N-oxides as prodrug of piperazine and piperidine derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to novel piperazine derivatives of formula (I) , where Q is methyl, benzyl or (1,1'-biphenyl)-3-ylmethyl, and pharmacologically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of preparing pharmaceutical compositions, to use of the compounds, as well as to a method of producing the compounds.

EFFECT: obtaining novel biologically active compounds with partial or complete agonist effect on dopamine D2 and 5-HT1A receptors.

9 cl, 6 ex, 1 tbl

 

DESCRIPTION

The present invention relates to N-oxides of certain derivatives of piperazine and piperidine derivatives and to methods of producing such compounds. The invention also relates to the application disclosed in this description of the compounds to obtain drugs, which have a beneficial effect. Favorable action is disclosed in this application is or becomes obvious to a person skilled in the art from the description and the prior art. The invention also relates to the use of compounds according to the invention to obtain drugs for treating or preventing the disease or condition. More specifically, the invention relates to a new use for the treatment of a disease or condition, opened in this application or obvious to a person skilled in the art from the description and the prior art. In embodiments of the invention specific compounds disclosed in this application is used for getting medicines for the treatment of CNS disorders, in particular for the treatment of anxiety disorders, including disorders generalized anxiety and panic disorder, obsessive-compulsive disorder, aggression, addiction including cravings and relapse), depression, autism, vertigo, schizophrenia and other psychotic disorders, Parkinson's disease and other movement disorders and impairment of cognitive ability and memory.

PSYCHOTROPIC DERIVATIVE of PIPERAZINE AND PIPERIDINE

Psychotropic derivative of piperazine and piperidine derivatives are known, for example, from WO 97/036893, WO 00/029397 and WO 01/085725. There are striking structural similarities between bifeprunox, SLV308 and SLV318, which are the protagonists of the three applications. However, equally striking are the differences in their pharmacological properties and, consequently, their healing abilities. Bifeprunox is a partial agonist of the dopamine receptor D2and a full agonist of the serotonin receptor 5-HT1Ain clinical trials as atypical antipsychotics (see R. Feenstra et al., Bioorganic & Medicinal Chemistry Letters, 11, 2345-2349, 2001). SLV318 is a full agonist of the dopamine receptor D2and partial agonist of the serotonin receptor 5-HT1Aand is currently estimated as a possible antidepressant and anxiolytic. SLV308 is a partial agonist of the dopamine receptor D2and at the same time a full agonist of the serotonin receptor 5-HT1A. The specified drug is undergoing clinical trials for treatment of Parkinson's disease (see R. Feenstra et al., Drugs of the future, 26(2), 128-132, 2001).

Metabolism studies on rats, monkeys and, much later, the people showed that SLV308 during metabolism is reterival, mainly, oxidation with subsequent glucuronidation. But after oral administration SLV308 in the plasma of all three species also found N-demetilirovanny similar and its N-oxide. In humans, the N-oxide is approximately 30% of the administered dose.

During the development of drug metabolites in a standard way to explore the activity, toxicity, etc. After it has been shown that the metabolite in humans was N-oxide SLV308, the connection was synthesized and subjected to screening. It was really inactive in vitro: its affinity receptor to which the original connection was shown high affinity, was either very low or below the detection limit. These results confirmed that in this case, one of the most common situations in which a is N-oxide, is a metabolic deactivation. It was expected that the first experiments in vivo, in which the N-oxide was injected intravenously, confirmed the validity of the in vitro findings: it was found that N-oxide has approximately one-tenth share of the activity of the parent compound. An unexpected result was obtained when testing N-oxide was performed after oral administration: then it turned out that he has the same efficiency that SLV308.

N-OXIDES

N-Oxides are known since 1894 the er is very well known, N-oxide metabolites are many tertiary amines and in most cases are also intermediate connections between tertiary amines and their N-dialkylamines counterparts. Most, but not all drugs are based on tertiary amines give rise to N-oxides. This occurs, for example, in the case of morphine, imipramine, promazine, Cinnarizine and nicotine, to name just a few substances. The degree to which N-oxidation, varies from trace amounts to almost quantitative conversion. It is shown that some N-oxides are more powerful than their corresponding tertiary amines. The most famous example of these is chlordiazepoxide (Librium®) is one of the most frequently used drugs in psychiatric medicine and therapy. However, in many other cases found that N-oxides are less powerful than their corresponding tertiary amines, and most traditionally, N-oxidation is considered as a metabolic deactivation. Although N-oxides are easily reduced to their corresponding tertiary amines by chemical methods, in the human body it happens in varying degrees. Some N-oxides undergo almost quantitative recovery conversion to their corresponding tertiary amines, in other cases, the type field, the Oia is nothing more than a weak reaction or even essentially, there is no (M.H. Bickel, "The pharmacology and Biochemistry of N-oxides", Pharmacological Reviews, 21(4), 325-355, 1969).

The result of the consideration of N-oxides and their corresponding tertiary amines is that everything is possible: there are examples of all kinds of extremes and any occasion in between. Tertiary amines may or may not give rise to metabolites N-oxides. When this occurs, the N-oxidation may be a trace reaction or quantitative conversion. N-Oxides can be more active than their corresponding tertiary amines, less active or completely inactive. N-Oxides can be restored to their corresponding tertiary amines or not to recover. When the N-oxides are recovered, the reaction may be nothing more than a weak reaction or almost quantitative.

N-OXIDE SLV308

The combination of those facts that N-oxide SLV308 is inactive in vitro, moderately active in vivo when administered intravenously, and is in fact equivalent when is administered orally, can be explained in only one way. Therefore, the fact that after oral administration to rats N-oxide SLV308 levels N-oxide in the plasma and the parent compound were approximately equal, was not unexpected.

N-OXIDES of BIFEPRUNOX AND SLV318

In humans, neither bifeprunox or SLV318 not metabolized to their respective N-oxides. Or more precisely, after the introduction is bifeprunox or SLV318 their N-oxides never found in sufficient concentrations in the plasma of human blood. For this reason never had the impulse to the synthesis and study of such compounds ... until then, until there were unexpected results are obtained with N-oxide SLV308.

N-Oxides of bifeprunox and SLV318 synthesized and injected into mice as intravenous and oral. Indeed, it turned out that, especially after oral administration, both connections are prototypes of prodrugs.

MICE AND HUMANS

As with people, SLV318, when injected to mice or intravenous or oral, will not cause a significant amount of N-oxide as a metabolite. With SLV308 the situation is different: people N-oxide is the principal metabolite, but in mice, this conversion is patently not the case. The opposite situation is in the case of bifeprunox: in the body of the mouse connection is substantially oxidized to N-oxide, while it turns out that people have this way of irrelevance.

PHARMACODYNAMICS

Since the time of Paracelsus ("increasing the dose of Sola facit venenum") generally recognized that therapeutic and toxic effects of drugs are related to their concentration in the appropriate places on target. As mentioned last, as a rule, are not readily available, use levels in plasma as the identity of the concentrations of the drugs. During the study, concentrations in plasma become of the local concentration, which are the lower limit for efficiency, and also the concentration at which starting to be revealed side effects. In ideal situations these two concentrations so far, it is easy to enter the drug so that it is effective, but does not give side effects. In reality, the situation is very far from ideal, and most drugs cause side effects. In most cases, the manifestation of side effects can be associated with the maximum concentration in plasma is greater than the lower level associated with the manifestation of side effects.

The possibility of achieving what the metabolites N-oxide derivatives of piperazine and piperidine, inactive by themselves, almost quantitatively will turn into the corresponding tertiary amines in oral administration, provides a good opportunity to use them as "prodrugs", providing clinical benefits increased duration of action and limited the maximum concentration in the plasma, leading to improved profile side effects.

The present invention relates to compounds of General formula (1)

where

- R1represents hydrogen, halogen, alkyl(C1-3), CN, CF3, OCF3SCF3, alkoxy(C1-3), amino is mono - or dialkyl(C 1-3)is substituted by amino or hydroxy,

- ---Z is =or-N

- R2represents hydrogen or alkyl(C1-3),

- R3and R4represent, independently, hydrogen or alkyl(C1-3), or

R3and R4together can form a bridge of 2 or 3 atoms,

- Q is a methyl, ethyl or cyclopropylmethyl, where ethyl or cyclopropylmethyl group optionally substituted by one or more fluorine atoms, or

Q represents a benzyl or 2-, 3 - or 4-pyridylmethyl, where these groups optionally substituted by one or more substituents selected from the group consisting of halogen, nitro, cyano, amino, mono - or dialkyl(C1-3)amino, alkoxy(C1-3), CF3, OCF3SCF3, alkyl(C1-3), alkyl(C1-3)sulfonyl or hydroxyl, or

Q represents a group of the formula

where

- R5represents halogen, hydroxy, alkoxy(C1-3) or alkyl(C1-3), and q is 0, 1, 2 or 3,

- Y represents a phenyl, furanyl or thienyl, where these groups may be substituted by 1-3 substituents selected from the group consisting of hydroxy, halogen, alkoxy(C1-3), alkyl(C1-3), cyano, aminocarbonyl, mono - or dialkyl(C1-3)aminocarbonyl,

and their tautomers, stereo is the Windows, pharmacologically acceptable salts, hydrate and solvate.

