Benzimidazolon and chinazolin derivatives as human orl1-receptor agonists

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I), their optically active stereoisomers, as well as to pharmaceutically acceptable salts possessing properties of ORL1 and µ-opiate receptors. In general formula , R1 represents H, alkyl(1-6C), []m represents-(CH2)m-, in which m equals 0 or 1, R2 represents halogen, CF3, alkyl(1-6C), phenyl, cyano, cyanoalkyl(1-3C), hydroxy, (1-3C)alkoxy, OCF3, acyl(2-7C), trifluoroacetyl, (1-3C)alkylsulfonyl or trifluoromethylsulfonyl, and n represents integer number 0-4 on condition that when n equals 2, 3 or 4, R2 substituents can be similar or different, A represents saturated ring, []0 and []p represents -(CH2)o and -(CH2)p, and o and p independently correspond to 0, 1 or 2, R3, R4, R5 and R6 independently represent hydrogen, alkyl(1-3C), or (R4 and R6) together can form alkylene bridge, containing 1-3 carbon atoms on condition that when o equals 2, R3 represents hydrogen, and when p equals 2, R5 represents hydrogen, R7 represents H, halogen, alkyl(1-6C). Invention also relates to pharmaceutical composition, intermediate compounds for obtaining formula (1) compounds.

EFFECT: compounds can be used for preparing medication for treating disorders and diseases such as alimentary behaviour disturbances, arterial hypertension.

8 cl, 3 dwg, 1 tbl, 45 ex

 

This invention relates to new derivatives of benzimidazolone and hintlian, which are agonists of the receptor ORL1 (nociceptin) person. The invention also relates to the production of these compounds, to pharmaceutical compositions containing a pharmacologically active amount of at least one of these derivatives imidazolone and hintlian as the active ingredient, as well as the application mentioned pharmaceutical compositions for treating disorders that involve the ORL1 receptors.

The invention relates to the use of the described compounds for the production of medicines, which have a beneficial effect. Favorable action is disclosed in the description or it is obvious to the person skilled in the art from the specification and General information in this area. The invention also relates to the use of compounds in accordance with the invention for the manufacture of a medicinal product for treating or preventing the disease or condition. More precisely, the invention relates to a new use for the treatment of a disease or condition referred to in the description or obvious to the person skilled in the art from the specification and General information in this area. In embodiments of the invention, certain compounds present in the description, use is for the manufacture of a medicinal product.

Receptor, "such opioid receptor 1" (ORL1), was identified from a cDNA library of human rights. It is established that named "orthanes-receptor" has close homology with µ-, κ - and δ-opioid receptors (Mollereau et al., FEBS Lett., 341, 33-38, 1994; Bunzow et al., FEBS Lett., 347, 284-288, 1994). Despite the close similarity of its consistency and its structural similarity with opioid receptors, ligands classical opioid receptor does not interact with the receptor ORL1. In 1995, the neuropeptide of the 17 amino acids was isolated from extracts of the brain and, as was subsequently shown, is a natural ligand of the ORL1 receptor associated G-protein (Reinscheid et al., Science, 270, 792-794, 1995; Meunier et al., Nature, 377, 532-535, 1995). The obtained peptide was named orphanin FQ or nociceptin. It is not associated with the three traditional opioid receptors. These data served as an important early studies of the functional role of the receptor ORL1 and new ligands for these receptors.

The studies appeared in hundreds of publications, including several reviews (see, for example, Grond et al., Anaesthesist, 51, 996-1005, 2002) and many patent applications that describe how the peptide, and ones ligands. The described connections largely differ on the effectiveness receptor ORL1, and selectivity (ORL1 against µ-opioid receptors). As µ-opiate p is the receptors have a wide distribution in the body, the lack of specificity can lead to a number of such unwanted opioid side effects, such as sedation, respiratory depression, tolerance and dependence (Drug News Perspect., 14, 335, 2001). Similarly,in vivopharmacodynamic and pharmacokinetic properties of the described compounds is highly variable.

The number of patent applications related to the ORL1, refer to the derivatives of benzimidazolone: for example, WO 98/54168, WO 99/36421, WO 00/006545, WO 00/08013, WO 01/39775 and US 20020128288. Of the latter WO 01/39775 is the closest application of this invention. However, the described derivatives benzimidazolone, as it turned out, did not meet the criteria, which are widely regarded as important for the applied therapeutics. They are characterized by:

(1) the greatest efficiency (affinity for the ORL1 receptors in the range 166-1252 nm);

(2) a small selectivity in respect to µ-opioid receptors (affinity in the range 19-457 nm);

(3) no evidence on the bioavailability after oral administration, and

(4) no evidence regarding the availability in the Central nervous system.

The most powerful is described ORL1 agonist is Ro 64-6198. The connection does not contain a fragment of benzimidazolone, but instead has a Spiro-core (see: EP0856514; Eur. J. Med. Chem., 35 (2000) 839-851 and Proc. Natl. Acad. Sci. USA., 2000, 97, 4938). Ro 64-6198 mention as a powerful and selective in the connection, easily penetrating the blood-brain barrier. However, despite its favorablein vitrobinding characteristics profilein vivothese ligand shows some disadvantages:

(1) it was less effective on the model state of fear than expected on the basis of datain vitro;

(2) "therapeutic window" between the desired efficiency as ORL1 agonist and unwanted opioid side effectsin vivoturned out to be less than expected on the basis of datain vitro.

Discussion of derivative benzimidazolone and Ro 64-6198, quoted above, does not give direction on how to improve the pharmacological profilein vivobest described compounds. In the review, considering the subject matter (“Characterization of opiates, neuroleptics and synthetic analog at ORL1 and opioid receptors”, Eur. J. Pharmacol., 428, 29-36, 2001), Zaveri et al. conclude: "In the absence of models of small molecules in the active site, or the crystal structure of the receptor ORL1 associated with a small molecule, it is necessary to be extremely careful in assessing SAR among the different classes of ligands of the receptor ORL1, even ligands with similar structural properties.

Suddenly it is now established that in a series of derivative benzimidazolone and hintlian with a new combination of substituents group of compounds, as shown, has a high SRO is ETS to the ORL1 receptors person. In addition, these compounds exhibiting good selectivity in receptor ORL1 relative to µ-opioid receptors are readily bioavailable after oral administration and penetrate the blood-brain barrier. Pharmacological profilein vitroandin vivosome of these compounds were better than the profile of Ro 64-6198, particularly regarding therapeutic window between the desired efficiency as ORL1 agonist and unwanted opioid side effectsin vivo. The invention relates to compounds of General formula (1):

in which:

R1represents H, alkyl(1-6C), alkyl(1-3C)cycloalkyl(3-6C), carbalkoxy(2-7C) or acyl(2-7C),

[]mmeans -(CH2)m-, in which m is 0 or 1,

R2represents halogen, CF3, alkyl(1-6C), alkyl(1-3C)cycloalkyl(3-6C), phenyl, amino, aminoalkyl(1-3C)alkyl(1-3C), amino, dialkyl(1-3C), amino, cyano, cianelli(1-3C), hydroxy, hydroxyalkyl(1-3C), (1-3C)alkoxy, OCF3, acyl(2-7C), TRIFLUOROACETYL, aminocarbonyl, (1-3C)alkylsulfonyl or trifloromethyl and n means an integer of 0-4, provided that when n is 2, 3 or 4, substituents R2may be the same or different,

Rather it represents a saturated or partially unsaturated ring,

[]about[]ppredstavlyaet a -(CH 2)about- and -(CH2)prespectively, provided that it is also possible value is-CH-when And represents a partially unsaturated ring, and o and p independently represent 0, 1 or 2.

