and concentrated under vacuum. The residue was purified by chromatography on silica gel (eluant: gradient heptane/ethyl acetate) to obtain the specified title compound as a colourless oil (1,00 g, 100%); MS (ISP): 170,2 ([{37Cl}M+H]+), 168,3 ([{35Cl}M+H] +).

b) (RS)-5-Chloro-1-(1H-imidazol-4-ylmethyl)-2-methyl-2.3-dihydro-1H-indol

Was obtained similarly to the compound of Example 1 from (RS)-5-chloro-2-methyl-2,3-dihydro-1H-indole, imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 250,2 ([{37Cl}M+H]+), 248,3 ([{35Cl}M+H]+).

The following compound was obtained analogously to the compound of Example 16.

Example 17

(RS)-5-Chloro-2-methyl-1-(2-methyl-1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indol

Received from (RS)-5-chloro-2-methyl-2,3-dihydro-1H-indole, 2-methyl-imidazol-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): AZN 264.2 ([{37Cl}M+H]+), 262,2 ([{35Cl}M+H]+).

The following compounds were obtained analogously to the compound of Example 1.

Example 18

4-(1H-Imidazol-4-ylmethyl)-3,4-dihydro-2H-benzo[1,4]oxazin

Was obtained from 3,4-dihydro-2H-benzo[]1,4]oxazine, imidazol-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 216,4 ([M+H]+).

Example 19

4-(2-Methyl-1H-imidazol-4-ylmethyl)-3,4-dihydro-2H-benzo[1,4]oxazin

Was obtained from 3,4-dihydro-2H-benzo[]1,4]oxazine, 2-methyl-imidazol-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid is the acid in 1,2-dichloroethane. MS (ISP): 230,4 ([M+H]+).

Example 20

1-(2-Butyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline

Received from 1,2,3,4-tetrahydro-quinoline, 2-n-butyl-imidazol-4-carboxaldehyde, cyanoborohydride sodium and acetic acid in THF (tetrahydrofuran). MS (ISP): 270,4 ([M+H]+).

Example 21

1-(2-Butyl-3H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indol

Received from indoline, 2-n-butyl-imidazol-4-carboxaldehyde, cyanoborohydride sodium and acetic acid in THF. MS (ISP): figure of € 256.4 ([M+H]+).

The following compounds were obtained analogously to the compound of Example 16.

Example 22

(2RS,3RS)-1-(1H-Imidazol-4-ylmethyl)-2,3-dimethyl-2,3-dihydro-1H-indol

Received by reacting 2,3-dimethylindole and cyanoborohydride sodium in acetic acid and subsequent treatment imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 228,6 ([M+H]+).

Example 23

7-Ethyl-1-(1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indol

Was obtained by reacting 7-ethylindole and cyanoborohydride sodium acetic xlate and subsequent processing imidazol-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 228,6 ([M+H]+).

Example 24

6-Chloro-1-(N-imidazol-4-ylmethyl)-2,3-dihydro-1H-indol

Was obtained by reacting 6-chloroindole and cyanoborohydride sodium in acetic acid and subsequent treatment imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 236,2 ([{37Cl}M+H]+), 234,1 ([{35Cl}M+H]+).

Example 25

4-Chloro-1-(1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indol

Was obtained by reacting 4-chloroindole and cyanoborohydride sodium in acetic acid and subsequent treatment imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 236,2 ([{37Cl}M+H]+), 234,1 ([{35Cl}M+H]+).

Example 26

1-(1H-Imidazol-4-ylmethyl)-5-methoxy-2,3-dihydro-1H-indol

Was obtained by reacting 5-methoxyindole and cyanoborohydride sodium in acetic acid and subsequent treatment imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 230,4 ([M+H]+).

Example 27

1-(1H-Imidazol-4-ylmethyl)-6-methoxy-2,3-dihydro-1H-indol

Was obtained by reacting 6-methoxyindole and cyanoborohydride sodium in acetic acid and subsequent treatment imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and kusnoy acid in 1,2-dichloroethane. MS (ISP): 230,4 ([M+H]+).

Example 28

1-(1H-Imidazol-4-ylmethyl)-7-methoxy-2,3-dihydro-1H-indol

Was obtained by reacting 7-methoxyindole and cyanoborohydride sodium in acetic acid and subsequent treatment imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 230,4 ([M+H]+).

Example 29

1-(1H-Imidazol-4-ylmethyl)-5-methyl-2,3-dihydro-1H-indol

Was obtained by reacting 5-methylindole and cyanoborohydride sodium in acetic acid and subsequent treatment imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 214,3 ([M+H]+).

Example 30

(RS)-1-(1H-Imidazol-4-ylmethyl)-5-methoxy-2-methyl-2,3-dihydro-1H-indol

Was obtained by reacting 5-methoxy-2-methylindole and cyanoborohydride sodium in acetic acid and subsequent treatment imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 244,4 ([M+H]+).

Example 31

1-(1H-Imidazol-4-ylmethyl)-4-methoxy-2,3-dihydro-1H-indol

Was obtained by reacting 4-methoxyindole and cyanoborohydride sodium in acetic acid and subsequent processing imidazol-4-carboxamide the house, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 230,4 ([M+H]+).

Example 32

7-Chloro-1-(1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indol

Was obtained by reacting 7-chloroindole and cyanoborohydride sodium in acetic acid and subsequent treatment imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 236,2 ([{37Cl}M+H]+), 234,1 ([{35Cl}M+H]+).

The following compound was obtained analogously to the compound of Example 1.

Example 33

6-Bromo-1-(1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline

Was obtained from 6-bromo-1,2,3,4-tetrahydro-quinoline, imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 294,1 ([{81Br}M+H]+), 292,1 ([{79Br}M+H]+).

The following compounds were obtained analogously to the compound of Example 16.

Example 34

1-(1H-Imidazol-4-ylmethyl)-6-methyl-2,3-dihydro-1H-indol

Was obtained by reacting 6-methylindole and cyanoborohydride sodium in acetic acid and subsequent treatment imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 214,1 ([M+H]+).

Example 35

(RS)-1-(1H-Imidazol-4-ylmethyl)-3-methyl-2,3-digitron-indol

Was obtained by reacting 3-methylindole and cyanoborohydride sodium in acetic acid and subsequent treatment imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 214,1 ([M+H]+).

Example 36

5-fluoro-1-(1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indol

Was obtained by reacting 5-farindola and cyanoborohydride sodium in acetic acid and subsequent treatment imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 218,3([M+H]+).

Example 37

6-Fluoro-1-(1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indol

Was obtained by reacting 6-farindola and cyanoborohydride sodium in acetic acid and subsequent treatment imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 218,3([M+H]+).

Example 38

5,6-Debtor-1-(1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indol

Received by reacting 5,6-difterinaya and cyanoborohydride sodium in acetic acid and subsequent treatment imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 236,4 ([M+H]+).

Example 39

(RS)-5-fluoro--(1H-imidazol-4-ylmethyl)-2-methyl-2,3-dihydro-1H-indol

Was obtained by reacting 5-fluoro-2-methyl-indole and cyanoborohydride sodium in acetic acid and subsequent treatment imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 232,1 ([M+H]+).

Example 40

1-(1H-Imidazol-4-ylmethyl)-7-methyl-2,3-dihydro-1H-indol

Was obtained by reacting 7-methyl-indole and cyanoborohydride sodium in acetic acid and subsequent treatment imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 214,1 ([M+H]+).

Example 41

1-(1H-Imidazol-4-ylmethyl)-4-methyl-2,3-dihydro-1H-indol

Was obtained by reacting 4-methyl-indole and cyanoborohydride sodium in acetic acid and subsequent treatment imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 214,1 ([M+H]+).