The invention relates to racemates, mixtures of diastereomers, and individual stereoisomers of compounds of formula (1), and their hydrate and solvate. "Alkyl(C1-3)" means methyl, ethyl, n-propyl or isopropyl".

Preferred compounds according to the invention are the compounds of formula (1), where R1, R2, R3and R4are hydrogen atoms, and "---Z and Q have the meanings indicated above, and their tautomers, stereoisomers, pharmaceutically acceptable salt, hydrate and solvate.

Especially preferred are compounds in which R1, R2, R3and R4are hydrogen atoms, "---Z is N, and Q is a methyl, ethyl, benzyl or (1,1'-biphenyl)-3-ylmethyl, and their tautomers, stereoisomers, pharmaceutically acceptable salt, hydrate and solvate.

Most preferred are compounds in which Q represents a methyl, benzyl or (1,1'-biphenyl)-3-ylmethyl - N-oxides SLV308, SLV318 and bifeprunox, respectively, represented by the formula (2-4).

GENERAL ASPECTS of SYNTHESIS

The synthesis of compounds of formula (1) shown in figure 1.

The selection of specific synthetic procedures depends on factors known to specialists in this field, those who IKI, such as the compatibility of functional groups with the reagents, the use of protective groups, catalysts, activating reagents and reagent combinations, and the main structural features present in the final compound, which is obtained.

Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by mixing the compounds of the present invention with a suitable acid, for example an inorganic acid or an organic acid. Preferred salts of the compounds according to the invention are mesylates.

PHARMACEUTICAL

The present invention relates to pharmaceutical compositions containing as active ingredients N-oxide derivatives of piperazine and piperidine derivatives or their pharmaceutically acceptable salts.

For clinical use of the compounds according to the invention include a pharmaceutical composition for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, transbukkalno, rectal, parenteral or some other way of introduction. The pharmaceutical composition contains compounds according to the invention in a mixture with a pharmaceutically acceptable adjuvant, diluent and/or novtel the M.

The total number of active ingredients is found, respectively, in the range of from about 0.1% (wt./wt.) to about 95% (wt./wt.) compositions, respectively, from 0.5% to 50% (wt./wt.), and preferably from 1% to 25% (wt./wt.).

Upon receipt of the pharmaceutical compositions of the present invention the active ingredients can be mixed with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as substances that contribute to the scattering, and lubricating agents such as magnesium stearate, calcium stearate, sodium fumarate and polietilenglikolya waxes. Then the mixture can be processed into granules or pressed into tablets.

The active ingredients can be mixed previously with other inactive ingredients before mixing to form the composition. The active ingredients can be mixed with each other before mixing with the inactive ingredients to form the composition.

Soft gelatin capsules can be obtained as capsules containing a mixture of active ingredients according to the invention, vegetable oil, fat or other suitable environment for soft gelatin capsules. Hard gelatin capsules may contain granules of the active ingredients. Solid yellow is tinavie capsules may also contain the active ingredients in combination with solid powdered ingredients, such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.

Standard dosage forms for rectal injection can be obtained (i) in the form of suppositories which contain the active substance is mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule which contains the active substance in a mixture with vegetable oil, liquid paraffin or other suitable environment for gelatin rectal capsules; (iii) in the form of ready-to-use microenemas or (iv) in the form of a dry composition for microenemas, which restores in a suitable solvent just before the introduction.

Liquid preparations can be obtained in the form of syrups or suspensions, for example solutions or suspensions containing the active ingredients and the remainder, consisting, for example, sugars or alcohols from sugars and ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, perfumes, preservatives, saccharin and carboxymethyl cellulose or other thickeners. Liquid preparations can also be obtained in the form of a dry powder, which restores a suitable solvent before use.

Solutions for parenteral administration can be obtained in the de solution composition according to the invention in a pharmaceutically acceptable solvent. Such solutions may also contain stabilizers, preservatives and/or buferiruemoi ingredients. Solutions for parenteral administration can also be obtained in the form of a dry preparation, which restores a suitable solvent before use.

The dose of injected compounds will depend on adequate evidence, age, weight and sex of the patient and can be determined by the attending physician. Dosage, preferably, will be in the range from 0.01 mg/kg to 10 mg/kg Typical daily dose of the active ingredients vary in a wide range and will depend on various factors such as an appropriate indication, route of administration, age, weight and sex of the patient, and may be determined by the attending physician. In General, oral and parenterally dosage will be in the range of 0.1 to 1000 mg per day of all active ingredients.

MEDICAL AND PHARMACEUTICAL APPLICATION

The invention also relates to compositions and composite sets for use in drug therapy, the application of the compositions of the present invention when getting medicines for use in the treatment of CNS disorders and treatment options drugs or involving the introduction of a therapeutically effective total amount of the compounds according to the invention to a patient suffering from resstr istwa CNS or Prednisolonum to him.

It is implied that the term "drug therapy", as used herein, includes preventive, diagnostic and therapeutic regimens carried out in vivo or ex vivo for humans or other mammals.

The composition according to the invention contain compounds of General formula (1) or as such or, in the case of prodrugs, become such after injection. Thus, it is expected that the composition according to the invention is applicable in the treatment of disorders of the Central nervous system.

Compounds according to the invention can be brought into forms suitable for administration by conventional methods, with the use of auxiliary substances such as liquid or solid media. The pharmaceutical compositions according to the invention it is possible to enter enterline, orally, parenterally (intramuscularly or intravenously), rectally or locally (topically). You can enter them in the form of solutions, powders, tablets, capsules (including microcapsules), ointments (creams or gels or suppositories. Suitable excipients for such compositions are conventional pharmaceutical practice, solid or liquid fillers and diluents, solvents, emulsifiers, lubricants, corrigentov, dyes and/or buferiruemoi substances. Commonly used excipients, which may be called, are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars or alcohols from sugars, talc, lactoprotein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, such as liver fat fish, sunflower oil, peanut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and one - and polyhydric alcohols, such as glycerin.

Compounds of the present invention, usually administered in the form of pharmaceutical compositions, which are important and new incarnations of the invention because of the presence of such compounds, more specifically, the specific compounds disclosed in this description. Types of pharmaceutical compositions that can be used include, but are not limited to, tablets, chewable tablets, capsules, solutions, parenteral solutions, suppositories, suspensions and other types disclosed herein or are obvious to those skilled in the art from the common information known prior art. The invention also relates to the production or manufacture of the above pharmaceutical compositions.

In embodiments of the invention offers a pharmaceutical package or kit containing one or more containers filled with one or more ingredients of the pharmaceutical compositions according to the invention. In connection with this(their) capacity(s) is there might be various written materials, such as instructions for use and a notice in the form prescribed by the state Agency regulating the manufacture, use or sale of pharmaceutical products which reflects approval by the specified body of the manufacture, use or sale for the purpose of people, or in veterinary medicine.

PHARMACOLOGICAL METHODS

The affinity in vitro against neurotransmitter receptors

Data binding collected in the table below (example 5, the results of pharmacological tests) obtained or CEREP (128, rue Danton, 92500 Rueil-Malmaison, France) or at Solvay Pharmaceuticals B.V., C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands) using documented standard procedures. The affinity in relation to, for example, receptors of dopamine D2and 5-HT1Awas measured as described in Creese I., Schneider R. and Snyder S.H., [3H]-Spiroperiodl labels dopamine receptors in rat pituitary and brain, Eur. J. Pharmacol., 1997, 46: 377-381, and Gozlan H., El Mestikawy S., L. Pichat, Glowinsky J. and Hamon M., 1983, Identification of presynaptic serotonin autoreceptors using a new ligand3H-PAT, Nature 1983, 305: 140-142.