R3, R4, R5and R6independently represent hydrogen, alkyl(1-3C)alkyl(1-3C)cycloalkyl(3-6C), CH2HE or (R3and R5) or (R3and R6), or (R4and R5), or (R4and R6together can form Allenby bridge containing 1-3 carbon atoms, provided that when o is 2, R3means hydrogen, and when R is 2, R5means hydrogen,

R7represents H, halogen, CF3, alkyl(1-6C), alkyl(1-3C)cycloalkyl(3-6C), amino, aminoalkyl(1-3C)alkyl(1-3C), amino, dialkyl(1-3C), amino, hydroxy, hydroxyalkyl(1-3C), (1-3C)alkoxy, OCF3, acyl(2-7C), aminocarboxyl or (1-3C)alkylsulfonyl,

and their pharmacologically suitable salts and prodrugs.

The invention includes any compounds of formula (1), the racemates, mixtures of diastereomers and individual stereoisomers. Thus, compounds in which the substituents on the potentially asymmetric carbon atoms have or R-configuration or S-configuration, refer to the invention. Also prodrugs, i.e. compounds that when administered to humans by any known method, into the compounds is of formula (1), refer to the invention. Prodrugs are bioapatite derivatives of drug molecules that are used to overcome some of the barriers to action of the parent drug molecule. Mentioned barriers include solubility, permeability, stability, presystemic metabolism and restrictions directed delivery, without limitation (J. Stella, “Prodrugs as therapeutics”, Expert Opin. Ther. Patents, 14(3), 277-280, 2004). In particular, it relates to compounds with primary or secondary amino or hydroxy groups. Such compounds can interact with organic acids to form compounds of formula (1), in which there is an additional group that is easily removed by use of, for example, amidine, enamine, Mannich bases, derived hydroxymethylene derived O-(acyloxymethyl carbamate), carbamate, complex, ester, amide or enaminone. A prodrug is an inactive compound that when suction is transformed into the active form (Medical Chemistry: Principles and Practice, 1994, ISBN 0-85186-494-5, Ed.: F.D. King, p. 216).

The invention relates in particular to compounds of the formula (1)in which: a represents a saturated ring, R1represents hydrogen, alkyl(1-3C) or acyl(2-4C), R3, R4, R5and R6independently represent alkyl(1-3C) or (R3and R 5), or (R3and R6), or (R4and R5), or (R4and R6together can form Allenby bridge containing 1-3 carbon atoms, provided that when o is 2, R3means hydrogen, and when R is 2, R5means hydrogen, R7represents H, halogen,

CF3, alkyl(1-3C), amino, aminoalkyl(1-3C)alkyl(1-3C), amino, dialkyl(1-3C), amino, hydroxy, (1-3C)alkoxy or OCF3and R2, m, n, o and p have the meanings above.

More precisely, the invention relates to compounds of formula (1)in which a represents a saturated ring; m = 0, n = 0 or 1, o = 1, p = 1, R1= H or acetyl, R2represents halogen, CF3, alkyl(1-3C), amino, cyano, OCH3or OCF3, R3, R4, R5and R6independently represent hydrogen or alkyl(1-2C), or (R4and R6together can form Allenby bridge containing 1-2 carbon atoms, and R7represents H, halogen, CF3, alkyl(1-3C), amino, hydroxy or OCF3.

More preferred is a compound of the formula (2) and its stereoisomer. By undermentioned the connection will be "example 1".

Compounds of the invention can be converted into a form suitable for administration using conventional methods, using excipients and/or liquid or a solid medium.

Pharmaceutically suitable salts can be obtained using standard procedures well known in this field, for example, by mixing the compounds of this invention with an appropriate salt. Suitable additive acid salt may be formed with inorganic acids such as hydrochloric acid, or organic acids such as fumaric acid.

Compounds of the invention of General formula (1)and their salts have activity ORL1 agonist. They are used in the treatment of disorders involving the receptor ORL1, or disorders that are treated by the treatment of these receptors. For example, use under conditions of acute or chronic pain, disorders of the Central nervous system, especially but not limited to, for reducing symptoms state of fear and stress-related disorders, depression, various forms of epilepsy, stroke, disorders characterized by impairment of cognitive ability and memory, such as Alzheimer's disease Creutzfeldt-Jakob disease, Huntington's disease, Parkinson's disease, neurorehabilitation (traumatic brain injury); acute damage to the brain or spinal cord disorders, related substances, including violations related to chemicals (such dependence and abuse), and disorders induced by substance p is such withdrawal syndrome substance); eating disorders, such neuropsychiatric anorexia and neuropsychiatric disorders, obesity, gastrointestinal disorders, in particular syndrome inflamed bowel, inflammatory bowel disease (Crohn's disease and ulcerative colitis, inflammation of the urinary tract, renal disorders, characterized by the imbalance of the retention/release of water or salt excretion; cardiovascular disorders such as myocardial infarction, arrhythmia, arterial hypertension, thrombosis, anemia, atherosclerosis, "angina pectoris"; skin diseases such as urticaria, lupus erythematosus and itching; eye diseases such as glaucoma; diseases of the respiratory system, which includes obstructive pulmonary disease, bronchitis and cystic fibrosis; diseases of the immune system and viral infections.

The compounds of this invention are usually administered in the form of pharmaceutical compositions, which constitute an important and new embodiments of the invention due to the presence of compounds, more specific compounds present in the description. Types of pharmaceutical compositions that can be used without limitation, include tablets, chewable tablets, capsules, solutions, solutions for parenteral administration, suppositories, suspensions and other types discussed in the description or obvious to a person skilled in the Anna area of specifications or General information in this area.

In embodiments of the invention are pharmaceutical package or kit containing one or more containers filled with one or more ingredients of the pharmaceutical compositions of the invention. Such container(s) can be attached descriptions, such as instructions for the application or notice in the form prescribed by the State Agency for regulation of production, use and safety of pharmaceutical products, and the notice reflects approval by the Agency of manufacture, use or safety in the use of human and in veterinary medicine.

GENERAL ASPECTS of SYNTHESIS

Compounds of the invention and their salts can be obtained in accordance with the General method presented in General terms below in figure 1:

The original connection presents a General method was prepared as follows:

Benzimidazolone [(i), when m = 0] can be synthesized by methods described in J. Med. Chem., 30., 814-819, 1987 and WO 99/36421. Hintline [(i), when m = 1] can be synthesized in accordance with Chem. Pharm. Bull., 33, 1116-1128, 1985. N-nitrooxide (substituted) 2,3,3A,4,5,6-hexahydro-1H-phenalen-1-it (ii) received from the corresponding ketones. Mentioned ketones in turn received from the corresponding (substituted) tetralones, as described in Eur. J. Med. Chem. 35, 839-851, 2000.

