Anetholdithiolthiones and other dithiolthiones for treating conditions associated with monoamine neurotransmission dysfunction

FIELD: chemistry.

SUBSTANCE: in embodiments of the invention, specific compounds are used to prepare a medicinal agent for treating, relieving and preventing conditions associated with dysfunction of monoamine transmission. The compounds have general formula (1) , where: R1 and R2 are identical or different and denote hydrogen, alkyl, alkenyl, alkynyl, aryl, thio or alkylthio, or R1 and R2 may have extra substitutes which are selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkyloxy, morpholin-4-ylalkoxy, piperidin-1-ylalkyloxy, alkylamino, dialkylamino, arylamino.

EFFECT: more efficient use of compounds in preparing medicinal agents.

8 cl, 3 tbl, 4 ex

 

The invention relates to a derivative dithiolthiones as monoamine oxidase inhibitors, in particular inhibitors of MAO-b, methods of producing such compounds and to novel intermediate compounds useful in the synthesis of these derivatives dithiolthiones. The invention also relates to the use of the disclosed here compounds in the manufacture of a medicinal product with a useful effect. The benefits disclosed here, or it is obvious to a person skilled from the description and the overall level of technology. The invention also relates to the use of compounds of the invention for the manufacture of a medicinal product for the treatment or prevention of a disease or condition. More specifically, the invention relates to a new use for the treatment of a disease or condition disclosed here or obvious to a person skilled from the description and the overall level of technology. In embodiments of the invention specific compounds disclosed here, are used for the manufacture of a medicinal product, applicable for treatment, relief or prevention of conditions associated with dysfunction monoamine neurotransmission.

Inhibitors of mitochondrial flavoparmelia monoamine oxidase (MAO; EC 1.4.3.4) can increase the level of norepinephrine, epinephrine, dopamine, tryptamine and serotonin in the brain or other tissues and thus call the ü many pharmacological effects, mediated by their effect on these neurotransmitters.

Currently available MAO inhibitors, such as L-deprenyl, mofegiline, rasagiline, lazabemide, cause a wide range of side effects, including psychiatric (delirium, hallucinations, agitation), cardiovascular (orthostatic hypertension, hypertension) and neurological (sedation, abnormal movements).

The aim of the present invention is the development of new MAO inhibitors with a different structure compared to currently available and with fewer side effects.

In the application WO 98/27970 disclosed the use of 1,2-dithiol-3-thiones for the treatment of diseases or prevention of cell damage caused by oxygen radicals. In WO 01/091118 disclosed dithiolthione compounds for the treatment of neurological disorders and enhance memory. It was shown that these compounds inhibit the oxidase D-amino acids (DAAO, E.C. 1.4.3.3) - an enzyme that stereoselective will desaminase D-amino acids with the formation of reactive oxygen species is hydrogen peroxide. Inhibition by dithiolthione totally different enzyme monoamine oxidase - previously was not known.

Unexpectedly, the authors found that dithiolthione inhibit the activity of MAO-b in cell extracts, the floor is obtained from cultivated veins astroglial cells of the rat, while they do not have a significant effect on the activity of MAO-A. the Invention relates to the use of compounds of General formula (1)

in which:

- R1and R2are the same or different and represent hydrogen, alkyl, alkenyl, quinil, aryl, fluorine, chlorine, bromine, hydroxyl, alkyloxy, alkenylacyl, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thiol, alkylthio, aaltio, cyano, nitro, acyl, amido, alkylamino, dialkylamino group, or

- R1and R2may, together with the carbon atoms to which they are linked, form a 5 - or 6-membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms, which are selected from nitrogen, oxygen or sulfur, such as furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazol, isothiazol, 1,2,3-oxadiazole, 1,2,3-triazole, 1,3,4-thiadiazole, pyridine, pyridazine, pyrimidine or pyrazin,

- R1and R2can have additional substituents that are selected from hydrogen, alkyl, alkenyl, quinil, aryl, fluorine, chlorine, bromine, hydroxyl, alkyloxy, aminoacylase, morpholine-4-jalkotzy, piperidine-1-iliskileri, alkenylacyl, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, aaltio, cyano, oxo, nitro, acyl, amido, alkylamino or dialkylamino groups,

and their tautomers, stereoisomers and N-oxide, as well as pharmacologically acceptable salt, hydrate and solvate of such compounds of formula (1) and their tautomers, stereoisomers and N-oxide to obtain a pharmaceutical composition for the treatment, improvement or prevention of conditions associated with dysfunction monoamine neurotransmission.

The invention especially relates to compounds of General formula (1)in which R1and R2are the same or different and represent hydrogen, alkyl or aryl, optionally substituted by one or more atoms or groups selected from hydrogen, alkyl, aryl, fluorine, chlorine, bromine, hydroxyl, alkyloxy, aryloxy, amino, alkylamino, dialkylamino, thio, oxo or nitro groups.

More specifically the invention relates to the use of 5-(p-methoxyphenyl)-3N-1,2-dithiol-3-thione (anatoliilyan ADT), 3N-1,2-dithiol-3-thione (D3T) and 4-methyl-5-(2-pyrazinyl)-3N-1,2-dithiol-3-thione (oltipraz):

Most preferred is the use of 5-(p-methoxyphenyl)-3N-1,2-dithiol-3-thione, anyadditional (ADT), lipophilic substituted analogue 3N-1,2-dithiol-3-thione (D3T), in clinical practice for decades as a choleretic and slumvillage funds without any negative p the shares ( Christen, M-O., Methods Enzymol., 252, 316-323, 1995).

In another aspect the invention relates to compounds of formula (1):

in which:

- R1is optionally substituted by phenyl, and R2is S-CH2-(4-were), or one of the subgroups:

in which n has the value 2, 3, 4 or 5 and R3represents hydrogen or (C1-3)alkyl, or

- R1is a 4-hexyloxyphenyl, and R2represents hydrogen, or

- R1is substituted by phenyl, and R2represents SH or subgroup:

- R1is hydrogen, and R2represents-CH=CH-4-(diethylaminophenyl), -CH=CH-(2-chinolin) or the subgroup of:

in which n has the same meaning as above, and R4and R5independently represent a (C1-3)alkyl or together with the nitrogen atom to which they are linked, form a saturated 5 - or 6-membered ring, optionally containing one or more heteroatoms, chosen from N, O or S, or

- R1is (C1-3)alkyl, and R2is 1-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazine-4-yl, or

- R1is cyano, and R2represents a subset of the-NH-C(O)-NH-phenyl, in which phenyl group is optionally Zam is banned or

- R1is-SO2CH3and R2represents an amino group,

and their tautomers, stereoisomers and N-oxides, as well as pharmacologically acceptable salts, hydrate and solvate of such compounds of formula (1) and their tautomers, stereoisomers and N-oxide.

The invention relates to racemates, mixtures of diastereomers, as well as to the individual stereoisomers of compounds of formula (1). In the description of the substituents abbreviation "alkylmeans (C1-3)alkyl, "alkenylmeans (C1-3)alkenyl, "quinil"means (C1-3)quinil, "acyl" means alkyl(C1-3)carbonyl, arylcarbamoyl or arylalkyl(C1-3)carbonyl and "arylmeans furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolin, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, phenyl, indazoles, indolyl, indolizinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, (2,3-dihydro-1,4-benzodioxin-5-yl), benzimidazolyl, benzothiazolyl, purinol, chinoline, ethanolic, hinely, phthalazine, hintline, honokalani, 1,8-naphthyridine, pteridine, naphthyl or azulene, preferably phenyl or (2,3-dihydro-1,4-benzodioxin-5-yl). "(With1-3)alkyl" means methyl, ethyl,n-propyl or isopropyl, "(With1-4)alkyl" means methyl, ethyl,n-propyl, ISO is ropel, n-butyl, 2-butyl, isobutyl or 2-methyl-n-propyl. "Optionally substituted" means that the group may not be substituted or may be substituted by one or more groups selected from alkyl, alkenyl, quinil, aryl, fluorine, chlorine, bromine, hydroxyl, alkyloxy, alkenylacyl, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, aaltio, cyano, oxo, nitro, acyl, amido, alkylamino, dialkylamino, carboxyl, or two optional substituent together with the carbon atoms to which they are linked can form a 5 - or 6-membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms, which are selected from nitrogen, oxygen or sulfur. Optional substituents may themselves be more optional substituents. Preferred optional substituents include (C1-3)alkyl, for example methyl, ethyl and trifluoromethyl, fluorine, chlorine, bromine, hydroxyl, (C1-3)alkoxy, for example methoxy, ethoxy, triptoreline and the amino group.