(Ant)agonistic activity against neurotransmitter receptors in vitro

(Ant)agonistic activity against neurotransmitter receptors in vitro is measured, for example, by the formation of adenylate cyclase in cell lines expressing these cloned receptors (e.g., receptors D2The 5-HT 1Aman, expressed in Cho cell line according to methods described in Solomon Y., Landos C., Rodbell M., 1974, A highly selective adenylyl cyclase assay, Anal. Biochem., 1974, 58: 541-548; and Weiss, S., Sebben M. and Bockaert J.J., 1985, Corticotropin-peptide regulation of intracellular cyclic AMP production in cortical neurons in primary culture, J. Neurochem., 1985, 45: 869-874).

Animal model for assessing (ant)agonistic activity towards serotonin receptor 5-HT1Ain vivo

The retraction of the lower lip, measured according to the method described in Berendsen et al. (Pharmacol. Biochem. Behav., 33: (1989), 821-827).

Animal model for assessing (ant)agonistic activity towards dopamine receptor D2in vivo

Caused by apomorphine behavior of climbing in mice (Costall b, Naylor RJ and Nohria V, Differential actions of typical and atypical agents on two behavioural effects of apomorphine in the mouse, Brit. J. Pharmacol., 1978, 63: 381-382).

Animal models in vivo, predict anxiolytic/antidepressant activity

The model is based on ultrasonic vocalizations in rats (Molewijk H.E., Van der Poel A.M., Mos j, Van der Heyden J.A.M. and Oliver B. (1995), Conditioned ultrasonic vocalisations in adult male rats as a paradigm for screening anti-panic drugs, Psychopharmacology, 1995, 117: 32-40).

Test the forced swimming in rats (Porsolt R.D., Anton g, Blavet n and Jalfre M., 1978, Behavioural despair in rats: A new model sensitive to antidepressant treatments, Eur. J. Pharmacol., 1978, 47: 379-391).

Rat model response to increased low doses (McGuire P.S. and L.S. Seiden, The effects of tricyclic antidepressants on performance under a diferential-reinforcment-of-low-rate schedule in rats J. Pharmacol. Exp. Ther., 1980, 214: 635-641; van Hest et al., differential reinforcment of low rate responses, Psychopharmacology, 1992, 107: 474-479).

Suppression of motor activity (File S.E. and Hyde J.R.G., A test of anxiety that distinguishes between the actions of benzodiazepines and those of other minor tranquillisers or stimulants, Pharmacol. Biochem. Behav., 1979, 11: 65-79).

Animal model in vivo predictive of antipsychotic activity

Inhibition of conditioned avoidance in rats (Van der Heyden J.A.M., Bradford L.D., A rapidly acquired one-way conditioned avoidance procedure in rats as a primary screening test for antipsychotics: influence of shock intensity on avoidance performance, Behav. Brain Res., 1988, 31: 61-67).

Animal models in vivo, predicting activity against Parkinson's disease

Monkey marmoset damage MRTR (Nomoto M., Jenner P., Marsden C.D., The dopamine agonist D2agonist LY 141865 but not the D1agonist SKF 38393, reverses Parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the common known as marmoset. Neurosci. Lett. (1985), 57: 37-41).

The change of direction in rats caused by 6-OH-dopamine (Understedt U., 6-OH-DA induced degeneration of central monoamine neurons, Eur. J. Pharmacol., 1968, 5: 107-110).

Specifically:

ANIMALS

Male rats (Wistar, Harlan, the Netherlands; 400-500 g at the time of the experiment) during the experiments contain in an environment with controlled temperature (20-21±2aboutC) and humidity and given water ad libitum. Use the 12-hour cycle of alternation of light and darkness (light in the period 07.00-19.00). All experimental procedures carried out in accordance with the law of Dutch and agree with the terms of local whom the Committee for the protection and use of animals.

OPERATION

Unilateral damage 6-hydroxydopamine (6-OHDA) substantia nigra zona compacta is performed with the use of stereotactic procedures. An hour before surgery impose desmethylimipramine (20 mg/kg, I.P.) to protect noradrenergic neurons. Rats give the anesthesia gas mixture of 3% halothane gas +0.8 l/min N2O +0.8 l/min O2at 1013 mbar. During operation of the gas Smeg regulate up to 1.75-2% halothane gas, 0.6 l/min N2O and 0.6 l/min O2. The cutting plate stereotaxic instrument (Kopf, CA, USA) set at -3,3 mm drill trepanation hole above the substantia nigra pars compacta, and injected 3 μl of a solution of 6-OHDA of 3.33 mg/ml) (flow rate = 0.75 in µl/min; needle left in place for 4 minutes before removing). Coordinates in the case of this procedure are the following: front and rear +3.2 mm from Interaural line; middle/lateral +1.8 mm from the midline and ventral -8,2 mm from the surface of the skull. Animals allow you to recover for about 2 weeks before the test. Rats with a good indicator of the change in direction is defined as animals that show at least 20 contralateral turns after amphetamine (2.5 mg/kg, P.K.) during 5 minutes, from 25 min after injection, and on average, at least 20 of the contralateral turns recorded during 30 min pic is e injection of apomorphine (0.25 mg/kg, P.K.). Conduct regular tests with apomorphine (0.1 or 0.25 mg/kg, P.K.) in order to verify the reliability of the animals in this procedure.

EQUIPMENT

Used to test eight commercially available devices "rotameters" (TSE systems, Bad Homburg, Germany; transparent plastic tanks; 57×55×52 cm). Rats "harness" and tied to the speed sensor, connected to an IBM-compatible personal computer (using software TSE Rotameter, v. 1.11, TSE systems, Bad Homburg, Germany), which detects motion clockwise and counterclockwise. Use an internal rotary filter program 10.

PROTOCOL

After statistical randomization rats in the treatment groups pre-treated with compounds according to the invention (0.1 to 0.3 mg/kg, P.O.) or medium (2 mg/kg) and placed in rotameters, then record the rotational behavior. In subsequent studies evaluate the effects of L-DOPA (1-10 mg/kg, P.O.) on the contralateral rotations. You can use a peripheral decarboxylase inhibitor the benserazida (30 mg/kg, I.P.). In the combined studies, you can combine a range of doses of L-DOPA (1-10) and doses of the compounds according to the invention (0.1 to 3 mg/kg).

Compounds according to the invention of General formula (1)and their pharmaceutically acceptable salts are prodrugs of the compounds, the possession is the corresponding (partial) agonistic activity against dopamine receptor D 2in combination with agonistic activity against receptor 5-HT1A. They are applicable in the treatment of CNS disorders, in particular anxiety disorders, including disorders generalized anxiety and panic disorder, obsessive-compulsive disorder, aggression, addiction including cravings and relapse), depression, autism, vertigo, schizophrenia and other psychotic disorders, Parkinson's disease and other movement disorders and impairment of cognitive ability and memory.

TREATMENT (PROCESSING)

The term "treatment (processing)", as used herein, refers to any treatment of a condition or disease of a mammal, preferably a human, and includes (1) preventing the disease or condition in a subject which may be predisposed to the disease or condition but not yet diagnosed as having it, (2) inhibiting the disease or condition, i.e. the suspension of its development, (3) the weakening of the disease or condition, i.e. induction of regression of the state, or (4) the weakening of States caused by the disease, i.e. the termination of development of symptoms.

ABBREVIATIONS

This application uses some abbreviations that may not be entirely clear to a person skilled in the art. These include AB is revelatory, below.

6-HE-DA = 6-hydroxydopamine

Bifeprunox = 7-[4-([1,1'-biphenyl]-3-ylmethyl)-1-piperazinil]-2(3H)-benzoxazolone

Cho = Chinese hamster ovary

CNS = Central nervous system

I.P. = IPR

VV = intravenous

MRCR = 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

P.O. = (per os) = oral

SLV308 = 7-[(4-methyl)-1-piperazinil]-2(3H)-benzoxazolone

SLV318 = 7-[(4-were)-1-piperazinil]-2(3H)-benzoxazolone

EXAMPLES

It is assumed that the specific compounds, the synthesis of which is described below, further more explain the invention and, therefore, not considered to limit the invention in any way. Other embodiments of the invention will be obvious to a person skilled in the art from consideration of the description and practical application of the invention disclosed in this description. Thus, it is assumed that the description and examples should be considered only as examples.

EXAMPLE 1. MATERIALS AND METHODS

Flash chromatography refers to the cleaning method using the specified eluent and silica gel (silica gel or Acros 0,030-0.075 mm or Merck 60 0,040-0,063 mm).

The melting temperature recorded on the device for measuring the temperature of a Büchi melting point B-545.

Liquid chromatography - mass spectrometry (LC-MS)

System LC-MS consists of 2 is Troncoso Perkin Elmer series 200. The pumps are connected to each other 50-ál T-shaped mixing device connected to an automatic sampler Gilson 215. The method described below.