SPECIAL INSTANCES SYNTHESIS

The synthesis of the compound of example 1

Detailed description of the synthesis of compounds of example 1 are presented in scheme 2

The first four stages of scheme 2 was performed in accordance with the Eur. J. Med. Chem. 35, 839-851, 2000. On the basis of intermediate compound 5*(see diagram 2), the synthesis was carried out as follows:

Stage 5(scheme 2): a Mixture of 52 g (0.28 mol) of 2,3,3A,4,5,6-hexahydro-1H-phenalen-1-she (compound 5*), with 28.1 g (0.40 mol) of hydroxylamine·HCl and 55 g (0.40 mol) of sodium acetate·3H2About 500 ml of 96% ethanol was stirred at 80°C for 4 hours and for an additional 16 hours at room temperature. The resulting mixture was concentrated in vacuo and added to 750 ml of dichloromethane and 300 ml of 5% aqueous NaHCO3. The aqueous layer was twice washed with 100 ml of dichloromethane, the combined organic layers were washed with 100 ml saturated salt solution, dried over MgSO4and concentrated in vacuum.

Stage 6(scheme 2): 58.8 x g (representing quantitative yield) was obtained not quite white solid oxime (compound 6*) suspended in 600 ml simple tert-butyl methyl ether. At room temperature to the resulting suspension was added 230 ml 41,4 g (0.6 mol) of sodium nitrite in water and then adding 290 ml 2 N. sulfuric acid. After the remesiana at 40°C for 16 hours the mixture was cooled to room temperature and was added 300 ml of a saturated aqueous solution of NaHCO 3. The aqueous layer was extracted twice with 300 ml simple tert-butyl methyl ether, and the combined organic layers were washed with 150 ml saturated salt solution, dried over MgSO4and concentrated in vacuum. The obtained brown oil was purified by the method of column chromatography (silica gel) with dichloromethane as eluent. The oily product obtained after concentration in vacuo, triturated with cyclohexane and the precipitate was collected by filtration and dried. Received net NO2-Imin (compound 7*) (34 g, 0,148 mol, yield 52%) as not quite white solid with a melting point 64-69°C.

Stage 7(scheme 2): a mixture of 6,51 g (30 mmol) of 4-(1-benzimidazole)piperidine (compound 8*, ACROS)and 6.9 g (30 mmol) of NO2-imine (compound 7*) and 5.25 ml of diisopropylethylamine in 450 ml of 1,2-dichloroethane was heated at 50°C and was stirred in an atmosphere of N2for 16 hours. After cooling to room temperature was added 12.7 g (60 mmol) NaBH(OAc)3and the resulting mixture was stirred at room temperature in an atmosphere of N2within 24 hours. After concentrating the reaction mixture under vacuum was added 500 ml of dichloromethane and 500 ml of aqueous 5% solution of NaHCO3under stirring. The aqueous layer was twice washed with 100 ml of dichloromethane, the combined organic layers about the Ali 100 ml saturated salt solution, dried over MgSO4and concentrated in vacuum. The crude product was purified by the method of column chromatography (silica gel) with a mixture of dichloromethane:methanol:ammonia (92:7,5 level:0.5) as eluent. Pure product was obtained by concentration in vacuum (of 8.09 g, 21 mmol, 70% yield, melting point 155-158°C). To 8,09 g (21 mmol) of pure product was added 60 ml of ethanol and of 2.44 g (21 mmol) of fumaric acid. Concentration in vacuo the resulting solution gave fumarate example 1 (10,53 g, 21 mmol, quantitative yield) as a white foam with M+358 m/z and a melting point of 232-234°C.

The synthesis of compounds of example 2

The mixture 2,31 g (10 mmol) of 4-(1-hintline)of piperidine and 2.3 g (10 mmol) of NO2-imine (compound 7*) in 100 ml of 1,2-dichloroethane under nitrogen atmosphere was heated and stirred at 50°C for 7 hours and for an additional 16 hours at room temperature. Subsequently were added to 4.2 g (20 mmol) NaBH(OAc)3and the resulting mixture was stirred at room temperature in an atmosphere of N2within 24 hours. After concentrating the reaction mixture under vacuum to 200 ml of dichloromethane and 200 ml of 5% aqueous NaHCO3was added under stirring. The aqueous layer was washed twice with 40 ml of dichloromethane, the combined organic layers were washed with 40 ml saturated salt solution, dried over MgSO4and concentrated in vacuo the E. The crude product was purified by the method of column chromatography (silica gel) with a mixture of dichloromethane:methanol:ammonia (or 94.5:5:0.5 to) as eluent. The pure product obtained after concentration in vacuum (2.5 g, 6.2 mmol), was dissolved in 50 ml of a solution of HCl in ethanol. Concentration in vacuo gave the chloride of the compound of example 2 (2,05 g, 4.7 mmol, yield 47%) as a white amorphous solid with M+402 m/z and melting point 172-180°C.

The synthesis of the compound of example 13

Detailed description of the synthesis of the compound of example 13 is shown in figure 3:

Stage 1(scheme 3): a Solution of 3.84 g (20 mmol) of 2,4-dichloronitrobenzene (compound 9*, Aldrich), with 4.1 ml (20 mmol) 4-amino-1-benzylpiperidine (compound 10*, Aldrich), 4,46 g (32 mmol) of K2CO3in 50 ml of dimethylformamide was stirred at 95°C in an atmosphere of N2within 18 hours. After cooling to room temperature the reaction mixture was poured into a mixture of water (150 ml)-dichloromethane (250 ml). The aqueous layer was twice extracted with 50 ml dichloromethane, and the combined organic layers washed twice with 50 ml water, dried over MgSO4and concentrated in vacuum. The crude product was purified by the method of column chromatography (silica gel) with a mixture of dichloromethane:methanol (97:3) as eluent. After concentration in vacuum is Uchali pure product as a yellow oily substance (4.8 g, of 13.8 mmol, yield 69%).

Stage 2(scheme 3): the Portion of Ni Raney (Aldrich R 2800 [7440-02-0], ~500 mg) twice washed with 10 ml of 96% ethanol and subsequently in an atmosphere of N2was added to a solution of 4.8 g (to 13.8 mmol) of compound (11)*in 200 ml of 96% ethanol. The solution was hydrational at room temperature and a pressure of 1 atmosphere for 2.5 hours. The mixture was subsequently filtered through Hyflo, washed with 300 ml of 96% ethanol and the filtrate was concentrated in vacuum to obtain a quantitative yield of compound 12*as colored oily substance (4,36 g of 13.8 mmol, 100% yield).

Stage 3(scheme 3): To a solution 4,36 g (to 13.8 mmol) of compound 12*product from the previous stage, in 200 ml of acetonitrile, stirred at room temperature under nitrogen atmosphere, was added to 3.36 g (20,7 mmol) of 1,1'-carbonyldiimidazole (CDI, ACROS). The precipitate, which began to form after 10 minutes and education which has increased up to 3 hours, collected by filtration, washed with acetonitrile (200 ml) and dried in vacuum, obtaining almost pure compound 13*(3,30 g, 9.7 mmol, 70% yield).

