Method of obtaining quinolone compounds

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to a method of obtaining a quinolone compound, which includes a stage of interaction of a dechloroquinolone compound, or its pharmaceutically acceptable salt, or ether with a chlorinating agent and acid, in which the molar ratio of the acid to the dechloroquinolone compound constitutes from 0.008 to 0.012 and in which less than 0.40% of a dimeric admixture is obtained in a percentage of the area counted per the obtained quinolone compound, and where the quinolone compound represents 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, or its pharmaceutically acceptable salt or ether, the dechloroquinolone compound represents 1-(6-amino-3,5-difluoropyridin-2-yl)-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinolin-3-carboxylic acid, or its pharmaceutically acceptable salt, or ether and the dimeric admixture represents 1-amino-3-(azetidin-3-yloxy)propane-2-olbis(H,H'-quinolonecarboxylic acid) or its pharmaceutically acceptable salt or ether.

EFFECT: improved method of obtaining a quinolone derivative, useful as an anti-infective agent, is elaborated.

15 cl, 21 dwg, 2 ex, 2 tbl

 

The technical field TO WHICH the PRESENT INVENTION REFERS

The present invention relates to the field of anti-infective compounds. More specifically, the present invention relates to the preparation of the quinoline family compounds suitable as anti-infective funds. The present invention relates to a method for producing quinoline compounds, according to which receive less than approximately 0,40% dimeric impurities quinolone.

Prior art

Since the discovery of penicillin in the 1920s and streptomycin in the 1940s or received a specially designed many new compounds for use as antibacterial agents. Once believed that applying a therapeutic agent to fight or to completely eradicate infectious diseases. Appeared resistant strains of gram-positive bacteria such as methicillin-resistant staphylococci, penicillin resistant streptococci, and vancomycin-resistant enterococci, which can cause serious and even fatal cases in patients infected data with resistant bacteria. Came bacteria that are resistant to macrolide antibiotics, i.e. antibiotics on the basis of 14-16 membered laktonovogo rings. In addition, the detected ustoichivost gram-negative bacteria such asH. influenzaeandM. catarrhalis. See, for example, F. D. Lowry, "Antimicrobial Resistance: The Examples of Staphylococcus aureus," J. Clin. Invest., 2003, 7/7(9), 1265-1273 and Gold, H. S. and Moellering, R. C., Jr., "Antimicrobial-Drug Resistance," N. Engl. J. Med, 1996, 335, 1445-53.

Despite the problem of increasing antibiotic resistance new major classes of antibiotics for clinical use have not been developed since the authorization in the United States in 2000 antibiotic containing oxazolidinone ring, N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methylacetamide, which is known as linezolid and is sold under the trade name Zyvox® (see compound A). Cm. R. C. Moellering, Jr., "Linezolid: The First Oxazolidinone Antimicrobial," Annals of Internal Medicine, 2003, 735(2), 135-142.

Linezolid is approved for use as an antibacterial agent, active against gram-positive organisms. Unfortunately, it was already reported about resistant to linezolid organisms. Cm. Tsiodras et al., Lancet, 2001, 358, 207; Gonzales et al., Lancet, 2001, 357, 1 179; Zurenko et al., Proceedings Of The 39thAnnual lnterscience Conference On Antibacterial Agents and Chemotherapy (ICAAC); San Francisco, CA, USA, (September 26-29, 1999).

Notwithstanding the foregoing there is a continuing need for new anti-infective tools, and methods for their preparation.

Brief description of figures

Fig.1 shows the predicted profiles for the number of dimeric impurities� 4, when the ethyl acetate (EtOAc) is the solvent. It is based on the original design of the experiments. Central line in each graph shows the predicted values and the two lines flanking the Central line represent approximately +95 percent confidence. The horizontal dotted line shows the concentration of dimer 4 0,235094 percent. Vertical dotted lines indicate variables for the 1.05 equivalents of N-chlorosuccinimide (NCS) and 3.5 mole percent of sulfuric acid, 17°C, of 0.05% of water content in the solvent and the speed of adding NCS 0.1 volume per minute. a 95% limit of confidence is a ±0,040991 for the quantities shown in the previous proposal.

Fig.2 shows the effect of H2SO4and time on the concentration of dimeric impurity 4.

Fig.3 shows the worst-case scenario for the predicted profile for the amount of dimeric impurity 4 for DoE sustainability, i.e. for the second design of experiments. Central line in each graph shows the predicted values and the two lines flanking the Central line, are approximately ±95 percent confidence. The horizontal dotted line shows the concentration of dimer 4 0,1045 percent. Vertical dotted lines indicate variables for the 1.04 equivalents of N-chlorosuccinimide (NCS), 2°C, speed add NCS 30 minutes and 0.8 mole percent of sulfuric acid. a 95% limit of confidence is a +0,009339 for the quantities shown in the previous proposal.

Fig.4 shows the initial experimental design table experiments.

Fig.5a shows the true values using the predicted schedule for the initial design of experiments of Fig.4.

Fig.5b shows the result of approximation for the initial design of experiments of Fig.4.

Fig.5c shows the analysis of variance for initial design Fig.4.

Fig.5d shows the estimated parameter values for the initial design of experiments of Fig.4.

Fig.5e shows the balance with the predicted schedule for the initial design of experiments of Fig.4.

Fig.5f shows the sorted evaluation values of the parameters for the initial design of experiments of Fig.4.

Fig.6a shows the predicted profiles for the initial design of experiments of Fig.4.

Fig.6b shows the interaction profiles for the initial design of experiments of Fig.4.

Fig.7 shows the steady experimental design table experiments for the second design of experiments.

Fig.8a shows the true values using the predicted schedule for the second design of experiments of Fig.7.

Fig.8b p�cauldron is the result of approximation for the second design of experiments of Fig.7.

Fig.8c shows the analysis of variance for the second design of experiments of Fig.7.

Fig.8d shows the disagreement for the second design of experiments of Fig.7.

Fig.8e shows the estimated parameter values for the second design of experiments of Fig.7.

Fig.8f shows the balance with the predicted schedule for the second design of experiments of Fig.7.

Fig.8g shows the predicted profiles for the second design of experiments of Fig.7.

The essence of the present invention

The present invention relates to the field of anti-infective compounds. More specifically, the present invention relates to the preparation of the quinoline family compounds suitable as anti-infective funds.

The present invention relates to a method for producing quinoline compounds, including the stage of interaction dechlorinating compound, or its pharmaceutically acceptable salt, or ester with a chlorinating agent and an acid, which get less than approximately 0.40 per cent per cent of the area, as quantified by analytical HPLC, dimeric impurity quinolone.

In other embodiments, the present invention relates to a method in which dechlorinate the compound is a 1-(6-amino-3,5-differencein-2-yl)-6-fluoro-7-(3-hydroxy-assetid�n-1-yl)-4-oxo-l,4-dihydroquinoline-3-carboxylic acid, or its pharmaceutically acceptable salt, or ester, quinoline the compound is a 1-(6-amino-3,5-differencein-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidine-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, or its pharmaceutically acceptable salt, or ester.

In other embodiments, the present invention relates to a method in which the dimeric impurity is a compound of 1-amino-3-(azetidin-3-yloxy)propane-2-Albis(N,N'-hinolincarbonova acid), or its pharmaceutically acceptable salt, or ester. In other embodiments, the present invention relates to a method in which the dimeric impurity is monoether. In other embodiments, the present invention relates to a method in which the dimeric impurity is a diester.

In other embodiments, the present invention relates to a method in which the chlorinating agent is an N-chlorosuccinimide.

In other embodiments, the present invention relates to a method in which the acid is selected from the group consisting of sulfuric acid, hydrochloric acid, Hydrobromic acid, phosphoric acid, trifluoroacetic acid, followed, methansulfonate, p-base or perchloro acid and mixtures thereof.

In each�x embodiments, the present invention relates to a method, in which the acid is a sulfuric acid.

In other embodiments, the present invention relates to a method in which the interaction is carried out at a temperature from about 0°C to about 30°C.

In other embodiments, the present invention relates to a method in which the interaction is carried out at a temperature from about 15°C to about 25°C.

In other embodiments, the present invention relates to a method in which the interaction is carried out at a temperature of about 13°C to about 21°C.

In other embodiments, the present invention relates to a method in which the mole ratio N-chlorosuccinimide to dechlorination is more than approximately 1.

In other embodiments, the present invention relates to a method in which the mole ratio N-chlorosuccinimide to dechlorination is approximately equal to 1.05 to 1.2.

In other embodiments, the present invention relates to a method in which the mole ratio N-chlorosuccinimide to dechlorination is approximately of 1.04 to 1.07.

In other embodiments, the present invention relates to a method in which the mole ratio of sulfuric acid to dechlorinate is approx�flax 0.005 to about 0.05.

In other embodiments, the present invention relates to a method in which the mole ratio of sulfuric acid to dechlorinate ranges from approximately 0.007 to approximately 0,02.

In other embodiments, the present invention relates to a method in which the mole ratio of sulfuric acid to dechlorinate is from about 0.008 to about 0,012.

In other embodiments, the present invention relates to a method in which used ether acetate as a solvent.

In other embodiments, the present invention relates to a method in which ether acetate is selected from the group consisting of methyl acetate, ethyl acetate and mixtures thereof.

In other embodiments, the present invention relates to a method in which the aforementioned ether acetate is an acetate.

In other embodiments, the present invention relates to a method comprising the additional step of interaction of quinoline compounds with a base.

In other embodiments, the present invention relates to a method, in which the base is a hydroxide.

In other embodiments, the present invention relates to a method in which a hydroxide selected from the group consisting of hydrox�Yes sodium, potassium hydroxide, lithium hydroxide, barium hydroxide and mixtures thereof.

In other embodiments, the present invention relates to a method in which the hydroxide is a hydroxide of potassium.

In other embodiments, the present invention relates to a method in which a mixture of C1-C6alcohol and water as solvent.

In other embodiments, the present invention relates to a method in which C1-C6alcohol is a isopropanol.

In other embodiments, the present invention relates to a method, which method is a method on a commercial scale.

In other embodiments, the present invention relates to a composition containing a quinoline compound or its salt or ester containing less than approximately 0,40% of dimeric impurity of quinoline compounds.

In other embodiments, the present invention relates to compositions in which the quinoline compound is a 1-(6-amino-3,5-differencein-2-yl)-8-chloro-6-fluoro-7-(3-hydroxy-azetidin-1-yl)-4-oxo-l,4-dihydroquinoline-3-carboxylic acid, or its pharmaceutically acceptable salt, or ester.

In other embodiments, the present invention relates to compositions, in which the dimeric impurity of pre�is a 1-amino-3-(azetidin-3-yloxy)propane-2-Albis(N,N'-hinolincarbonova acid), or its pharmaceutically acceptable salt, or ester.

In other embodiments, the present invention relates to compositions in which the composition is a composition on a commercial scale.

In other embodiments, the present invention relates to a method or composition, in which the dimeric impurity is less than about 0.35%.

In other embodiments, the present invention relates to a method or composition, in which the dimeric impurity is less than approximately 0.30% of the.

In other embodiments, the present invention relates to a method or composition, in which the dimeric impurity is less than approximately 0.25%.

In other embodiments, the present invention relates to a method or composition, in which the dimeric impurity is less than approximately 0.20 per cent.

In other embodiments, the present invention relates to a method or composition, in which the dimeric impurity is less than approximately 0.15 percent.

In other embodiments, the present invention relates to a method or composition, in which the dimeric impurity is less than approximately 0,10%.

In other embodiments, the present invention relates to a method or composition, in which� dimeric impurity is less than about 0.05%.