Example 42

1-(5-fluoro-1H-imidazole-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline

a) 5-fluoro-1-(2-trimethylsilyl-ethoxymethyl)-1H-imidazole-4-carboxylic acid ethyl ester

To a stirred suspension of NaH (276 mg; 55% dispersion in mineral oil) in DMF (15 ml) at 0°C in an atmosphere of argon was added portions is within 10 min 5-fluoro-3H-imidazole-4-carboxylic acid ethyl ester (1.0 g) (strong bubbling!). The ice bath was removed, and the mixture (almost transparent light brown solution) was stirred at room temperature for 1 h 30 min the Mixture was again cooled in an ice bath and for 5 min was added 2-(trimethylsilyl)-ethoxymethylene (1,24 ml). Then the mixture is slowly heated to room temperature) was stirred for 16 hours Obtained yellow suspension was diluted with EtOAc (ethyl acetate) and washed with H2O. did the back extraction of the aqueous phase EtOAc (ethyl acetate) (25 ml). The combined organic phases are washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane → cyclohexane/EtOAc 3:2) to give 5-fluoro-1-(2-trimethylsilyl-ethoxymethyl)-1H-imidazole-4-carboxylic acid ethyl ester (of 1.57 g) as a pale yellow oil. MS (ISP): 288,9 ([M+H]+).

b) [5-fluoro-1-(2-trimethylsilyl-ethoxymethyl)-1H-imidazol-4-yl]-methanol

To a stirred solution of 5-fluoro-1-(2-trimethylsilyl-ethoxymethyl)-1H-imidazole-4-carboxylic acid ethyl ester (400 mg) in toluene (10 ml) at -78°C in an argon atmosphere was added dropwise DEBUG (diisobutylaluminium) (1,72 ml; 20% (by weight) solution in toluene) for 10 min (during the addition the temperature below -75°C. After stirring for 2 h at -78°C was recorded incomplete conversion of ester. Within 5 min was added another portion of the solution DEBUG (1,17 ml), and stirring was continued at -78°C for 1 h 30 min the Mixture was suppressed by adding 10 ml of concentrated aqueous solution of tartrate of potassium-sodium. Performed back extraction of the aqueous phase EtOAc (ethyl acetate). The combined organic phases are washed with H2O and brine, dried over MgSO4, filtered and concentrated to obtain [5-fluoro-1-(2-trimethylsilyl-ethoxymethyl)-1H-imidazol-4-yl]-methanol in the form of a yellowish solid (346 mg). This crude product without further purification was used in the next stage of the reaction. MS (ISP): 247,3 ([M+H]+).

C) 5-fluoro-1-(2-trimethylsilyl-ethoxymethyl)-1H-imidazole-4-carbaldehyde

To a stirred solution of [5-fluoro-1-(2-trimethylsilyl-ethoxymethyl)-1H-imidazol-4-yl]-methanol (339 mg) in dichloromethane (15 ml) at room temperature in an argon atmosphere was added MnO2(1.20 g). Received the dark suspension was heated to the temperature of reflux distilled and continued to stir at the same temperature for 18 h, then cooled to room temperature, filtered and the filter cake washed with dichloromethane. The filtrate was concentrated to obtain 5-fluoro-1-(2-trimethylsilyl-ethoxymethyl)-1H-imidazole-4-carbaldehyde (262 mg) as a pale yellow what about the thick oil. This crude product without further purification was used in the next stage of the reaction. MS (EI) mass spectrometry with ionization by electrons): RUB 171.1 ([M-Si(Me)3]).

g) 1-[5-fluoro-1-(2-trimethylsilyl-ethoxymethyl)-1H-imidazol-4-ylmethyl]-1,2,3,4-tetrahydro-quinoline

To a stirred solution of 5-fluoro-1-(2-trimethylsilyl-ethoxymethyl)-1H-imidazole-4-carbaldehyde (202 mg) in methanol (10 ml) at room temperature in an argon atmosphere was added zinc chloride (409 mg) and 1,2,3,4-tetrahydroquinoline (100 mg). The obtained transparent light-yellow solution was stirred for 4 h 30 min Then added at one time NaBH3CN (141 mg). This mixture was heated to 60°C. and continued to stir at the same temperature for 22 hours, the Reaction mixture was immediately adsorbing on silica gel. The crude product was isolated by column chromatography (silica gel; gradient: cyclohexane → cyclohexane/EtOAc 65:35) to give 1-[5-fluoro-1-(2-trimethylsilyl-ethoxymethyl)-1H-imidazol-4-ylmethyl]-1,2,3,4-tetrahydroquinoline (238 mg) as a colorless thick oil. MS (ISP): 362,3 ([M+H]+).

d) 1-(5-fluoro-1H-imidazole-4-ylmethyl)-1,2,3,4-tetrahydroquinolin

To a stirred solution of 1-[5-fluoro-1-(2-trimethylsilyl-ethoxymethyl)-1H-imidazol-4-ylmethyl]-1,2,3,4-tetrahydroquinoline (103 mg) in THF (5 ml) and anatoy temperature in the argon atmosphere was added TBAF (tetrabutylammonium fluoride) (1.1 ml; 1 M solution in THF). This mixture was heated to 60°C. and continued to stir at the same temperature for 20 min, then the mixture was immediately adsorbing on silica gel. The crude product was isolated by column chromatography (silica gel; gradient: cyclohexane → EtOAc) to give 1-(5-fluoro-1H-imidazole-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline (32 mg) as a pale yellow solid. (MS (ISP): 232,1 ([M+H]+).

The following compounds were obtained analogously to the compound of Example 1.

Example 43

1-(3H-Imidazol-4-ylmethyl)-7-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin

Obtained from 7-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine hydrochloride (CAS: 23561-82-2), imidazol-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 258,3 ([M+H]+).

Example 44

1-(3H-Imidazol-4-ylmethyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin

Received from 2,3,4,5-tetrahydro-1H-benzo[b]azepine, imidazol-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): to 228.1 ([M+H]+).

Example 45

(RS)-4-(1H-Imidazol-4-ylmethyl)-3-methyl-3,4-dihydro-2H-benzo[1,4]oxazin

a) (RS)-3-Methyl-3,4-dihydro-2H-benzo[1,4]oxazin

To a solution of 2H-1,4-benzoxazin-3(4H)-she (2.00 g, a 13.4 mmol) in tetr is hydrofuran (20 ml) was added dropwise at 5°C. a solution of chloride Metalmania (to 17.9 ml, 3 M of 53.7 mmol) in THF, and then this reaction mixture was stirred at 50°C for 90 minutes Then the reaction mixture was cooled to 5°C and extinguished by adding dropwise 20 ml of acetic acid. Then added in portions sodium borohydride (1.27 g, a 33.5 mmol) and the mixture was stirred at room temperature overnight. Then, the resulting suspension was cooled to 0°C and added dropwise 3 N. aqueous sodium hydroxide solution until the pH of the mixture was brought to 10. Then added ethyl acetate, the phases were separated and the organic phase was dried over sodium sulfate and concentrated under vacuum. The residue was purified by chromatography on silica gel (eluant: gradient heptane/ethyl acetate) to obtain the specified title compound as a colourless oil (0,92 g, 46%); MS (ISP): 150,3 ([M+H]+).

b) (RS)-4-(1H-Imidazol-4-ylmethyl)-3-methyl-3,4-dihydro-2H-benzo[1,4]oxazin

Was obtained similarly to the compound of Example 1 from (RS)-3-methyl-3,4-dihydro-2H-benzo[1,4]oxazine, imidazol-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 230,4 ([M+H]+).