StageThe total timeFlow (µl/min)A (%)In (%)
002000955
11,820000100
22,520000100
32,72000955
43,02000955

A = 100% water with 0.025% HCOOH and 10 mmol NH4HCOO, pH +/-3

B = 100% ACN with 0.025% HCOOH

Automatic sampler has a 2-µl loop injection. Automatic sampler is connected with the column is th Waters Atlantis C18, 30×4.6 mm, 3 μm particles. Column thermostatic at 40aboutWith thermostat for the columns Perkin Elmer series 200. Column connects to the meter UV radiation Perkin Elmer series 200 2,7-ál flow cell. Set the wavelength of 254 nm. Measuring UV radiation is connected with a mass spectrometer (Sciex API 150EX. The mass spectrometer has the following options: scan interval 150-190 a.m.u.; polarity positive; scan profile; Q1 unit (UNIT); the step size of 0.10 a.m.u.; time at the scan cycle 0,500; NEB 10; CUR 10; IS 5200; TEM 325; DF 30; FP 225 and EP 10. The light scattering detector is connected with a Sciex API 150. The light scattering detector is a Sedere Sedex 55, operating at 50aboutC and 3 bar N2. The whole system is regulated by the control unit (powermac) G3.

All reactions involving moisture sensitive compounds or conditions that are affected by moisture, carried out in an atmosphere of anhydrous nitrogen. The reaction is controlled by using thin-layer chromatography (TLC) on plastic plates coated with silica (Merck pre-coated silica gel 60 F524) with the indicated eluent. Spot visualize under UV light (254 nm) or iodine (I2). Dichloromethane (phosphorus pentoxide and calcium hydride), tetrahydrofuran (sodium/benzophenone) and petroleum ether (60-80), and again distilled before use. All other commercially available is imitate used without further purification.

EXAMPLE 2. SYNTHESIS of INTERMEDIATE COMPOUNDS

N-Oxides according to the invention are synthesized from the corresponding tertiary amines - compounds, the synthesis of which is described in WO 97/036893, WO 00/029397 and WO 01/085725.

EXAMPLE 3. The SYNTHESIS of SPECIFIC COMPOUNDS

It is assumed that the specific compounds, the synthesis of which is described below, also more illustrate the invention, and, therefore, does not in any way limit the scope of the invention. Other embodiments of the invention will be obvious to a person skilled in the art from consideration of the description and practical application of the invention described in this specification. Thus, it is understood that the description and examples should be considered only as examples.

Compound 1: N-oxide SLV308

A suspension of 1.17 g (5.00 mmol) of 7-[(4-methyl)-1-piperazinil]-2(3H)-benzoxazolone in 30 ml of absolute ethanol warm until then, until you get a clear solution. Then to the hot solution add one dose of 0.41 ml of 30% H2About2, after which the mixture is heated under reflux on an oil bath. After a 5-hour boiling under reflux add another portion of 0.41 ml of 30% H2About2and continue boiling under reflux for 16 hours. Then add a small amount of 10% Pd/C, and after 45 minutes of boiling under reflux reactionuses allowed to cool to room temperature, and get a brown suspension. The suspension is concentrated using a rotary evaporator to a brown solid, which was purified flash chromatography on silica gel (230-400 mesh mesh, eluent a mixture of DCM:MeOH:NH3, 68:30:2), and obtain 1.06 g (of 4.25 mmol, yield 85%) of the corresponding N-oxide, compound 1 (TPL 242-243aboutC).

Compound 2: N-oxide SLV318

To a solution of 1.5 g (4,85 mmol) SLV318 (7-[(4-were)-1-piperazinil]-2(3H)-benzoxazolone) in 150 ml of acetone added 1.26 g (5,14 mmol) of 70% m-chloroperbenzoic acid, and the mixture is stirred for one hour and evaporated on the silicon dioxide. N-Oxide SLV318 (compound 2) extract flash chromatography (DCM:MeOH:NH3, 84:15:1). Yield 1.48 g (94%). TPL 238-240aboutC.

Compound 3: N-oxide of bifeprunox

Dissolve 30 g (66 mmol) of bifeprunox (7-[4-([1,1'-biphenyl]-3-ylmethyl)-1-piperazinil]-2(3H)-benzoxazolone) in 500 ml of acetonitrile and 130 ml of water. Then add 20 ml of 35% H2About2and the mixture is stirred at 50aboutC. Add N2About2after 2 hours (100 ml), 24 hours (100 ml) and 48 hours (100 ml). After 120 hours part of the acetonitrile is evaporated, and add 3000 ml of water. The reaction product is extracted with DCM extraction and evaporation. N-Oxide of bifeprunox (compound 3) purify by crystallization from 700 ml of acetonitrile and 100 ml of water and recrystallization from 200 ml of isopropanol. TPL 178-181aboutC.

<> EXAMPLE 4. COMPOSITIONS USED IN ANIMAL STUDIES

For oral (P.O.) introduction: to the desired quantity (0.5 to 5 mg) solid test compounds in a glass test tube add a few glass beads, and solid ground, performing a circular motion for 2 minutes. After adding 1 ml of 1% solution of methylcellulose in water and 2% (vol./about.) poloxamer 188 (Lutrol F68) connection is suspended, carrying a circular motion for 10 minutes. Bring the pH to 7. The remaining particles in suspension suspended next, using an ultrasonic bath.

For intravenous (I.V) injection: compound dissolved in physiological solution (0.9% NaCl)and adjusted pH to 7.

For intraperitoneal (I.P.) injection: to the desired quantity (0.5 to 15 mg) solid test compounds in a glass test tube add a few glass beads, and solid ground, performing a circular motion for 2 minutes. After adding 1 ml of 1% solution of methylcellulose and 5% solution of mannitol in water connection is suspended, carrying a circular motion for 10 minutes. Finally, bring the pH to 7.

EXAMPLE 5. The RESULTS of PHARMACOLOGICAL TESTS

From the data obtained in vitro (see table 1 below), it is obvious that N-oxide SLV308 significantly less active than the parent compound. It is also clear that metering is fair activity N-oxide is real and not caused by, for example, the possibility that the N-oxide "contaminated" by a small number of SLV308. From this we can conclude that their affinity against dopamine receptor D4vary 10 times, while the ratio of affinely against dopamine receptor D2is 100 times or more.

ED50SLV308 as antagonist of apomorphine test caused by the behaviour of climbing is 0.07 mg/kg, centuries In the same test conditions ED50N-oxide is more than ten times of 0.90 mg/kg However, in the trials when administered orally it is shown that both compounds - SLV308 and its N-oxide are equivalent (the value of the ED50of 0.75 and 0.79 mg/kg, respectively). From these results it is obvious that after oral administration of the N-oxide is restored to the corresponding tertiary amine SLV308.

These results are confirmed by measurements of the levels of SLV308 and its N-oxide in plasma after oral administration SLV308 and N-oxide. After oral administration SLV308 in plasma detected only trace amounts of N-oxide, however, after oral administration of N-oxide levels N-oxide and SLV308 in plasma was approximately equal.

Table 1
Pharmacology SLV308 and its N-oxide in vitro and in vivo
Affinity to receptors in vitroSLV308N-Oxide
ReceptorS1RadioligandKi(nm)Ki(nm)
Dopamine D1people[3H]-SCH 23390160>1000
Dopamine D2people[3H]-spiperone10>1000
Dopamine D2Speople[3H]-spiperone10>1000
Dopamine D4people[3H]-spiperone16130
Dopam the new D 5people[3H]-SCH 23390250>1000
5-HT1Apeople[3H]-8-OH-DPAT3200
5-HT1Bcu[3H]-serotonin1300>1000
5-HT1Dcor[3H]-serotonin400>1000
5-HT2Apeople[3H]-ketanserin1600>1000
5-HT2Cpeople[125I]-DOI800>1000
5-HT3to the [3H]-GR 38032F3200>1000
5-HT7people[3H]-LSD63>1000
Adrenergic α1cu[3H]-prazosin16>1000
Adrenergic α1Acu[3H]-prazosin32630
Adrenergic α1Bcu[3H]-prazosin10400
Adrenergic α2cu[3H]-RX 82100240500
Adrenergic α2C people[3H]-MK91263400
Adrenergic β1people[3H]-CGP 12177320>1000
Adrenergic β2people[3H]-CGP 121771000>1000
Opiate µcu[3H]-DAMGO400>1000
Opiate κcu[3H]-U 695931000>1000
The functional activity of the receptor in vitroSLV308N-Oxide
the
Antagonism to the human dopamine receptor D3(pA2)9,0<5,0
Agonism to the human dopamine receptor D3(RES50)8,97,3
The inherent activity of the human dopamine receptor D3(α)0,670,60
Farmacologia in vivoSLV308N-Oxide
The resistance caused by apomorphine behavior lasagna after intravenous reception: ED50mg/kg0,070,90
The resistance caused by apomorphine behavior lasagna after oral administration: ED50mg/kg0,79
The resistance caused by 6-OH-dopamine change of direction after oral administration: ED50mg/kgto 0.032<1,0*
S1(species): cor (b) = cow, per (h) = man, cu (rat)= rat; * quantification

Pharmacological results collected in the table above, obtained according to the above Protocol.