Prodrugs of the above compounds are also included in the present invention. Prodrugs are therapeutic agents that are not activeper sebut transformed into one or more active metabolites. Prodrugs are bioapatite derived medicines used to overcome some of the backdrop when using the original drug molecules. These barriers include, but are not limited to, solubility, permeability, stability, presystemic metabolism and target constraints (Medicinal Chemistry: Principles and Practice, 1994, ISBN 0-85186-494-5, Ed.: F.D.King, p.215; J.Stella, “Prodrugs as therapeutics”,Expert Opin. Ther. Patents, 14(3), 277-280, 2004; P. Ettmayer et al., “Lessons learned from marketed and investigational prodrugs”, J.ed.Chem., 47, 2393-2404, 2004). Prodrugs, i.e. compounds that when administered to humans by any known method into the metabolism in the compounds of formula (1)are included in the invention. In particular, it relates to compounds with primary or secondary amino or hydroxy groups. Such compounds can react with organic acids to form compounds of formula (1)where there is an additional group that is easily removed after the introduction, for example, but not limited to, amicin, enamine, the basis of manniche, derived hydroxymethylene derived O-(acyloxymethyl), carbamate, ester, amide or enamine.

N-oxides of the aforementioned compounds included in the scope of the present invention. Tertiary amines can lead or not to lead to N-oxides in the process of metabolism. The proportion of N-oxidation may vary from trace amounts to almost quantitative conversion. N-oxides can be more or less active than the corresponding tertiary amines. While N-OKS the water easily chemically restored to the corresponding tertiary amines, in humans this occurs in varying degrees. Some N-oxides almost quantitatively recovered in the corresponding tertiary amines, and in other cases, the conversion is almost trace or even completely absent (M.H. Bickel: “The pharmacology and Biochemistry of N-oxides”,Pharmacological Reviews, 21(4), 325-355, 1969).

General principles of synthesis

The choice of a particular method of synthesis depends on factors known to the experts in this field, such as compatibility of functional groups of used reagents, use of protective groups, catalysts, reagents activation and combinations and subtle structural features of the destination of the resulting connection.

Pharmaceutically acceptable salts

Pharmaceutically acceptable salts can be obtained by well-known standard methods, for example by mixing the compounds of the present invention with a suitable acid, for example with inorganic acid, such as hydrochloric acid or organic acid.

Pharmaceuticals

The compounds of this invention can be used in suitable for the introduction of forms using conventional methods with the use of auxiliary substances such as liquid or solid media. The pharmaceutical compositions of this invention can be entered enterline, the pen is real, parenterally (intramuscularly or intravenously), perfectline or locally (topically). You can enter them in the form of solutions, powders, tablets, capsules (including microcapsules), ointments (creams or gel) or suppositories. Suitable excipients for such drugs are conventional pharmaceutical solid or liquid fillers, solvents, emulsifiers, lubricants, fragrances, dyes and/or buffer substances. You can call such frequently used auxiliary substances, such as magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars or carbohydrates, talc, lactoprotein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, such as fish oil, sunflower oil, peanut or sesame oil, polyethylene glycol and solvents such as, for example, sterilized water and monatomic or polyatomic alcohols, such as glycerin.

Compounds of the present invention is usually administered in the form of pharmaceutical compositions, which constitute an important and new variants of the invention due to the presence of such compounds, more particularly compounds disclosed here. Types of pharmaceutical compositions that can be used include, but are not limited to, tablets, chewable tablets, capsules, solutions, solutions for parenteral administration, supposito the AI, suspensions and other types disclosed here or obvious experts from the description and General knowledge of the prior art. In embodiments, the invention features a pharmaceutical pack or a set of one or more containers filled with one or more ingredients of the pharmaceutical compositions according to the invention. Such containers attached a work support, such as instructions for use or prescribed by a governmental Agency, a notice regulating the manufacture, use or sale of pharmaceutical products, which contains a certification by the Agency of manufacture, use or sale of the drug for administration to humans and animals.

Pharmacological methods

Determination of MAO activity

As the source activity as MAO-a and MAO-b were used veins astroglial cells of newborn rats (Carlo et al., Brain Res. 711, 175-183, 1996). Astroglial cells were grown by well-known methods (Langeveld et al., Neurosci. Lett. 192, 13-16, 1995). After a week of growing in culture in a mixture of 5% CO2/95% air at 37°C. cells were trypsinization and treated with ultrasound in a chilled on ice, 25 mm Tris-HCl buffer (pH of 7.4)containing 1 mm EDTA. Then the lysates were centrifuged for 5 min at 10000 g and 4°C and selected aliquot fraction of the top layer to define MAO Akti the surface using a set of Amplex Red MAO (Molecular Probes, Leiden, The Netherlands) according to the method described by Zhou and Panchuk-Voloshina (Anal. Biochem. 253, 169-174, 1997). Measurement was carried out according to the manufacturers ' instructions. In short, before the addition of substrate samples incubated for 30 min in 96-well tablet with drugs or solvent (total volume 50 μl). Then added 50 ál Amplex Red, containing 2 μg/ml of horseradish peroxidase (HRP),p-tyramine hydrochloride (2 mm, a substrate for both MAO a and MAO B (Youdim and Finberg, Biochem. Pharmacol., 41, 155-162, 1991) and Amplex Red (10 mm). Under these conditions, thanks MAO catalyzed oxidation tiramina in the reaction combination with HRP Amplex Red becomes fluorescent resorufin. To measure MAO-a activity was measured time-dependent increase in education resorufin every 2 minutes for 30 min at room temperature on a microplate fluorimeter (BMG Labtechnologies GmbH, Germany), at a wavelength of excitation 544 nm and emission of 595 nm. It was found that in this time interval the intensity of the fluorescence increases linearly. For calculation of the results was amended on the intensity of the background (i.e. in the absence of substrate MAO tiramina) and data were expressed in relative fluorescence units per minute. The protein content was determined by the method of Bradford et al. (Anal. Biochem. 72, 248-254, 1976) using BSA as the standard. Statistical comparison of groups was performed using fashion and one-way analysis of variance ANOVA with subsequent test of Newman-Keuls. Significant considered values of P<0,01.

MAO-b inhibitory activity of compounds A1-D6 was determined in medical research centre CEREP (Paris, France) according to the method described J.L.Salach,Arch. Biochem. Biophys., 192, 128, 1979.

Anatoliilyan and related dithiolthione active in doses of 0.1-100 mg/kg after oral administration, and selective inhibition of monoamine oxidase-makes them particularly useful in the treatment of psychiatric and/or neurological diseases caused by violations of fundamental monoaminergic systems, or these diseases can be treated by the management of these systems, and these diseases are selected from the group including: mood disorders, such as bipolar disorder type I, bipolar II disorder and unipolar depressive disorders such as minor depression, seasonal affective disorder, postpartum depression, mental depression and major depression; anxiety disorders, including panic disorder (with or without agoraphobia), social phobia, obsessive-compulsive disorder (with painful chronic TIC or without him and schizophrenic disorder), post-traumatic stress disorder and generalized anxiety disorder; disorders associated with drug use, including disorders associated with receiving desig the Chennai medicines (type dependence and abuse), and disorders induced by drug use (type of the syndrome), attention deficit and aggressive behavior, such as hyperactivity, attention deficit and narcolepsy; disorders of control motivation type of pathological gambling; eating disorders type anorexia nervosa and bulimia nervosa; tick the type of Tourette's disorder; tired leg syndrome; disorders associated with impaired cognition and/or memory, such as Alzheimer's disease, Parkinson's disease and dementia in AIDS and/or morbid psychiatric disorders and neurorehabilitation (traumatic brain injury), and other diseases of the Central nervous system such as epilepsy, down syndrome, Huntington's disease, some types of pain, including headache, atypical facial pain, pain syndrome and chronic pain; amyotrophic lateral sclerosis and sexual dysfunction; disorders of cerebral or peripheral vascular system, including essential, renovascular, lung or ocular hypertension, thrombosis, myocardial infarction and cerebrovascular stroke; disorder of non-vascular smooth muscles, including the obstruction of the respiratory tract, asthma or other respiratory diseases, and disorders of contractility of the gastrointestinal tract, hemorrhoids, spasm of the sphincter and is a Lada muscles in the gastrointestinal tract and bladder dysfunction. In addition, MAO inhibitors can stop premature birth and relax the birth canal during childbirth, they are applicable to relax the urinary tract when removing kidney stones and can be used to relieve the contraction of smooth muscles and spasm.