In other embodiments, the present invention relates to a method or composition, in which the dimeric impurity is less than about 0.04 percent.

In other embodiments, the present invention relates to a method or composition, in which the dimeric impurity is less than about 0.03%.

In other embodiments, the present invention relates to a method or composition, in which the dimeric impurity is less than approximately 0.02 per cent.

In other embodiments, the present invention relates to a method or composition, in which the mentioned dimeric impurity is less than about 0.01%.

Detailed description of the present invention

Quinolones

The methods and compositions of the present invention include quinoline compound.

Quinoline compounds such as derivatives pyridonecarboxylic acid suitable in the present invention, describe, including receipt, formulation and application, in U.S. patent No. 6156903, Yazaki et al., published December 5, 2000 and a list of seen typos on 13 November 2001 and 11 December 2001; in U.S. patent No. 6133284, Yazaki et al., published October 17, 2000; U.S. patent No. 5998436, Yazaki et al., published December 7, 1999 and a list of seen typos on January 23, 2001, October 30, 2001 and December 17, 2002; in Mstsave No. WO 2006/1 10815, Abbott Laboratories, published October 1, 2006; PCT application no WO 2006/042034, Abbott Laboratories, published on 20 April 2006, in the PCT application number WO 2006/015194, Abbott Laboratories, published 9 February 2006; in PCT application no WO 01/34595, Wakunaga Pharmaceutical Co., Ltd., published on may 17, 2001, and PCT application no WO 97/1 1068, Wakunaga Pharmaceutical Co., Ltd., published March 27, 1997.

Derivatives pyridonecarboxylic acid of the present invention include compounds corresponding to the following structure. (Derived 1 pyridonecarboxylic acid)

Derived 1 pyridonecarboxylic acid, in which R1represents a hydrogen atom or a protective group of the carboxyl function; R2represents a hydroxyl group, a lower alkoxygroup, or substituted or unsubstituted an amino group; R3represents a hydrogen atom or a halogen atom; R4represents a hydrogen atom or a halogen atom; R5represents a halogen atom or optionally substituted saturated cyclic amino group; R6represents a hydrogen atom, a halogen atom, a nitro group or optionally protected amino group; X, Y and Z may be the same or different and respectively represent a nitrogen atom, CH or CR7(in which R7represents a lower alkyl group, a halogen atom or a cyano group), providing, at least one of X, Y and Z represents a nitrogen atom, and W represents a nitrogen atom or CR8(in which R8represents a hydrogen atom, a halogen atom or a lower alkyl group), and provided that when R1represents a hydrogen atom, R2represents an amino group, R3and R4represent a fluorine atom, R6represents a hydrogen atom, X represents a nitrogen atom, Y is a CR7(in which R7represents a fluorine atom), Z represents CH, and W is a CR8(in which R8represents a chlorine atom), then R5is not a 3-hydroxyazetidine-1-ilen group, or their pharmaceutically acceptable salt, ester or prodrug.

As described above, when R1represents a protective group of the carboxyl function, it can be any residue of the ether carboxylic acids, which are relatively easily cleaved, yielding the corresponding free carboxyl group. Examples of protective groups of carboxyl functions include protecting groups, which are tiny by hydrolysis, catalytic reactions and other treatments under mild conditions, such as lower alkyl groups such as methyl group, ethyl group, n-propyl group, isop�opalina group, n-butyl group, isobutylene group,tert-butyl group, pencilina group, exilda group and heptylene group; lower alkenyl groups such as vinyl group, allyl group, 1-protanilla group, botenanna group, penttila group, examilia group and leptanillinae group; kalkilya groups such as benzyl group; and aryl groups such as phenyl group and naftalina group; and groups that can easily be removed in several stages, such as the lower alkanoyloxy lower alkyl groups, such as acetoxymethyl group and pivaloyloxymethyl group; the lower alkoxycarbonyl lower alkyl group, such as methoxycarbonylmethylene group and 1-ethoxycarbonylmethylene group; lower alkoxymethyl group such as methoxymethyl group; Victorina group such as phthalidyl; di - lower alkylamino lower alkyl group such as 1-dimethylaminomethylene group; and (5-methyl-2 - oxo-1,3-dioxol-4-yl)methyl group.

It should be noted that the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, A, J1, J2, J3, W, X, Y, Z, e, f and g define the present invention for the convenience regarding chemical structure derived pyridonecarboxylic acid.

In other embodiments, p�implementing the present invention relates to a method for producing a derived pyridonecarboxylic acid, having structure derived 1 pyridonecarboxylic acid, in which W is a CR8in which R8represents a hydrogen atom, a halogen atom or a lower alkyl group.

In other embodiments, the present invention relates to a method of producing the derived pyridylcarbinol acid having the structure derived 1 pyridylcarbinol acid in which R5is a group represented by the following formulas (a) or (b):

(a)

(b)

in which A represents an oxygen atom, a sulfur atom or NR9(in which R9represents a hydrogen atom or a lower alkyl group), e represents a number from 3 to 5, f represents a number from 1 to 3, g represents a number from 0 to 2, J1, J2and J3that may be the same or different from each other, represent a hydrogen atom, hydroxyl group, lower alkyl group, amino lower alkyl group, an amino group, a lower alkylamino, the lowest alkoxygroup or a halogen atom.

In other embodiments, the present invention relates to a method of producing the derived pyridylcarbinol acid having the structure derived 1 pyridylcarbinol acid, in which� R 5is a group represented by the formula (a).

(a)

In other embodiments, the present invention relates to a method of producing the derived pyridylcarbinol acid having the structure derived 1 pyridylcarbinol acid, in which e in the formula (a) is equal to 3 or 4.

(a)

In other embodiments, the present invention relates to a method of producing the derived pyridylcarbinol acid having the structure derived 1 pyridylcarbinol acid in which R1represents a hydrogen atom; R2represents an amino group, a lower alkylamino or di - lower alkylamino; R3represents a halogen atom; R4represents a halogen atom; R represents a hydrogen atom; X represents a nitrogen atom; Y and Z represent CH or CR7(in which R7represents a lower alkyl group or a halogen atom; and W represents CR8(in which R8represents a halogen atom or a lower alkyl group).

In other embodiments, the present invention relates to a method of producing the derived pyridylcarbinol acid having the structure derived 1 pyridylcarbinol acid, which 2represents an amino group; R3represents a fluorine atom; R4represents a fluorine atom; Y represents CF; Z represents CH; W represents CR8(in which R8represents a chlorine atom, a bromine atom or a methyl group), and e in the formula (a) is 3.

(a)

In other embodiments, the present invention relates to a method for producing pyridonecarboxylic acid where mentioned piridoksina acid corresponds to the following structure:

or its pharmaceutically acceptable salt, ester or prodrug. This above piridoksina acid is also known by the publicly available code names Abbott Laboratories ABT-492, Wakunaga Pharmaceutical Co., Ltd. WQ 3034, Rib-X Pharmaceuticals, Inc., RX-3341, the USAN delafloxacin and also under chemical names 1-(6-amino-3,5-debtor-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxy-1-azetidine)-4-oxo-3-quinolinecarboxylic acid, 1-(6-amino-3,5-debtor-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidine-1-yl)-4-oxo-3-quinolinecarboxylic acid, 3-quinolinecarboxylic acid, 1-(6-amino-3,5-debtor-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxy-1-azetidine)-4-oxo and 1-(6-amino-3,5-differencein-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidine-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. �data form compounds carboxylic acid corresponds to the CAS registry number 189279-58-1. In addition, WO 2006/042034, cited above, describes D-glucitol salt of the compound [D-glucitol 1-(6-amino-3,5-debtor-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxy-1-azetidine)-4-oxo-3-chinainternational (Sol)] trihydrate and D-glucitol salt of the compound [D-glucitol 1-(6-amino-3,5-debtor-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxy-1-azetidine)-4-oxo-3-chinainternational trihydrate (salt)]. D-luzitania salt trihydrate and D-glucitol salts correspond to the CAS registration numbers 352458-37-8 and 883105-02-0 respectively. D-glucitol corresponds to the CAS registry number 6284-40-8. WO 2006/042034 also describes crystalline form D-glucitol salts described when measured at about 25°C with Cu-Ka radiation, by a powder diffraction pattern shown in Fig.1 (see WO 2006/042034), and crystalline form of trihydrate D-glucitol salt when measured at about 25°C with Cu-Ka radiation, by a powder diffraction pattern shown in Fig.2 (see WO 2006/042034). Data D-glucitol salts are suitable in the present invention. In addition, see A. R. Haight et al., "Synthesis of Quinolona ABT-492: Crystallizations for Optimal Processing", Organic Process Research & Development(2006), 10(4), 751-756.

The terms "method on a commercial scale" and "composition on a commercial scale" refers to a method and composition, respectively, which carry out or get for Odie� cycle in the amount of at least about 100 grams.

Detection and suppression of formation of dimeric impurities in obtaining delafloxacin

Cm. Hanselmann, R., et al., "Identification and Suppression of a Dimer Impurity in the Development of Delafloxacin", Organic Process Research & Development, vol. 13, pages 54-59 (2009).

Delafloxacin is a 6-ftorhinolonovy antibiotic that is being developed by Rib-X Pharmaceuticals, Inc. During the initial attempts at scaling to obtain delafloxacin formed up to 0.43% new impurities on the penultimate stage of chlorination. She was identified as a dimeric adduct delafloxacin. The subsequent application of DoE (design of experiments) led to the discovery of factors responsible for the formation of this impurity. Using the knowledge obtained from DoE, let reproducibly suppress the impurity to an acceptable level.

Antimicrobial resistance in a familiar social environment and in hospital is a growing health concern due to the continuous emergence of bacterial strains resistant to many medicines. Cm. (a) Cosgrove, S. E.; Carmeli, Y. Clin. Infect. Dis. 2003, 36, 1433. (b) Seybold, U.; Kourbatova, E. V.; Johnson, J. G.; Halvosa, J. S.; Wang, Y. F.; King, M. D.; Ray, S. M.; Blumberg, H. M. Clin. Infect. Dis. 2006, 42, 647 and (c) Tenover, F. C; McDougal, L. K.; Goering, R. V.; Killgore, G.; Projan, S. J.; Patel, J. B.; Dunman, P. M. J. Clin. Microbiol. 2006, 44, 108.

Methicillin-resistant zolototysyachnik (MRSA) ranks first as the most frequently isolated pathogenic organism in hospital intensive care units in the United States and the frequency of MRSA cases increased from 35.9% in 1992 to 64.4% in 2003. Cm. Klevens, R. M.; Edwards, J. R.; Tenover, F. C; McDonald, L. C; Horan, T.; Gaynes, R. Clin. Infect. Dis. 2006, 42, 389.

Since the introduction of nalidixic acid for approximately 40 years ago, quinoline antibiotics occupy an important place in the list of antibiotics. 6-Fluoroquinolones, such as ciprofloxacin, particularly the increased role in the treatment of infections due to its wide range of applications. Cm. (a) Bush, K. Clin. Microbiol. Infect. 2004, 10 (Suppl. 4), 10. and (b) Emmerson, A. M.; Jones, A. M. J. Antimicrob. Chemother. 2003, 51 (Suppl. Sl), 13.

Delafloxacin is a 6-ftorhinolonovy antibiotic with excellent antibacterial activity against gram-positive organisms, including methicillin-sensitiveS aureusand MRSA. He is currently undergoing phase II clinical trials. Delafloxacin originally received Wakunaga Pharmaceuticals and Abbott Laboratories and was subsequently patented Rib-X Pharmaceuticals, Inc.