Example 46

(+)-1-(1H-Imidazol-4-ylmethyl)-2-methyl-1,2,3,4-tetrahydro-quinoline

The enantiomers (RS)-1-(1H-imidazol-4-ylmethyl)-2-methyl-1,2,3,4-tetrahydro-quinoline (Example 3) were separated using chiral Ehud liquid chromatography high pressure) (column: Chiracel OD; eluent: isopropanol/heptane (10:90); flow rate: 35 ml/min; pressure: 15 bar (1,5·106PA); retention time: 65 min). MS (ISP): 228,4 ([M+H]+).(s=0,52, Meon).

Example 47

(-)-1-(1H-Imidazol-4-ylmethyl)-2-methyl-1,2,3,4-tetrahydro-quinoline

The enantiomers (RS)-1-(1H-imidazol-4-ylmethyl)-2-methyl-1,2,3,4-tetrahydro-quinoline (Example 3) were separated using chiral ghvd (column: Chiracel OD; eluant isopropanol/heptane (10:90); flow rate: 35 ml/min; pressure: 15 bar (1,5·106PA); retention time: 87 min). MS (ISP): 228,4 ([M+H]+).(s=0,52, Meon). 96% EE.

Example 48

(+)-4-(1H-Imidazol-4-ylmethyl)-3-methyl-3,4-dihydro-2H-benzo[1,4]oxazin

The enantiomers (RS)-4-(1H-imidazol-4-ylmethyl)-3-methyl-3,4-dihydro-2H-benzo[1,4]oxazine (Example 45) was separated using chiral ghvd (column: Chiracel OD; eluent: isopropanol/heptane (10:90); flow rate: 35 ml/min; pressure: 15 bar (1,5·106PA); retention time: 59 min). MS (ISP): 228,4 ([M+H]+).(C=0,60, Meon).

Example 49

(-)-4-(1H-Imidazol-4-ylmethyl)-3-methyl-3,4-dihydro-2H-benzo[1,4]oxazin

The enantiomers (RS)-4-(1H-imidazol-4-ylmethyl)-3-methyl-3,4-dihydro-2H-benzo[1,4]oxazine (Example 45) was separated using chiral ghvd (column: Chiracel OD; eluant: isopro anal/heptane (10:90); flow rate: 35 ml/min; pressure: 15 bar (1,5·106PA); retention time: 67 min). MS (ISP): 228,4 ([M+H]+).(C=0,58, Meon). 76% EE.

The following compound was obtained analogously to the compound of Example 45.

Example 50

(RS)-2-Ethyl-1-(1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline

Received by reacting 3,4-dihydro-2(1H)-Hinayana and chloride of etermine in tetrahydrofuran, followed by treatment with sodium borohydride in acetic acid and tetrahydrofuran, followed by treatment imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 242,3 ([M+H]+).

The following compound was obtained analogously to the compound of Example 1.

Example 51

1-(3H-Imidazol-4-ylmethyl)-6-methoxy-1,2,3,4-tetrahydro-quinoline

Was obtained from 6-methoxy-1,2,3,4-tetrahydro-quinoline, imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 244,4 ([M+H]+).

Example 52

1-(3H-Imidazol-4-ylmethyl)-7-methoxy-1,2,3,4-tetrahydro-quinoline

a) 7-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl methyl ether

To a suspension of 1,2,3,4-tetrahydro-quinoline-7-ol (0.50 g, 3.35 mmol) in dichloromethane (40 ml) we use the and di-tert-BUTYLCARBAMATE (1.54 g, ? 7.04 baby mortality mmol) and triethylamine (of 1.86 ml of 13.4 mmol)and this reaction mixture was stirred at 45°C for 48 hours Then the mixture was acidified to pH 6 by adding 10% aqueous citric acid solution and was extracted with dichloromethane. The combined organic phase was washed with saturated saline solution, dried over sodium sulfate and concentrated under vacuum. The residue was dissolved in methanol (40 ml), was added aqueous sodium hydroxide solution (6,70 ml of 13.4 mmol, 2 M). After stirring for 16 h at 60°C. the mixture was cooled to room temperature, acidified to pH 6 by adding 10% aqueous citric acid solution and was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated under vacuum to obtain specified in the title compounds as colorless oil, which was used in the next stage without additional purification (0.33 g, 40%); MS (ISP): 250,3 ([M+H]+), 194,4 ([M+H-IU2C=CH2]+).

b) 7-Methoxy-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl methyl ether

To a solution of 7-hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (120 mg, 0.48 mmol) in N,N-dimethylformamide (6 ml) was added sodium hydride (23 mg, or 0.57 mmol, 60% dispersion in oil), and this reaction mixture was stirred at room t is mperature within 10 minutes Then the mixture was cooled to 0°C and added dropwise methyl iodide (0.04 ml, 0.64 mmol). After stirring for 16 h at room temperature the mixture was suppressed by addition of water (10 ml) and three times were extracted with ethyl acetate. The combined organic phase was washed with saturated saline solution, dried over sodium sulfate and concentrated under vacuum. The residue was purified by chromatography on silica gel (eluant: gradient heptane/ethyl acetate) to obtain the specified title compound as a colourless oil (52 mg, 41%); MS (ISP): 264,0 ([M+H]+), 208,1 ([M+H-IU2C=CH2]+).

b) 7-Methoxy-1,2,3,4-tetrahydro-quinoline

To a solution of 7-methoxy-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (52 mg, 0.20 mmol) in dichloromethane (7 ml) at 0°C was added dropwise triperoxonane acid (0,23 ml, a 3.01 mmol), and then this reaction mixture was stirred at room temperature for 24 h Then the mixture was podslushivaet to pH 9 by adding dropwise a saturated aqueous solution of sodium carbonate. The mixture three times were extracted with a mixture (1:1) of ethyl acetate and tetrahydrofuran, the phases were separated, and the organic phase was dried over sodium sulfate and concentrated under vacuum to obtain specified in the title compound as a light brown oil (37 mg, 92%); M is (ISP): 164,4([M+H] +).

g) 1-(3H-Imidazol-4-ylmethyl)-7-methoxy-1,2,3,4-tetrahydro-quinoline

Was obtained similarly to the compound of Example 1 from 7-Methoxy-1,2,3,4-tetrahydro-quinoline, imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 244,4 ([M+H]+).

The following compounds were obtained analogously to the compound of Example 52.

Example 53

1-(1H-Imidazol-4-ylmethyl)-5-methoxy-1,2,3,4-tetrahydro-quinoline

Received by reacting 1,2,3,4-tetrahydro-quinoline-5-ol, di-tert-BUTYLCARBAMATE and triethylamine in dichloromethane, followed by treatment with sodium hydroxide in methanol, followed by treatment iodide stands and sodium hydride in N,N-dimethylformamide, then processing triperoxonane acid and then processing the imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 244,4 ([M+H]+).

Example 54

6-Benzyloxy-1-(1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline

Received by reacting 1,2,3,4-tetrahydro-quinoline-6-ol, di-tert-BUTYLCARBAMATE and triethylamine in dichloromethane, followed by treatment with sodium hydroxide in methanol, followed by treatment with benzylbromide and sodium hydride in N,N-dimethylformamide, and then the processing is TKA triperoxonane acid and then processing the imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 320,3 ([M+H]+).

Example 55

5-Benzyloxy-1-(1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline

Received by reacting 1,2,3,4-tetrahydro-quinoline-5-ol, di-tert-BUTYLCARBAMATE and triethylamine in dichloromethane, followed by treatment with sodium hydroxide in methanol, followed by treatment with benzylbromide and sodium hydride in N,N-dimethylformamide, then processing triperoxonane acid and then processing the imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 320,3 ([M+H]+).