Stage 4(scheme 3): To a suspension 3,30 g (9.7 mmol) of compound 13*in 90 ml of 1,2-dichloroethane, and stirred in an atmosphere of N2and cooled to 0°C was added dropwise a portion of 1-chloroethyl-chloroformate (1,17 ml and 10.7 mmol). After stirring at 0°C for 30 minutes is at 80°C for 90 minutes the mixture was cooled again to 0°C. and was added dropwise second portion of 1-chloroethyl-chloroformate (1,17 ml, of 10.7 mmol). The mixture was stirred again at 0°C for 30 minutes and at 80°C for 16 hours. After cooling to room temperature the mixture was concentrated in vacuo and to the residue was added 75 ml of methanol. The resulting solution was stirred at 65°C for 1 hour and concentrated in vacuum. After adding 75 ml of dichloromethane to the resulting brown semi-solid substance, it hardened under stirring for 1 hour. The precipitate was collected by filtration, washed with 100 ml of dichloromethane and dried. The crude product was purified by the method of column chromatography (silica gel) with a mixture of dichloromethane-methanol-ammonia (92:7,5 level:0.5) as eluent. After concentration in vacuo, the received connection 14*in the form of a white solid (1,61 g, 6.4 mmol, yield 66%).

Stage 5(scheme 3): a Mixture of 1.61 g (6.4 mmol) of compound 14*and 1.47 g (6.4 mmol) of NO2-imine (compound 7*) in 200 ml of 1,2-dichloroethane in an atmosphere of N2was heated and stirred at 50°C for 16 hours. After cooling to room temperature was added 2.76 g (13 mmol) NaBH(OAc)3and the resulting mixture was stirred at room temperature in an atmosphere of N2within 24 hours. Slightly colored solution was poured into a mixture of 300 ml of dichloromethane, 100 ml of water and 50 ml of aqueous 5% solution of NaHCO3. The aqueous layer was washed twice with 70 ml of dihl smetana, the combined organic layers were dried over MgSO4and concentrated in vacuum. The crude product was purified by the method of column chromatography (silica gel) with a mixture of dichloromethane:methanol:ammonia (92:7,5 level:0.5) as eluent. The purified product was concentrated in vacuo and he zagustevat subsequent simultaneous evaporation with acetonitrile. After stirring in 100 ml of simple diisopropyl ether precipitate was collected by filtration and dried, obtaining the compound of example 13 (1.35 g, 3.2 mmol, yield 50%) as a slightly colored pure solids with M+422 m/z and melting point 185-188°C.

These and comparable ways synthesized following specific examples. They are intended to further illustrate the invention in more detail and therefore are not intended to limit the scope of the invention in any way. Information on the structure of these compounds, all of which depict the General formula (1)shown in the table below.

0 24
No.R1mR2nA opR3R4R6R5R7
1H0-0rich11HHHHH
1S,SH0-0rich11HHHHH
1S,RH0-0rich11HHH HH
1R,SH0-0rich11HHHHH
1R,RH0-0rich11HHHHH
2H1-0rich11HHHHH
3CH30-rich11HHHHH
4CH31-0rich11HHHHH
5H04-F1rich11HHHHH
6H05-F1rich11HH HHH
7H06-F1rich11HHHHH
8H07-F1rich11HHHHH
9H05-CF31rich11HHHHH
10H0 6-CF31rich11HHHHH
11H04-Cl1rich11HHHHH
12H05-Cl1rich11HHHHH
13H06-Cl1rich11H HHHH
14H07-Cl1rich11HHHHH
15H04-CH31rich11HHHHH
16H05-CH31rich11HHHHH
17H 06-CH31rich11HHHHH
18H07-CH31rich11HHHHH
19H04-OCH31rich11HHHHH
20H05-OCH31rich1 1HHHHH
21H06-OCH31rich11HHHHH
22H06-OH1rich11HHHHH
23H06-NHCOCH31rich11HHHHH
H06-CN1rich11HHHHH
25H06-CN2CN1rich11HHHHH
26H06-SO2CH31rich11HHHHH
27H06-SO2CF31 rich11HHHHH
28H06-COCH31rich11HHHHH
29H06-COCF31rich11HHHHH
30H06-CONH21rich11HH HHH
31H06-OCF31rich11HHHHH
32H06,7-F2rich11HHHHH
33H04-F, 6-OCH32rich11HHHHH
34H0 4-CH3, 6 OCH32rich11HHHHH
35H0-0rich10HHHHH
36H0-0rich00HHHHH
37H0-0rich11CH 3HHHH
38H0-0rich11HCH3HHH
39H0-0rich11HHHCH3H
40H0-0rich11HHCH3HH
1 H0-0rich11H-CH2-CH2-HH
42H0-0rich11HHHH8-F
43H0-0rich11HHHH7-CH3
44H0-0rich 11HHHH8-CH3
45H0-0rich11HHHH9-F

PHARMACOLOGICAL STUDIES

In vitroandin vivoinvestigated the properties of the compounds of the invention as agonists of the receptor ORL1, and their µ-opioid activity (lack of it), using the methods described below.

Affinity receptor ORL1 man

The affinity of compounds to the receptor ORL1 man was determined, using the study of receptor bindingin vitrodescribed Ardati et al., Mol. Pharmacol., 51, 816, 1997. Briefly, the membrane preparations were obtained from CHO cells in which the receptor ORL1 person consistently expressively. Membranes were incubated with [3H]-nociception in the absence or in the presence of test compounds at various concentrations, diluted in a suitable buffer. No specific binding of the Oia is not observed, when the binding occurred in the presence of 10-6M nociceptin. Separation of bound radioactivity from free produced by filtration through filters of glass fibers Packard GF/B multiple washings ice buffer using a cell harvester Packard. Bound radioactivity was determined by scintillation counter (Topcount, Packard)using a scintillation cocktail (Microscint O, Packard). Determine the radioactivity was drawn as a curve against the concentration of the replacement of the tested compounds, and the curves of substitution was calculated by the method of logistic regression on four parameters, resulting in the value of the IC50then there is this concentration of test compound at which 50% of radioligand replaced. The magnitude of the affinity pKiwas calculated by the correction of the IC50for concentration radioligand and its relative affinity of the receptor ORL1 man by the equation of Cheng-Prusoff:

PKi= -log(IC50/(1 + S/Kd))

in which the IC50is the same as describe above, S denotes the concentration of [3H]-nociceptin used in the study, expressed in mol/l (typically 0.2 nm), and Kdis the dissociation constant equilibrium [3H]-nociceptin for receptor ORL1 person (0.4 nm).

Compounds of the invention have a high the affinity for ORL1 receptors according to the above research associate. This property makes the compounds useful for treating disorders that involve the ORL1 receptors or which can be treated by correction of these receptors.

Affinity for µ-opioid receptors of the man

The affinity of compounds to the µ-opiate receptor was determined using the study of receptor bindingin vitrodescribed Childers et al, Eur. J. Pharm. 55, 11, 1979. Briefly, the membrane preparations were obtained from CHO cells that stably expressively µ-opiate receptor of human rights and the membranes were incubated with [3H]-naloxone in the absence or in the presence of test compounds in a concentration range from 10 μm with a reduction to 0.1 nm, diluted with a suitable buffer. No specific binding was not observed when the binding occurred in the presence of 10-7M tartrate of levallorphan. Separation of bound radioactivity from free produced as described above, and the affinity of the compounds was calculated similarly, using the concentration (S) 1 nm [3H]-naloxone, and when the value of Kd1.3 nm.

Most of the compounds of the invention had a low affinity for µ-opioid receptors in the aforementioned study linking. Thus, it is unlikely that they will cause unwanted side effects, which are known to occur with opiates, like morphine.

In vitro

Activation of the ORL1 receptor associated with protein G, inhibits adenylate cyclase activity and reduces the intracellular concentration of the second messenger camp. Using the method described Jenck et al., Proc. Natl. Acad. Sci. USA, 97, 4938-4043, 2000, determined the activity of compounds on the ORL1 receptors. Demonstrated that the compounds are strong agonists.