Getting delafloxacin was originally developed by Abbott Laboratories (Scheme 1) and a key stage in this scheme is the selective chlorination of 8-position functionalized quinolone 1 (dechlorination). Cm. (a) Haight, A. R.; Ariman, S. Z.; Barnes, D. M.; Benz, N. J.; Gueffier, F. X.; Henry, R. F.; Hsu, M. C.; Lee, E. C; Morin, L.; Pearl, K. B.; Peterson, M. J. ; Plata, D. J.; Willcox, D. R. Org. Process Res. Dev. 2006, 4, 751. and (b) Barnes, D. M.; Christesen, A. C; Engstrom, K. M.; Haight, A. R.; Hsu, M. C.; Lee, E. C; Peterson, M. J.; Plata, D. J.; Raje, P. S.; Stoner, E. J.; Tedrow, J. S.; Wagaw, S. Org. Process Res. Dev. 2006, 4, 803.

In this method, a solution of 1 in �MESI of methyl acetate (MeOAc) and ethyl acetate were chlorinated, using NCS in the presence of 3.5 mol % H2SO4getting 2. This was followed by replacement of the solvent and KOH saponification in order to obtain 3. Delafloxacin received after the formation of salts with N-methyl-D-glucamine.

Scheme 1: Getting delafloxacin

Despite the initial success in the implementation of this method, the inventors have encountered difficulties when scaling this stage, namely that up to 0.43% square new impurities are detected using HPLC and RRT 1.60 after separation 3. In addition, it was found that this new impurity is difficult to remove during the final salt formation. Thus, the inventors decided to start the research finding of this contaminant, to understand how it is formed and to suppress its formation.

Results and discussion

Despite numerous attempts to allocate this new admixture preparative HPLC the inventors failed to do this and was only fitted molecular weight using HPLC-MS 880 Yes. The measured molecular weight of this contaminant is exactly twice the molecular weight acid 3, which involves a dimeric derivative of this compound. A careful study of the profile of the purity of the substrate chlorination reaction did not lead to detection of any impurity, which m�zhno would be the same as to ascribe dimeric structure and its formation, consequently, it was of the sequence attributed to chlorination-hydrolysis. Considered a number of potential dimeric adducts, which could be formed at this stage, including 4, which could be the result of splitting azetidinone groups in one molecule of 3 and the reaction of the hydroxyl group of the second molecule. In order to further explore this possibility, the inventors proceeded to obtain 4.

Scheme 2: Restreintes alleged impurity 4

Retrosynthetic (Scheme 2) molecule 4 is easily broken at the appropriately protected amino 5 and the quinolone 6; the latter is a known compound. Fragment 5 can be obtained from the commercially available hydrochloride salt of azetidin-3-ol 7. Cm. (a) Yazaki, A.; Niino, Y.; Ohshita, Y.; Hirao, Y.; Amano, H.; Hayashi, N.; Kuramoto, Y. PCT international application WO 9711068, 1997. CAN: 126, 305587 and (b) Yazaki, A.; Aoki, S. PCT international application WO 2001034595, 2001. CAN: 134, 366811.

Thus, the synthesis started with 7, in which the nitrogen atom was protected in the form of benzylcarbamoyl to get 8 with a quantitative yield. This adduct racemic alkylated with epichlorohydrin to obtain 9 with the release of 84%. Disclosure of epoxide 9 with ammonia gave 10, which was condensible without treatment with 6 to 11 c obtain a total yield of 83%. Removal of the Cbz group in terms of Guidry�hardware gave 12 with the release of 93%. A second condensation with 6 resulted in the formation of dimeric compounds 13 with 71% yield. After saponification of the alleged impurity 4 was obtained with a yield of 98%.

Scheme 3: Synthesis of impurity 4

Synthetic 4 in the presence of an unknown impurity in the contaminated portions delafloxacin compared with those obtained 4 using the experiments and compared using HPLC-MS and HPLC-UV. It turned out that synthetic 4 uniquely corresponded to unknown impurities observed in the previously received portions delafloxacin.

In order to understand the dynamics of the formation of the impurity 4, the inventors decided to study the reaction in studies of design of experiments (DoE). The following factors were selected for study in the DoE study of fracture IV, in the ranges as shown: temperature (15-25°C), the number of NCS (1,05-1,2 EQ.), the number of H2SO4(2-5 mol %), the water content in solvent (0-0,5%), the volume of the solvent (about 2-3.), the solvent (methyl acetate/ethyl acetate) and the rate of addition of NCS (0,05-0,3 rpm). Cm. Fig.4, Fig.5a, 5b, 5c, 5d, 5e and 5f, Fig.6a and 6b, Fig.7 and Fig.8a, 8b, 8c, 8d, 8e, 8f and 8g. Spent only 19 of chlorination reactions in MultiMaxTM reactor, obtained from Mettler-Toledo, Inc., 1900 Polaris Parkway, Columbus, OH, 43240.

In each case, the samples from the reactions were quenched after 5 h, omalale KOH and the crude reaction mixture was analyzed by HPLC. For �CSOs to determine the number of 4, chlorinated samples 2 omalale to 3. The amount of area in percent for the impurity 4, which was obtained in each case were processed and analyzed using DoE software. The design of the experiment and the analysis was carried out using JMP, Design of Experiments, Version 7, SAS Institute Inc., Cary, NC, 1989-2007, by applying the step-by-step approach, followed by a standard method of least squares.

Excellent correlation of R20,997 were received for following data processing. Main effects: large amounts of NCS, the temperature reduction and more rapid addition of a solution of NCS, as well as the use of dry solvents, had a most favourable effect on the suppression of impurity 4 (Fig.1). Used methyl acetate containing less than 500 parts per million of water, before adjustment, as required in a suitable experiment in DoE. In addition, a strong interaction was observed between the number of NCS and solvent that methyl acetate was preferred when used only a small excess of NCS. To suppress any excess chlorination 2, 1.05 equivalent of NCS was preferred and, therefore, the methyl acetate was chosen as the preferred solvent for this stage. A more detailed analysis can be found in Fig.4, Fig.5a, 5b, 5c, 5d, 5e and 5f, Fig.6a and 6b, Fig.7 and Fig.8a, 8b, 8c, 8d, 8e, 8f and 8g.

From the point of view of the mechanisms�and reactions the inventors concluded that the admixture of 4 could arise as a result of the initial acid-catalyzed activation azetidinone ring that causes isobutyryl ether/chloride induced sequence of disclosure to 16. In the subsequent saponification 16 reacts with the intermediate compound 17 or hydrolysis of 3 to 4 (Scheme 4). Saponification and subsequent formation of epoxide 16 before condensation with 3 or 17 cannot be ruled out. The validity of this sequence was further strengthened subsequent HPLC-MS analysis of the crude chlorination reaction mixture prior to saponification. In it an admixture with a molecular weight of 574 Yes, which corresponds to 16, were found in approximately equal amounts compared to 4 after saponification.

Scheme 4: Proposed mechanism of formation of impurities 4

On the basis of this hypothetical mechanism, the time dependence for the formation of 4 in the chlorination process can not be excluded, and since the reaction time is kept constant in the DoE study, it was decided to estimate this parameter independently. The chlorination reaction was carried out using a 3.5% H2SO4and methyl acetate as the solvent at 15°C, and the sample was quenched after believed that the reaction was completed. Additional samples quenched after 2 � and 6 h, omilami and were analyzed by HPLC. Quite naturally, observed a continuous increase in the number of impurities 4 over time. This result affects the control of the chlorination process that adequate change versus time for HPLC monitoring of the reaction could be necessary in order to minimize the formation 4. However, subsequent experiments showed that the reduction in the number of H2SO4up to 1% reduces the amount of impurity 4, obtained over time with no significant effect on the reaction time of the chlorination or 3 (Fig.2). Thus, an acceptable time change for process control can be achieved when the concentration of 1% H2SO4used as a catalyst.

After establishing the critical parameters relating to the formation of this impurity, conducted a second DoE study to study the stability of the reaction of the intended operating range of the method. In it DoE study of the decomposition of IV designed the following factors subject to variation: temperature (13-21°C), the number of NCS (1,04-1,07 EQ.), the speed of adding NCS (30-75 min) and H2SO4(0.8 to 1.2 mol %). Spent just 10 of chlorination reactions in MultiMaxTM reactor. In each case, the samples were quenched and omalale after passing control to the process. Semi�enny as a result, the size in percentage 4 was processed and analyzed, using DoE software. As expected, the temperature, the number of NCS and H2SO4had a statistically significant effect on the quantity of impurity 4 in the studied parameter ranges. However, taking the worst option in the expected profile, the impurity 4 had a value of 0.11 square in % ±0,01%, which is within the acceptable range, which is established from Toxicological portions delafloxacin (Fig.3).

Two consecutive laboratory series for this reaction in kilogram quantities confirmed the effectiveness of changes in the parameters and substance of high purity with impurity concentration of 4 0,07% was obtained after saponification.

In conclusion, the inventors successfully identified dimeric impurity that was detected in the process of scaling obtaining delafloxacin. Subsequent DoE experiments allowed us to discover ways of reducing the creation of this contaminant to an acceptable concentration in the small scale as well as in laboratory series in kilogram scale.

Examples

EXAMPLE 1

1-(6-Amino-3,5-differencein-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidine-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 3, improved method.

To a suspension of 1 (3.1 kg, 6,15 mol) in methyl acetate (8.6 kg) was added a solution of H2SO4(5.9 g, 62 mmol) and NCS (088 kg, of 6.46 mol) in methyl acetate (14,4 kg) at 10-17°C for 45 min. the Solution was stirred at 13-19°C for 2 hours, quenched with 1.6% aqueous NaHCO3(12.6 kg) and the organic layer was washed with an 11% aqueous Na2SO3(7 kg). Methylacetate solution was replaced by 2-profanely solution at 50°C/vacuum, then added a solution of KOH (1.1 kg, to 19.7 mol) in water (24,8 kg) and the mixture stirred at 55°C for 3 hours. Was added at 40°C 13% aqueous acetic acid (2.6 kg) and the solution was seeded 3 (27 g, 61 mmol). The suspension was stirred for 1 hour at 40°C and then slowly added 13% aqueous acetic acid (11.7 kg). After stirring for an additional hour at 40°C the suspension was cooled to room temperature, filtered, washed with water (41 kg) and dried at 60°C/vacuum to obtain 3 as yellow crystals (2.5 kg, 91%). Selected 3 had the same spectroscopic properties as reported.

EXAMPLE 2

1-Amino-3-(azetidin-3-yloxy)propane-2-Albis(N,N'-hinolincarbonova acid), 4.

Benzyl ester of 3-hydroxyazetidine-1-carboxylic acid, 8.

To a solution of the hydrochloride azetidin-3-ol 7 (25 g, 0,23 mol) in water (150 ml) and THF (300 ml) was added K2CO3(63.1 g, 0.46 mole). The mixture was stirred for 30 min at 20-25°C. Then was added over 30 min benzylchloride (40,9 g, 0,24 mol) at 0-5°C, followed by stirring of the mixture at t�chenie nights at 20-25°C. THF was removed on a rotary evaporator at 30°C / vacuum and the mixture was extracted with ethyl acetate (2×150 ml). The combined organic layer was washed with water (1×50 ml), dried over Na2SO4and concentrated. The residue was purified column flash chromatography on silica gel, elwira ethyl acetate-heptane 1:1 and 4:1 in order to obtain 8 as a clear oil (47,3 g, 100%).

