Diarylmetyhylpyperazine derivatives, their obtaining and application

FIELD: medicine.

SUBSTANCE: there are described compound of formula, its pharmaceutically acceptable salt or their mixture, enentiomerically pure 4-{(R)-(3-aminophenyl)[4-(4-fluorobenzyl)pyperazin-1-yl]-N,N-diethylbenzamide or its pharmaceutically acceptable salt. Also described are method of anxiety therapy, method of pain therapy and method of depression therapy in animal.

EFFECT: compounds are of use in therapy, in particular for elimination of pain, depression and anxiety.

5 cl, 1 tbl, 9 ex

 

This application is based on provisional patent application U.S. 60/602363, filed August 18, 2004, which is incorporated in this description by reference, and claimed priority under 35 U.S.. §119(a)-(d) based on Swedish patent 0401968-3, filed August 2, 2004.

The scope of the invention

The present invention relates to new compounds, method of their production, their use and pharmaceutical compositions containing the new compounds. The new compounds are useful in therapy, in particular, in the treatment of pain, anxiety, and functional gastrointestinal disorders.

Prior art

It is established that Delta ("δ") receptor plays a role in many body functions such as blood and bollapragada system. Thus, the ligands of the δ receptor can be potentially used as analgesics and/or as antihypertensive agents. Also it is shown that the ligands of the δ receptor possess immunomodulatory activities.

Identify at least three different populations of opioid receptors (µ, δ and κ) is now well proven, and all three populations found in the Central and peripheral nervous systems of many species, including humans. The analgesia observed in various animal models, when activated, one or more than on the in of these receptors.

With few exceptions, current selective ligands of the δ-opioid receptor by nature are peptides and are not suitable for systemic administration. One example ones δ-agonist is a SNC80 (E.J. Bilsky et al., Journal of Pharmacology and Experimental Therapeutics, 273 (1), pp.359-366 (1995)).

Many compounds representing δ agonists identified in the prior art have many disadvantages, namely that they show poor pharmacokinetics and do not possess analgesic properties when the system introduction. In addition, it is noted that many of these compounds representing δ agonists, shows significant convulsive actions with the systemic administration.

In PCT publication WO 02/094794 describes some δ agonists.

However, there is still a need for improved δ-agonists.

Description of the invention

The inventors have unexpectedly found that some compounds exhibit one or more than one improved property, i.e. enhanced δ-agonistic activity, activity in vivo pharmacokinetics, bioavailability, stability, in vitro stability, in vivo, the penetration into the brain, and/or low toxicity.

If this description does not state otherwise, the nomenclature used in this about what Isani, as a rule, corresponds to the examples and the rules established in Nomenclature of Organic Chemistry, Sections A, B, Q, D, E, F, and H, Pergamon Press, Oxford, 1979, incorporated herein by reference to examples of the names of chemical structures in it and naming chemical structures. Perhaps the connection name can be created by use of an education program for chemical names: ACD/ChemSketch, Version 5.09/September 2001, Advanced Chemistry Development, Inc., Toronto, Canada.

"Enantiomerically pure" refers to a compound containing at least 75% of the named enantiomer of the total number of two possible contained enantiomers. In a specific embodiment "enantiomerically pure" refers to a compound containing at least 90% of the named enantiomer of the total number of two possible contained enantiomers. In a more specific embodiment "enantiomerically pure" refers to a compound containing at least 95% of the named enantiomer of the total number of two possible contained enantiomers.

"A warm-blooded animal" includes humans.

In one aspect of the invention proposed compound of formula I, its pharmaceutically acceptable salt, solvate, prodrug, diastereoisomer, one or more than one enantiomer and mixtures thereof:

In one of the embodiments of the connection on izobreteny which may be chosen from:

,,,

their pharmaceutically acceptable salts, one or more than one selected enantiomer and mixtures thereof.

In yet another embodiment of the connection according to the invention may be chosen from:

,,,

and their pharmaceutically acceptable salts.

In yet another embodiment of the connection according to the present invention can be selected from the

and its pharmaceutically acceptable salts.

In yet another embodiment of the connection according to the present invention can be selected from the

and its pharmaceutically acceptable salts.

In yet another embodiment of the connection according to the present invention can be selected from the

and its pharmaceutically acceptable salts.