In vivoORL1-receptor agonism

Intraperitoneal and/or oral administration of the compounds of the invention have been shown that they are highly active in air-conditioned ultrasonic distress vocalizations (CUDV), the procedure described by Van der Poel et al., Psychopharmacology, 97, 147-148, 1989. This demonstrates not only that the compounds have good bioavailability after oral administration, but that they also pass through the blood-brain barrier. Peptide nociceptin was also active in the mentioned study, but to demonstrate his action was necessary to enter nociceptin directly into the brain (using intracerebral ventricular injection).

ORL1 agonist induces a lower blood pressure

At intervals of 5 minutes to rats, shot by pentobarbital sodium 80 mg/kg, intraperitoneally injected increasing intravenous doses of ORL1 agonist, leading to lower blood pressure. Describes the reduction was expressed as the ratio ED 80(average effective dose):dose causing a 20% decrease in blood pressure compared to control.

In experiments on the interaction of a single intravenous dose of 2 mg/kg opiate antagonist naloxone or 1 mg/kg selective ORL1 antagonist J-113397 was injected 10 minutes before the first dose of the agonist. This dose of J-113397 was able to completely counteract the effect nociceptin. This dose of naloxone, as is well known, prevents morphine-induced reduction in blood pressure, but does not influence induced nociception reduction in blood pressure.

The action induced by the ORL1 agonist and morphine on food consumption

Recent studies have shown that food consumption can pharmacologically be regulated by ligands of opioid receptors. Sanger and McCarthy (Increased food and water intake produced in rats by opiate receptor agonist. Psychopharmacology, 74(3): 217 to 220, 1981) showed that systemic injection of morphine leads to increased food intake, the action that is the opposite of action non-selective opiate antagonist naloxone. In addition, Ciccocioppo et al. (Reversal of stress - and CRF-induced anorexia in rats by the synthetic nociceptin/orphanin FQ receptor agonist, Ro 64-6198. Psychopharmacology, 161(2): 113-119, 2002) reported that systemic injection of ORL1 agonist Ro 64-6198 also increases food intake in rats.

Male Wistar rats were placed singly and predostawlali free access to food and water. A single dose of filler Ro 64-6198 (1, 3, 6, 10 mg/kg), compound of example 1 (0,3, 1, 3, 6, 10 mg/kg) or morphine (1, 3, 10 mg/kg) was injected intraperitoneally, and food was removed beyond the reach of animals. 15 minutes after the introduction of the weighted amount of food (5-6 balls = 25-30 grams) was re-introduced into the cage of the animal. Then food again weighed after 60 and 120 minutes. All animals re-used during 4 separate experiments with a minimum time interval of 5 days between experiments. Took precautions to ensure that no extraneous noise is not induced any additional stress to the animal. In those experiments in which the opiate antagonist naloxone (1, 3, 10 mg/kg) or ORL1 antagonist J113397 (3, 10, 30 mg/kg) was administered prior to the introduction of agonist Ro 64-6198, 6 mg/kg; example 1, 10 mg/kg or morphine, 2 mg/kg), the antagonist was administered intraperitoneally 30 minutes before injection of the agonist. In all experimental groups attended a minimum of six animals per group.

DRUGS are COMPOUNDS THAT ARE USED IN ANIMAL STUDIES

Preparation of compounds example 1

For oral (r.o.) introduction:to the required amount (0.5 to 15 mg) of the solid compound of example 1 in a glass test tube was added a few glass granules and the solid is crushed under intensive displaced is Ivanyi for 2 minutes. After adding 1 ml of 1% solution of methylcellulose in water connection is suspended under intensive stirring for 10 minutes. With regard to concentrations of up to and above 1 mg/ml, the remaining particles in suspension is still suspended, using an ultrasonic camera.

For intraperitoneal (I.P. Pavlova.) introduction:to the required amount (0.5 to 15 mg) of the solid compound of example 1 in a glass test tube was added a few glass beads, and a solid substance was crushed with vigorous stirring for 2 minutes. After adding 1 ml of 1% methylcellulose and 5% mannitol in water connection suspended with vigorous stirring for 10 minutes. Finally, the pH was brought to 7.

The preparation of compounds of example 2

For oral (r.o.) introduction:to the required amount (0.5 to 15 mg) of the solid compound of example 2 in a glass test tube was added a few glass beads, and a solid substance was crushed with vigorous stirring for 2 minutes. After adding 1 ml of 1% solution of methylcellulose in water connection suspended with vigorous stirring for 10 minutes. The PH was brought to 7 by addition of several drops of aqueous NaOH (0.1 N.). Remaining in suspension particles are suspended using ultrasonic camera.

For intraperitoneal (I.P. Pavlova.) introduction:the drugs were given is on the way similar to the method used for r.o. introduction using 1% methylcellulose and 5% mannitol instead of 1% methylcellulose in water.

PHARMACOLOGICAL DATA

In vitroaffinity for ORL1 and µ-opiate receptors
functional ORL1-agonism
AffinityAgonismin vitro
ORL1µ-opioidStudy camp
Example No.pKipKipEC50
(rat.)-Ro 64-61989,07,38,7
example 18,47,09,6
example 1S,S8,87,59,8
example 1S,R8,5 7,79,8
example 1R,S8,76,89,8
example 1R,R7,56,68,7
example 28,27,39,5
example 68,46,4
example 78,26,99,2
example 87,8
example 107,3<6,0
example 138,16,67,1
example 158,67,5
example 217,3
example 317,5
example 327,4<6,0
example 357,5<6,09,1
example 418,56,8
example 427,96,9
example 439,28,1
example 458,47,5

In vivoORL1-agonism: anxiolytic activity
Agonismin vivo
CUDV*
I.P. Pavlova. p.o.
ConnectionED50(mg/kg)ED50(mg/kg)
example 10,20,9
(rat.)-Ro 64-61981,92,8

*CUDV = air-conditioned ultrasonic distress vocalizations; I.P. Pavlova. = intraperitoneally; r.o. = per os (oral).

From the data presented in the table above, it is evident that the compound of example 1 is ten times more powerful than Ro 64-6198, with the introduction of intraperitoneal way and three times more potent when administered orally.

Effects on blood pressure
ED80in µg/kg (the dose causing a 20% reduction in blood pressure compared with control values)
One connection+1 mg/kg J11397+2 mg/kg naloxone
Example 1356at 1,138 334
Ro 64-619884264141

The above data show that blood pressure-lowering action of the compound of example 1 (range 10-3000 mg/kg) counteracted J-113397 (offset according to the dose-response from 356 to 1138 mg/kg) and the effect of naloxone he was not prevented (no bias based dose-response 356 and 334 mg/kg). The effect of Ro 64-6198 (range 10-1000 µg/kg) prevented the J-113397 (offset according to the dose-response from 84 to 264 mg/kg) and the two higher doses of naloxone was also sensitive (offset according to the dose-response from 84 to 141 mg/kg). Obviously, Ro 64-6198 has µ-opioid component.