1H NMR (300 MHz, CDCl3): δ and 3.72 (1H, d, J=6,2 Hz), 3,85 (2H, DD, J=9,5, 4,4 Hz), 4,17 (2H, DD, J=9,5, 6,7 Hz), 4,49-up 4.57 (1H, m), of 5.06 (2H, s), 7,31-7,38 (5H, m);

13C NMR (75 MHz, CDCl3): δ 59,2, 61,6, 66,9, 127,9, 128,1, 128,5, 136,5, 156,6; IR: (film) 3406, 1686, 1438 cm-1; ES-HRMS m/z: (M+ +1) (h) calculated for C11H14NO3208,0968 found 208,0967.

Benzyl ether of 3-oxiranylmethyl-azetidin-1-carboxylic acid, 9.

To a solution of 8 (30 g, 0.15 mole) in DMSO (250 ml) was slowly added a solution of NaOH (9,9 g, 0.25 mol) in water (195 ml) at 15-25°C. was Added epichlorohydrin (93.8 g, 1.01 mole) and the mixture stirred at 20-25°C for 24 hours. The mixture was diluted with water (300 ml) and was extracted with ethyl acetate (2×150 ml). The combined organic layer was washed with water (2×50 ml), dried over Na2SO4and concentrated. The residue was purified column flash chromatography on silica gel, elwira ethyl acetate: heptane 3:2, yielding 9 as a clear oil (32.1 g, 84%).

1H NMR (300 MHz, CDCl3): δ 2,60 (1H, DD, J=4,8, 2,6 Hz), of 2.81 (1H, DD, J=4,9, 4,2 Hz), 3,09-3,16 (1H, m), of 3.25 (1H, DD, J11,4, 6,2 Hz), 3,68 (1H, DD, J=11,5, 2.5 Hz), 3,89-at 3.97 (2H, m), 4,15-4,24 (2H, m), 4,29-4,37 (1H, m), 5,09 (2H, s), 7,28-of 7.36 (5H, m);

13C NMR (75 MHz, CDCl3): δ 44,2, 50,4, 56,7, 56,9, 66,7, 68,6, 70,0, 128,0, 128,1, 128,5, 136,6, 156,5; IR: (film) 2951, 1709, 1420 cm-1; ES-HRMS m/z: (M+ +1) (h) calculated for C14H18NO4264,1230 found 264,1230.

Ethyl ester 1-(6-amino-3,5-differencein-2-yl)-7-[3-(1-benzyloxycarbonylamino-3-yloxy)-2-hydroxypropylamino]-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 11.

A mixture of 9 (19 g, of 72.2 mmol) in conc. NH4OH (380 ml) and 7M NH3in MeOH (86 ml) was stirred for 5 h at room temperature. The clear solution was concentrated and azeotrope dried with toluene. The residue in the form of a clear oil and 6 (20 g, which is 48.1 mmol) was dissolved in NMP (150 ml). Was added N,N-diisopropylethylamine (12,4 g, to 96.2 mmol) and the solution was stirred at 70°C for 3 hours. The solution was poured into a mixture of 1N citric acid/ice (300 ml) and was extracted with ethyl acetate (2×150 ml). The combined organic layer was washed with water (2×100 ml), dried over Na2SO4and concentrated. The residue was purified column flash chromatography on silica gel, elwira ethyl acetate-heptane 1:1, followed by elution ethyl acetate-MeOH 95:5, yielding 11 as a yellow foam (27,1 g, 83%).

1H NMR (300 MHz, CDCl3): δ of 1.35 (3H, t, J=7,1 Hz), 3,35-3,52 (4H, m), 3,62-of 3.77 (1H, m), 3,84-of 3.91 (2H, m), 3,95-4,08 (1H, m), is 4.15 (2H, DD, J=9,3, 6,5 Hz), to 4.23-4,30 (1H, m), 4,35 (2H, kV, J=7,1 Hz), 4,5-5,13 (3H, ush. C) 5,08 (2H, s), 7,18-of 7.25 (1H, m), 7,31-of 7.35 (5H, m), 7,99 (1H, DD, J=13,7, at 3.1 Hz), 8,31 (1H, s);

13C NMR (75 MHz, CDCl3): δ 14,4, 48,5 (d, JF=10 Hz), 56,6, 61,1, 66,9, 68,6, 69,3, 70,8, 107,2, 111,5, 112,6 (d, JF=24 Hz), of 113.2 (m), 120,6, 128,0, 128,1 , 128,5, 134,1 (d, JF=5 Hz), 134,7 (m), 136,5, of 139.2 (d, JF=13 Hz), to 144.9 (d, JF=253 Hz), 144,4 (d, JF=13 Hz)that 145,6 (DD, JF=262,4 Hz), 149,9 (d, JF=246 Hz), 150,0, 156,5, 164,7, 172,9; IR: (KBr) 2949, 1700, 1615 cm-1; ES-HRMS m/z: (M+ +1) (h) calculated. for C31H30ClF3N5O7676,1780 found 676,1762.

Ethyl ester 1-(6-amino-3,5-differencein-2-yl)-7-[3-(azetidin-3-yloxy)-2-hydroxypropylamino]-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 12.

To a suspension of 10% Pd on coal (2.1 g) in MeOH (20 ml) was added a solution of 11 (13,7 g, 20.3 mmol) in MeOH (230 ml). The mixture was gidrirovanie at 1 ATM. in for 1 hour, filtered through Hyflo and evaporated, yielding 12 in the form of beige crystals (10.3 g, 93%). TPL148-152°C;

1H NMR (300 MHz, DMSO-d6): δ of 1.27 (3H, t, J=7,1 Hz), 3,27 (1H, d, J=5.0 Hz), or 3.28-of 3.80 (10H, m), 4,19 (1H, ush. (C), is 4.21 (2H, kV, J=7,1 Hz), 5,86 (1H, s), 6,74 (2H, s), 7,84 (1H, d, J=13,8 Hz), 7,94 (1H, DD, J=9,7, 9,0 Hz), 8,43 (1H, s);

13C NMR (75 MHz, CDC13): δ 14,1, 48,4 (d, JF=10 Hz), 53,6, 60,2, 68,4, 70,4 (d, JF=4 Hz), 72,1 , 106,4 (d, JF=6 Hz), 111,0, to 111.3 (d, JF=23 Hz), to 113.6 (DD, JF=23,21 Hz) 118,9 (d, JF=6 Hz), 133,8 (d, JF=13 Hz), 134,2, 139,5 (d, JF=12 Hz), 143,3 (DD, JF=248,4 Hz) 145,0 (DD, JF=259,5 Hz), to 145.6 (d, JF=14 Hz), 149,3 (d, JF=245 Hz), at 149.5, 163,5, 171,0; IR: (KBr) 1697, 1614, 1496, 1457 cm-1; ES-HRMS m/z: (M+ +1) (h) calculated for C23H24ClF3N5O5542,1413 found 542,1391.

1-Amino-(azetidin-3-yloxy)propane-2-Albis(N,N'-quinoline diester), 13.

A solution of 12 (9.6 g, 17.7 mmol), 6 (7.8 g, 18,6 mmol) and N,N - diisopropylethylamine (4.6 g, of 35.4 mmol) in NMP (150 ml) was stirred at 55°C for 3 hours. The solution was poured into a mixture of 1N citric acid/ice (300 ml) and was extracted with ethyl acetate (3×100 ml). The combined organic layer was washed with water (2×100 ml), dried over Na2SO4and concentrated. The residue was purified column flash chromatography on silica gel, elwira ethyl acetate-MeOH 95:5. The obtained yellow foam was crystallized in CH2Cl2-MeOH 9:1 (160 ml), giving 13 in the form of beige crystals (11,8 g, 71%). TPL184-187°C;

1H NMR (300 MHz, DMSO-d6): δ 1.26 in (6H, t, J=7,1 Hz), 3,29-3,48 (3H, m), 3,49-3,62 (1H, m), 3,73-3,82 (1H, m), 4,12-4,30 (3H, m), is 4.21 (4H, q, J=7,1 Hz), 4,52-a 4.65 (2H, m), 5,13-with 5.22 (1H, m), of 5.83 is 5.92 (1H, m), 6,72 (4H, s), 7,73 (1H, d, J=a 13.9 Hz), 7,82 (1H, d, J=a 13.9 Hz), 7,92 (1H, t, J=9,6 Hz), of 7.93 (1H, t, J=8,7 Hz), to 8.41 (2H, s);

13C NMR (75 MHz, CDCl3): δ 12,3 (2x), 46,4 (d, JF=11 Hz), 58,4 (2x), 61,9 (2x), 66,7, 67,3 (d, JF=4 Hz), 69,1, 103,4 (d, JF=6 Hz) 104,6 (d, JF=6 Hz), to 108.7 (d, JF=23 Hz), 109,2, 109,4 (d, JF=23 Hz), 109,5, 111,7 (DD, JF=25, 24 Hz), 111,8 (DD, JF=25,24 Hz) 117,1 (d, JF=7 Hz), 1 to 17.8 (d, JF=6 Hz), 132,1 (DD, JF=17,4 Hz), 132,2, 132,5, 133,5, 137,7 (d, JF=12 Hz), 139,4 (d, JF=12 Hz), 141,0 (DD, JF=of 247.5 Hz) 141,5 (DD, JF=248,5 Hz) 143,0 (DD, JF=259,5 Hz), 143,3 (DD, JF=259,5 Hz), 143,8 (2x, d, JF=15 Hz), is 147.5 (d, JF=245 Hz), of 147.7, 147,8, 148,1 (d, JF=247 Hz), over 161.7 (2x), 169,1, 169,2; IR: (KBr) 1728, 1615, 1491, 1448 cm-1; ES-HRMS m/z: (M+ +1) (h) calculated for C40H33Cl2F6N8O8937,1697 found 937,1696.

1-Amino-3-(azetidin�-3-yloxy)propane-2-Albis(N,N'-hinolincarbonova acid), 4.

To a suspension of 13 (17,0 g of 18.1 mmol) in 2-propanol (75 ml) was added 1N KOH solution (127 ml, 126,7 mmol). After stirring the mixture at 55°C for 3.5 hours the solution was cooled to 30°C and was added over 1 hour a solution of AcOH (12,4 g, 206,5 mmol) dissolved in water (94 ml). The suspension was stirred at room temperature for 2 hours, filtered, washed with water (3×40 ml) and dried at 50°C/vacuum to give 4 as yellow crystals (15,7 g, 98%). TPL198-205°C (Razlog.);

1H NMR (300 MHz, DMSO-d6): δ or 3.28 is-3.45 (2H, m), 3.45 points-of 3.78 (2H, m), 3,79-3,88 (1H, m), 4,16-4,33 (3H, m), 4,61-of 4.75 (2H, m), a 5.25 (1H, ush. C) a 6.23-6.35 mm (1H, m), 6,76 (4H, s), 7,79 (1H, d, J=13,7 Hz), 7,90 (1H, d, J=13,8 Hz), of 7.93 (2H, DD, J=9,7, 2.4 Hz), to 8.70 (1H, s), of 8.71 (1H, s), 14,59 (2H, ush. C);

13C NMR (75 MHz, CDCl3): δ 48,1 (d, JF=11 Hz), 63,8, 68,4, 69,0 (d, JF=5 Hz), and 70.6 (d, JF=6 Hz), of 104.5 (d, JF=6 Hz), 105,9 (d, JF=7 Hz), to 107.8, 108,2, 109,8 (d, JF=23 Hz) 110,8 (d, JF=23 Hz), 113,4 (d, JF=23 Hz), to 113.7 (d, JF=23 Hz)that 115,8 (d, JF=8 Hz), 116,6 (d, JF=8 Hz), and 133.3 (DD, JF=14,3 Hz) 133,5 (DD, JF=14,4 Hz), 134,8, 135,9, 141,0 (d, JF=12 Hz), to 142.1 (d, JF=12 Hz), of 142.8 (DD, JF=249,5 Hz) 143,3 (DD, JF=249,5 Hz), 145,1 (DD, JF=259,5 Hz), 145,4 (DD, JF=of 260.5 Hz), to 145.6 (2x, d, JF=15 Hz), at 149.5 (d, JF=248 Hz), 150,1 (2x), 150,2 (d, JF=249 Hz), of 164.7, 164,8, 175,8 (d, JF=3 Hz), 175,9 (d, JF=3 Hz); IR: (KBr) 1727, 1622, 1489, 1439 cm-1; ES-HRMS m/z: (M+ +1) (h) calculated for C36H25Cl2F6N8O8881,1071 found 881,1090.