Example 56

1-(1H-Imidazol-4-ylmethyl)-5-isopropoxy-1,2,3,4-tetrahydro-quinoline

Received by reacting 1,2,3,4-tetrahydro-quinoline-5-ol, di-tert-BUTYLCARBAMATE and triethylamine in dichloromethane, followed by treatment with sodium hydroxide in methanol, followed by treatment with isopropylamino and sodium hydride in N,N-dimethylformamide, then processing triperoxonane acid and then processing the imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 272,3 ([M+H]+).

Example 57

7-Benzyloxy-1-(1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline

Received by reacting 1,2,3,4-tetrahydro-quinoline-7-ol, di-tert-BUTYLCARBAMATE and triethylamine in dichloromethane, followed by treatment with sodium hydroxide in methanol, followed by treatment with benzylbromide and sodium hydride in N,N-dimethylformamide, then processing triperoxonane acid and then processing the imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 320,3 ([M+H]+).

Example 58

7 Ethoxy-1-(1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline

Received by reacting 1,2,3,4-tetrahydro-quinoline-7-ol, di-tert-BUTYLCARBAMATE and triethylamine in dichloromethane, followed by treatment with sodium hydroxide in methanol, followed by treatment with idtana and sodium hydride in N,N-dimethylformamide, then processing triperoxonane acid and then processing the imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 258,0 ([M+H]+).

Example 59

1-(1H-Imidazol-4-ylmethyl)-7-isopropoxy-1,2,3,4-tetrahydro-quinoline

Received by reacting 1,2,3,4-tetrahydro-quinoline-7-ol, di-tert-BUTYLCARBAMATE and triethylamine in dichloromethane, followed by treatment with sodium hydroxide in methanol, followed by treatment bromopropane and sodium hydride in N,N-dimethylformamide, then processing triperoxonane acid and then processing the imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 272,5 ([M+H]+).

Example 60

1-(1H-Imidazol-4-ylmethyl)-7-phenoxy-1,2,3,4-tetrahydro-quinoline

a) 7-Phenoxy-1,2,3,4-tetrahydro-quinoline

To a solution of 0.15 g (1.01 mmol) of 1,2,3,4-tetrahydro-quinoline-7-ol in 10 ml of dichloromethane was added to 0.19 g (1.56 mmol) of phenylboronic acid, 0.27 g (1,49 mmol) of copper acetate (II), 4Å molecular sieves (on the tip of a spatula) and 0.64 ml (to 5.03 mmol) of triethylamine. This reaction mixture was stirred at room temperature for 72 h and then filtered through celite, washing with dichloromethane. The obtained filtrate was concentrated under vacuum, and the residue was purified by flash chromatography (silica gel, gradient ethyl acetate/heptane) to give 15 mg (7%) indicated in the title compound as a pale yellow oil. MS (ISP): 226,3 ([M+H]+).

b) 1-(1H-Imidazol-4-ylmethyl)-7-phenoxy-1,2,3,4-tetrahydro-quinoline

Was obtained similarly to the compound of Example 1 from 7-phenoxy-1,2,3,4-tetrahydro-quinoline, imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 306,4 ([M+H]+).

The following compound was obtained analogion the compound of Example 60.

Example 61

1-(1H-Imidazol-4-ylmethyl)-5-phenoxy-1,2,3,4-tetrahydro-quinoline

Received by reacting 1,2,3,4-tetrahydro-quinoline-5-ol, phenylboronic acid, copper acetate (II) and triethylamine in dichloromethane and subsequent treatment imidazole-4-carboxaldehyde, triacetoxyborohydride sodium and acetic acid in 1,2-dichloroethane. MS (ISP): 306,1 ([M+H]+).

1. The compound of the formula

where R1represents a hydrogen atom or a C1-7alkyl;
R2represents a C1-7alkyl;
R3represents a C1-7alkyl, C1-7alkoxy, phenyloxy, benzyloxy, halogen atom or With1-7alkyl, substituted by a halogen atom;
R4represents a hydrogen atom or a C1-7alkyl;
X represents-CH2-, -CHR2- or-O-;
Y represents-CH2-, -CH2CH2or communication; when X represents-O-, Y represents-CH2-;
Z represents-CH2- or-CHR2-;
if R2meets twice simultaneously for X and Z, which are CHR2then R2can be the same alkilani or different;
n is 0, 1 or 2; when n is set to 2, R3may be the same or different;
and its pharmaceutically acceptable salts joining KIS is on, with the exception of the following compounds:
1-(1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydroquinolin and
1-(3H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indole.

2. The compound of formula I according to claim 1, where X represents CH2and Y represents a bond, except 1-(3H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indole.

3. The compound of formula I according to claim 2, which is a
(RS)-1-(1H-imidazol-4-ylmethyl)-2-methyl-2,3-dihydro-1H-indole,
5-bromo-1-(1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indole,
5-chloro-1-(1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indole,
(RS)-5-chloro-1-(1H-imidazol-4-ylmethyl)-2-methyl-2,3-dihydro-1H-indole,
7-ethyl-1-(1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indole,
4-chloro-1-(1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indole,
1-(1H-imidazol-4-ylmethyl)-5-methoxy-2,3-dihydro-1H-indole,
1-(1H-imidazol-4-ylmethyl)-6-methoxy-2,3-dihydro-1H-indole,
1-(1H-imidazol-4-ylmethyl)-7-methoxy-2,3-dihydro-1H-indole,
1-(1H-imidazol-4-ylmethyl)-5-methyl-2,3-dihydro-1H-indole,
1-(1H-imidazol-4-ylmethyl)-4-methoxy-2,3-dihydro-1H-indole,
7-chloro-1-(1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indole,
1-(1H-imidazol-4-ylmethyl)-6-methyl-2,3-dihydro-1H-indole,
(RS)-1-(1H-imidazol-4-ylmethyl)-3-methyl-2,3-dihydro-1H-indole,
5-fluoro-1-(1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indole,
6-fluoro-1-(1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indole,
5,6-debtor-1-(1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indole,
(RS)-5-fluoro-1-(1H-imidazol-4-ylmethyl)-2-methyl-2,3-dihydro-1H-indole,
1-(1H-imidazol-4-ylmethyl)-7-methyl-2,3-dihydro-1H-indole or
1-(1H-imidazol-4-ylmethyl)-4-methyl-2,3-dihydro-1H-indole.

4. The compound of formula I according to claim 1, where X represents CH2and Y is CH2except 1-(1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydroquinoline.

5. The compound of formula I according to claim 4, which is a
(RS)-1-(1H-imidazol-4-ylmethyl)-2-methyl-1,2,3,4-tetrahydro-quinoline,
(RS)-6-fluoro-1-(1H-imidazol-4-ylmethyl)-2-methyl-1,2,3,4-tetrahydro-quinoline,
6-bromo-1-(1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline,
(-)-1-(1H-imidazol-4-ylmethyl)-2-methyl-1,2,3,4-tetrahydro-quinoline,
5-benzyloxy-1-(1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline,
7-benzyloxy-1-(1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline
or
1-(1H-imidazol-4-ylmethyl)-5-phenoxy-1,2,3,4-tetrahydro-quinoline.

6. The compound of formula I according to claim 1, where X represents O, and Y is CH2.

7. The compound of formula I according to claim 6, which is a
4-(1H-imidazol-4-ylmethyl)-3,4-dihydro-2H-benzo[1,4]oxazin,
(RS)-4-(1H-imidazol-4-ylmethyl)-3-methyl-3,4-dihydro-2H-benzo[1,4]oxazin or
(-)-4-(1H-imidazol-4-ylmethyl)-3-methyl-3,4-dihydro-2H-benzo[1,4]oxazin.