In yet another embodiment of the connection according to the present invention can be selected from 4-{(S)-(3-AMINOPHENYL)[4-(4-terbisil)piperazine-1-yl]methyl}-N,N-diethylbenzamide; 4-{(R)-(3-AMINOPHENYL)[4-(4-terbisil)piperazine-1-yl]methyl}-N,N-diethylbenzamide; 4-[(R)-(3-AMINOPHENYL)[4-[(2-forfinal)methyl]-1-piperazinil]methyl]-N,N-diethylbenzamide; 4-[(R)-(3-AMINOPHENYL)[4-[(3-forfinal)methyl]-1-piperazinil]methyl]-N,N-diethylbenzamide and their pharmaceutically acceptable salts.

<> In yet another embodiment of the compound of the present invention may be selected from enantiomerically pure 4-{(S)-(3-AMINOPHENYL)[4-(4-terbisil)piperazine-1-yl]methyl}-N,N-diethylbenzamide; enantiomerically pure 4-{(R)-(3-AMINOPHENYL)[4-(4-terbisil)piperazine-1-yl]methyl}-N,N-diethylbenzamide; enantiomerically pure 4-[(R)-(3-AMINOPHENYL)[4-[(2-forfinal)methyl]-1-piperazinil]methyl]-N,N-diethylbenzamide; enantiomerically pure 4-[(R)-(3-AMINOPHENYL)[4-[(3-forfinal)methyl]-1-piperazinil]methyl]-N,N-diethylbenzamide and their pharmaceutically acceptable salts.

It is clear that the compounds of the present invention contain one or more than one chiral center, the compounds according to the invention can exist in enantiomeric or diastereoisomeric forms or as racemic mixtures, and can be allocated in the form of enantiomeric or diastereoisomeric forms or as racemic mixtures. The present invention includes any possible enantiomers, diastereoisomers, the racemates of the compounds of formula I or mixtures thereof. Optically active forms of the compounds according to the invention can be obtained, for example, by chiral chromatographic separation of a racemate, by synthesis from optically active starting compounds or by asymmetric synthesis based on the following methods.

It is also clear that some compounds according to the present izobreteniya to exist in solvated, for example hydrated, as well as resolutional forms. Additionally, it is clear that the present invention encompasses all such solvated forms of the compounds of formula I.

In the scope of the invention are also salts of the compounds of formula I. generally, pharmaceutically acceptable salts of the compounds of the present invention can be obtained using standard methods, well known in the technical field, for example by reacting a sufficiently basic compound, for example, alkylamine, with a suitable acid, for example, HCl or acetic acid, to obtain a physiologically acceptable anion. May also be possible to obtain the corresponding salts of alkali (such as sodium, potassium or lithium) or alkaline earth metal (such as calcium) by treating the compounds of the present invention, with a suitable acidic proton, such as a carboxylic acid or a phenol with one equivalent of hydroxide or alkoxide (such as ethoxide or methoxide) alkaline or alkaline-earth metal, or a suitable basic organic amine (such as choline or meglumine) in the aquatic environment with subsequent conventional cleaning methods.

In one of the embodiments of the compound of formula I above can be transformed into its pharmaceutically acceptable salt or MES, in particular salt n is soedineniya acid, such as hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulfonate or para-toluensulfonate.

The new compounds of the present invention are useful in therapy, in particular for the treatment of various pain conditions such as chronic pain, neuropathic pain, acute pain, pain and cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain, etc. However this list should not be interpreted as exhaustive.

Compounds according to the invention is useful in the treatment of diarrhea, depression, anxiety and/or disorders associated with stress, such as post-traumatic stress disorder, panic disorder, generalized anxiety disorder, social phobia, and obsessive-compulsive disorder, urinary incontinence, premature ejaculation, various mental disorders, cough, lung edema, various gastro-intestinal disorders, e.g. constipation, functional gastrointestinal disorders such as irritable bowel syndrome and functional dyspepsia, Parkinson's disease and other motor disorders, traumatic brain injury, stroke, to protect the heart after myocardial infarction, in the treatment of spinal cord injury and substance abuse, including treatment of alcohol, nicotine, opioid, and d the natives of drug dependence, and disorders of the sympathetic nervous system, such as hypertension.

Compounds according to the invention are useful as immunomodulators, particularly in autoimmune diseases, such as arthritis, transplantation, skin, organ transplants and similar surgical needs, collagen diseases, various allergies, for use as antitumor agents, and antiviral agents.