The impact on food consumption
ConnectionDose (mg/kg intraperitoneally)Average ± S.E.M. food intake (g), 120 minutes after administration of the ligand
Filler00,01±0,002
Morphine1,251,47±0,39
Morphine2,52,18±0,40
Morphine53,50±0,64
Morphine101,13±0,29
Example 10,30,05±0,04
Example 110,34±0,33
Example 130,73±0,36
Example 161,75±0,40
Example 1101,93±0,50
Ro 64-619810,97±0,38
Ro 64-6198/td> 30,67±0,37
Ro 64-6198102,13±0,53
Naloxone30,09±0,09
Naloxone300,05±0,001
J113397300,06±0,003

Morphine (1,25, 2,5, 5 and 10 mg/kg), Ro 64-6198 (1, 3 and 10 mg/kg, intraperitoneally) and connection example 1 (0,3, 1, 3, 6, 10 mg/kg, intraperitoneally), all led to a dependent dose-dependent increase in food intake, which in all cases was significant compared with the group treated filler. Systemic injection of the opiate antagonist naloxone (3 or 30 mg/kg, intraperitoneally) and one of the ORL1 antagonist J-113397 (30 mg/kg, intraperitoneally), one had no effect on food consumption.

-
The prevention of food intake induced by morphine
Ro 64-6198 or soy what inanam example 1
Naloxone (opiate antagonist)J-113397 (ORL1 antagonist)
Compound (mg/kg)Dose (mg/kg)Consumption (g)Dose (mg/kg)Consumption (g)
Morphine (5)02,92±0,38--
Morphine (5)0,032,34±0,66--
Morphine (5)0,31,96±0,59--
Morphine (5)30,45±0,32-
Example 1 (6)01,02±0,3001,25±0,39
Example 1 (6)0,30,51±0,1630,15±0,08
Example 1 (6)10,74±0,27100,08±0,002
Example 1 (6)30,78±0,23300,07±0,002
Ro 64-6198 (6)01,50±0,5301,55±0,56
Ro 64-6198 (6)0,31,00±0,353 1,49±0,40
Ro 64-6198 (6)30,73±0,29101,62±0,39
Ro 64-6198 (6)300,68±0,35300,85±0,26

The increase in food intake after administration of morphine was prevented in the presence of the antagonist of opiate receptor naloxone. The increase in food intake associated with the compound of example 1, was completely prevented by the ORL1 antagonist J-113397, but not an antagonist of opioid receptors by naloxone. J-113397 not prevented (statistically significant) increase in food intake associated with Ro 64-6198, whereas pre-treatment with naloxone resulted in a significant change in the induction of food intake by Ro 64-6198.

The presented data suggest that the increase in food consumption associated with the compound of example 1-mediated agonism to the ORL1 receptors and neopytnym receptors. The increase in food intake associated with Ro 64-6198, was partially prevented by naloxone, but not J-113397, indicating that Ro 64-6198 has opiate component that is not present in the compound of example 1. In conclusion, the connection is confident 1 acts as a more selective ORL1 agonist compared to Ro 64-6198.

1. Compounds of General formula (1)

in which R1represents H, alkyl(1-6C),
[]mmeans -(CH2)m-, in which m is 0 or 1,
R2represents halogen, CF3, alkyl(1-6C), phenyl, cyano, cianelli(1-3C), hydroxy, (1-3C)alkoxy, F3, acyl(2-7C), TRIFLUOROACETYL, (1-3C)alkylsulfonyl or trifloromethyl, and n means an integer of 0-4, provided that when n is 2, 3 or 4, substituents R2may be the same or different,
And means a saturated ring,
[]about[]prepresent -(CH2)about- and -(CH2)pand o and p independently correspond to 0, 1 or 2,
R3, R4, R5and R6independently represent hydrogen, alkyl(1-3C), or (R4and R6together can form Allenby bridge containing 1-3 carbon atoms, provided that when o is 2, R3means hydrogen, and when R is 2, R5means hydrogen,
R7represents H, halogen, alkyl(1-6C),
or their optically active stereoisomers, and pharmaceutically usable salt.

2. Compounds according to claim 1 of General formula (1)in which a represents a saturated ring, R1represents hydrogen, alkyl(1-3C),
R3, R4, R5and R6independently represent hydrogen or alkyl(1-3C, or (R4and R6together can form Allenby bridge containing 1-3 carbon atoms, provided that when o is 2, R3means hydrogen, and when R is 2, R5means hydrogen, R7represents H, halogen, alkyl(1-3C), and R2, m, n, o and p have the meanings above.

3. Compounds according to claim 1 of General formula (1)in which a represents a saturated ring; m=0, n=0 or 1, o=1, R=1, R1=N, R2represents halogen, CF3, alkyl(1-3C), cyano, co3or F3, R3, R4, R5and R6independently represent hydrogen or alkyl(1-2C), or (R4and R6together can form Allenby bridge containing 1-2 carbon atoms, and R7represents H, halogen, alkyl(1-3C).

4. The compound according to claim 1 of formula (2) and its stereoisomers:

5. Compounds of General formula (3):

in which R7has the meaning given in claim 1.

6. Pharmaceutical compositions having the properties of ORL1 and µ-opioid receptors, containing a pharmacologically active amount of at least one of the compounds according to any one of claims 1 to 4 as an active ingredient.

7. The use of compounds according to any one of claims 1 to 4 for the preparation of pharmaceutical compositions for treating disorders, op is radovanic effect of ORL1 receptors.

8. The use according to claim 7, where the above conditions and disorders selected from the eating disorders, arterial hypertension.



 

Same patents:

FIELD: chemistry; pharmacology.

SUBSTANCE: method involves production of N-substituted 3β-aminonortropanes of formula I or one of acid-additive salts , where R1 represents optionally substituted residue chosen from group, including C1-C8alkyl, C2-C8alkenyl, C3-C8cycloalkyl and C6-C10aryl-C1-C8alkyl, characterised that either a) related 3-oxonortropane of formula IIA reacts with arylmethylamine of formula IIIA H2N-CH2-Ar (IIIA) where Ar stands for optionally substituted phenyl residue or optionally substituted 5 or 6-merous heteroaromatic residue with at least one heteroatom chosen from group including N, O and S, or b) related 3α-aminonortropane of formula IIB reacts with arylaldehyde of formula IIIB O-CH-Ar (IIIB). Produced in each case imine of formula IVA or IVB is transformed to thermodynamically stable tautomer, respectively isomer of formula V , then hydrolysed and if required transformed to related acid-additive salt.

EFFECT: produced compounds of formula I are valuable intermediate in chemical synthesis of various pharmaceutical reactants or represent pharmaceutical reactant, first of all as NMDA-receptor modulators; method allows for high-yield commercial production of high-purity 3-aminonortropanes.

9 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a compound with general formula where R' stands for phenyl, unsubstituted or substituted with one or more substitutes, chosen from a group comprising alkyl, alkoxy group, halogen, -(CH2)oOH, -C(O)H, CF3, CN, S-alkyl, -S(O)1,2-alkyl, -C(O)NR'R", -NR'R"; R2 and R3 independently stand for hydrogen, halogen, alkyl, alkoxy group, OCHF2, OCH2F, OCF3 or CF3 and R4 and R5 independently stand for hydrogen, -(CH2)2SCH3, -(CH2)2S(O)2CH3, -(CH2)2S(O)2NHCH3, -(CH2)2NH2, -(CH2)2NHS(O)2CH3 or -(CH2)2NHC(O)CH3, R' stands for hydrogen, alkyl, -(CH2)oOH, -S(O)2- alkyl, -S(O)-alkyl, -S-alkyl; R" stands for hydrogen or alkyl; o stands for 0, 1, 2 or 3. The invention also relates to use of formula I compounds in making medicinal preparations for treating schizophrenia, for treating positive and negative symptoms of schizophrenia and medicine for treating schizophrenia.