8. The compound of formula I according to claim 1, where X represents CH2and Y is CH2CH2.

9. The compound of formula I according to claim 6, which is a
1-(3H-imidazol-4-ylmethyl)-7-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin or
1-(3H-imidazol-4-metil)-2,3,4,5-tetrahydro-1H-benzo[b]azepin.

10. The method of obtaining compounds of formula I, including
reductive amination, where the compound of the formula

interacts with the compound of the formula

obtaining the compounds of formula

where R1, R2, R3, R4X, Z and n are as defined according to claim 1.

11. Medication containing one or more than one compound of formula I according to claim 1 and pharmaceutically acceptable excipients, for the treatment of bipolar disorder, disorders caused by stress, psychotic disorders, schizophrenia, neurological diseases, Parkinson's disease, neurodegenerative disorders, Alzheimer's disease.

12. Medicine in claim 11, containing one or more than one compound according to claims 1 to 9, for the treatment of psychosis and Parkinson's disease.

13. The use of the compounds of formula I according to claim 1 in the preparation of drugs for the treatment of bipolar disorder, disorders caused by stress, psychotic disorders, schizophrenia, neurological diseases, Parkinson's disease, neurodegenerative disorders or Alzheimer's disease.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula (II)

or to its pharmaceutically acceptable salt wherein the ring A represents a group presented by formula 2 R1 represents hydrogen or C1-6alkyl; R2 represents -SR5, halogen, halogenated C1-6alkyl, etc., R3 represents a group presented by formula: -CH=CH-C(RaRb)-Rc-Rd, or a group presented by formula: -(CReRf)m-C(RaRb)-Rc-Rd wherein radicals and symbols have the values presented in the patent claim, R4 represents -OR6, -CONR7R8, -NR9CONR7R8, -(CR10R11)POH, -(CR10R11)pOCONR7R8, -NR9COR12, -(CR10R11)pNR9COR12, -C(=O)NR9OR12, -CONR9CONR7R8, -CN, halogen or NR9(C=O)OR12; R5 represents C1-6alkyl; R6 represents -CONR7R8; each of R7 and R8 independently represents hydrogen or etc., R10 and R11 independently represents hydrogen; R12 represents C1-6alkyl; each of m and p independently represents an integer 1 to 3. This compound is applicable as a type 1 11β-hydroxysteroiddehydrogenase inhibitor.

EFFECT: invention also refers to single compounds, pharmaceutical compositions on the basis of the declared compounds, to a method for preventing and treating diabetes and the use of the compound of formula (II).

21 cl, 289 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel clathrate complex of β-cyclodextrin with 1-{[6-bromo-1-methyl-5-methoxy-2-phehylthiomethyl-1-H-indol-3-yl]carbonyl}-4-benzylpiperazine of formula : with molar ratio 1-{[6-bromo-1-methyl-5-methoxy-2-phehylthiomethyl-1-H-indol-3-yl]carbonyl}-4-benzylpiperazine: β-cyclodextrin from 1:1 to 1:10, synthesis method and use thereof as an antiviral agent for treating influenza. The disclosed method involves mixing solutions of β-cyclodextrin and 1-{[6-bromo-1-methyl-5-methoxy-2-phehylthiomethyl-1-H-indol-3-yl]carbonyl}-4-benzylpiperazine in molar ratio from 1:1 to 1:10 while stirring and heating to temperature not higher than 70°C and then maintaining said conditions until a homogeneous solution is obtained and extraction of the obtained complex.

EFFECT: clathrate complex is a novel effective anti-influenza virus agent which is obtained using a novel efficient method.

13 cl, 2 ex, 3 tbl, 11 dwg

FIELD: chemistry.

SUBSTANCE: present invention relates to a method for synthesis of 2-substituted azole

compounds of formula , (a) reaction of an aldehyde of formula

with an azole of formula in the presence of a carbonylating agent of formula to obtain an oxazolidone of formula , reaction of the oxazolidone of formula (Ia) so as to perform hydrolysis of a triarylmethyl group, splitting the O-(C=Q) bond and opening the oxazolidone, followed by reaction of the obtained intermediate compound with Prot-Z, where Prot-Z is an agent which protects an amino group, to obtain an azole-containing intermediate compound of formula (lb) and and oxidation of the intermediate compound of formula (Ib) to obtain a 2-substituted azole derivative of formula (I). The invention also relates to azole compounds of formulae (I), (la), (lb), (Ic) and (II).

EFFECT: novel method of obtaining azoles of formula (I), as well as obtaining novel compounds of formulae (I), (la), (lb), (Ic) and (II), having useful biological properties.

41 cl, 5 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I:

or pharmaceutically acceptable salts thereof, in which Q is a divalent or trivalent radical selected from C6-10aryl and heteroaryl; where said aryl or heteroaryl in Q is optionally substituted up to 3 times with radicals independently selected from halogen, C1-6 alkyl, C1-6 alkyl substituted with halogen, C1-6 alkoxy group, C1-6 alkoxy group substituted with halogen, -C(O)R20 and -C(O)OR20; where R20 is selected from hydrogen and C1-6 alkyl; and where optionally, the carbon atom neighbouring W2 can be bonded through CR31 or O with a carbon atom of Q to form a 5-member ring condensed with A and Q rings; where R31 is selected from hydrogen and C1-6 alkyl; W1 and W2 are independently selected from CR21 and N; where R21 is selected from hydrogen and -C(O)OR25; where R25 denotes hydrogen; ring A can contain up to 2 carbon ring atoms substituted with a group selected from -C(O)-, -C(S)- and -C(=NOR30)- and can be partially unsaturated and contain up to 2 double bonds; where R30 denotes hydrogen ; L is selected from C1-6alkylene, C2-6alkenylene, -OC(O)(CH2)n-, -NR26(CH2)n- and -O(CH2)n-; where R26 is selected from hydrogen and C1-6 alkyl; where n is selected from 0, 1, 2, 3 and 4; q is selected from 0 and 1; t1, t2, t3 and t4 are each independently selected from 0, 1 and 2; R1 is selected from -X1S(O)0-2X2R6a, -X1S(O)0-2X2OR6a, -X1S(O)0-2X2C(O)R6a, -X1S(O)0-2X2C(O)OR6a, -X1S(O)0-2X2OC(O)R6a and -X1S(O)0-2NR6aR6b; where X1 is selected from a bond, O, NR7a and C1-4alkylene; where R7a is selected from hydrogen and C1-6alkyl; X2 is selected from a bond and C1-6alkylene; R6a is selected from hydrogen, cyanogroup, halogen, C1-6alkyl, C2-6alkenyl, C6-10aryl, heteroaryl, heterocycloalkyl and C3-8cycloalkyl; where said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in R6a is optionally substituted with 1-3 radicals independently selected from hydroxy group, halogen, C1-6alkyl, C1-6alkyl substituted with a cyano group, C1-6alkoxy group and C6-10aryl-C1-4alkoxy group; and R6b is selected from hydrogen and C1-6alkyl; R3 is selected from hydrogen, halogen, hydroxy group, C1-6alkyl, C1-6alkyl substituted with halogen, C1-6alkyl substituted with a hydroxy group, C1-6alkoxy group, C1-6alkoxy group substituted with halogen, -C(O)R23 and -C(O)OR23; where R23 is selected from hydrogen and C1-6alkyl; R4 is selected from R8 and -C(O)OR8; where R8 is selected from C1-6alkyl, heteroaryl, C3-8cycloalkyl and heterocycloalkyl; where said heteroaryl, cycloalkyl or heterocycloalkyl in R8 is optionally substituted with 1-3 radicals independently selected from halogen, C1-6alkyl, C3-8cycloalkyl and C1-6alkyl substituted with halogen; R5 is selected from hydrogen, C1-6alkyl substituted with a hydroxy group, and a C1-6alkoxy group; heteroaryl denotes a monocyclic or condensed bicyclic aromatic ring complex containing 5-9 carbon atoms in the ring, where one or more ring members are heteroatoms selected from nitrogen, oxygen and sulphur, and heterocycloalkyl denotes a saturated monocyclic 4-6-member ring in which one or more said carbon atoms in the ring are substituted with a group selected from -O-, -S- and -NR-, where R denotes a bond, hydrogen or C1-6alkyl. The invention also relates to pharmaceutical compositions containing said compounds, and methods of using said compounds to treat or prevent diseases or disorders associated with GPR119 activity, such as obesity, type 1 diabetes, type 2 sugar diabetes, hyperlipidemia, type 1 autopathic diabetes, latent autoimmune diabetes in adults, type 2 early diabetes, child atypical diabetes, adult diabetes in children, malnutrition-associated diabetes and diabetes in pregnant women.