It is preferable to use the compounds of this invention for the treatment of mood disorders, bipolar disorder type I, bipolar disorder type II, unipolar depressive disorder, minor depression, seasonal affective disorder, postpartum depression, mental depression, major depression; anxiety disorders, panic disorder, social phobia, obsessive-compulsive disorders, post traumatic stress disorder, generalized anxiety disorder; disorders associated with drug use; disorders associated with scheduled drugs; disorders induced by drug abuse; withdrawal syndrome, attention deficit and aggressive behavior, hyperactivity, attention deficit, narcolepsy; disorders control motivation, pathological gambling; eating disorders, anorexia nervosa, bulimia nervosa; TIC disorders, Tourette's syndrome tired legs; pain, headache, atypical facial pain, pain syndrome and chronic Bo and; sexual dysfunction, airway obstruction, asthma, disorders of contractility of the gastrointestinal tract, hemorrhoids, spasm of the sphincter and smooth muscles in the gastrointestinal tract and bladder dysfunction.

Dosage

The effectiveness of the compounds of the present invention as inhibitors of MAO-b was determined as described above. Their effectiveness is defined for the compounds of formula (1), it is possible to determine theoretical lower effective dose. When the concentration of the compound equal to twice the measured constant of inhibition, the enzyme is likely to be inhibited by the compound at 100%. Translating this concentration in mg compound per kg weight of the patient to determine theoretical lower effective dose assuming perfect bioavailability. From the viewpoint of pharmacokinetics, pharmacodynamics, and other aspects can replace actually injected dose at higher or lower. It is convenient to introduce a dose of 0.001-1000 mg/kg, preferably 0.1 to 100 mg/kg of body weight of the patient.

Treatment

Used herein, the term "treatment" refers to any treatment of a mammalian, preferably of conditions or diseases of a human, and includes: (1) prevention of the disease or condition in a patient who may be predisposed to the disease but has not yet been installed for automotive technician is h, that the patient is sick, (2) inhibiting the disease or condition, i.e. the termination of their development, (3) facilitation of the disease or condition, i.e. the call regression of the state, or (4) facilitating conditions caused by the disease, i.e. the cessation of symptoms.

Examples

Example 1: materials and methods

All reactions involving compounds that are sensitive to moisture, conducted in an atmosphere of dry nitrogen. Over the course of the reaction was monitored using thin-layer chromatography (TLC) on plastic plates coated with silica gel (Merck silica gel 60 F254) using the indicated eluent. Compounds were detected visually under UV light (254 nm) or by using the I2. Flash chromatography for purification of compounds was performed on silica gel Acros (0,030-0.075 mm) using the specified solvent. The spectra of nuclear magnetic resonance (1H NMR and13With NMR, ART) was recorded in the specified solvent. Constant interactionJare given in Hz. The shape of the peaks in the NMR spectra are indicated by symbols "kV" (Quartet), "DQC" (double Quartet), t (triplet), dt (double triplet), d (doublet), DD (double doublet), "s (singlet), "OSS" (broadened singlet) and m (multiplet).

Example 2: Synthesis of specific compounds

Specific compounds, the synthesis of which is described below, serve to further illustrate the invention and therefore in no way about rancimat scope of the invention.

The structure of the specific compounds of the invention
Connection.R1R2
A14-hexyloxyphenylH
A2H
A3H
B1phenyl
B24-were
B34-were4-phenylpiperazin the Nile
C1H-CH=CH-(4-diethylaminophenyl)
C2H-CH=CH-(2-chinoline)
D1phenyl-S(CH2)2CH(CH3)NH-2-PROPYNYL
D2phenyl-S(CH2)3CH(CH3)NH-2-PROPYNYL
D3phenyl-S(CH2)4CH(CH3)NH-2-PROPYNYL
D4phenyl-S(CH2)4CH(CH3)N(CH3)-2-PROPYNYL
D5phenyl-S(CH2)3CH(CH3)N(CH3)-2-PROPYNYL
D6phenyl-S-CH2-(4-were)

Other variants of the invention will be obvious to specialists from the analysis of the description and practice of the disclosed invention here. The description and examples should be considered only as illustrative, and the true scope and essence of the invention defined by the claims.

Connection A1

Stage i of the scheme A.1.

32 g (1 mol) of sulfur was added to 150 ml of DMF (N,N-dimethylformamide) and the resulting mixture was heated at boiling under reflux until almost complete dissolution of sulfur. Dropwise added 43,6 g (200 mmol) of 2-(4-n-hexyloxyphenyl)of propene. After continued stirring and heating of the reaction mixture with subsequent analysis by TLC (thin layer chromatography, eluent: toluene), and then for 4 h the mixture allowed to cool to room temperature. After filtering the reaction mixture and evaporation in vacuum received the remainder, which was chromatographically in column (SIO, SIS2, eluent: toluene). The combined product containing fractions were concentrated in vacuo, the residue was recrystallized from cyclohexane and received 5 g (8,1%) of the desired compound A1. Melting point: 121°C.

Connection A2

Article is Diya i scheme A.2

To a solution of 2 equiv of ateleta sodium (NaOEt) in absolute ethanol was added 1 EQ of 4-hydroxyacetophenone with 1 equiv of N-(2-chloroethyl)of the research. After that the reaction mixture boiled under reflux for 5 h, then heating was stopped and stirring continued for 12 h at room temperature. The solvent was removed in vacuo, the residue was placed in an aqueous solution of hydrogen chloride (~2 BC) and the resulting solution was washed with diethyl ether. The aqueous layer was neutralized with sodium hydroxide solution (~2 N.), then was extracted with diethyl ether. The combined organic extracts were dried (Na2SO4). The desiccant was removed by filtration and the solvent was removed in vacuum and received simple phenolic ester as an orange-yellow oil with a yield of 91%.

Stage ii scheme A.2(according Thuiller et al.,Bull. Chim. Soc., (1959) 1398)

To cold absolute toluene containing 2 equivtert-Aminata sodium (NaOC(CH3)2CH2CH3), was added 1 EQ of simple phenolic ether with stage i and 1 EQ of a solution of carbon disulfide. Then the reaction mixture was stirred 6 hours After this was added 1 equiv of 1,2-dibromethane and stirring continued for 12 h, the Reaction mixture was washed with an aqueous solution of sodium hydroxide (~2 N.) and water to a pH of 7. The organic fraction was dried over Na2SO4. The desiccant was removed, filtratio and the solvent was removed in vacuum and received net derivative of 1,3-dithiolane in the form of orange crystals with a yield of 70%.

Stage iii scheme A.2

Derived dithiolane with stage ii was treated with tetratetracontane (P4S10) in xylene boiling under reflux for 15 minutes and After cooling the suspension was washed water 1 N. a sodium hydroxide solution, then added chloroform, and the organic fraction was dried over Na2SO4. The desiccant was filtered and the solvent was removed in vacuum and the obtained residue, which was purified by chromatography on a column (SIO, SIS2, eluent: diethyl ether/toluene 1/1), you needconnection A2received in the form of orange crystals with a yield of 4%. Melting point: 102°C. Range1H NMR (CDCl3, δ ppm): at 2.59 (t, 4H), and 2.83 (t, 2H), of 3.73 (t, 4H), to 4.17 (t, 2H), 6,98 (d, 2H), 7,60 (d, 2H), was 7.36 (s, 1H).

Compound A3(red oil, range1H NMR (CDCl3, δ ppm): 1,49 (kV, 2H), 1,67 (t, 4H), 2.63 in (t, 4H), of 2.97 (t, 2H), 4,24 (t, 2H), 7,00 (d, 2H), 7,38 (s, 1H), 7,60 (d, 2H)) was obtained according to the method similar to that which was described for compoundsA2.

Connection B1

Stage i of the scheme B.1.