Additional experimental materials

Experimental tables and analyses DoE further research presented at Phi�.4, Fig.5a, 5b, 5c, 5d, 5e and 5f, Fig.6a and 6b, Fig.7 and Fig.8a, 8b, 8c, 8d, 8e, 8f and 8g.

The formulation and introduction

Compounds of the present invention can be used in practice, delivering them using a suitable carrier. The dose of the active compound, the route of administration and the use of a suitable carrier will depend on the intended patient or subject and target microorganism, such as a bacterial target organism. Compositions of the compounds according to the present invention for medical use in humans and for veterinary use, generally contain these compounds in combination with a pharmaceutically acceptable carrier.

The carrier must be "acceptable" in the sense of being compatible with the compounds of the present invention and should not be harmful to the recipient. It is assumed that the pharmaceutically acceptable carriers, in this sense, includes any and all solvents, dispersion medium, coating agents delaying absorption, and the like, compatible with pharmaceutical administration. The use of these environments and tools for pharmaceutically active substances is known in the art. Except when any conventional medium or agent is incompatible with the active compound, its use in the compositions assumed. Additional�ing the active compound (s) installed or designed according to the present invention and/or known in the art) can also be entered in the composition. The compositions can conveniently find in a standard dosage form and may be obtained by any of the methods well known in the field of pharmacy/Microbiology. In General, some of the composition is prepared by mixing the compound with a liquid carrier or finely divided solid carrier or both and then, if necessary, shaping the product into the desired composition.

The pharmaceutical composition of the present invention should be formulated so that it was compatible with the proposed way of introduction. The solutions or suspensions may contain the following components: a sterile diluent, such as water, brine, fatty oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for adjusting toychest, such as sodium chloride or dextrose. the pH can be adjusted with acids or bases, such as chlorodane acid or sodium hydroxide.

A wide range of compositions and methods of administration, including, for example, intravenous compositions and methods of administration can be found in S. K. Niazi ed., Handbook of Pharmaceutical Composition, Vols. 1-6 [Vol. 1 Compressed Solid Products, Vol. 2 Uncompressed Drug Products, Vol. 3 Liquid Products, Vol. 4 Semi-Solid Products, Vol. 5 Over the Counter Products, and Vol. 6 Sterile Products], CRC Press, April 27, 2004.

Useful solutions for oral or parenteral administration can be obtained by any method known in the pharmaceutical field, for example described in Remington's Pharmaceutical Sciences, 10th ed. (Mack Publishing Company, 1990). Compositions for parenteral administration may also include glycocholate for buccal administration, maoxicillin for rectal administration, or citric acid for vaginal administration. Parenteral preparation can be enclosed in capsules, disposable syringes or vials for multiple applications received from glass or plastic. Suppositories for rectal administration can also be obtained by mixing the drug with a non-irritating auxiliary substance, such as cocoa butter, other glycerides, or other compositions that are solid at room temperature and liquid at body temperatures. The compositions may also contain, for example, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes. Compositions for direct introduction may include glycerol and other compositions of high viscosity. Other potentially useful parenteral n�sitely for these drugs include copolymer particles ethylenevinyl-acetate, osmotic pumps, implantable system for infusion and liposomes. Compositions for administration by inhalation may contain as excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to apply vnutripuzarno. Retention enemas can also be used for rectal delivery.

The compositions of the present invention suitable for oral administration may be in the form of: discrete units such as capsules, gelatin capsules, sachets, tablets, pastilles or lozenges, each contains a predetermined amount of drug; powder or granular compositions; solutions or suspensions in an aqueous liquid or nonaqueous liquid; or emulsion oil in water, emulsion water in oil. The drug can also be administered in the form of a bolus, electuary or paste. The tablet can be obtained by compression or molding of the drug optionally with one or more auxiliary ingredients. Compressed tablets can be obtained by compression in a suitable machine the drug freely in a fluid form, such as powder or granules, �obazatelno mixed with a binder, lubricating agent, inert diluent, surface active or dispersing agent. Compressed tablets can be obtained by molding in a suitable machine a mixture of powdered drug and suitable carrier moistened with an inert liquid diluent.

Oral compositions generally contain an inert diluent or edible carrier. For the purposes of oral therapeutic administration, the active compound can be entered with excipients. Oral compositions obtained by applying a liquid carrier, for use as a liquid mouthwash, contain the compound in the liquid carrier, and use oral and them rinse your mouth and spit out or swallow. Pharmaceutically compatible binding agents and/or auxiliary materials can be included as part of the composition. Pills, pills, capsules, lozenges and the like can contain any of the following ingredients, or compounds with similar properties: binder, such as microcrystalline cellulose, tragacanth gum or gelatin; an auxiliary substance, such as starch or lactose; a disintegrant such as alginic acid, primogel or corn starch; a lubricant such as magnesium stearate or stearate; a regulator of the flow properties, such as colloi�hydrated silicon dioxide; sweetener, such as sucrose or saccharin; or a flavoring, such as peppermint oil, methyl salicylate, or orange flavoring.

Farmatsevticheskii composition, suitable for application by injection, contain sterile aqueous solutions (where water soluble) or dispersions and sterile powders prepared for immediate administration of the drug of sterile solutions or dispersions for injection. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate-buffered saline (PBS). They must be stable in the conditions of production and storage and must be protected from contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol) and appropriate mixtures. Appropriate fluidity can be maintained, for example, the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by using surfactants. In many cases it will be preferable to include isotonic agents, for example, sugars, property such as manitol, sorbitol, sodium chloride in the composition. About�liteline absorption of injectable compositions can be cause inclusion in the composition of the agent, which slows down the absorption, for example, aluminum monostearate and gelatin.

Sterile solutions for injection can be obtained by the introduction of active compounds in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, if required, followed by sterilization by filtration. Generally, dispersions are obtained by introducing the active compound into a sterile environment, which contains the basic dispersion medium and the required other ingredients from the ingredients listed above. In the case of sterile powders for obtaining sterile solutions for injection methods of obtaining include vacuum drying and freeze-drying, which give a powder of the active ingredient plus additional desired ingredient from a previously sterilized by filtration of the solution.

Compositions suitable for intra-articular administration may be in the form of a sterile aqueous preparation of the drug, which may be in microcrystalline form, for example in the form of an aqueous microcrystalline suspension. Liposomal compositions or biodegradable powder systems can also be used to provide drugs for intra-articular and ophthalmic administration.

Compositions suitable for topical administration, including eye treatment, include W�dcie or semi-liquid preparations such as liniments, lotions, gels, lotions, emulsions of oil in water or water in oil, such as creams, ointments or pastes; or solutions or suspensions such as drops. Compositions for topical administration to the skin surface can be obtained by dispersing the drug with a dermatologically acceptable carrier such as a lotion, cream, ointment or soap. Suitable carriers are capable of forming a film or layer on the skin to localize application and deceleration of removal. For topical administration to internal tissue surface, the agent can be dispersed in a liquid tissue adhesive or other substance, which is known as it enhances adsorption on the fabric surface. For example, solutions of hydroxypropyl cellulose or FibroGen/thrombin can be applied to obtain benefits. Alternatively, you can apply the solutions for coating fabrics, such as pectin-containing composition.

For inhalation treatments can be applied inhalation powder (kumarapalayam or spray composition), dispensed using an aerosol can, spray gun or aerosol inhaler. These compositions can be in the form of a fine powder for pulmonary administration from devices for powder inhalation or kumarapalayam spray powder composition. In the case of samoraspadayutsya races�thief and aerosol composition effect can be achieved or the selection valve, having the required characteristics of the aerosol (i.e., compatible with the receipt of a spray having the desired particle size) or by the introduction of the active ingredient in the form of a suspended powder with controlled particle size. For administration by inhalation the compounds can also be delivered in the form of an aerosol spray from a tank under pressure or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or an aerosol can.

Systemic administration can also be carried out transmucosal or transdermal means. For transmucosal or transdermal administration of the composition applied penetrants suitable for penetration through the barrier. In General, these penetrants are known in the art and include, for example, for transmucosal the introduction of detergents and salts of bile acids. Transmucosally introduction can be carried out through the use of nasal sprays or suppositories. For transdermal administration, the active compound is usually formulated into ointments, salves, gels, or creams as generally known in the art.

The active compounds can be obtained with carriers that will protect the compound against rapid elimination from the body, such as the composition of controlled release, including implants and micro - �encapsulated system for delivery. You can apply a biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydride, polyglycol acid, collagen, polyarteritis and polylactic acid. Methods of obtaining these compositions will be obvious to experts in this field of technology. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. They can be obtained according to methods known to those skilled in the art, for example as described in U.S. patent No. 4522811.

Oral or parenteral compositions can be formulated in a standard dosage form for ease of administration and uniformity of dosage. Standard dosage form refers to physically discrete units suitable as unit dosage for the subject, which shall be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in combination with the required pharmaceutical carrier. Specification standard dosage forms of the present invention is determined by and directly dependent on the unique characteristics of the active compounds and therapeutic effect to be achieved, and the limitations inherent in the art of obtaining this AK�active compounds for the treatment of individuals. In addition, administration may be by periodic injections of a bolus, or it can be implemented more continuously intravenous, intramuscular or intraperitoneal introduction of an external container (e.g., container for intravenous administration).

When required adhesion on the surface of the fabric, the composition may contain a drug dispersed in FibroGen-thrombin composition or other bioadhesive. Then the connection can be applied, spraying or, in other words, apply to the desired surface of the fabric. Alternatively, the medicament may be formulated for parenteral or oral administration to humans or other mammals, for example, in effective amounts, e.g., amounts which provide appropriate concentrations of the drug in the target tissue for a time sufficient to cause the desired effect.

When the active compound to be applied as part of the transplant process, it can be delivered to living tissue or organ that will be transplanted, before removal of the tissue or organ from the donor. The connection can be granted to the owner which is a donor. Alternative or in addition, after removal from the donor, the organ or living tissue can be placed in the solution for containing Akti�Noah connection. In all cases, the active compound can be introduced directly to the desired tissue, as by injection into the tissue, or it may be provided systemically, or oral, or parenteral administration, using any of the methods and compositions described in this invention and/or known in the art. When a drug contains a part of the solution for the storage of the tissue or organ, for more benefits, you can use any commercially available solution for storage. For example, suitable solvents, known in the art include solution, Collins solution of Wisconsin-Madison, solution of Belzer, "Eurocollins" solution and lactated ringer's solution.

In conjunction with the methods of the present invention can take into account the pharmacogenomics (i.e., the study of the genotype of an individual and the response of an individual to a foreign compound or drug). Differences in drug metabolism can lead to severe toxicity or therapeutic failure by changing the ratio between dose and blood concentration of the pharmacologically active drug. Thus, the doctor or therapist may consider applying knowledge obtained in relevant pharmacogenomics studies, to determine whether to enter Leka�governmental means, and whether to vary the dosage and/or therapeutic regimen of treatment with the medicine.