EXAMPLE 6. PLASMA CONCENTRATIONS of TERTIARY AMINES AND THEIR N-OXIDES

Bifeprunox, SLV308 and SLV318, and their corresponding N-oxides injected separately (or intravenously (I.V) or oral (P.O.)) mice (3 animals each), and then analyze their blood by LC-MS (method see above) as the starting amine and its N-oxide. Data are averages (n=3) and bring in the table below.

InputAnalyzed in blood
Time (hour) Bifeprunox [ng/ml]N-Oxide [ng/ml]
Bifeprunox, 0.5 mg/kg, I.V03610
0,1733457
0,528867
117535
321235
76911
2440
N-Oxide, 0.5 mg/kg, I.V00170
0,17133134
0,517685
113433
3 8010
7335
241,60
Bifeprunox, 5 mg/kg, P.O.0--
0,1714932
0,548590
152099
336463
722136
24332
N-Oxide, 5 mg/kg, P.O.0--
0,172611
0,5310 37
152070
357674
731048
24386
Conclusion. When administered to mice (VV or P.O.) bifeprunox to a certain extent metabolized to its N-oxide, but its concentration never approaches the concentration of the parent compound. When injected himself N-oxide, within ten minutes (0,17 hour) concentration in the plasma is equal to or greater than the concentration of the parent molecule. In particular, after oral administration of the N-oxide is clearly a prodrug of bifeprunox. Plasma concentrations of bifeprunox not significantly differ after the reception or in a dose of 5 mg/kg P.O. or the same dose of its N-oxide.

/tr>
InputAnalyzed in blood
Time (hour)SLV308 [ng/ml]N-Oxide [ng/ml]
SLV308, 0.5 mg/kg, I.V0--
0,173038
0,5530
1240
320
70,20
2400
N-Oxide, 0.5 mg/kg, I.V0--
0,1724130
0,5830
1312
30,31
700
2400
SLV308, 5 mg/kg, P.O.0--
0,173005
0,5532
1242
321
70,23
2404
N-Oxide, 5 mg/kg, P.O.0--
0,17--
0,54884
15580
35933
7147
2400
Conclusion. When administered to mice (or centuries, or BP) SLV308 metabolized significantly to its N-oxide. When the N-oxide is injected, it is to some extent restored to the original connection, but its concentration never exceeds the concentration of N-oxide. However, when N-oxide injected oral, pretty soon its concentration in the plasma becomes equal to the concentration of the parent molecule. After oral administration of the N-oxide is clearly Proletarsk the om SLV308. Plasma concentrations SLV308 not significantly differ after the reception or in a dose of 5 mg/kg P.O. or the same dose of its N-oxide.

1
InputAnalyzed in blood
Time (hour)SLV318 [ng/ml]N-Oxide [ng/ml]
SLV318, 0.5 mg/kg, I.V0--
0,171641
0,5510
1180
320
70,20
2400
N-Oxide, 0.5 mg/kg, I.V0--
0,178845
0,55014
1173
330
700
2400
SLV318, 5 mg/kg, P.O.0--
0,17710
0,5330
190
390
720
2400
N-Oxide, 5 mg/kg, P.O.0--
0,1711
0,571
1202
3300
770
2400
Conclusion. When suggesting the mice (or centuries, or P.O.) SLV318 not metabolized to its N-oxide. When N-oxide is injected, it is quickly restored to its original connection after 10 minutes of concentration SLV318 higher concentrations of N-oxide. When N-oxide administered orally, within ten minutes of its concentration in the plasma becomes equal to the concentration of the parent molecule. Obviously, after oral administration of the N-oxide is a prodrug SLV318. After 1 hour the concentration in the plasma SLV318 not significantly different after the reception or in a dose of 5 mg/kg P.O. or the same dose of its N-oxide.

1. Derivatives of piperazine of the formula (1)

where Q represents methyl, benzyl or (1,1'-biphenyl)-3-ylmethyl, and their pharmacologically acceptable salts.

2. The compound according to claim 1, where Q is a methyl, presents, therefore, formula (2)

and its pharmacologically acceptable salts.

3. The compound according to claim 1, where Q is a benzyl, represented, therefore, by formula (3)

and its pharmacologically acceptable salts.

4. The compound according to claim 1, where Q is a (1,1'-biphenyl)-3-ylmethyl,
presents, thus, formula (4)

and its pharmacologically acceptable salts.

5. Pharmaceutical composition having frequent who offered or full agonistic activity against receptors of dopamine D 2and 5-HT1Acontaining in addition to the pharmaceutically acceptable carrier and/or at least one pharmaceutically acceptable auxiliary substances pharmacologically active amount of at least one compound according to any one of claims 1 to 4, or its salt as an active ingredient.

6. The method of obtaining pharmaceutical compositions according to claim 5, characterized in that the compound according to any one of claims 1 to 4 include in a form suitable for injection.

7. The compound according to any one of claims 1 to 4, or its salt for use as drugs having full or partial agonistic activity against receptors of dopamine D2and 5 - HT1A.

8. The use of compounds according to any one of claims 1 to 4 to obtain a pharmaceutical composition for the treatment of CNS disorders, including anxiety disorder generalized anxiety and panic disorder, obsessive-compulsive disorder, aggression, addiction, craving and relapse, depression, autism, vertigo, schizophrenia and other psychotic disorders, Parkinson's disease and other movement disorders and disorders of cognitive ability and memory.

9. Method of preparing compounds according to claim 1, characterized in that the compound of General formula (1*) are oxidized by hydrogen peroxide with the formation of compounds of General formula ()



 

Same patents:

FIELD: organic chemistry, chemistry of polymers, chemical technology.

SUBSTANCE: invention relates to using hydroxylamine esters for decreasing molecular mass of polypropylene, propylene copolymers or polypropylene mixtures. Method involves addition to propylene polymers subjected for destruction at least one hydroxylamine ester chosen from group including compound of the formula (IA): wherein n means 1; Ra means aliphatic carboxylic acid acyl radical comprising from 2 to 18 carbon atoms; R'1, R'2 and R'3 mean independently of one another hydrogen atom or methyl group; G means aliphatic carboxylic acid acyl-acyl radical comprising from 1 to 18 carbon atoms or aromatic carboxylic acid acyl-acyl radical comprising from 7 to 18 carbon atoms of the formula (IB): wherein n means 1; Ra means aliphatic carboxylic acid acyl radical comprising from 2 to 18 carbon atoms; each R'1, R'2 and R'3 means independently of one another hydrogen atom or methyl group; G1 means hydrogen atom, (C2-C18)-alkanoyl; G2 means hydrogen atom, (C1-C8)-alkyl, aliphatic carboxylic acid acyl-acyl radical comprising from 1 to 18 carbon atoms of the formula (IC): wherein n means 1; Ra means aliphatic carboxylic acid acyl radical comprising from 2 to 18 carbon atoms; each R'1, R'2 and R'3 means independently of one another hydrogen atom or methyl group; G means (C2-C8)-alkylene, (C4-C22)-acyloxyalkylene or aliphatic carboxylic acid acyl radical comprising from 1 to 18 carbon atoms and this mixture is heated to temperature below 280°C. Addition of hydroxylamine esters results to increasing the destruction degree of used polypropylene polymer that is reflected by the melt efflux velocity value in comparison with this index of the parent polymer.

EFFECT: improved method for molecular mass decreasing.