2 EQ piperazine and 1 equiv of 5-methylsulfanyl-4-phenyl-[1,2]dithiol-3-thione (Grandin, A. et al.,Bull.Soc.Chim.Fr.,11(1968)4555) was dissolved in absolute ethanol and the reaction mixture is boiled under reflux. After 7 days the solvent was removed in vacuum and the residue was purified by chromatography (SO 2;eluent 2% ethanol in toluene.vol.). The collected fractions were concentrated in vacuo, the residue was recrystallize from acetone and got orange crystals with a yield of 12%:connection B1. Melting point: 174°C. Range1H NMR (CDCl3, δ ppm): of 2.97 (t, 4H), 3,44 (t, 4H), to 4.23 (m, 4H), 6.42 per-6,76 (m, 3H), 7,34-7,49 (m, 5H).

Compound B2(yellow crystals, melting point 108°C, range1H NMR (CDCl3, δ ppm): is 2.37 (s, 3H), 2,98 (t, 4H), of 3.45 (t, 4H), to 4.23 (m, 4H), to 6.43-6,76 (m, 3H), 7,22-7,28 (m, 4H)) was obtained according to the method similar to that described for compoundsB1.

Compound B3 (red crystals, melting point 148-150°C decomp.) received by the method similar to that described for compoundsB1.

Connection C1

Stage i of the scheme C.1.

1 g (6.8 mmol) of 5-methyl-[1,2]dithiol-3-thione was dissolved in 50 ml of absolute ethanol. Then added 2.5 g (14.1 mmol) of 4-(diethylamino)benzaldehyde and 1 ml of piperidine, and then the reaction mixture was heated on a water bath for 2 hours, the Reaction mixture was concentrated in vacuo and the residue was placed in a freezer, where he formed crystals. The crystals were separated and recrystallize from isopropyl alcohol and received 1.5 g (4.9 mmol, 35%) of the desired compoundC1, melting point: 130°C. Cm. the patent JP1319477.

Connection C2(TLC (SIO, SIS 2, eluent toluene), Rf=0.36 in the presence of initial substances), obtained by the method similar to that described for compoundsC1.

Connection D1

Stage i of the scheme D.1.

17.5 g (87.9 mmol) 1-bromo-2-phenylpropane was dissolved in 300 ml of DMF, and then added 14.1 g (441 mmol) of sulfur. The reaction mixture is boiled under reflux overnight, and then continued stirring at room temperature over night. The reaction mixture was concentrated in vacuo and then added ~100 ml of toluene, the resulting crystals were collected and dried in vacuum. Yield: 13 g (45,3 mmol, 52%) as yellow solid containing dimethylammonium salt of 4-phenyl-5-mercapto-[1,2]dithiol-3-thione.

Stage ii scheme D.1.

3.5 g (10.4 mmol) of iodide (synthesis of iodide see below) was dissolved in 40 ml of methanol and then added 3 g (10.4 mmol) dimethylammonium salt (from step i). The reaction mixture was stirred overnight, then concentrated in vacuo and the residue was chromatographically in column (SIO, SIS2, eluent: heptane/ethyl acetate 6/1). After concentration of the fractions containing the product received 700 mg (1.6 mmol, 15%) as a red oil.

Stage iii scheme D.1.

700 mg (1.6 mmol) of product from step ii was dissolved in a small amount of dichloromethane are then added n is the number 7 N. HCl in isopropanol) to a final concentration of approximately 3 H. the Reaction mixture was stirred overnight, then concentrated in vacuo and got 265 mg of orange solid containingD1.HCl, melting point 243°C.

Connection D2(melting point: 96-101°C decomp.), received by the method similar to that described for compoundsD1. Used iodide can be synthesized in the same way as when the connectionD1(see below).

Connection D3(melting point: 82-87°C) was obtained by the method similar to that described for compoundsD1. Used iodide can be synthesized in the same way as when the connectionD1.

Connection D4(melting temperature: 65-70°C decomp.) received by the method similar to that described for compoundsD1. Used iodide can be synthesized in the same way as when the connectionD1.

Connection D5(melting point: 65-72°C), was prepared by the procedure similar to that described for compoundsD1. Used iodide can be synthesized in the same way as when the connectionD1.

Compound D6(melting point: 134-135°C) was obtained by the method similar to that described for compoundsD1based onpair-bromelicola as alkylating reagent.

Synthesis of iodide used for connection D1 (figure D.2).

Stage i of the scheme D.2.

6.4 g (to 72.6 mmol) 4-hydroxy-2-butanone dissolved in 250 ml of 1,2-dichloroethane and added 5.5 ml (80 mmol) of propargylamine. The reaction mixture was stirred 10 min and then cooled to 0°C. To the reaction mixture were added portions 20 g (94 mmol) NaBH(OAc)3the stirring was continued for 48 h, after which the mixture was poured into a saturated aqueous solution NaHC3. After extraction of the resulting aqueous solution with methylene chloride and concentration in vacuo received 3 g of the desired product. The aqueous layer was parselocale NaOH solution (33%, aq.), saturated NaCl (TV.) and re-Proektirovanie with ethyl acetate. The combined organic extracts were dried (Na2SO4) and after removal of the desiccant by filtration and removal of solvent by concentration in vacuum obtained 7.6 g (82%) of the desired product as an orange oil). It was used at the second stage without additional purification.

Stage ii scheme D.2.

7.6 g (59,8 mmol) derived aminopropanol (stage i) was dissolved in 200 ml of methylene chloride and added to 9.2 ml (~65 mmol) of triethylamine and 14 g (65 mmol) of (Boc)2On (Boc=tert-butyloxycarbonyl). The resulting mixture was stirred overnight and then concentrated in vacuo and the residue re-dissolved in utilize the ATA. The organic fraction was washed with a saturated solution NaHC3(aq.), water and saturated sodium chloride solution, then dried over Na2SO4. The desiccant was filtered, solvent removed by concentration in vacuo and got to 13.7 g (100%) of a brown oil containing aminopropanol with a protective N-Boc group.

Stage iii scheme D.2.

33 g (126 mmol) of triphenylphosphine were dissolved in 600 ml of methylene chloride, was added 19 g (280 mmol) of imidazole and the mixture was cooled to 0°C. To the reaction mixture was added dropwise a solution of 35.5 g (140 mmol) of iodine in 300 ml of methylene chloride and stirred 10 minutes Then dissolved 8 g (35 mmol) of aminopropanol containing a protective group of N-Boc (stage ii) in 50 ml of methylene chloride, and stirred at 0°C for 20 minutes and Then the reaction mixture allowed to cool to room temperature and stirred 16 hours the Reaction the mixture was filtered, the filtrate washed with a saturated solution of sodium chloride and concentrated in vacuum. The remnant was filtered through a short column with SIO, SIS2(eluent: heptane/EtOAc 6/1), the eluate was concentrated in vacuo and got a 5.1 g (%) of the corresponding iodide as a pale yellow oil. This iodide was used for obtaining compounds of D1 (see figure D.1).

The corresponding iodides required to obtain compoundsD2,D3,D4andD5you can get services which were described in the synthesis of iodide used to obtain theD1(figure D.2). For compoundsD4andD5stage protect and unprotect (N-Boc) are not necessary because of the presence of the methyl group on the nitrogen atom.

Example 3: preparation of compound A1

For oral (p.o.) introduction: to the desired quantity (0.5 to 5 mg) solid connections A1 in a glass tube was added a few glass beads and solid grind, rotating it within 2 minutes After adding 1 ml of 1% solution of methylcellulose in water and 2% (vol./about.) Poloxamer 188 (Lutrol F68) connection suspended, stirring for 10 minutes has Established pH 7 by adding a few drops of aqueous NaOH (0.1 N.). Remaining in suspension the particles are then suspended in an ultrasonic bath.

For intraperitoneal(I.P. Pavlova.)introduction:to the desired quantity (0.5 to 15 mg) solid connections A1 in a glass tube was added a few glass beads and solid grind, rotating it within 2 minutes After adding 1 ml of 1% solution of methylcellulose and 5% solution of mannitol in water connection is suspended, stirring for 10 minutes has Established a final pH of 7.

Example 4: the results of the pharmacological test

Σ MAO activity is here
(% inhibition)
MAO-B activity
(% inhibition)
MAO-A activity
(% inhibition)
Conc. (µm)L-depADTL-depADTD3TClorADT
0,0032-4----
0,0110-18----
0,0328-430---
0,156148015-100-
0,373359740---
17960100732--
3-70-896-0
10-81-9624 -3
30-85-10059-14
100----82--
300----92--
1000----91--

The effect of deprenyl (L-dep) and anyadditional (ADT) on the total activity of monoamine oxidase (MAO) (columns 2 and 3); the effect of L-dep, ADT and 3H-1,2-dithiol-3-thione (D3T) on the activity of monoamine oxidase-B (MAO-B) (columns 4, 5 and 6); the impact clorgyline (Clor) and ADT on the activity of monoamine oxidase-A (MAO-A) (columns 7 and 8) in cell extracts obtained from cultures veins of astroglial the cells of newborn rats, on the activity of MAO and the effects of drugs on it were defined in detail above.