Typically, an effective amount of dosage of active compound will be in the range from approximately 0.1 to approximately 100 mg/kg body weight/day, more preferably from about 1.0 to about 50 mg/kg body weight/day. The quantity entered will be also likely to depend on variables such as type of surgery or invasive medical procedure, the General health of the patient, the relative biological efficacy of the delivered compounds, the composition of the drug, the presence and types of excipients in the composition, and method of administration. In addition, it should be clear that the initial injected dose can be increased beyond the upper level in order to quickly achieve the desired concentration in the blood or tissue, or the initial dosage may be smaller than optimal.

Non-limiting dose of the active compounds include from about 0.1 to about 1500 mg per dose. Non-limiting examples of doses that can be formulated in the form of single doses for common introduction to the patient include: about 25 mg, about 50 mg, about 75 mg, about 100 mg, approximately 125 mg, approximately 150 mg, approximately mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325, about 350 mg, about 375 mg, approximately 400 mg, approximately 425 mg, approximately 450 mg, approximately 475 mg to approximately 500 mg, approximately 525 mg, approximately 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, approximately 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1125 mg, about 1150 mg, about 1,175 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg and about 1500 mg. of the Above dose are suitable for administration of the compounds of the present invention according to the methods of the present invention.

As is clear to experts in this region�STI technology, usually, when they describe the dosage for the pharmaceutically active compound, the dosage given relative to the source or active molecules. Therefore, if you apply salt, hydrate or another form of source molecules, carry out the appropriate recalculation of the weight of the connection, although the dose is still delivered relatively original or active molecules. As a non-limiting example, if you are interested in initial or active molecule is a monocarboxylic acid having a molecular weight of 250, and if you want to deliver the monosodium salt of the acid at the same dosage, then recalculates, considering that monosodium salt will have a molecular weight of approximately 272 (i.e. minus 1H or 1,008 atomic mass units and plus 1 Na or 22,99 atomic mass units). Therefore, 250 mg source or dose of active compound will be approximately 272 mg of the monosodium salt, which will also deliver 250 mg of a source or active compounds. In other words, about 272 mg of the monosodium salt would be equivalent to 250 mg dose source or active connection.

All percentages and rates used in the present invention, unless otherwise specified, are by weight. The percentage of dimeric impurity is given in per cent of the area, usually as to�icestone analytical HPLC.

Throughout the description, when describing the songs as having, containing, or comprising specific components, it is assumed that the compositions also consist essentially or consist of the components. Similarly, when describing the methods or processes as having, including, or containing specific process steps, the processes also consist essentially or consist of the above-mentioned stages of the process. In addition, it should be clear that the order of the stages or the order of carrying out of certain actions is not essential because the present invention remains operable. Moreover, two or more stages or actions can be carried out simultaneously.

Examples of compositions

Composition for intravenous injection

IngredientNumber
Antimicrobial compound0,1-1500 total amount in mg
Dextrose50 mg/ml
Citrate sodium1,60-1,75 mg/ml
Citric acid0,80-0,90 mg/ml
Water q.s

The composition for intravenous injection formulated by heating water for injection to about 60°C. was Then added sodium citrate, citric acid and dextrose and stirred until dissolved. Added to this mixture, a solution or aqueous suspension of antimicrobial compounds and stirred until dissolved. The mixture was cooled to 25°C with stirring. Measured pH and regulated if necessary. The mixture was brought up to the required volume, if necessary, water for injections. The mixture was filtered, filled into the desired container (vial, syringe, container for infusion, etc.), wraps and thermally sterilized steam.

This composition is suitable for intravenous injection or bolus, or infusion, to a patient.

Tablets for oral administration

IngredientsPer tablet4000 tablets
Antimicrobial compound0.1 to 1500 mg0.4 to 6000 mg
Anhydrous lactose110,45 mg441,8 mg
Microcrystalline TSE�lulose 80,0 mgof 320.0 mg
Magnesium stearate, fine powder1,00 mg4,0 mg
Crosscarmelose sodium2,00 mg8.0 mg

Antimicrobial compound (any of compounds equivalent to desired input quantity, for example, 50-1500 mg per tablet) was mixed with 1/3 microcrystalline cellulose NF, and 1/2 of the anhydrous lactose NF in a ribbon mixer for 5 minutes at 20 rpm. To the mixture was added the remaining 2/3 microcrystalline cellulose NF, and the remaining 1/2 of the anhydrous lactose NF. The mixture was stirred for 10 minutes at 20 rpm was Added to the mixed powder crosscarmelose sodium and stirred for 5 minutes at 20 rpm was Added to a mixture of magnesium stearate by passing through a 90 mesh sieve and mixed for an additional 5 minutes at 20 rpm. the Lubricated mixture was crushed to obtain tablets with 500 mg of the active ingredient.

These tablets are suitable for oral administration to a patient.

Introduction with links

A full description of each of patent documents, including a certificate of correction of errors in the description, patent applications, scientific papers, father�s, provided by state agencies, websites and other materials that are referenced in the present invention, is introduced by reference completely in all respects. In the event of a conflict in terminology should be guided by the present description.

Equivalents

The present invention can be implemented in other specific forms without going beyond or essential characteristics. Therefore, the above implementation options should be considered in all aspects as illustrative, and not limiting the present invention described in the present description. Thus, the scope of the present invention defined by the attached claims and not the foregoing description, and it is assumed that all changes that fall within the meaning and range of equivalence of the claims are covered by it.

1. A method of obtaining a quinoline compounds, including the stage of interaction dechlorinating compound, or its pharmaceutically acceptable salt, or ester with a chlorinating agent and an acid in which the mole ratio of acid to dikhlorpikolinovoi connection is to 0,008 0,012 and which receive less than 0,40% dimeric impurities in % area in the calculation obtained quinoline compound, and where the quinoline compound performance�et a 1-(6-amino-3,5-differencein-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidine-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, or its pharmaceutically acceptable salt, or ester, dechlorinating the compound is a 1-(6-amino-3,5-differencein-2-yl)-6-fluoro-7-(3-hydroxyazetidine-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, or its pharmaceutically acceptable salt, or ester, and dimeric impurity is a 1-amino-3-(azetidin-3-iloxi)propan-2-ol bis(Ν,Ν'-hinolincarbonova acid)or its pharmaceutically acceptable salt, or ester.

2. A method according to claim 1, wherein the chlorinating agent is an N-chlorosuccinimide.

3. A method according to claim 1, wherein the acid is selected from the group consisting of sulfuric acid, hydrochloric acid, Hydrobromic acid, phosphoric acid, trifluoroacetic acid, followed, methansulfonate, p-base or perchloro acid and mixtures thereof.

4. A method according to claim 1, wherein the acid is a sulfuric acid.

5. A method according to claim 1, wherein the reaction is conducted at a temperature from 0°C to 30°C.

6. A method according to claim 1, wherein the molar ratio of chlorinating agent to dechlorination is more than 1.

7. A method according to claim 1, wherein the acetate ester is used as solvent.

8. A method according to claim 7, in which the acetate ester is selected from the group consisting of methyl acetate, ethyl acetate and mixtures thereof.

9. A method according to claim 8, in which the acetate ester isone methyl acetate.

10. A method according to claim 1, comprising the additional step of interaction of quinoline compounds with a base.

11. A method according to claim 10, in which the base is a hydroxide.

12. A method according to claim 11, wherein the hydroxide is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide and mixtures thereof.

13. A method according to claim 12, wherein the hydroxide is a hydroxide of potassium.

14. A method according to claim 10, whereby a mixture of isopropanol and water as the solvent.

15. A method according to claim 1, designed for industrial applications.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to pyrazine derivatives of formula I, as well as to their enanthiomers, diastereomers and pharmaceutically acceptable salts, wherein R1 is specified in a group consisting of ii) pyridinyl optionally having one substitute specified in a group consisting of C1-4alkoxy and cyano; and iii) pyrimidin-5-yl; or R1 optionally represents methoxymethyl, when Y represents ethinyl; Y represents ethinyl or a bond; R2 represents phenyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxol-5-yl, indolyl or pyridinyl substituted by methyl, phenyl has one to two substitutes independently specified in a group consisting of C1-4alkyl, C1-4alkoxy, fluorine, chlorine, cyano, cyanomethyl, difluoromethyl, trifluoromethyl and hydroxy; or R2 represents phenyl having one C1-4alkylcarbonylamino or 1H-imidazol-1-yl substitute; X represents O or CH2; L is absent, and R3 represents 4-aminocyclohexyl, or L represents methylene, while R3 is specified in a group consisting of i) pyrrolidin-2-yl; ii) 1-aminoeth-1-yl; and iii) 1-aminocyclopent-1-yl; or R3 is combined into one cycle with L nitrogen atom to which L is attached to form piperazinyl. Besides, the invention refers to specific compounds, a pharmaceutical compound based on a compound of formula I, a method of treating pain and some neurodegenerative diseases.

EFFECT: there are produced new pyrazine derivative effective in treating pain and some neurodegenerative diseases.

21 cl, 3 tbl, 13 ex

FIELD: medicine.

SUBSTANCE: present invention refers to compounds having formula III such as below, wherein: Q represents C(Y3) or N; R represents H, -R1, -R1-R2-R3, -R1-R3 or -R2-R3; R1 represents heteroaryl or heterocyclyl each of which is optionally substituted by one or more C1-6alkyls, hydroxyC1-6alkyls, oxogroups or halogenC1-6alkyls; R2 represents -C(=O), -O, -C(R2')2, -C(R2')2C(=O), -C(R2')2C(=O)NR2', C(R2')2 N(R2')C(=O), -C(=NH), -C(R2')2NR2' or -S(=O)2; each R2' independently represents H or C1-6alkyl; R3 represents H or R4; R4 represents C1-6alkyl, C1-6alkoxygroup, aminogroup, C1-6alkylaminogroup, di(C1-6alkyl)aminogroup, heterocyclyl, C1-10alkylheterocycloalkyl, heterocycloalkylC1-10alkyl each of which is optionally substituted by one or more C1-6alkyls, C1-6alkylaminogroups, di(C1-6alkyl)aminogroups, hydroxygroups, hydroxyC1-6alkyls, C1-6alkoxygroups, oxogroups or halogenC1-6alkyls; X represents CH; X' represents CH; and the rest symbols have values as specified in the patent claim. The compounds of formula III inhibit Bruton's tyrosine kinase (Btk). There are also described compositions containing the compounds of formula III, and at least one carrier, thinner or excipient, and a method for producing the compound of formula X in accordance with the following procedure.

EFFECT: compositions are effective for modulating Btk activity and treating diseases related to Btk hyperactivity, and can be used for treating inflammatory and autoimmune diseases related to disturbed B-cell proliferation, such as rheumatoid arthritis.