EFFECT: obtaining new compounds with useful biological properties.

55 cl, 421 ex, 1 tbl

The invention relates to new cyclic amine derivatives of General formula I, where R1represents a phenyl group substituted by halogen atom,2represents C1- C8aliphatic acyl group or (C1- C4alkoxy)carbonyl group, R3represents a 3 - to 7-membered saturated cyclic amino group which may form a condensed ring, where the specified cyclic amino group substituted by the Deputy selected from the group comprising: mercaptopropyl, which can be unprotected or protected by a group selected from a number of protective groups, C1- C4alkyl group, substituted mercaptopropyl, which can be unprotected or protected by a group selected from a number of protective groups, and the number of protective groups for the specified mercaptopropyl includes C1- C20alcoholnye group, C3- C20alkenone group and benzoline group, and the said cyclic amino group, furthermore preferably a substituted group of the formula =CR4R5where R4represents a hydrogen atom, and R5represents a hydrogen atom, a C1- C4alkyl group, carboxypropyl, (C1- C4-alkoxy)carbonyl GRU

The invention relates to therapeutic active usacycling or azabicyclic compounds, method of their preparation and to pharmaceutical compositions comprising these compounds

The invention relates to derivatives of 3-(piperidinyl-1)-chroman-5,7-diol and 1-(4-hydroxyphenyl)-2-(piperidinyl-1)alkanol General formula I or their pharmaceutically acceptable salts accession acid, in which (a) R2and R5taken individually and R1, R2, R3and R4independently represent hydrogen, (C1-C6)-alkyl, halogen, HE or or7and R5represents methyl; or (b) R2and R5taken together form a ring chroman-4-ol, a R1, R3and R4each independently represent hydrogen, (C1-C6)-alkyl, halogen, HE or or7; R7represents methyl; and R6represents a substituted piperidinyl or 8-azabicyclo[3,2,1]octenidine derived; provided that (a) if R2and R5taken separately, at least one of R1, R2, R3and R4is not hydrogen; and (b) if R2and R5taken together, at least one of R1, R3and R4is not hydrogen, with the property that the NMDA antagonist

FIELD: chemistry.

SUBSTANCE: invention relates to aryl or heteroarylpiperazines with general formula II , where R2 is hydrogen or C1-4-alkyl (i) R1 is branched C4-6-alkyl, branched C4-6-alkenyl or branched C4-6-alkynyl, under the condition that R1 is not isobutyl, - C3-5-cycloalkyl, C3-7-cycloalkenyl, C3-6-cycloalkyl-C1-3-alkyl or C3-6-cycloalkenyl-C1-3-alkyl, -R1 and R2 together form a C3-6-alkylene bridge, and A is or or (ii) R1 - is ethyl, n-propyl or isopropyl, - R1 and R2 together form a C3-6-alkylene bridge, and A is or . Described also is a pharmaceutical composition based on formula II compounds, use of formula II compounds and method of treatment.

EFFECT: compounds exhibit high and selective bonding affinity to histamine H3 receptor and can be used for treating diseases and disorders, related to histamine H3 receptor.

49 cl, 149 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with general formula (I) or pharmaceutically acceptable salts thereof, where R1 is chosen from a group containing optionally substituted C1-C6alkyl, lower alkoxy group, (lower)alkoxy(lower)alkyl, cycloalkyoxy(lower)alkyl, lower thioalkyl, (lower)alkylthio(lower)alkyl, cycloalkyl, cycloalkyl(lower)alkyl; R2 is chosen from a group containing optionally substituted (lower)alkyl, cycloalkyl, cycloalkyl(lower)alkyl; R3 is chosen from a group containing halogen, cyano group, optionally substituted (lower alkyl, lower thioalkyl, aryl, aryl(lower)alkyl, lower alkenyl, lower alkynyl); R4 is chosen from a group containing hydrogen, halogen, cyano group, hydroxyl group, optionally substituted (lower alkyl, lower alkoxy group, aryl, pyridyl, aryl(lower)alkyl, heteroaryl, which is an aromatic mono- or bicyclic hydrocarbon, containing from 5 to 9 ring atoms, from which one or more is a heteroatom, chosen from O, N or S, and an amino group) and a group, with formula R8-Z-(CH2)n-; where Z is a single bond or chosen from a group consisting of O, NH, CH2, CO, SO, SO2 or S; where R8 is chosen from a group containing optionally substituted (aryl, pyridyl); and where n=0, 1 or 2; R5 represents hydrogen; R6 is chosen from a group containing halogen, optionally substituted lower alkoxy group; R7 is one or more substitutes, independently chosen from a group containing hydrogen, optionally substituted lower alkoxy group; where the optional substitute or substitutes when R1-R8 are independently chosen from a group containing halogen, hydroxyl group, lower alkyl, mono- or di(lower)alkylamino group, aminocarbonyl, sulfinyl, sulfonyl, sulfanyl, mono- or di(lower)alkylaminocarbonyl, amino group, carboxyl group, lower alkoxy group, C3-C12cycloalkyl, (lower)alkylcarbonyl, (lower)alkoxycarbonyl, nitrile, aryl; all of which, except halogen, are independently optionally substituted with one or more substitutes, chosen from a group containing halogen, hydroxyl group, lower alkyl, sulfinyl, sulfonyl, sulfanyl, amino group, carboxyl group, lower alkoxy group, carbamoyl. Invention also relates to formula (I'), to a pharmaceutical composition, as well as use of formula (I) compounds given in paragraph 1.

EFFECT: obtaining new biologically active compounds, for preventing or treating bone diseases, associated with very low or resorption of calcium.

6 cl, 151 ex

FIELD: chemistry.

SUBSTANCE: in new compounds with general formula (I): , R1 stands for a naphthyl group, which can be substituted with a halogen atom, W represents a bond, a equals 0, 1 or 2, X1 represents C1-4alkylene, which can be substituted with a hydroxy group, Y1 represents -C(O)-,A represents a piperazine ring or piperidine ring, X2 represents a bond, Y2 represents -C(O)-, -S(O)2- or -C(=NR7)- (where R7 represents a hydrogen atom), X3 represents C1-4alkylene, which can be substituted with a hydroxyl group, oxo group or C1-6alkyl group; or C2-4alkylene, which can be substituted with a C1-6alkyl group, where two alkyl groups can be bonded to each other forming, together with carbon atoms to which they are bonded, an aryl ring when X3 represents C2-4alkylene, substituted with two alkyl groups, Z3 represents -N(R4)- or a bond (where R4 represents a hydrogen atom, C1-6alkyl group, which can be substituted with a hydroxy group or methoxy group, or acyl group), represents a single or double bond, where if represents a single bond, then Z1 represents -C(R2)(R2')-, -N(R2)- or -O- and Z2 represents C(R3)(R3')-, -N(R3)-, -O- or a bond (under the condition that, when Z2 represents -O-, then Z is different from -O-), and when represents a double bond, then Z1 represents -C(R3)= or a nitrogen atom and Z2 represents =C(R3)- or a nitrogen atom, each of R2, R2', R3 and R3' represents a hydrogen atom or C1-6alkylene. The invention also relates to salts of the given new compounds. The invention also relates to compounds, chosen from the group, to pharmaceutical compositions, to use of compounds in sub-paragraph 1 or 2, to prevention or treatment methods, as well as to the method of obtaining compounds in paragraph 1.