Data are expressed as percentages relative to the corresponding control experience and represent average values from two to five independent experiments, repeated three times. Total MAO activity was determined in the presence of solvent (0,03% DMSO), MAO-B activity was determined in the presence of 0.1 μm of the selective inhibitor of MAO-clorgyline and MAO-A activity was determined in the presence of 1 μm of the selective inhibitor of MAO-B of deprenyl.

It is known that astroglial cells primarily Express MAO-B (Thorpe et al., J. Histochem. Cytochem., 35, 23-32, 1987). With the use of nonselective substrate tiramina and deprenyl, a selective inhibitor of MAO-B (Youdim and Finberg, Biochem. Pharmacol., 41, 155-162, 1991it was found that up to 80% of the total MAO activity astroglial cells due to MAO-B. the Remaining activity of MAO (about 20%) in the presence of maximally effective concentrations of deprenyl was completely ingibirovany adding clorgyline - selective inhibitor of MAO-A. Deprenil inhibited total MAO activity astroglial cells depending on the concentration when the value of the IC50around 0.04 μm. Similarly, depending on the concentration of ADT inhibited total MAO activity when the value of the IC50approximately 0.5 μm, reaching the maximum effect (about 80% of ing is berbania) at a concentration of 30 μm. For identical ratios of the concentration-effect in the case of deprenyl and ADT has the following effects of selective and complete blockade of MAO-A activity by clorgyline compared with the effect of inhibition of total MAO activity. In these conditions, i.e. in the presence of clorgyline, similar effects of the blockade of MAO-b, depending on the concentrations were found for D3T when the value of the IC50about 20 microns and the maximum effective concentration of 300 μm. After selective and complete blockade of MAO-B activity deprenyl statistically significant effect of ADT on MAO activity was not detected.

MAO-B inhibiting activity of the compounds A1-D6 was determined in a medical research centre CEREP (Paris, France) according to the method described J.L. Salach,Arch. Biochem. Biophvs.,192, 128, 1979.

Connection% inhibition of MAO-b at 10-5M
A1100
A281
A383
B165
B274
B354
C1 52
C256
D125
D2100
D395
D481
D575
D671

1. The use of compounds of General formula (1)

where R1and R2are the same or different and represent hydrogen, alkyl, alkenyl, quinil, aryl, thio or alkylthio, or
R1and R2can have additional substituents selected from hydrogen, alkyl, alkenyl, quinil, aryl, alkyloxy, morpholine-4-jalkotzy, piperidine-1-iliskileri, alkylamino, dialkylamino, arylamino,
and its pharmacologically acceptable salts, pharmaceutical composition having MAO-b inhibitory activity, for the treatment, improvement or prevention of disorders associated with dysfunction monoamine neurotransmission selected from: mood disorders, bipolar disorder type I, bipolar disorder type II, unipolar depressive disorder, minor depression, seasonal is about affective disorders, postpartum depression, mental depression, major depression; anxiety disorders, panic disorder, social phobia, obsessive-compulsive disorder, post traumatic stress disorder, generalized anxiety disorder; disorders associated with drug use; disorders associated with scheduled drugs; disorders induced by drug abuse; withdrawal syndrome, attention deficit and aggressive behavior, hyperactivity, attention deficit, narcolepsy disorder control for motivation, pathological gambling, eating disorders, neurotic anorexia, neurotic disorders; TIC disorders, Tourette's.

2. The use according to claim 1, characterized in that the compounds of General formula (1) represent 5-(p-methoxyphenyl)-3H-1,2-dithiol-3-tion or 3H-1,2-dithiol-3-tion.

3. The use according to claim 1, characterized in that the compound of General formula (1) represents 5-(p-methoxyphenyl)-3H-1,2-dithiol-3-tion.

4. Compounds of General formula (I):

where R1represents optionally substituted phenyl, where the substituents are selected from hydrogen, alkyl, and alkyloxy; and R2is S-CH2-(4-were), or one of the subgroups:

where n has a value of 2, 3, 4 or 5 and R3represents hydrogen or (C1-3)alkyl, or
R1is a 4-hexyloxyphenyl and R2is hydrogen, or
R1is hydrogen and R2represents-CH=CH-4-(diethylaminophenyl), -CH=CH-(2-chinolin) or the subgroup of:

in which n has the same values as above, and R4and R5together with the nitrogen atom to which they are linked, form a saturated 6-membered ring, optionally containing another heteroatom selected from N or O, or
R1is (C1-3)alkyl and R2represents 1-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazine-4-yl
and their pharmacologically acceptable salts.

5. The compound according to claim 4 General formula (I):

where R1is a 4-hexyloxyphenyl and R2represents hydrogen,
R1represents hydrogen and R2represents,
R1represents hydrogen and R2represents,
R1represents phenyl and R2represents,
R1is 4-were and R2represents,
R1is 4-were and R2the present is the focus of 4-phenylpiperazine,
R1represents hydrogen and R2represents-CH=CH-(4-diethylaminophenyl),
R1represents hydrogen and R2represents-CH=CH-(2-chinoline),
R1represents phenyl and R2is-S(CH2)2CH(CH3)NH-2-PROPYNYL,
R1represents phenyl and R2is-S(CH2)3CH(CH3)NH-2-PROPYNYL,
R1represents phenyl and R2is-S(CH2)4CH(CH3)NH-2-PROPYNYL,
R1represents phenyl and R2is-S(CH2)4CH(CH3)N(CH3)-2-PROPYNYL,
R1represents phenyl and R2is-S(CH2)3CH(CH3)N(CH3)-2-PROPYNYL,
R1represents phenyl and R2is-S-CH2-(4-were).

6. Pharmaceutical composition having MAO-b inhibitory activity, containing, in addition to pharmaceutically acceptable carrier and/or at least one pharmaceutically acceptable auxiliary substances, pharmacologically active amount of at least one compound according to claim 4 or its salt as an active ingredient.

7. A method of obtaining a pharmaceutical composition according to claim 6, characterized in that the compound according to claim 4 together with a pharmaceutically acceptable carrier and/or at least one pharmaceutically when mimim auxiliary substance, and then turn into a form suitable for injection.

8. The compound according to claim 4 or its salt for use as a medicine with MAO-b inhibitory activity.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to novel quinoline or quinazoline derivatives of general formula

Ib, where R1 is C1-6-alkyl or C1-6-alkoxy; X is N or CH; R3 and R4 independently denote hydrogen, C1-6-alkyl, C1-6-alkylsulphonyl or a group of formula (IIa), where A is oxygen or sulphur; D is -(CH2)t, -(CH2)tO- or -O(CH2)t, where t equals 0, 1, 2, 3 or 4; and E is C1-6-alkyl, C3-7-cycloalkyl, or a 3-7-member monocyclic aromatic ring or a 6-10-member bicyclic aromatic ring in which 1-3 carbon atoms in the ring(s) are optionally substituted with a heteroatom which is independently selected from nitrogen, oxygen and sulphur, (optionally substituted with 1 or 2 substitutes independently selected from halogen, C1-6-alkyl, CF3, cyano, hydroxy and C1-6-alkoxy); or a group of formula (IIb), where A is oxygen or sulphur; D is -(CH2)t-, -(CH2)tO- or -O(CH2)t, where t equals 0, 1, 2, 3 or 4; and E is C1-6-alkyl, C3-7-cycloalkyl, or a 3-7-member monocyclic aromatic ring or a 6-10-member bicyclic aromatic ring in which 1-3 carbon atoms in the ring(s) are optionally substituted with a heteroatom which is independently selected from nitrogen, oxygen and sulphur (optionally substituted with 1 or 2 substitutes independently selected from halogen, C1-6-alkyl, CF3, cyano, hydroxy and C1-6-alkoxy); or R3 and R4 together with the nitrogen atom with which they are bonded form a 3-7-member ring or a 6-10-member bicyclic ring which can be saturated, partially saturated or unsaturated and contain 1, 2 or 3 heteroatoms selected from nitrogen, sulphur and oxygen, where each group is optionally substituted with 1 or 2 substitutes selected from oxo, C1-6-alkyl, C1-6-alkoxy, aryl and aryl-C1-6-alkyl (where aryl and aryl-C1-6-alkyl are also optionally substituted with 1 or 2 with C1-6-alkyls or C1-6-alkoxy). The invention also relates to use of formula Ib compounds in preparing a medicinal agent, to a pharmaceutical composition based on formula Ib compound and preparation method thereof.