EFFECT: improved properties of compounds.

27 cl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

and pharmaceutically acceptable salts and solvates thereof, in which R1 is an optionally substituted alkyl or similar, R2 is a group of formula: -Y-R5, where Y is -O- or S; R5 is a substituted alkyl (the substitute is an optionally substituted cycloalkyl or similar), a branched alkyl or similar; R4 is hydrogen or C1-10 alkyl; R3 is a group of formula: -C(=O)-Z-R6, where Z is -NR7- or -NR7-W-; R6 is an optionally substituted cycloalkyl or similar; R7 is hydrogen or C1-10 alkyl, W is C1-10 alkylene; X is =N- provided that a compound in which R2 is 2-(4-morpholino)ethoxy, 2-, 3- or 4-pyridylmethoxy, 1-methylpiperidinyl-2-methoxy, benzyloxy or 4-substituted benzyloxy is excluded; and R3 is N-(1-adamantyl)carbamoyl, N-(2-adamantyl)carbamoyl and N-(3-noradamantyl)carbamoyl. Said compound is an 11β-hydroxysteroid dehydrogenase type 1 inhibitor. The invention also relates to a pharmaceutical composition containing said compound as an active ingredient.

EFFECT: improved properties of the compound.

23 cl, 72 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I): where R1 and R2 represent hydrogen and a group which is hydrolysed in a physiological environment, optionally substituted lower alkanoyl or aroyl; X represents a methylene group; Y represents oxygen atom; n represents the number 0, 1, 2 or 3 and m represents the number 0 or 1; R3 represents a group of pyridine N-oxide according to formula A, B or C which is attached as shown by an unmarked linking: where R4, R5, R6 and R7 independently represent aryl, heterocycle, hydrogen, C1-C6-alkyl, C1-C6-alkylthio, C6-C12-aryloxy or C6-C12-arylthio group, C1-C6-alkylsulphonyl or C6-C12-arylsulphonyl, halogen, C1-C6-haloalkyl, trifluoromethyl, or heteroaryl group; or where two or more residues R4, R5, R6 and R7 taken together represent an aromatic ring, and where P represents a central part, preferentially chosen from regioisomers 1,3,4-oxadiazol-2,5-diyl, 1,2,4-oxadiazol-3,5-diyl, 4-methyl-4H-1,2,4-triazol-3,5-diyl, 1,3,5-triazine-2,4-diyl, 1,2,4-triazine-3,5-diyl, 2H-tetrazol-2,5-diyl, 1,2,3-thiadiazol-4,5-diyl, 1-alkyl-3-(alkoxycarbonyl)-1R-pyrrol-2,5-diyl, where alkyl is presented by methyl, thiazol-2,4-diyl, 1H-pyrazol-1,5-diyl, pyrimidine-2,4-diyl, oxazol-2,4-diyl, carbonyl, 1H-imidazol-1,5-diyl, isoxazol-3,5-diyl, furan-2,4-diyl, benzole-1,3-diyl and (Z)-1-cyanoethene-1,2-diyl, and where the regioisomers of the central part include both regioisomers produced by exchanging the nitrocatechol fragment and the -(X)n-(Y)m-R3 fragment. Also, the invention refers to a method for making a compound of formula I, as well as to a method for treating an individual suffering central and peripheral nervous system disorders, to a pharmaceutical composition based on the compounds of formula I, and also to their application for preparing the drug and as COMT inhibitor.

EFFECT: there are produced and described new compounds which show a potentially effective pharmaceutical properties in treating a number of central and peripheral nervous system disorders.

25 cl, 64 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I), in which (i) R1 denotes C1-C6-alkyl or hydrogen; and R2 denotes hydrogen or a -R7, -Z-Y-R7, -Z-NR9R10, -Z-CO-NR9R10, -Z-NR9-C(O)O-R7 or -Z-C(O)-R7 group; and R3 denotes an undefined pair or C1-C6-alkyl; or (ii) R1 and R3 together with a nitrogen atom with which they are bonded form a 5-6-member heterocycloalkyl ring; and R2 denotes an undefined pair or a -R7 , -Z-Y-R7 group; or (iii) R1 and R2 together with a nitrogen atom with which they are bonded form a 6-member heterocycloalkyl ring, where said ring is substituted with a -Y-R7 group, and R3 denotes an undefined pair or C1-C6-alkyl; R4 and R5 are independently selected from a group consisting of phenyl, C3-C6-cycloalkyl; R6 denotes -OH, C1-C6-alkyl, C1-C6-alkoxy or a hydrogen atom; A denotes an oxygen or sulphur atom; X denotes a C1-C6-alkylene group; R7 denotes C1-C6-alkyl, phenyl, phenyl(C1-C6-alkyl)-, dihydrobenzofuran or pyridine, where any phenyl in group R7 can be optionally substituted with one or two groups independently selected from halogen, aminoacyl, C1-C6-alkoxycarbonyl, aminosulphonyl, C1-C6-alkyl, C1-C6-alkylamino-C1-C6-alkyl, -COOH; and any pyridine in group R7 can be optionaly substituted with C1-C6-alkyl; R8 denotes C1-C6-alkyl or a hydrogen atom; Z denotes a C1-C10-alkylene or C2-C10-alkenylene group; Y denotes a bond or an oxygen atom; R9 and R10 independently denote a hydrogen atom, C1-C6-alkyl group, isoxazole or 8-hydroxy-1H-quinolin-2-one-(C1-C6-hydroxyalkyl); and pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition having activity with respect to M3 muscarinic receptor; use of the compounds of formula (I) to produce a medicinal agent for treating and a method of treating diseases or conditions in which M3 muscarinic receptor activity is involved.

EFFECT: compounds of given formula have activity with respect to M3 muscarinic receptor.

26 cl, 8 dwg, 91 ex

FIELD: chemistry.

SUBSTANCE: invention relates to tetrahydroquinoline derivatives of formula (I), where values of C3-C4, R2, R3, R4, R5, L1, L2, Y and X are given in claim 1, as muscarinic receptor agonists; compositions containing said compounds; methods of inhibiting muscarinic receptor activity using said compounds; methods of treating diseased conditions associated with the muscarinic receptor using said compounds, and methods of identifying a subject suitable for treatment using said compounds.

EFFECT: improved properties of compounds.