3 cl, 15 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), their enatiomers, racemates and pharmaceutically acceptable salts, as well as a pharmaceutical composition based on said inhibitors and method of treating, preventing or suppressing inflammation and other conditions which are mediated by activity of leukotriene A4-hydrolase. In general formula (II) , X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is O; Z is chosen from a group which consists of O and a bond; W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to the nitrogen atom which is bonded to the said W; R4 is chosen from a group which consists of H, OCH3 and Cl; R6 is H or F; and R2' and R3' are each independently chosen from a group which consists of: A) H, C1-7alkyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-7alkyl, where each of substitutes (A) is independently substituted with 0 or 1 RQ, where each of said RQ is a carbon atom substitute, which is at least one carbon atom, separate from nitrogen atom; B) HetRa substitute; C) -C1-7alkyl-C(O)Rx; H) -C0-4alkyl-Ar5, where Ar5 is a 5-member heteroaryl, which has one heteroatom, chosen from a group >NRY, and 0 or 1 additional heteroatom -N=, and optionally contains two carbonyl groups, and optionally benzo-condensed; I) -C0-4alkyl-Ar5' , where Ar5' is a 5-member heteroaryl, which contains 3 or 4 nitrogen atoms; M) SO2C1-4alkyl; alternatively, R2' and R3', taken together with a nitrogen atom with which they are bonded, form a heterocyclic ring which contains at least one heteroatom, which is the said bonded nitrogen atom, where the said heterocyclic ring is chosen from a group which consists of i) 4-7-member heterocyclic ring HetRb, where the said 4-7-member heterocyclic ring HetRb has one heteroatom, which is the said bonded nitrogen atom, and is substituted with 0, 1 or 2 identical or different substitutes, where the said substitutes are chosen from a group which consists of -RY, -CN, -C(O)RY, -C0-4alkyl-CO2RY, -C0-4alkyl-C(O)CO2RY, -C0-4alkyl-ORY, -C0-4alkyl-C(O)NRYRZ-, -C0-4alkyl-NRYC(O)RZ-, -C(O)NRZORY, -C0-4alkyl-NRYCO2RY, -C0-4alkyl-NRYC(O)NRYRY, -C0-4alkyl-NRYC(S)NRYRZ, -NRYC(O)CO2RY, -C0-4alkyl-NRWSO2RY, 1,3-dihydrobenzoimidazol-2-on-1-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol- 5-yl, -C0-4alkyl-C(O)N(RY)(SO2RY), -C0-4alkyl-N(RY)(SO2)NRYRY, -C0-4alkyl-N(RY)(SO2)NRYCO2RY, halogen, , ,; ii) 5-7-member heterocyclic ring HetRC which has one additional heteroatom separated from the said bonded nitrogen atom by at least one carbon atom, where the said additional heteroatom is chosen from a group which consists of O, S(=O)2 and >NRM, where the said 5-7-member heterocyclic ring HetRC has 0 or 1 carbonyl group and is substituted with 0, 1 or 2 substitutes at identical or different substituted carbon atoms, where the said substitutes are chosen from a group which consists of -C(O)RY and RZ; iii) one of 1H-tetrazol-1-yl, where 1H-tetrazol-1-yl is substituted at the carbon atom by 0 or 1 substitute such as -C0-4alkyl-RZ, -C0-4alkyl-CO2RY; and iv) one of benzimidazol-1-yl, 2,8-diazospiro[4.5]decan-1-on-8-yl, 4-{[(2-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 4-{[(2-aminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 9-yl-tert-butyl ether 3,9-diazaspiro[5.5]undecane-3-carboxylic acid, 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl, and where substitute HetRa is a 6-member heterocyclic ring, with a carbon atom at the bonding site and contains a >NRM group as a heteroatom, where the said heteroatom is separated from the said carbon atom at the bonding site with at least 1 additional carbon atom; Rk is chosen from a group which consists of H and -C1-4alkyl; RL is chosen from a group which consists of -CO2RS; RS is hydrogen; RM is chosen from a group which consists of RZ, -C(O)RY; RN is chosen from a group which consists of OCH3, CI, F, Br, I, OH, NH2, CN, CF3, CH3 and NO2; RQ is chosen from a group which consists of -CN, -C0-4alkyl-ORY, -C0-4alkyl-CO2RY, -C0-4alkyl-NRYRY, -C0-4alkyl-NRYCORY, -C0-4alkyl-NRYCONRYRZ, -C0-4alkyl-NRYSO2RY; RW is chosen from a group which consists of RY; RX is chosen from a group which consists of -ORY, -NRYRZ, -C1-4alkyl and -C1-4alkyl-RAr; RY is chosen from a group which consists of H, C1-4alkyl, -C0-4alkyl-RAr and -C0-4alkyl-RAr', each of which is substituted with 1 or 2 RN substitutes; RZ is chosen from a group which consists of RY, -C1-2alkyl-CO2RY ; RAr is a radical with a carbon atom at the bonding position, where the said radical is chosen from a group which consists of phenyl, pyridyl and pyrazinyl, where each carbon atom with permissible valence in each of the said groups is independently substituted with at least 0, 1 or 2 RN or 0 or 1 RL; RAr' is a 5-6-member ring which has 1 or 2 heteroatoms, chosen from a group which consists of O, S, N and >NRY, and has 0 or 2 unsaturated bonds and 0 or 1 carbonyl group, where each member with permissible valence in each of the said rings is independently substituted with 0 or 1 or 2 RK; Description is given of inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), a composition which contains these inhibitions, and their use for inhibiting activity of the LTA4H enzyme, as well as for treating, preventing or suppressing inflammation and/or conditions which are associated with such inflammation. In the said formula (I): X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is chosen from a group which consists of CH2 and O, W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to a nitrogen atom; R4 is chosen from a group which consist of H, OCH3, CI, F, Br, OH, NH2, CN, CF3 and CH3; R6 is H or F; and R2 and R3 are each independently chosen from different groups.

EFFECT: new compounds have useful biological activity.

43 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry; medicine.

SUBSTANCE: invention relates to 3-phenylpropionic acid derivatives of formula (I) as ligand of peroxisome proliferator-activated gamma-receptor (PPARγ), to their pharmaceutically acceptable salts, as well as to their application, treatment method and based on them pharmaceutical composition. Compounds can be applied for treatment and prevention of diseases mediated by peroxisome proliferator-activated gamma-receptor (PPARγ), for instance type 2 diabetes, insulin-resistance, metabolic syndrome, complications resulting from or connected with diabetes, cardio-vascular dysfunctions, atherosclerosis, obesity, cognition disturbances and lipid metabolism derangements. In general formula (I): W represents COOH or -COO-C1 - C4-alkyl group; Y represents NH; Z represents S or O; X represents O; R1 - R8 each independently represents hydrogen atom or halogen atom; A represents mono-, bi- or tri-cyclic 5-13-member heteroaryl with 1 or 2 heteroatoms selected from N, S or O, aryl, selected from phenyl and naphtyl, or -N(C1-C4-alkyl)-CO-C3-C7-cycloalkyl, where heteroaryl is optionally substituted with 1-3 substituents, independently selected from group, consisting of C1-C4-alkyl, CN, phenyl halogen and phenyl, optionally substituted with 1-3 substituents, independently selected from C1-C4alkoxy, halogen and ethylenedioxy-group; and n represents integer number from 0 to 3 including; and their pharmaceutically acceptable salts.

EFFECT: increased efficiency of composition and treatment method.

20 cl, 14 dwg, 10 ex

FIELD: chemistry.