EFFECT: obtaining novel quinoline and quinazoline derivatives having high affinity to 5-HT1-receptors.

12 cl, 171 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medication, reducing desire for alcohol, which represents substituted 1H-benzimidazoles of general formula 1 or their pharmaceutically acceptable salts and/or hydrates, pharmaceutical composition, and medication on their basis. Compounds can be applied in treatment of alcohol abuse with application of ethanol-containing products, if necessary, together with antidepressants. In compounds of general formula 1 , where: W represents sulfur atom or group S=O; R1 represents one or more substituents, selected from hydrogen, halogen, C1-C4alkyl, C1-C4alkyloxy, optionally substituted 5-6-member azaheterocyclyl with 1-2 atoms of nitrogen and/or oxygen in cycle; R2 represents atom of hydrogen or optionally substituted C1-C4alkyl; R3 and R4 independently on each other represent optionally similar substituents, selected from hydrogen, optionally substituted C1-C4alkyl, C3-C6cycloalkyl; R5 represents alkyl substituent, selected from hydrogen or optionally substituted C1-C7alkyl, C1-C7alkenyl, C1-C4alkynyl, optionally substituted phenyl, optionally substituted 5-6-member heterocyclyl with 1-3 heteroatoms, selected from nitrogen, oxygen and sulfur, possibly condensed with benzene ring; C1-C4-alkoxycarbonyl, optionally substituted amino carbonyl, or group CR3R4R together stands for group , where Alk stands for C1-C4alkyl.

EFFECT: medication allows to reduce symptoms of alcohol abuse considerably as compared with earlier known compounds and does not produce unfavorable effect on liver function.

12 cl, 3 tbl, 2 ex, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel 5-6-member nitrogen-containing heterocyclic compounds, selected form derivatives of pyridine, pyrimidine, imidasoline, oxadiasoline, such as, for instance , which possess inhibiting activity with respect to aspartylprotease, such as "ВАСЕ-1".

EFFECT: obtaining pharmaceutical composition, method of aspartylprotease inhibition aimed at application of compounds for preparation of medication intended for treatment of state, mediated by aspartylprotease, such as "ВАСЕ-1".

4 cl, 1 tbl, 1832 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine derivatives having FAK inhibitory activity of formula (I), where R0 is hydrogen; R1 is a 5- or 6-member heterocycle containing 1 or 2 nitrogen atoms substituted with (C1-C7)alkyl, hydroxyl group, dialkylamino group or a 6-member heterocycle containing one nitrogen atom; R2 is hydrogen; R3 is carbamoyl substituted once or twice with (C1-C7)alkyl; a 5-member heterocycle containing 4 nitrogen atoms; SO2N(R12)R13, where R12 is hydrogen or (lower)alkyl, and R13 is hydrogen, (C1-C7)alkyl, (C1-C7)alkoxy(C1-C7)alkyl, di(C1-C7)alkylamino(C1-C7)alkyl, hydroxy(C1-C7)alkyl, or R12 and R13 together a nitrogen atom with which they are bonded form a 6-member heterocycle containing two nitrogen atoms, where the said heterocycle is not substituted or substituted with (C1-C7)alkyl; R4 is hydrogen; R5 is a halide; R6 is hydrogen; R7 is hydrogen; (C1-C7)alkoxy; carbamoyl which is not substituted or substituted with (lower)alkyl; a 5- or 6-member heterocycle containing 1 or 2 nitrogen or oxygen atoms, unsubstituted or substituted with di(C1-C7)alkylamino, (C1-C7)alkyl, hydroxy, 6-member heterocycle containing 1 or 2 nitrogen or oxygen ring atoms, unsubstituted or substituted with (C1-C7)alkyl; 6-member heterocycle-oxy containing 1 nitrogen ring atom, unsubstituted or substituted with (C1-C7)alkyl; heterocycle(C1-C7)alkyloxy, where heterocycle denotes a 5- or 6-member heterocycle containing 1 or 2 nitrogen or oxygen ring atoms which is not substituted or substituted with (C1-C7)alkyl; R8 is hydrogen; halide; (C1-C7)alkoxy, carbamoyl unsubstituted or substituted with (C1-C7)alkyl; heterocycle(C1-C7)alkyloxy, where heterocycle denotes a 5-member heterocycle containing 1 nitrogen ring atom, unsubstituted or substituted with (C1-C7)alkyl; 5- or 6-member heterocycle containing 1 or 2 nitrogen or oxygen atoms, unsubstituted or substituted with one or two substitutes independently selected from hydroxy, (C1-C7)alkyl, aminocarbonyl and (C1-C7)alkylamino; 6-member heterocycle-oxy, containing 1 nitrogen ring atom, unsubstituted or substituted 1-5 times with (C1-C7)alkyl or di(C1-C7)alkylamino; or R7 and R8 together with atoms with which they are bonded form a 6-member heterocycle containing two nitrogen or oxygen atoms, unsubstituted or substituted once or twice with (C1-C7)alkyl or oxo group; R9 is hydrogen; R10 is (C1-C7)alkoxy, as well as to their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition and synthesis method.

EFFECT: novel compounds have useful biological activity.

4 cl, 167 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry, and specifically to compounds of general formula I , where A is an oxygen atom, an alkylene, alkenyl or hetero alkylene group, in which the CH2 group is substituted with a NH group, where the said groups can be optionally substituted with OH, =O or CH2OH groups, X1, X2, X3, X4 and X5 independently represent nitrogen atoms or groups of formula CH or CR4, Cy is cycloalkylene or heterocycloalkylene group containing at least one nitrogen atom, R1 is a hydrogen atom, an alkyl or alkyloxy group, R2 is a halogen atom, a hydroxy group, an alkyl or heteroalkyl residue, where the said groups can be optionally substituted with OH, NH2 groups and/or a =O group, R3 is a group of formula -B-Y, in which B denotes an alkylene, alkenyl or heteroalkylene group, where the said groups can be optionally substituted with OH, NH2, COOH groups or a =O group, and Y is an optionally substituted phenyl, optionally substituted heteroaryl group containing 5 or 6 ring atoms, or an optionally substituted bicyclic heterocycle in which one ring is phenyl or pyridyl, and the other is a 5-, 6- or 7-member heteroaryl or heterocycloalkyl group which contains up to 3 heteroatoms selected from nitrogen, oxygen and sulphur atoms, R4 is a halogen atom, n equals 0, 1 or 2 and m equals 0 or 1, or their pharmaceutically acceptable salts, solvates and hydrates. The invention also relates to a pharmaceutical composition based on the formula I compound and use of the compound or the pharmaceutical composition to treat bacterial infections.

EFFECT: obtaining novel compounds possessing useful biological properties.