22 cl, 1 tbl, 3 ex, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) (lb) in which A denotes a benzene ring; Ar denotes naphthalenyl which optionally contains 1-3 substitutes independently selected from a group comprising C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, hydroxy group, C1-C6alkoxy group, halogen, heteroalkyl, heteroalkoxy group, nitro group, cyano group, amino- and mono- or di- C1-C6alkyl-substuted amino group; R1 denotes hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy group, carboxy group, heteroalkyl, hydroxy group optionally substituted with heterocyclylcarbonyl-C1-C6alkyl or R1 denotes N(R')(R")-C1-C6alkyl or N(R')(R")-carbonyl- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, heteroalkyl, phenyl-C1-C6alkyl; or R1 denotes R'-CO-N(R")-C1-C6alkyl, R'-O-CO-N(R")- C1-C6alkyl- or R'-SO2-N(R")- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cyclalkyl, C3-C7cycloalkyl- C1-C6alkyl or optionally substituted phenyl; R2, R2' and R2" independently denote hydrogen, halogen, cyano group, C1-C6alkyl, halogenated C1-C6alkyl or C1-C6alkoxy group; n equals 1; and pharmaceutically acceptable salts thereof. The invention also relates to use of compounds in any of claims 1-9, as well as to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds with chymase inhibiting activity.

14 cl, 128 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted oxadiazole derivatives of general formula , where X denotes CH, CH2, CH=CH, CH2CH2, CH2CH=CH or CH2CH2CH2, R1 denotes an unsubstituted or mono- or disubstituted phenyl or pyrrolyl residue or an unsubstituted or mono- or disubstituted phenyl connected through a C1-C3alkyl or a thienyl or indolyl residue, where the said substitutes are selected from a group comprising F, Cl, Br, OCF3, O-C1-C6alkyl or C1-C6alkyl, R2 denotes an unsubstituted or mono- or disubstituted phenyl or thienyl residue or an unsubstituted or mono- or disubstituted phenyl residue connected through a C1-C3alkyl, where the said substitutes are selected from a group comprising F, Cl, and R3 and R4 denote a saturated straight C1-C6alkyl in form of a racemate, diastereomers, mixture of enantiomers and/or diastereomers, or a specific diastereomer, bases and/or salts with physiologically compatible acids. The invention also relates to a method of producing said compounds and a medicinal agent based on said compounds and having affinity to the µ-opioid receptor.

EFFECT: obtaining novel compounds and a medicinal agent based on said compounds, which can be used in medicine to pain killing and for treating depression, enuresis, diarrhoea, skin itching, alcohol and drug abuse, drug induced addiction, aspontaneity or for anxiolyis.

11 cl, 2 tbl, 331 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted pyrimidine derivatives, having HIV replication inhibiting properties, or pharmaceutically acceptable salts thereof. In formula (1): R1 denotes hydrogen; R2 and R3 independently denote hydrogen; R7 and R8 denote C1-6alkyl; R4 denotes cyano; R9 denotes C1-6alkyl optionally substituted with cyano, C2-6alkenyl substituted with cyano, C2-6alkynyl optionally substituted with cyano; R5 denotes C1-6alkyl optionally substituted with Ar or Het; C2-6alkenyl optionally substituted with Ar or Het; C2-6alkynyl optionally substituted with Ar or Het; C3-7cycloalkyl; Ar; Het; R6 denotes H, Het; Y denotes -OR11, -NR12R13; R11 denotes hydrogen or C1-6alkyl optionally substituted with hydroxy, C1-6alkoxy or pyridyl; R12 denotes hydrogen or C1-6alkyl; R13 denotes hydrogen or C1-6alkyl; or R12 and R13 together with a nitrogen atom, which is substituted by said two substitutes, form a morpholinyl; imidazolyl; X denotes -NR1-; Het denotes 5- or 6-member completely saturated ring, where one or two ring members are heteroatoms, each independently selected from nitrogen and sulphur, and where the rest of the ring members are carbon atoms; and where any member of the heterocycle with a nitrogen heteroatom can optionally be substituted with C1-6alkyl; where the 5- or 6-member ring can optionally be annelated with a benzene or thiophene ring; each aryl independently denotes phenyl or phenyl substituted with one substitute selected from C1-6alkoxy.

EFFECT: high efficiency of using said compounds.

7 cl, 4 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula

wherein: m, n, R0, R1, R2, R3 and R4 have the values presented in clause 1 of the patent claim provided the compound of formula (I) cannot represent N-methyl-1-(phenylsulphonyl)-1H-indole-4-methanamine.

EFFECT: compounds show 5-NT6 receptor antagonist activity that that allows them being used in the pharmaceutical composition.

19 cl, 3 tbl, 192 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel clathrate complex of β-cyclodextrin with 1-{[6-bromo-1-methyl-5-methoxy-2-phehylthiomethyl-1-H-indol-3-yl]carbonyl}-4-benzylpiperazine of formula : with molar ratio 1-{[6-bromo-1-methyl-5-methoxy-2-phehylthiomethyl-1-H-indol-3-yl]carbonyl}-4-benzylpiperazine: β-cyclodextrin from 1:1 to 1:10, synthesis method and use thereof as an antiviral agent for treating influenza. The disclosed method involves mixing solutions of β-cyclodextrin and 1-{[6-bromo-1-methyl-5-methoxy-2-phehylthiomethyl-1-H-indol-3-yl]carbonyl}-4-benzylpiperazine in molar ratio from 1:1 to 1:10 while stirring and heating to temperature not higher than 70°C and then maintaining said conditions until a homogeneous solution is obtained and extraction of the obtained complex.

EFFECT: clathrate complex is a novel effective anti-influenza virus agent which is obtained using a novel efficient method.

13 cl, 2 ex, 3 tbl, 11 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

and pharmaceutically acceptable salts and solvates thereof, in which R1 is an optionally substituted alkyl or similar, R2 is a group of formula: -Y-R5, where Y is -O- or S; R5 is a substituted alkyl (the substitute is an optionally substituted cycloalkyl or similar), a branched alkyl or similar; R4 is hydrogen or C1-10 alkyl; R3 is a group of formula: -C(=O)-Z-R6, where Z is -NR7- or -NR7-W-; R6 is an optionally substituted cycloalkyl or similar; R7 is hydrogen or C1-10 alkyl, W is C1-10 alkylene; X is =N- provided that a compound in which R2 is 2-(4-morpholino)ethoxy, 2-, 3- or 4-pyridylmethoxy, 1-methylpiperidinyl-2-methoxy, benzyloxy or 4-substituted benzyloxy is excluded; and R3 is N-(1-adamantyl)carbamoyl, N-(2-adamantyl)carbamoyl and N-(3-noradamantyl)carbamoyl. Said compound is an 11β-hydroxysteroid dehydrogenase type 1 inhibitor. The invention also relates to a pharmaceutical composition containing said compound as an active ingredient.

EFFECT: improved properties of the compound.