22 cl, 2 tbl, 260 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to bis-benzimidazole derivatives of formula I and their optional stereoisomers, pharmaceutically acceptable salts and solvates, wherein R and R' are independently specified in -CR1R2R3, phenyl substituted by 1 substitute specified in halogen; and tetrahydrofuranyl, wherein R1 is specified in C1-4alkyl optionally substituted by methoxy, hydroxyl or dimethylamino; C3-6cycloalkyl; phenyl optionally substituted by 1, 2 or 3 substitutes optionally specified in halogen, C1-4alkoxy, trifluoromethoxy, or 2 substitutes on adjoining atoms of the ring form 1,3-dioxolane group; benzyl substituted by halogen or methoxy; pyridinyl; indolyl; pyridinylmethyl or indolylmethyl; R2 is specified in hydrogen, hydroxyl, di-C1-4alkylamino, (C3-6cycloalkyl) (C1-4alkyl)amino, C1-4alkylcarbonylamino, phenylamino, C1-4alkyloxycarbonylamino, (C1-4alkyloxycarbonyl)(C1-4alkyl)amino, C1-4alkylaminocarbonylamino, tetrahydro-2-oxo-1(2H)-pyrimidinyl, pyrrolidin-1-yl, piperidin-1-yl, 3,3-difluoropiperidin-1-yl, morpholin-1-yl, 7-azabicyclo[2.2.1]hept-7-yl and imidazol-1-yl; and R3 represents hydrogen or C1-4alkyl or CR2R3 together form carbonyl; or CR1R3 form cyclopropyl group. The invention also refers to a pharmaceutical composition based on a compound of formula I.

EFFECT: there are prepared bis-benzimidazole derivatives possessing the inhibitory activity on hepatitis C virus.

9 cl, 4 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compound of formula or to its pharmaceutically acceptable salt, where Alk represents linear C1-6 alkylene group, branched C1-6 alkylene group or C1-6 alkylene group, which has ring structure, where part of carbon atoms, constituting ring structure can be optionally substituted with oxygen atom, in ring X, X1 represents N or CRX1, X2 represents N or CRX2, X3 represents CRX3, X4 represents N or CRX4, where RX1, RX2, RX3 and RX4 each independently represents hydrogen atom; linear or branched C1-6alkyl group; linear or branched C1-6alcoxygroup; or halogen atom, in ring Y, Y1 represents CRY1, Y2 represents N or CRY2, Y3 represents N or CRY3, Y4 represents N or CRY4, RY1, RY2, RY3 and RY4 each independently represents hydrogen atom; linear or branched C1-6alkyl group, which can be substituted with halogen atom(s); C3-7alkyl group, which has ring structure; linear or branched C1-6alkoxygroup; halogen atom or cyanogroup, in ring Z, RZ represents linear or branched C1-6alkyl group, which can be substituted with halogen atom(s), or C3-7alkyl group, which has ring structure, which can be substituted with halogen atom(s). Invention also relates to particular compounds, DGAT1 inhibitor based on formula (I) compound, application of formula (I) compound, method of prevention or treatment of diseases, mediated by DGAT1 inhibition.

EFFECT: obtained are novel compounds, possessing useful biological activity.

19 cl, 19 tbl, 149 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compounds of general formula I

or to pharmaceutically acceptable salts or solvates or stereoisomers thereof, where R and R* are each independently -CR1R2R3, C1-4alkylamino, benzylamino, C6-10arylamino, heteroC4-7cycloalkyl containing 1 heteroatom selected from O; where R1 is selected from C1-4alkyl; phenyl, optionally substituted with 1, 2 or 3 substitutes independently selected from halogen, C1-4alkyl, C1-4alkoxy, trifluoromethoxy or 2 substitutes at neighbouring ring atoms, which form a 1,3-dixolane group; benzyl, optionally substituted with a halogen or methoxy; phenylsulphonylmethyl; C3-5heteroaryl containing 1 to 2 heteroatoms independently selected from N and O; C3-5heteroarylmethyl containing 1 to 2 heteroatoms selected from N and C3-6cycloalkyl; R2 is selected from hydrogen, hydroxyl, di-C1-4alkylamino, C1-4alkylcarbonylamino, C1-4alkyloxycarbonylamino, C1-4alkylaminocarbonylamino, piperidin-1-yl or imidazol-1-yl; R3 is hydrogen or, alternatively, R2 and R3 together form an oxo group; or R1 and R3 together form cyclopropyl; under the condition that if one of R and R* is -CH(C6H5)N(CH3)2, the other cannot be -CH(C6H5)NHC(=O)OCH3; and if R and R* are identical, R1 is not phenyl, when R2 is hydroxyl, acetylamino, methoxycarbonylamino or tert-butoxycarbonylamino, and R3 is hydrogen; and R1 is not C1-4alkyl, when R2 is C1-4alkyloxycarbonylamino, and R3 is hydrogen. The invention also relates to a pharmaceutical composition based a compound of formula I and use thereof.

EFFECT: obtaining novel compounds which are useful in preventing or treating HCV infection.

9 cl, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

,

wherein pyridine rings A, B and C are independently unsubstituted or substituted by one or more substitutes independently specified in a group consisting of: C1-6-alkyl, halogen alkyl having 1-6 carbon atoms, Hal or OR13; L1 and L2 are independently specified in residues having formula or , wherein at least one of L1 or L2 has formula (b); R1 and R2 are independently specified in a group consisting of hydrogen, C1-6-alkyl and phenyl; R3 is specified in hydrogen and C1-6-alkyl; R4, R5, R6 and R7 are independently specified in a group consisting of hydrogen and C1-6-alkyl; R8, R9, R10 and R11 are independently specified in a group consisting of hydrogen and C1-6-alkyl; R12 is specified in a group consisting of hydrogen and C1-6-alkyl; R13 is independently specified in a group consisting of hydrogen, C1-6-alkyl and phenyl; p is equal to 1 or 2; q is equal to 0, 1 or 2, and Hal is specified in a group consisting of F, Cl, Br, and I, which can be used in treating a group of amyloid protein related disturbances and disorders.

EFFECT: preparing the compounds which can be used in treating a group of amyloid protein related disturbances and disorders.

17 cl, 1 dwg, 6 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

,

where R2 is a heteroaryl group and where said monocyclic heteroaryl group is unsubstituted or substituted with one or more groups selected from F, Cl, Br, I, -NR10R11 and C1-C12 alkyl; and groups selected from F, -NH2, -NHCH3, -N(CH3)2, -OH, -OCH3, -C(O)CH3, -NHC(O)CH3, -N(C(O)CH3)2, -NHC(O)NH2, -CO2H, -CHO, -CH2OH, -C(=O)NHCH3, -C(=O)NH2, and -CH3; R3x, R3y, R3z and R3p is hydrogen; R4x, R4y, R4z and R4p are independently selected from a group consisting of: hydrogen, F, Cl, Br, I, and -C(C1-C6 alkyl)2NR10R11; and R10 and R11 are hydrogen, which are phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitors.

EFFECT: high effectiveness of compounds.

7 cl, 7 tbl, 50 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

possessing inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases. In formula (I-b), ring A and ring B represents phenyl; Ry represents -CN, -CF3, C1-4 aliphatic group, C1-4 halogenaliphatic group, -OR, -C(O)R or -C(O)N(R)2; each group R independently represents hydrogen or a group specified in C1-6 aliphatic group optionally containing a substitute presented by halogen, -(CH2)0-4R°, -(CH2)0-4OR°, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -(CH2)0-4S(O)2R°, or 5-6-merous substituted or aryl ring containing 1-2 heteroatoms independently specified in nitrogen or oxygen optionally substituted by group =O, -(CH2)0-4R°, -(CH2)0-4N(R°)2 or -(CH2)0-4OR°; phenyl; 5-6-merous heterocyclic ring containing 1-2 heteroatoms independently specified in nitrogen, oxygen or sulphur optionally substituted by group -(CH2)0-4R°, -(CH2)0-4OR° or =O; or 6-merous monocyclic heteroaryl ring containing 1 nitrogen atom; W1 and W2 represent -NR2-; R2 represents hydrogen, C1-6aliphatic group or -C(O)R; m and p are independently equal to 0, 1, 2, 3 or 4; Rx is independently specified in -R, -OR, -O(CH2)qOR or halogen, wherein q=2; Rv is independently specified in -R or halogen; R1 and R° radical values are presented in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds.

EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compound of formula (I) or its racemate, enantiomer, diastereoisomer and their mixture, as well as to their pharmaceutically acceptable salt, where A is selected from the group, consisting of carbon atom or nitrogen atom; when A represents carbon atom, R1 represents C1-C6-alkoxyl; R2 represents cyano; when A represents nitrogen atom, R1 hydrogen atom or C1-C6-alkoxyl; where said C1-C6-alkoxyl is optionally additionally substituted with one C1-C6-alkoxyl group; R2 is absent; R3 represents radical, which has the formula given below: or , where D represents phenyl, where phenyl is optionally additionally substituted with one or two halogen atoms; T represents -O(CH2)r-; L represents pyridyl; R4 and R5 each represents hydrogen atom; R6 and R7 each is independently selected from hydrogen atom or hydroxyl; R8 represents hydrogen atom; R9 represents hydrogen atom or C1-C6-alkyl; r equals 1 and n equals 2 or 3. Invention also relates to intermediate compound of formula (IA), method of obtaining compound of formulae (I) and (IA), pharmaceutical composition based on formula (I) compound and method of its obtaining and to application of formula (I) compound.

EFFECT: novel heterocyclic compounds, inhibiting activity with respect to receptor tyrosine kinases EGFR or receptor tyrosine kinases HER-2 are obtained.

18 cl, 12 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: group of inventions relates to an imine derivative, represented by formula , where "Ar" stands for pyridine, containing a chlorine atom on a ring or thiazole, which can contain the chlorine atom on a ring; "X" stands for a sulphur atom or CH2; when "Y" represents COR1, "R1" stands for a hydrogen atom or a C1-C5alkyl group, halogenated methyl group, except trifluoromethyl group, halogenated C2-C5alkyl group, C2-C5alkenyl group, halogenated C2-C5alkenyl group, C3-C5alkinyl group, non-substituted or substituted with an atom of chlorine, fluorine, methyl group or acetamide phenyl group, non-substituted (C6) aryl(C1-C3)alkyl group, (C1-C4)alkoxy (C1-C5)alkyl group, C1-C3alkoxycarbonyl group, (C1-C3) alkylsulphonyl (C1-C3)alkyl group, (C1-C3)alkylthio (C1-C3)alkyl group, non-substituted or substituted with a methyl group or a fluorine atom C3-C7cycloalkyl group, cyano(C1-C3) alkyl group, non-substituted phenoxy(C1-C3) alkyl group, non-substituted pyridylmethyl group, non-substituted imidazolylmethyl group, furanyl group, morpholine group, adamantly group, isothiocyanate group or a heterocyclic ring selected from quinoline, indole, pyridine, pyrazine, pyridazine or tetrahydrofurane, substituted with one, two or five substituents, selected from chlorine, bromine, trifluoromethane or fluorine, and a non-substituted heterocyclic ring, selected from quinoline, indole, pyridine, pyrazine, pyridazine or tetrahydrofurane, when "Y" represents CONR3R4 "R3" and "R4" stands for a hydrogen atom or C1-C5alkyl group, C1-C3alkoxygroup, non-substituted phenyl group, (C1-C3)alkoxy(C1-C3)alkyl group, C1-C3alkoxycarbonylmethyl group, non-substituted C3-C7cycloalkyl group, non-substituted benzenesulphonyl group; except the cases, when "R3" and "R4" simultaneously stand for hydrogen; when "Y" represents CONHCOR5, "R5" stands for a halogenated C1-C5alkyl group, non-substituted phenyl group; when "Y" represents CO2R9, "R9" stands for C1-C7alkyl group, halogenated C1-C5alkyl group, C2-C5alkenyl group, halogenated C2-C5alkenyl group, C3-C5alkinyl group, non-substituted or substituted with chlorine, fluorine or a nitro group naphthyl or a phenyl group, non-substituted (C6)aryl(C1-C3)alkyl group, (C1-C3)alkoxy (C1-C3) alkyl group, (C1-C3)alkylthio (C1-C3)alkyl group, tri(C1-C3alkyl)silyl(C1-C3)alkyl group, non-substituted C3-C7cycloalkyl group, 3-6-membered non-substituted heterocycloalkyl group, containing an oxygen atom as the heteroatom, non-substituted or substituted with methoxygroup phenylmethyl group, non-substituted furanylmethyl group, non-substituted thienylmethyl group, non-substituted pyridylmethyl group, succinimide group. The group of inventions also relates to methods of obtaining imine derivative of formula (1) (versions). The compound by the invention can be obtained from compounds, selected from the group, consisting of compounds, represented by formulas ACO-B (5), ACOOCOA (6), ACOOH (7), D-N=C=O (8) or HCO2Et(10) in the interaction with the compound of formula .