SUBSTANCE: invention is related to compounds of formula (II) as inhibitor of leukotriene A4-hydrolase (LTA4H) and their enantiomers, racemic compounds and pharmaceutically acceptable salts, and also to treatment methods, method inhibition and pharmaceutical composition on their basis. In general formula (II) , X is selected from group that consists of O and S; Y is selected from group that consists of CH2 and O; R4 represents H; R6 represents H or F; and R2' is determined as R2, and R3' is determined as R3, as follows: R2 and R3, each, is independently selected from group that consists of A) H, C1-7alkyl, C3-7cycloalkyl, where each of substitutes of A) is independently substituted with 0 or 1 RQ, and each of mentioned RQ is substitute at carbon, which is distanced from nitrogen at least by one carbon atom; alternatively, R2 and R3, taken together with nitrogen, to which they are connected, create heterocyclic ring, which contains at least one heteroatom, which is specified nitrogen of connection, and specified heterocyclic ring is selected from group that consists of i) (4-7)-member heterocyclic ring HetRb, where specified (4-7)-member heterocyclic ring HetRb has single heteroatom, which is specified nitrogen of connection, and 0, 1 or 2 are substituted by substitutes at the same or different substituted atoms, at that specified substitutes are selected from group that consists of -RY, -C(O)RY, -C0-4alkylCO2RY, -C0-4alkylC(O)NRYRZ, -C0-4alkylNRYC(O)Rz, -C0-4alkylNRYC(O)CH2ORY, -C0-4alkylNRYCO2RY, -C0-4alkylNRYC(O)NRYRz, -C0-4alkylNRyC(S)NRyRz, -NRyC(O)CO2Ry, -C0-4alkylNRwSO2RY, tetrazol-5-yl, -C0-4alkylN(RY)(SO2)NRYRY, -C0-4alkylN(RY)(SO2)NRYCO2RY, ii) (5-7)-member heterocyclic ring HetRc, where specified (5-7)-member heterocyclic ring has single additional heteroatom distanced from specified nitrogen of connection at least by one carbon atom, thereat the specified additional heteroatom is selected from group that consists of O, S(=O)0-2 and >NRM, and where mentioned (5-7)-member heterocyclic ring HetRc has 0 or 1 carbonyl group; iv) one of 2,8-diazaspyro[4.5]decan-1-on-8-yl, 4-{[(2-tret- butoxycarbonylaminocyclobutancarbonyl)amino]methyl}-piperidine-1-yl, 4-{[(2-aminocyclobutancarbonyl)amino]methyl}piperidine-1-yl, tret-butyl ether of 3,9-diazaspyro [5.5]undecan-3-carbonic acid-9-yl; where RK is selected from group that consists of H, -C1-4alkyl, each not necessarily substituted by 1 substitute RN; RM is selected from group that consists of -SO2RY, -C(O)RY, -C(O)C1-4alkylORY, each not necessarily substituted by 1 substitute RN; RN is selected from group that consists of OH, NH2, CF3; RQ is selected from group that consists of -C0-4alkylRAr', -C0-4alkylCO2RY, -C0-4alkylNRYRz, -C0-4alkylNRYCORY, -C0-4alkylNRyCONRyRz; Rw is selected from group that consists of RY and -C3-7cycloalkyl; RY is selected from group that consists of H, -C1-4alkyl, -C0-4alkylRAr and -C0-4alkylRAr', each not necessarily substituted by 1 substitute RN; Rz is selected from group that consists of RY, -C1-2alkylCO2RY; RAr represents fragment connected via carbon atom, and specified fragment is selected from phenyl, pyridyl; RAr' represents (5-6)-member cyclic ring, having 1 or 2 heteroatoms selected from group that consists of O, N and >NRY, having 0 unsaturated connections, having 0 or 1 carbonyl group, where each atom, when allows for valency, in every of mentioned cyclic rings is independently substituted by 0 or 1 RK; provided that (a) specified R2' and R3', moreover, satisfy the following requirements: (e1): specified R2' and R3', both, are not H, when Y represents O and X represents S; (e3): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperazine group, when X represents O and Y is one of O and CH2; (e4): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperidine group, which is mono-substituted by 6-member cyclic group, when X represents O and Y is one of O and CH2; and (e5): specified R2' and R3', taken together with nitrogen, with which they are connected, create neither substituted piperidine group or substituted piperazine group, where specified substituted piperidine group or specified substituted piperazine group is substituted in position 4 by substitute XG, at that specified XG has structure , where n=0, 1, and when ne=1, then XL represents C1-6alkyl, OSG represents O or S, and XR1 and XR2, taken together with nitrogen, with which they are connected, create one of piperidine group, piperazine group, morpholine group, thiomorpholine group and pyrrolidine group, or each of XR1 and XR2, taken independently, represent one of H, C1-6alkyl, aryl, aralkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, heteroalkyl, heteroaryl-C1-6alkyl, heterocycloalkyl and heterocycloalkyl-C1-6alkyl; where aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be not necessarily substituted by one or several substitutes, independently selected from halogen, hydroxy, C1-6alkyl, C1-6alkoxy, halogenated C1-6alkyl, halogenated C1-6alkoxy, nitro, cyano, amino, C1-4alkylamino, di(C1-4alkyl)amino, heteroaryl or heterocycloalkyl; and (b) further provided that when X represents S and Y represents O, then one of R2' and R3' is not XCG, while the other represents C1-6alkyl, where XCG represents group , where HC16 represents one of H, C1-6alkyl, halogenC1-6alkyl, allyl and C1-6alcoxymethyl, and GO represents group connected to carbon atom, which has substitute =0, creating amido group with nitrogen, with which all mentioned GO group is connected.

EFFECT: compounds may find application for treatment and prevention of diseases mediated by LTA4H, for instance, asthma, chronic obstructive lung disease, atherosclerosis, rheumatoid arthritis, disseminated sclerosis, inflammatory disease of bowels and psoriasis.

39 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of formula (I) and its pharmaceutically acceptable salts and esters. Compounds of the present invention are characterised with properties of DGAT-1 inhibitor. In general formula (I) , Q represents O, S or NR5; A represents a linker chosen from where p is equal to 1 or 2, and , where m is equal to 0, and n is equal to 1, 2, 3 or 4, or m is equal to 1, while n is equal to 1, 2 or 3, where specified linker is optionally substituted with one or two groups R8; R1 and R2 are independently chosen from hydrogen, haloid; R3 is chosen from hydrogen, (C1-C6)alkyl optionally substituted with hydroxyl and phenyl optionally substituted with haloid; R4 is chosen from hydrogen, nitro and (C1-C6)alkyl; or R3 and R4 together with carbon atoms whereto attached, can form benzene ring optionally substituted with 1-2 substitutes. The invention also concerns compounds of formula (Ia) and (Ib) with structural formulas presented in the patent claim, and also to a pharmaceutical composition, a medical product, to application of compounds for making a medical product and compound process.

EFFECT: new compounds possess useful biological activity.

19 cl, 2 tbl, 7 dwg, 215 ex

FIELD: chemistry.

SUBSTANCE: invention refers to benzothiazole derivatives of general formula I and to their pharmaceutically acceptable acid-additive salts as adenosine receptor ligands and based medicinal product. Compounds can be applied for treatment and prevention of diseases mediated by adenosine receptors, e.g., epilepsy, depressions, narcomania, Parkinson's disease. In general formula I R denotes phenyl unsubstituted or substituted with halogen or -SN2N(CH3) (CH2)nOCH3, or denotes benzyl, lower alkyl, lower alkoxy-group, - (CH2)nOCH3, or denotes pyridine-3- or -4-yl unsubstituted or substituted with lower alkyl, halogen, morpholinyl, - (CH2)n-halogen, - (CH2)nOCH3, - (CH2)n-diethylene-imide oxide-4-yl, or (CH2)n-tetrahydropyrrole-1-yl; R1 denotes phenyl unsubstituted or substituted with halogen tetrahydropyran-4-yl, 3,6-2H-2n-pyran-4-yl or morpholine-4-yl; n denotes mutually independent 1 or 2.

EFFECT: production of benzothiazole derivatives which can be applied for treatment and prevention of diseases mediated by adenosine receptors.

9 cl, 4 dwg, 27 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel ester compounds represented by the formula (1): wherein values for R1, R2, A, X, R3, R4, Alk1, Alk2, l, m, D, R8 and R9 are determined in the invention claim. Also, invention relates to inhibitor of matrix metalloproteinase (MTP), a pharmaceutical composition able to inhibit activity of MTP selectively, agents used in treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes mellitus or hypertension wherein the pharmaceutical composition is prepared in capsulated formulation, and to a biphenyl compound of the formula (100) given in the invention description.

EFFECT: valuable medicinal properties of compounds.

53 cl, 78 tbl, 17 ex

FIELD: organic chemistry, herbicide.

SUBSTANCE: invention describes (R)-phenoxypropionic acid N-methyl-N-2-fluorophenylamide of the formula (1):

. Also, invention describes a method for control of barnyard-grass (Panicum crus-galli) growing in culturing rice that involves using the effective amount of compound of the formula (1) and herbicide composition based on compound of the formula (1). Compound of the formula (1) is stable with respect to rice and prevents growing barnyard-grass plants.

EFFECT: enhanced effectiveness and valuable properties of herbicide and composition.