23 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the field of organic chemistry, notably to derivatives of dihydroimidazole with the general formula (I) and to its pharmaceutically acceptable salts where X1 and X2 denote halogen; R1 and R2 are chosen from the group including -H, -CH3, -CH2CH3 on the condition that both R1 and R2 do not denote hydrogen; R3 denotes -H or -C(=O)-R7; and if R6 denotes hydrogen, then R4 denotes -OCH3, -OCH2CH3 or -OCH(CH3)2; R5 denotes -H, - halogen, -CF3, -OCH3, -C(CH3)2, - cyclopropyl, - cyano group, -C(CH3)3, -C(CH3)2OR (where R denotes -H), -C(CH3)2CH-OR (where R denotes -CH3), -C(CH3)2CN, -C(CH3)2COR (where R denotes -CH3), -SR (where R denotes -CH2CH3) or -SO2R (where R denotes -CH3, -CH2CH3, 1-pyrrolidine, -NH-tert-butyl); and if R6 does not denote hydrogen, then R4 denotes -OCH2CH3; R5 denotes hydrogen, -Cl, -OCH3, tert butyl; R6 denotes -Cl, cyclopropyl, -SO2R (where R denotes -CH3, 1-pyrrolidine, -NH-tert-butyl or -N(CH3)2); and R7 is chosen from the group including i) -CH3, -CH(CH3)2, -CH2CH(CH3)2, cyclopropyl, cyclobutyl, -CH2CH2Ph, 2-furanyl, phenyl or phenyl substituted with chlorine, -OCH3 or cyano group, ii) 1-piperidinyl, iii) -NRc2 (where Rc denotes -CH2CH2OH, -CH2CH2OCH3 or -CH2CH(OH)CH2OH, iv) substituted piperazidine with the formula where R is chosen from the group including a) hydrogen, c) -CH(CH3)2, k) -CH2CH2Rd (where Rd denotes -OH, -OCH3, -CF3, -SO2CH3, -NH2, -NHCOCH3, -NHSO2CH3, 4-morfolinil, 2-izotiazolidinil-1, 1-dioxide), l) -CH2CH2CH2Re (where Re denotes -OCH3, -SO2CH3, -SO2CH2CH3, -CN), m) -CH2-CO-Rh (where Rh denotes -NH2, 1-pyrrolidinyl, 4-morfolinil), n) -SO2Ri (where Ri denotes -CH3, -CH2CH3), o) -CORj (where Rj denotes -CH3, 2-tetrahydrofuranyl, -NH2, -N(CH3)2), p) 4-tetrahydro-2H-thiopiranyl-1,1-dioxide, q) 4-piperidinyl-1-acetyl, r) 4-piperidinyl-1-dimethylcarboxamide, and s) 3-tetrahydrothiophenyl-1,1-dioxide; v) substituted oxopiperazine with the formula where R denotes -H; and vi) substituted piperidine with the formula where R denotes -CONH2, -OH, -CH2OH, -CH2CH2OH, 1-pyrrolidinyl, 1-piperidinyl, 1-(4-methylpiperazinyl) or 4-morfolinil. Moreover, the invention refers to the pharmaceutical composition based on the compound with the formula (I), to application of the formula (I) compound for production of a drug, to the production process of the formula (I) compound.

EFFECT: new derivatives of dihydroimidazole that may be used as anticancer drugs.

40 cl, 204 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of diazepane of formula , where A, X, R3, R4, R5, R6, R8, R9, R10, R11, R12, R13, n and m have values, given in description and formula of invention, as well as their physiologically acceptable salts. Said compounds are antagonists of chemokine receptors CCR-2, CCR-5 and/or CCR-3 receptor and can be used in medicine as medications.

EFFECT: obtaining novel diazepane derivatives.

20 cl, 505 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazolidinone derivatives of formula and pharmaceutically acceptable salts thereof, where X denotes N or CH; R1 denotes a lower alkyl, fluoro-lower alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-lower alkyl, phenyl, naphthyl, pyridine, where the phenyl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of a halide, lower alkyl, fluoro-lower alkyl, lower alkoxy group and fluoro-lower alkoxy group; R2 denotes lower alkyl, halide-lower alkyl, lower alkenyl, C3-C6-cycloalkyl, pheny, phenyl-lower alkyl, tetrahydropyran, pyridine, where the phenyl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of halide; R3 denotes phenyl or heteroaryl (pyridinyl, thienopyridinyl, benzoisothiazolyl, benzooxazolyl, tetrahydropyrazinyl, pyrazinyl), where the phenyl or heteroaryl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of halide, CN, lower alkyl, fluoro-lower alkyl, lower alkoxy group; R4, R5, R6, R7, R8, R9, R10 and R11 independently denote hydrogen or lower alkyl. The invention also relates to a pharmaceutical composition based on compounds of formula I.

EFFECT: obtaining novel imidazolidinone derivatives, having LXRalpha or LXRbeta receptor agonist activity.

26 cl, 98 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to potentiating preparation for radiation therapy, which as effective component contains uracyl derivative, represented by formula (1) where R1 represents halogen atom or cyanogroup; and R2 represents (4-8)-member heterocyclic group, which has from 1 to 3 nitrogen atoms and optinally has as substituent C1-C4 alkyl group, iminogroup, hydroxyl group, hydroxymethyl group, methansulphonyloxy group or aminogroup; amidinothiogroup, in which hydrogen atom, bound to nitrogen atom, can be substituted by C1-C4 alkyl group; guanidinogroup, in which hydrogen atom, bound to nitrogen atom, can be substituted by C1-C4 alkyl group or cyanogroup; C1-C4 alkylamidinogroup; or 1-pyrrolidinylmethyl group or its pharmaceutically acceptable salt. Invention also relates to method of radiation therapy potentiation, and to method of cancer treatment, which include introduction of described above uracyl derivative of formula (1) to patient who needs it.

EFFECT: invention ensures reduction of negative effect of radiation therapy, reduction of radiotherapy dose and enhancement of therapeutic effect.

18 cl, 3 tbl, 1 dwg, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) (lb) in which A denotes a benzene ring; Ar denotes naphthalenyl which optionally contains 1-3 substitutes independently selected from a group comprising C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, hydroxy group, C1-C6alkoxy group, halogen, heteroalkyl, heteroalkoxy group, nitro group, cyano group, amino- and mono- or di- C1-C6alkyl-substuted amino group; R1 denotes hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy group, carboxy group, heteroalkyl, hydroxy group optionally substituted with heterocyclylcarbonyl-C1-C6alkyl or R1 denotes N(R')(R")-C1-C6alkyl or N(R')(R")-carbonyl- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, heteroalkyl, phenyl-C1-C6alkyl; or R1 denotes R'-CO-N(R")-C1-C6alkyl, R'-O-CO-N(R")- C1-C6alkyl- or R'-SO2-N(R")- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cyclalkyl, C3-C7cycloalkyl- C1-C6alkyl or optionally substituted phenyl; R2, R2' and R2" independently denote hydrogen, halogen, cyano group, C1-C6alkyl, halogenated C1-C6alkyl or C1-C6alkoxy group; n equals 1; and pharmaceutically acceptable salts thereof. The invention also relates to use of compounds in any of claims 1-9, as well as to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds with chymase inhibiting activity.

14 cl, 128 ex

FIELD: chemistry.

SUBSTANCE: described is a method of producing optically pure voriconazole via: a) coupling reaction of 1-(2,4-difluorophenyl)-2(1H-1,2,4-triazol-1-yl)ethanone with 4-(1-bromoethyl)-6-(4-chlorophenylsulphanyl)-5-fluoropyrimidine in Reformatsky reaction conditions to obtain the desired (2R,3S)/(2S,3R) enantiomeric pair, b) splitting the thiol fragment from the enantiomer to obtain racemic voriconazole; and c) extracting the desired optically pure voriconazole via optical separation of the enantiomer using an optically active acid.

EFFECT: improved method.

4 cl, 7 ex, 1 tbl

FIELD: chemistry; pharmaceutics.

SUBSTANCE: invention concerns novel compounds of formula: where R1 denotes - OH; R2, R3 and R4 denote H; X denotes a pharmaceutically acceptable anion such as Br; Y denote a group of formula VIa: where the dotted line together with the nitrogen atom form an unsubstituted 6-member heteroaryl; X is as defined above; the compounds can be used in a pharmaceutical composition which inhibits tumour growth and intensifies immune response. Described is a method of producing a compound I, which further contains R1 -ORa, where Ra denotes an unsubstituted C1-8alkyl; R2 denotes -(O=)C-O-Ra, where Ra denotes an unsubstituted C1-8alkyl alkyl; described also are intermediate compounds and use thereof in producing compound I.

EFFECT: obtaining novel compounds.

18 cl, 11 dwg, 29 tbl, 16 ex

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