EFFECT: imine derivative, used as an insecticide, possessing the prolonged effect and wide spectrum of action.

5 cl, 22 tbl, 1 dwg

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of dihydropyrimidine of the general formula (I):

or its isomeric form of the formula (Ia):

that can be used, for example, for treatment and prophylaxis of hepatitis B. In indicated formulas R1 means unsubstituted phenyl or phenyl substituted once or many times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, nitro-, amino-group, hydroxyl and alkyl with 1-6 carbon atoms, or residues of formulas:

, or ; R2 means residue of the formula -XR5 wherein X means a bond or oxygen atom; R5 means alkenyl with 2-4 carbon atoms or alkyl with 1-4 carbon atoms that can be unsubstituted or substituted with phenoxy-group; R3 means amino-group, alkyl with 1-4 carbon atoms or cyclopropyl; R4 means pyridyl that is substituted with up to three times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, alkoxy-group with 1-6 carbon atoms and alkyl with 1-6 carbon atoms, and their salts. Also, invention relates to 3,5-difluoro-2-pyridincarboxyimidamide and 3,5-difluoro-2-pyridincarbonitrile that can be sued as intermediates products for preparing compounds of the formula (I) or (Ia) and to a medicinal gent.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

10 cl, 2 sch, 4 tbl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indolylpiperidine of the formula (I): wherein A1 means (C1-C7)-alkylene, (C1-C7)-alkyleneoxy-, (C1-C7)-alkylenethio-, (C1-C7)-alkanoyl, hydroxy-(C1-C7)-alkylene; A2 means a single bond, (C1-C7)-alkylene, (C2-C5)-alkenylene; W means a single bond, phenylene, furanylene that is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkoxy- and/or alkyl groups; R1 means hydrogen atom (H), (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C2-C5)-alkoxyalkyl, (C3-C7)-alkenyloxyalkyl, (C3-C7)-alkynyloxyalkyl, (C3-C7)-alkoxyalkoxyalkyl, phenyl-(C1-C7)-alkyl wherein phenyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy- or arylalkoxy- (preferably with phenylalkoxy-) groups, or means (C3-C10)-cycloalkyl-(C1-C7)-alkyl wherein cycloalkyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy-groups; R2 means hydrogen atom (H), halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-; R3 means carboxyl, tetrazolyl, and to their pharmaceutically acceptable salts. Compounds of the formula (I) elicit antihistaminic and anti-allergic activity that allows their using in composition used for treatment of allergic diseases including bronchial asthma, rhinitis, conjunctivitis, dermatitis and nettle rash. Also, invention describes methods for preparing compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds.

15 cl, 2 sch, 3 tbl, 162 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine of the formula (I): , wherein X represents 1) group of the formula (1): , wherein S1 means hydrogen, halogen atom; S2 and S3 mean independently of one another hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl; S4 means two hydrogen atoms, oxo-group; S5 means hydrogen atom (H), (C1-C4)-alkyl; Y means CH2, oxygen atom (O), sulfur atom (S); or 2) group of the formula (2): , wherein S1 has above given values; R means hydrogen atom (H), (C1-C4)-alkyl, (C2-C6)-alkoxyalkyl, (C2-C4)-alkenyl or (C2-C4)-alkynyl; or 3) group of the formula (3): wherein S1 has above given values; Z means CH2, oxygen atom (O), nitrogen atom (N); or 4) group of the formula (4): , wherein S1 has above given values; or 5) group of the formula (5): , wherein S1 has above given values; A means oxygen atom (O), nitrogen atom (N) linked with piperazine ring at position 5 or 8; or 6) group of the formula (6): , wherein S1 has above given values; S6 and S7 mean hydrogen atom or oxo-group; or 7) group of the formula (7): , wherein one of dotted line can represent a double bond; S1 has above given values; P = T = Q mean nitrogen atom or P = T mean nitrogen atom; Q means CH or CH2; or P = Q mean nitrogen atom; T means CH, CH2, CH-CH3, C-CH3; or P means nitrogen atom; T means CH, CH2; Q represents sulfur atom; m = 2-6; n = 0-2; R5 and R6 mean independently of one another hydrogen atom (H), (C1-C3)-alkyl; or R5 + R6 represent group -(CH2)p- wherein p = 3-5; R7 means (C1-C3)-alkyl, (C1-C3)-alkoxy-, halogen atom, cyano-group; or R6 + R7 (R7 at position 7 of indole ring) mean group -(CH2)q wherein q = 2-4, and their salts. Compound of the formula (I) elicit high affinity both to dopamine D2-receptor and to serotonin reuptake site that allows their applying in treatment of the central nervous system diseases.

EFFECT: valuable medicinal properties of compounds.

5 cl, 3 tbl, 4 sch, 8 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to nitrogen-containing heterocyclic derivatives of the formula (I): A-B-D-E (I) wherein A means 5- or 6-membered heteroaryl comprising one or two nitrogen atoms in ring; B means ethenylene; D mean phenylene; E means group -N(COR)-SO2-G wherein G means phenyl; R means 5- or 6-membered heteroaryl or heteroarylmethyl comprising one or two nitrogen atoms in ring, or group -(CH2)n-N(R5)R6 wherein n means a whole number from 1 to 5; R5 and R6 are similar or different and mean: hydrogen atom, (C1-C6)-alkyl, hydroxyalkyl, aminoalkyl; or R5 and R6 in common with nitrogen atom can form 5-7-membered cyclic amino-group -N(R5)R6 that can comprise, except for nitrogen atom, also oxygen, sulfur or nitrogen atom as a component forming the ring, or their N-oxides. Compounds of the formula (I) elicit anticancer activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 1 tbl, 24 ex

FIELD: organic chemistry and pharmaceutical compositions.

SUBSTANCE: invention relates to new 3-(5)-heteroaryl-substituted pyrazoles of formula I , tautomers or pharmaceutically acceptable salt of compounds and tautomers. In formula R1 is hydride, piperidinyl substituted with methyl, lower alkyl optionally substituted with halogen, hydroxyl, lower alkylanimo or morpholino; R2 is hydride, lower alkyl, amino, aminocarbonylamino, lower alkylaminocarbonylamino, lower alkylsulfonylamino, aminosulfonylamino, lower alkylaminosulfonylamino; Ar1 is phenyl optionally substituted with one or more independently selected halogen; HetAr2 is pyridinyl with the proviso that R2 is not amino or n-propyl when HetAr2 is pyridinyl; and HetAr2 is not 2-pyriridinyl when R2 is hydrogen or lower alkyl. Compounds of formula I have kinase p38 inhibitor activity and are useful in pharmaceutical compositions for treatment of various diseases.

EFFECT: new effective kinase p38 inhibitors.

23 cl, 6 dwg, 1 tbl, 1 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to substituted 3-oxo-1,2,3,4-tetrahydroxinoxalines of general formula 1 , wherein R1 represents substituted sulfanyl or substituted sulfonyl group, containing as substituent optionally substituted C1-C4-alkyl, optionally substituted C3-C8-cycloalkyl, aryl-(C1-C4)alkyl optionally substituted in aril or alkyl group, heterocyclyl-(C1-C4)alkyl optionally substituted in heterocycle or alkyl group; R2 and R3 independently represent hydrogen, halogen, CN, NO2, optionally substituted hydroxyl, optionally substituted amino group, optionally substituted carboxylic group, optionally substituted carbamoyl group, optionally substituted arylcarbonyl group or optionally substituted heterocyclylcarbonyl group; R4 and R5 independently represent hydrogen or inert substituent. Claimed compounds are high effective kaspase-3 inhibitors and are useful in production of pharmaceutical compositions for treatment of diseases associated with excess apoptosis activation, as well as for experimental investigations of apoptosis in vivo and in vitro. Also disclosed are pharmaceutical composition in form of tablets, capsules or injections in pharmaceutically acceptable package, as well as method for production thereof and therapy method.

EFFECT: pharmaceutical composition for apoptosis treatment and investigation.

6 cl, 3 dwg, 8 ex, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of aminomethylpyrrolidine of the formula (I) , their salts or hydrates wherein R1 represents aryl with from 6 to 10 carbon atoms or heteroaryl wherein heteroaryl is a five-membered ring or a six-membered ring and comprises from 1 to 2 heteroatoms taken among nitrogen, oxygen and sulfur atom; aryl and heteroaryl can comprise one or more substitutes taken among the group consisting of halogen atom or (C1-C6)-alkoxyl; each radical among R2, R3, R4, R5, R6, R7 and R8 represents hydrogen atom (H) independently; Q represents incomplete structure representing by the following formula: wherein R9 means (C3-C6)-cyclic alkyl that can be substituted with halogen atom; R10 means hydrogen atom (H); R11 means hydrogen atom (H), NH2; X1 means halogen atom; A1 represents incomplete structure representing by the formula (II): wherein X2 means hydrogen atom (H), halogen atom, halogenmethoxyl group, (C1-C6)-alkyl or (C1-C6)-alkoxyl group; X2 and above indicated R9 can be combined to form the ring structure and inclusion part of the main skeleton and such formed ring comprises oxygen, nitrogen or sulfur atom as a component atom of the ring and the ring can comprise (C1-C6)-alkyl as a substitute; Y means hydrogen atom (H). Compounds of the formula (I) elicit an antibacterial effect and can be used for preparing a therapeutic agent.

EFFECT: valuable medicinal properties of compounds.

2 tbl, 61 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I)

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

EFFECT: improved method for preparing, valuable medicinal properties of compounds.

10 cl, 1 tbl, 173 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivative of aroylpiperazine of the formula (I):

wherein Y means lower alkylene; R1 means phenyl with 1 or 2 substitutes taken among group consisting of trihalogen-(lower)-alkyl, halogen atom, lower alkylamino-, di-(lower)-alkylamino- and nitro-group; R2 means phenyl or indolyl and each comprises 1 or 2 substitutes taken among group consisting of lower alkyl, trihalogen-(lower)-alkyl, lower alkylene dioxy-, hydroxy-group, hydroxy-(lower)-alkyl, lower alkoxy- lower alkylamino- and di-(lower)-alkylamino-group; R3 means hydrogen atom; R4 means morpholinyl-(lower)-alkyl comprising 1 or 2 substitutes taken among group consisting of ethyl, hydroxy-(lower)-alkyl, halogen-(lower)-alkyl and lower alkoxy-(lower)-alkyl, or morpholinyl-(lower)-alkynyl that can comprise 1 or 2 substitutes taken among group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo-(lower)-alkyl, lower alkoxy-(lower)-alkyl, hydroxy-(lower)-alkyl, carboxy-(lower)-alkyl, di-(lower)-alkyl-carbamoyl, lower alkoxycarbonyl and halogen-(lower)-alkyl. Also, invention relates to a method for preparing, pharmaceutical composition based on these compounds and a method for treatment of tachykinine-mediated diseases, such as respiratory diseases, ophthalmic, cutaneous, inflammatory diseases, and as analgetic agents. Describes compounds are antagonists of tachykinine.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 94 ex

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