4 cl, 5 tbl, 1 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new heterocyclylsulfonyl alkylcarboxylic acids and their derivatives of the general formula (1): or their pharmaceutically acceptable salts, N-oxides or hydrates possessing the inhibitory effect on kinase activity and to the focused library for search of active leader-compounds comprising at least abovementioned compound. In the general formula 91) W represents optionally substituted heterocyclic radical, among them: pyrrole-3-yl, thiophene-2-yl, isooxazole-4-yl, pyrazole-4-yl, imidazole-4-yl, pyridine-3-yl, 1H-2,4-dioxopyrimidine-5-yl, 2,3-dihydro-1H-indole-5-yl, 2,3-dihydro-1H-indole-7-yl, 1,3-dihydro-2-oxoindole-5-yl, 2,3-dioxo-1H-indole-5-yl, 2-oxo-3H-benzoxazole-6-yl, benzothiazole-6-yl, 1H-benzimidazole-5-yl, benzo[1,2,5]oxadiazole-4-yl, benzo[1,2,5]thiadiazole-4-yl, 1,2,3,4-tetrahydroquinoline-6-yl, 3,4-dihydro-2-oxo-1H-quinoline-6-yl, quinoline-8-yl, 1,4-dihydro-2,3-dioxoquinoxaline-6-yl, 3-oxo-4H-benzo[1,4]oxazine-7-yl, 3-oxo-4H-benzo[1,4]thiazine-7-yl, 2,4-dioxo-1H-quinazoline-6-yl, 2,4-dioxo-1,5-dihydrobenzo[b][1,4]diazepine-7-yl or 2,5-dioxo-3,4-dihydrobenzo[b][1,4]diazepine-7-yl; Y represents optionally substituted methylene group; R1 represents chlorine atom, optionally substituted hydroxyl group, optionally substituted amino-group, optionally substituted azaheterocyclyl; n = 1, 2 or 3; or Yn represents carbon atom of optionally substituted (C3-C7)-cycloalkyl or optionally substituted (C4-C7)-heterocyclyl. Also, invention relates to a pharmaceutical composition in form of tablets, capsules or injections placed into pharmaceutically acceptable package.

EFFECT: valuable properties of compounds.

5 cl, 3 sch, 5 tbl, 6 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacology.

SUBSTANCE: invention relates to gyrase inhibitors that reduce amount of microorganisms in biological sample by contacting the indicated sample with compound of the formula (I): , to a method for treatment of bacterial infection by using compounds of the formula (I), compounds of the formula (I) and a pharmaceutical composition comprising compounds of the formula (I). Invention provides the enhanced effectiveness of treatment.

EFFECT: valuable medicinal properties of gyrase.

54 cl, 5 tbl, 13 ex

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: new isoindoline-1-on-glucokinase activators of general formula I , as well as pharmaceutically acceptable salts or N-oxide thereof are disclosed. In formula A is phenyl optionally substituted with one or two halogen or one (law alkyl)sulfonyl group, or nitro group; R1 is C3-C9cycloalkyl; R2 is optionally monosubstituted five- or six-membered heterocyclic ring bonded via carbon atom in cycle to amino group, wherein five- or six-membered heteroaromatic ring contains one or two heteroatoms selected form sulfur, oxygen or nitrogen, one of which is nitrogen atom adjacent to carbon atom bonded to said amino group; said cycle is monocyclic or condensed with phenyl via two carbon atoms in cycle; said monosubstituted with halogen or law alkyl heteroaromatic ring has monosubstituted carbon atom in cycle which in not adjacent to carbon atom bonded to amino group; * is asymmetric carbon atom. Claimed compounds have glucokinase inhibitor activity and useful in pharmaceutical composition for treatment of type II diabetes.

EFFECT: new isoindoline-1-on-glucokinase activators useful in treatment of type II diabetes.

23 cl, 3 dwg, 43 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine, namely to neurosurgery and tissue engineering of organs. Neuroendoprostetic system is obtained by perfusion of autologic cell composition into heterogeneous collagen-containing matrix for implantation with obtaining resilient-elastic cellular-biopolymeric biologically active mass. Biocomposition contains present in NaCl solution neutral stem cells (NSC), neuroglial sheathing cells (NGSC), endothelial cells with marker CD34+(EK) and purified mononuclear cells (MN). In carrying out reconstructive neurosurgical operation neuroendoprosthetic system is implanted into nervous tissue defect.

EFFECT: elaborated neuroprosthetic system allows to ensure stimulation of regeneration and growth of affected axons of nervous cells in carrying out reconstructive neurosurgical operations.

3 tbl, 2 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to chemical-pharmaceutical industry, namely to creation of substance, which has anxiolytic action, containing water extract of over ground part of dropwort (Filipendula vulgaris).

EFFECT: medication extends arsenal of medications of vegetable origin, which possess anxiolytic action.

5 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine, namely to therapy and can be applied in treatment of group of mitochondrial malfunctions or risk of such malfunction appearance. Methods by invention include introduction of formula I compounds which represent pyrimidine-based nucleosides.

EFFECT: methods ensure reduction of clamed malfunctions manifestations due to correction of processes in synthetic path of pyrimidines.

20 cl, 1 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: there is claimed application of dipeptidyl peptidase IV inhibitor (DPP-IV inhibitor), vildagliptin or its salt for production of medication for prevention, retardation of progress or treatment of peripheral diseases such as peripheral neuropatia, neurodegenerative disorders, cognitive disorders, as well as for improvement of memory and ability to learn, and pharmaceutical composition for the same purpose. It is demonstrated: vildagliptin increases stage of wakefulness and response to external stimuli, increases REM sleep phase.

EFFECT: combination of vildagliptin with donepezil considerably improves disturbed ability to learn.

23 cl, 5 ex

FIELD: medicine.

SUBSTANCE: there is claimed application of dipeptidyl peptidase IV inhibitor (DPP-IV inhibitor), vildagliptin or its salt for production of medication for prevention, retardation of progress or treatment of peripheral diseases such as peripheral neuropatia, neurodegenerative disorders, cognitive disorders, as well as for improvement of memory and ability to learn, and pharmaceutical composition for the same purpose. It is demonstrated: vildagliptin increases stage of wakefulness and response to external stimuli, increases REM sleep phase.

EFFECT: combination of vildagliptin with donepezil considerably improves disturbed ability to learn.

23 cl, 5 ex

FIELD: medicine.

SUBSTANCE: there is claimed application of dipeptidyl peptidase IV inhibitor (DPP-IV inhibitor), vildagliptin or its salt for production of medication for prevention, retardation of progress or treatment of peripheral diseases such as peripheral neuropatia, neurodegenerative disorders, cognitive disorders, as well as for improvement of memory and ability to learn, and pharmaceutical composition for the same purpose. It is demonstrated: vildagliptin increases stage of wakefulness and response to external stimuli, increases REM sleep phase.

EFFECT: combination of vildagliptin with donepezil considerably improves disturbed ability to learn.

23 cl, 5 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and to psychiatry. Electroencephalography and coherent analysis of EEG are applied before administration of an oral test dose of Paxyl 20 mg. It is followed with homolateral calculation of the average zonal indexes in the right and left cerebral hemispheres between frontal and anterior temporal, anterior temporal and middle, and between middle and frontal cortical regions. An interhemispheric asymmetry parametre is calculated by dividing the average zonal index in the right hemisphere by the average zonal index of the left hemisphere. If the interhemispheric asymmetry parametre is decreased more than 3.8% as compared with the reference value, a positive effect of Paxyl in the integrated treatment of anxious disorders is predicted.

EFFECT: method extends the range of products for prediction of Paxyl effectiveness in the integrated treatment of anxious disorders.

2 ex

FIELD: medicine.

SUBSTANCE: invention refers to a compound of the formula , where R1 and R2 are different independent groups and are selected from the group consisting of OR3 and N (R3') (R3"); or R1 and R2 are different groups connected through a single bond and selected from the group consisting of O and NR3; R3, R3', and R3" are independently selected from the group consisting of H, phenyl, substituted phenyl, where substituents are independently selected from the group consisting of C1-C6 alkyl, halogen; R4 and R4': (a) independently selected from the group consisting of H, OH, a group of the formula ; R5, R6, and R7 are independently selected from the group consisting of OCH3; R8 and R9 are joined by (i) a single bond and represent CH2 or (ii) double bond and are CH; R15 are selected from the group consisting of C=O; n is equal to 2. The invention also refers to method for obtaining these compounds.

EFFECT: obtaining new compounds which can be used in medicine as neurodefensive and neurogenerative, antiproliferative and anti-inflammatory drugs.

43 cl, 7 tbl, 13 ex

FIELD: medicine.

SUBSTANCE: invention refers to 3 - (2-methoxy-4-pyrazol-1-ilfenil) -2,5-dimethyl-7-(3-methylpyridine-2-yl) pyrazolo [1.5-a] pyrimidine or its pharmaceutically acceptable salts, solvate, stereoisomer, having the following structural formula, which are antagonists of CRF-receptors and can be used in treatment of various disorders that cause hypersecretion of CRF in warm-blooded animals, such as at the sudden attack. Also the invention refers to intermediate compounds, pharmaceutical compositions on the basis of this compound and method of treating disorder causing hypersecretion of CRF in mammals.

EFFECT: improvement of composition.

15 cl, 14 tbl, 28 ex

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