EFFECT: obtaining new biologically active compounds, which inhibit activated factor X of blood clotting and have anticoagulation activity and antithrombotic activity.

33 cl, 46 ex, 1 tbl

FIELD: chemistry; medicine.

SUBSTANCE: in novel triazole derivatives of general formula I or their pharmaceutically acceptable salts R4 is hydrogen; X is selected from group, consisting of single bond, NH- and groups: , values of R1-R3 radicals are given in description, pharmaceutical composition containing them, and application of novel compounds for obtaining medication for treating hyperglycemia, insulin-resistance, type 2 diabetes, fat exchange derangements, obesity, atheroslerosis and metabolic syndrome.

EFFECT: medications possess higher efficiency.

26 cl, 8 ex, 2 tbl

FIELD: chemistry; medicine.

SUBSTANCE: compounds of claimed invention possess properties of positive allosteric modulator mGluR5. In general formula I , W represents 6-member heterocycloalkyl ring with 1-2 heteroatoms, selected from N, O; R1 and R2 independently represent hydrogen, C1-C6-alkyl; P and Q each independently is selected from: , R3, R4, R5, R6 and R7 independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-member heteroaryl with 1-2 atoms N as heteroatoms; 6-member heterocycle with 2 heteroatoms representing N, O; phenyl, optionally substituted with halogen; naphtyl; -OR8; where optionally two substituents together with located between them atoms form 9-10-member bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S; R8 represents hydrogen, C1-C6-alkyl; D, E, F, G and H independently represent -C(R3)=, -O-, -N=, -N(R3)- or -S-; A represents ethinyl, -C(=O)NR8- or group of formula . B represents -C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6-alkenyl-. Invention also relates to pharmaceutical composition based on invention compounds.

EFFECT: novel compounds possess useful biological proprties.

20 cl, 3 dwg, 75 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the group including hydronopol-substituted benzimidazolone- and quinazolinone-derivatives as agonists of human ORL1 receptors (nociceptors). In addition, the invention refers to making specified compounds, to pharmaceutical compositions containing pharmacologically active amount of at least one specified new benzimidazolone- and quinazolinone-derivatives as an active component, and to application of said pharmaceutical compositions in treatment of disorders involving ORL1 receptors. The invention concerns compounds of general formula where symbols take on values specified in the description.

EFFECT: higher effectiveness of the composition and therapy.

7 cl, 17 ex, tbl

FIELD: chemistry.

SUBSTANCE: invention concerns novel bicyclic imidazol derivatives of the general formula I , where: W is CH or N; R is selected out of group including hydrogen, (C1-C10)alkyl, substituted (C1-C10)alkyl, (C3-C10)cycloalkyl and substituted (C3-C10)cycloalkyl; Z is selected out of group including a) -C(=O)OR7, where R7 is selected out of group including hydrogen and alkyl; b) -C(=O)NR8R9, where R8 and R9 are independently selected out of group including hydrogen, alkyl, aryl, substituted aryl, heterocyclic group, or alternatively R8 and R9 form heterocyclic group or substituted heterocyclic group, together with nitrogen atom linked to them; c) tetrazolyl; HET is condensed 6,6-bicycle maintained by condensed link of any two 6-member cycles selected out of aryl, cycloalkyl, cycloalkenyl, heterocyclic or heteroaryl cycles optionally substituted by (Y)q; on the condition that at least one 6-member cycle in bicycle is heterocyclic or heteroaryl; each Y is independently selected out of group including halogen, (C1-C10)alkyl, substituted (C1-C10)alkyl, (C3-C10)cycloalkyl, substituted (C3-C10)cycloalkyl, heterocyclic group, substituted heterocyclic group, aryl, substituted aryl, heteroaryl, substituted heteroaryl, -CO2R7, -NR14R15, -NHNR14R15, -C(=O)NR14R15, -OR14, -SR14; where R7 is as defined above, and each of R14 and R15 is independently selected out of group including hydrogen, (C1-C10)alkyl, substituted (C1-C10)alkyl, aryl, substituted aryl; n is integer equal to 0, 1 or 2; q is integer equal to 1, 2 or 3; where heterocyclic group relates to substituted or non-substituted group with 1 ring or several condensed rings including 1 to 10 carbon atoms and 1 to 2 heteroatoms selected out of group including nitrogen, sulfur and oxygen, inside the ring including optionally 1 to 2 exocarbonyl groups; and pharmaceutically accepted salts or tautomers. Additionally, invention concerns compounds of general formulae II-VIII

and pharmaceutical composition based on compounds of the general formulae I- VIII, XI and XII, and treatment method for mammal virus infection partially mediated by a virus of Flaviviridae virus family, using claimed pharmaceutical composition.

EFFECT: obtaining new compounds, with useful biological effect.

82 cl, 9 tbl, 261 ex

FIELD: chemistry.

SUBSTANCE: invention concerns novel compounds of the formula (I): , where R1 is -COOH or -(CH2)n-R14; R2 is or , where X is -CH or -N; each of R3, R4, R5 and R6 is selected out of group including -H, -(lower) alkyl, -N(CH3)2, -O-(lower) alkene, -(lower) alcoxy, or where R5 and R6 are substitutes in adjoining carbon atoms in ring, R5 and R6 optionally form 5- or 6-member saturated carbocyclic ring together with adjoining carbon atoms, R14 is unsaturated 5-member substituted or non-substituted heterocyclic ring including 1 to 4 heteroatoms selected out of N, O and S, n is 0 or 1, or their pharmaceutically acceptable salts or complex ethers. Invention also concerns pharmaceutical composition.

EFFECT: obtaining new bioactive compounds and pharmaceutical composition based on them, with inhibition effect on glutamine fructose-6-phosphate amidotransferase (GFAT).

16 cl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention claims compounds of the formula (I) with radicals as described in the claim, and medicine with inhibition effect on glycine absorption, based on compound of the formula (I) .

EFFECT: medicine for diseases treatment where glycine absorption inhibition can be effective.

21 cl, 1 tbl, 173 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compounds of formula (I), their obtaining and application as elastase inhibitors, and can be applied in medicine, where Y = CH; R№ represents H or alkyl; RІ represents phenyl or 5-6-memner heteroaryl, G1 represents phenyl; R5 represents H, halogen, alkyl, CN or fluorinated alkyl; n=1-3; R4 = H; L represents bond, O, NR29 or alkyl; or R4 and L are bound together in such way that group -NR4L- represents 5-7-member asacyclic ring; G2 represents phenyl, 5-6-member heteroaryl, cycloalkyl, C4-7-heterocycle, bicycle from two condensed, bound with direct bond or separated with O atom rings, selected from phenyl, 5-6-member heteroaryl, cycloalkyl or C4-7-heterocycle; or when L does not represent bond, G2 represents H; s = 0-2; R25 represents H, alkyl or cycloalkyl; R29 represents H or alkyl.

EFFECT: obtaining novel biologically active compounds.

10 cl, 95 ex, 1 tbl

The invention relates to a new and improved method for producing (+)-enantiomer of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenide] methanamine the interaction of (+)-enantiomer of 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naftalina with monomethylamine and titanium chloride or molecular sieves
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