12 cl, 7 ex

Amide derivatives // 2396259

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compound of formula I where m equals 0 or 1; R1 represents halogeno, (C1-6)alkyl, (C1-6)alkoxy, amino-(C2-6)alkoxy, (C2-6)alkylamino-(C2-6)alkoxy, di-[(C1-6)alkyl]amino-(C2-6)alkoxy, (C1-6)alkoxy-(C2-6)alkoxy, carbamoyl-(C1-6)alkoxy, N-(C1-6)alkylcarbamoyl-(C1-6)alkoxy, amino-(C1-6)alkyl, (C1-6)alkylamino-(C1-6)alkyl, di(C1-6)alkyl]amino-(C1-6)alkyl, carbamoyl-(C1-6)alkyl, N-(C1-6)alkylcarbamoyl-(C1-6)alkyl, (C1-6)alkoxy-(C2-6)alkylamino, heteroaryloxy, heterocyclyl-(C1-6)alkyl, heterocyclyloxy or heterocyclyl-(C1-6)alkoxy, and where any heteroaryl or heterocyclyl group in substituent R1 probably can have 1 or 2 substituents, selected from hydroxy, halogeno, (C1-6)alkyl, (C1-6)alkoxy, (C2-6)alkanoyl, hydroxy-(C1-6)alkyl, (C1-6)alkoxy-(C1-6)alkyl, and where any of determined above R1 substituents, which contains CH2 group bound with 2 carbon atoms, or group CH3, bound with an atom of carbon or nitrogen, probably can have on each said CH2 or CH3 group one or more substituents, selected from halogeno, hydroxy, amino, oxo, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkinyl,. (C3-6)cycloalkyl, (C3-6)cycloalkoxy, (C1-6)alkoxy, (C1-6)alkoxy-(C1-6)alkyl, (C1-6)alkylsulphamoyl, heteroaryl, heteroaryl-(C1-6)alkyl and heterocyclyl, and where any heterocyclyl group in substituent R1 probably can have 1 or 2 oxo or tioxo substituents; R2 represents (C1-6)alkyl; R3 represents hydrogen; R4 represents (C3-6)cycloalkyl, (C1-6)alkyl or heteroaryl, and R4 probably can be substituted with one or more substituents, selected from halogeno, (C1-6)alkyl, (C1-6)alkoxy; and R5 represents hydrogen, halogeno or (C1-6)alkyl; or its pharmaceutically acceptable salt, to method of obtaining said compounds, to pharmaceutical composition for application in treatment of diseases mediated by based on them cytokines. Invention also relates to methods of inhibiting p38α-kinase enzymes, TNFα production and production of cytokines.

EFFECT: obtained and described are novel compounds, which can be applied in treatment of medical conditions mediated by cytokines.

14 cl, 31 ex, 9 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, pharmaceutical compositions based on the said compounds, as well as methods of using said compounds in preparing medicinal agents.

EFFECT: obtaining compounds and a composition which can inhibit phosphatase cdc25, particularly phosphatase cdc25-C and can be particularly used for treating cancer.

12 cl, 56 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula I in the form of salt where J means a C1-C2 alkylene; R1 means cyclopentane, cyclohexyl, phenyl or thiophenes; R2 means hydroxy; R3 means a cyclopentane, cyclohexyl, phenyl or thiophenes; with R1 and R3 are not identical, or -CR1R2R3 together form a group of the formula , where Ra means a chemical bond, and Rb means hydroxy; R4 means methyl; R5 means C1 alkyl substituted with -CO-NH-R6; R6 means 5- or 6-membered heterocyclic group that contains in a cycle at least one heteroatom selected from nitrogen, oxygen and sulfur; or J means C1-C2 alkylene; R1 and R3 both mean phenyl; R2 means hydroxy; R4 means methyl, R5 means C1 alkyl substituted with -CO-NH-R9; and R9 means 5- or 6-membered heterocyclic group that contains in a cycle at least one heteroatom selected from nitrogen, oxygen and sulfur. The invention also refers to pharmaceutical composition, to application of compound according to any of clauses 1-3, as well as to method for obtaining a compound of formula I according to clause 1.

EFFECT: obtaining new biologically active compounds having antagonistic activity against muscarinic receptor M3.

7 cl, 21 ex

FIELD: chemistry.

SUBSTANCE: in the formula (I) , R1 is metoxymethyl; R2 is selected out of -C(O)NR4R5, -SO2NR4R5, -S(O)PR4 and HET-2; R3 is selected out of halogeno, fluoromethyl, metoxy and cyano; HET-1 is 5- or 6-member heteroaryl ring linked by C atom and containing nitrogen atom in 2 position and possibly 1 or 2 additional ring heteroatoms selected independently out of O, N and S, which is possible substituted at available carbon atom or at ring nitrogen atom by 1 substitute selected independently out of R6, provided that it would not cause ring quaternisation. The other radicals are indicated in the invention claim. Also invention refers to pharmaceutical composition containing claimed compound as active component, and methods of obtaining compound of the formula (I).

EFFECT: compounds with glucokinase inhibition effect.

19 cl, 2 tbl, 61 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel 5-6-member nitrogen-containing heterocyclic compounds, selected form derivatives of pyridine, pyrimidine, imidasoline, oxadiasoline, such as, for instance , which possess inhibiting activity with respect to aspartylprotease, such as "ВАСЕ-1".

EFFECT: obtaining pharmaceutical composition, method of aspartylprotease inhibition aimed at application of compounds for preparation of medication intended for treatment of state, mediated by aspartylprotease, such as "ВАСЕ-1".

4 cl, 1 tbl, 1832 ex

FIELD: chemistry.

SUBSTANCE: in formula (1) A is a nitrogen atom or CH; when A is a nitrogen atom, B is NR9 (where R9 is a C1-10alkyl group), when A is CH, B is a sulphur atom, R1 is a phenyl group (where the phenyl group is substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-10alkyl group and C1-10alkoxy groups (where C1-10alkyl groups and C1-10alkoxy groups are not substituted of substituted with one or more halogen atoms)); L1 is a bond; X is OH; R2 is a C1-6alkyl group; L2 is a bond; L3 is NH; L4 is a bond or NH; Y is an oxygen atom or sulphur atom; R3 is a thienyl group (where the thienyl group is substituted with CONR29R30 (where R29 is hydrogen or a C1-10alkyl group, and R30 is an amino group (where the amino group is not substituted or substituted with a pyridyl group), mono- or di-C1-10alkylamino group, N-methylpiperzinyl group, piperidine group, morpholine group or C1-10alkyl group (C1-10alkyl group is substituted with one or more substitutes selected from a group consisting of a carboxyl group, carbamoyl groups, pyrroldinyl groups, tetrahydrofuryl groups or morpholine groups) or R29 and R30 together denote -(CH2)m3-G-(CH2)m4- (where G is CR31R32 (where R31 is a hydrogen atom and R32 is a C1-10alkylcarbonylamino group or pyrrolidinyl group) and each of m3 and m4 is independently equal to an integer from 0 to 5 provided that m3+m4 equals 3, 4 or 5), or NR29R30 as a whole denotes a piperidine group or pyrrolidinyl group (where the piperidine group or pyrrolidinyl group is substituted with two substitutes independently selected from a group consisting of: hydroxyl groups and C1-10alkoxy groups) or 2-(4-oxopyrridin-1(4H)-yl)acetyl group), phenyl group (where the phenyl group is substituted with one substitute selected from a group consisting of C1-10alkyl groups, C1-10alkylcarbonyl groups and C1-10alkylaminocarbonyl groups, (where C1-10alkyl group, C1-10alkylcarbonyl group and C1-10alkylaminocarbonyl group are substituted with one or two substitutes selected from a group consisting of hydroxyl groups, carboxyl groups and carbamoyl groups)), phenyl group (where the phenyl group is substituted with one C1-10alkylaminocarbonyl group or one halogen atom), dihydrobenzo[1,4]dioxine group or benzo[1,4]oxazine group. The invention also relates to a medicinal agent containing the disclosed compound as an active ingredient and to a thromopoeitin receptor activator which is a formula (1) compound.

EFFECT: disclosed compounds have thrombopoietin receptor agonist properties.

8 cl, 11 tbl, 128 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds, specifically to 4-substituted-3-(1-alkyl-2-chloro-1H-indol-3-yl)furan-2,5-diones of general formula I , where R1=H, C1-C6 alkyl; R2=H, C1-C6 alkyl, C1-C6 alkoxy; R3=phenyl, naphthyl, 2-phenyl-1-ethenyl, thienyl, furyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, synthesis method thereof and use as compounds capable of photochemical generation of stable fluorophores of formula II, which can be used, for instance in information storage systems, particularly as photosensitive components of material for three-dimensional recording and storage of information. The invention also relates to novel 4,5-substituted-6-alkyl-1H-furo[3,4-c]carbazole-1,3(6H)diones of general formula II , where R1=H, C1-C6 alkyl; R2=H, C1-C6 alkyl, C1-C6 alkoxy; R4=H, R5=phenyl, R4, R5=benzo, naphtho, thieno, furo, pyrrolo, benzothieno, benzofuro, indolo, method for synthesis of said compounds and use as fluorophores.

EFFECT: obtaining novel compounds and possibility of using said compounds as fluorophores.

14 cl, 2 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula I or its pharmaceutically acceptable salt , where R, R9, Z, X, Q and Y are defined in the formula of invention. The compounds are chemokine receptor 2 and chemokine receptor 5 antagonists and can be used as a medicinal agent for preventing, relieving or treating autoimmune or inflammatory diseases or conditions.

EFFECT: obtaining a formula (I) compound, a pharmaceutical composition based on the formula (I) compound, use of the compound in paragraph 1 to prepare a medicinal agent for treating an autoimmune or inflammatory disease or condition, as well as use of the compound in paragraph 1 to prepare a medicinal agent for treating HIV infection or AIDS.

11 cl, 181 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1), their tautomers and pharmaceutically acceptable salts. The disclosed compounds have thromobopoietin receptor agonist properties. In formula (1) , A is a nitrogen atom or CH, when A is a nitrogen atom, B is NR9 (where R9 is a C1-10 alkyl group), and when A is CH, B is a sulphur atom, R1 is a phenyl group (the phenyl group is substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-10 alkyl groups and C1-10 alkoxy groups (C1-10 alkyl groups and C1-10 alkoxy groups are unsubstituted or substituted with one or more halogen atoms)), L1 is bond, X is OH, R2 is a C1-10 alkyl group, L2 is a bond, L3 is NH, L4 is a bond or NH, Y is a sulphur atom, and when L4 is a bond, R3 is a piperidinyl group, a piperazinyl group (the piperidinyl group and the piperazinyl group are substituted with substitutes selected from a group containing C1-10 alkoxycarbonyl groups, carboxyl group, hydroxyl groups, di-C1-10 alkylaminocarbonyl groups, C1-10 alkylaminocarbonyl groups and C1-10 alkyl groups (C1-10 alkylaminocarbonyl groups and C1-10 alkyl groups are substituted with a substitute selected from a group containing pyridyl groups, hydroxyl groups and carboxyl groups)), or when L4 is NH, R3 is a C1-10 alkyl group (C1-10 alkyl group is substituted with a substitute selected from a group containing C1-10 alkoxy groups, C1-10 alkoxycarbonyl groups or carboxyl groups).

EFFECT: obtaining a thrombopoietin receptor activator which is a formula (1) compound and a medicinal agent which contains the disclosed compound as an active ingredient.

10 cl, 3 tbl, 47 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzene derivatives of general formula (I) or salts thereof: [Chem. 12]

(Symbols in the given formula have the following values X1:-NR12-C(=O)- or -C(=O)-NR12-, X2 : -NR13 -C(=O)-, Ring A is a 6-member ring, if necessary having 1 or 2 double bonds and if necessary having 1-3 heteroatoms selected from N, O, Ring B is a benzene ring or a 6-member heteroaryl ring having 1-3 heteroatoms selected from N, R is a hydrogen atom or a residue of β-D- glucopyranoside uronic acid; R1-R8 are identical or different and each denotes a hydrogen atom, a halogen atom, -O-(lower alkyl), R9-R11 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-(lower alkyl), -(CH2)n-N(lower alkyl)2, -(CH2)n-NH(lower alkyl), -(CH2)n-N(lower alkyl) (if necessary substituted with -C=O; a 6-member heterocycle having 1-3 heteroatoms selected from N, S, O) -(CH2)n-(C=O)-N(lower alkyl)2, -(CH2)n-(C-O)-N(lower alkyl) (if necessary substituted with -C=O, alkyl, a 6-member heterocycle having 1-3 heteroatoms selected from N) -(CH2)n- if necessary substituted with alkyl, -COCH3, -SO2CH3, -COOCH3, -C=O, CF3, -OCH3, OH, halogen; 5-7-member heterocycle having 1-3 heteroatoms selected from N, S, O), -(CH2)n-O- (if necessary substituted with alkyl; 6-member heterocycle having 1-3 heteroatoms selected from N), n is an integer from 0 to 3, R12 and R13 denote a hydrogen atom, provided that in R1-R11, when two lower alkyls are bonded to a nitrogen atom, they can together form a 3-8-member nitrogen-containing heterocycle.) The invention also relates to benzene derivatives of general formula (II), to a pharmaceutical composition, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds which are active as inhibitors of activated blood-coagulation factor X.

16 cl, 365 ex, 42 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel 1-thio-D-glucitol compounds of formula I or to pharmaceutically acceptable salts thereof or hydrates of the compound or salts: , [where R1, R2, R3 and R4 are identical or different, and each is a hydrogen atom, C1-C6-alkyl group), A is -(CH2)n-, -CONH(CH2)n-, -O- or -(CH2)nCH=CH- (where n is an integer from 0 to 3, Ar1 is an arylene group, heteroarylene group, which is an unsaturated 5-9-member mono- or bicyclic group, containing 1-2 heteroatoms, selected from S and N, Ar2 is an aryl group or heteroaryl group which is an unsaturated 5-9-member mono- or bicyclic group containing 1-2 heteroatoms selected from O, S and N, and R5, R6, R7, R8, R9 and R10 are identical or different, and each is (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, (iv) C1-8-alkyl group, optionally substituted with hydroxyl group(s), (v) -(CH2)m-Q {where m is an integer from 0 to 4, and Q is -CO2H, -ORc1, -CO2Ra3, -SRe1, -NHRa6 or -NRa7Ra7 (where each of Ra3, Ra6 and Ra7 is a C1-6-alkyl group, Rc1 is a C1-6-alkyl group, and Rc1 is a C1-6-alkyl group)}, (vi) -O-(CH2)m'-Q' {where m' is an integer from 1 to 4, and Q' is a hydroxyl group,-CO2H, -CO2Ra8, -CONRa10Ra10, -NRa12Ra12 (where each of Ra8, Ra10 and Ra12 is a C1-6-alkyl group)}, (vii) -ORf {where Rf is C3-7-cycloalkyl group or tetrahydropyranyl group)}, (viii) morpholine group, (ix) phenyl group, (x) pyridyl group]. The invention also relates to 1-thio-D-glucitol compounds of formulae IA, II, III, IV, to a pharmaceutical agent, to methods of obtaining 1-thio-D-glucitol compounds, as well as to compounds of formulae XIII, XIV.

EFFECT: obtaining novel biologically active compounds which are inhibitors of sodium-dependent co-transporter-2-glucose.

25 cl, 140 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel quinoline or quinazoline derivatives of general formula

Ib, where R1 is C1-6-alkyl or C1-6-alkoxy; X is N or CH; R3 and R4 independently denote hydrogen, C1-6-alkyl, C1-6-alkylsulphonyl or a group of formula (IIa), where A is oxygen or sulphur; D is -(CH2)t, -(CH2)tO- or -O(CH2)t, where t equals 0, 1, 2, 3 or 4; and E is C1-6-alkyl, C3-7-cycloalkyl, or a 3-7-member monocyclic aromatic ring or a 6-10-member bicyclic aromatic ring in which 1-3 carbon atoms in the ring(s) are optionally substituted with a heteroatom which is independently selected from nitrogen, oxygen and sulphur, (optionally substituted with 1 or 2 substitutes independently selected from halogen, C1-6-alkyl, CF3, cyano, hydroxy and C1-6-alkoxy); or a group of formula (IIb), where A is oxygen or sulphur; D is -(CH2)t-, -(CH2)tO- or -O(CH2)t, where t equals 0, 1, 2, 3 or 4; and E is C1-6-alkyl, C3-7-cycloalkyl, or a 3-7-member monocyclic aromatic ring or a 6-10-member bicyclic aromatic ring in which 1-3 carbon atoms in the ring(s) are optionally substituted with a heteroatom which is independently selected from nitrogen, oxygen and sulphur (optionally substituted with 1 or 2 substitutes independently selected from halogen, C1-6-alkyl, CF3, cyano, hydroxy and C1-6-alkoxy); or R3 and R4 together with the nitrogen atom with which they are bonded form a 3-7-member ring or a 6-10-member bicyclic ring which can be saturated, partially saturated or unsaturated and contain 1, 2 or 3 heteroatoms selected from nitrogen, sulphur and oxygen, where each group is optionally substituted with 1 or 2 substitutes selected from oxo, C1-6-alkyl, C1-6-alkoxy, aryl and aryl-C1-6-alkyl (where aryl and aryl-C1-6-alkyl are also optionally substituted with 1 or 2 with C1-6-alkyls or C1-6-alkoxy). The invention also relates to use of formula Ib compounds in preparing a medicinal agent, to a pharmaceutical composition based on formula Ib compound and preparation method thereof.

EFFECT: obtaining novel quinoline and quinazoline derivatives having high affinity to 5-HT1-receptors.

12 cl, 171 ex

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