Compounds according to the invention are useful in disease States in which degeneration or dysfunction of opioid receptors is present or implicated in this model. Can be enabled using radiolabelled variants of the compounds according to the invention in diagnostic methods and imaging applications such as positron emission tomography (PET).

Compounds according to the invention are useful as an analgesic agent for use during General anesthesia and monitored anesthesia. Combinations of agents with different properties, are often used to balance the effects required to maintain the anesthetic state (such as amnesia, analgesia, muscle relaxation and sedation). This combination enabled inhalation anesthetics, sleeping pills, anxiolytics, neuromuscular blockers and opioids.

p> In the scope of the invention is the use of any of the compounds of formula I in accordance with defined above for the manufacture of a medicinal product.

In the scope of the invention is the use of any of the compounds according to the invention for the manufacture of a medicine for the treatment of pain, including acute pain, chronic pain, neuropathic pain, back pain, pain and cancer pain, and visceral pain but not limited to.

In the scope of the invention is the use of any of the compounds according to the invention for the manufacture of a medicine for the treatment of anxiety, including social phobia, generalized anxiety disorder, acute anxiety, but not limited to.

In the scope of the invention is the use of any of the compounds according to the invention for the manufacture of a medicine for treating depression.

In the scope of the invention is the use of any of the compounds according to the invention for the manufacture of a medicine for the treatment of Parkinson's disease.

In the scope of the invention is the use of any of the compounds according to the invention for the manufacture of a medicinal product for the treatment of any of the discussed above conditions.

Another aspect of the invention is a method of treatment of a subject suffering from any of the discussed above conditions, wherein the patient in need of such treatment is administered an effective amount of the compounds of the present invention.

Thus, in the proposed invention the compound of formula I or its pharmaceutically acceptable salt or MES in accordance with defined above for use in therapy.

In the context of the present description, unless specifically stated otherwise, the term "therapy" also includes "prevention". The terms "therapeutic" and "therapeutically" shall be interpreted accordingly. The term "therapy" in the context of the present invention further includes introducing an effective amount of the compounds of the present invention to mitigate the pre-existing painful conditions, acute or chronic, or recurrent condition. This definition also encompasses methods for the prophylactic therapy to prevent recurrent States and continuous therapy for chronic disorders.

When applying for therapy in a warm-blooded animal, such as man, the connection according to the invention can be introduced in the form of a conventional pharmaceutical composition by any route including oral, intramuscular, subcutaneous, local, intranasal, intraperitoneal, vnutrigrudne, intravenous, epidural, vnutriobolochechnoe, intracere proventricular path and by injection into the joints.

In one of the embodiments of the invention, the route of administration can be oral, intravenous or intramuscular.

The dose depends on route of administration, severity of disease, age and weight of the patient, and other factors normally considered by the attending physician in determining the most appropriate for a particular patient individual regimen drug and dose.

Additionally, the proposed pharmaceutical composition comprising a compound of the present invention, its solvate or pharmaceutically acceptable salt in combination with a pharmaceutically acceptable carrier.

In particular, the proposed pharmaceutical composition comprising a compound of the present invention, its solvate or pharmaceutically acceptable salt in combination with a pharmaceutically acceptable carrier, for therapy, more particularly for the treatment of pain and anxiety.

In addition, the proposed pharmaceutical composition comprising a compound of the present invention, its solvate or pharmaceutically acceptable salt in combination with a pharmaceutically acceptable carrier, for use in any of the discussed above conditions.

For preparing pharmaceutical compositions from the compounds according to the invention, inert, pharmaceutically acceptable carriers can be solid or liquid. Preparations in the form of TV is rdeu forms include powders, tablets, dispersible granules, capsules, sachets and suppositories.

A solid carrier can be one or more than one substance, which may also act as diluents, corrigentov, solubilization, lubricants, suspendida agents, bonding agents or baking powder for tablets; it may also be an encapsulating material.

In powders, the carrier is a finely ground solid material, which is mixed with finely ground connection according to the invention, or the active component. In tablets, the active ingredient is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and to the desired size.

For preparation of compositions in the form of suppositories low-melting wax such as a mixture of glycerides of fatty acids or cocoa butter, is first melted and the active ingredient dispersed therein, for example by stirring. The molten homogeneous mixture is then poured into molds with a convenient size and allow to cool and harden.

Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth gum, methylcellulose, sodium carboxymethylcellulose, low-melting in the to, cocoa butter, etc.

Also assume that the term "composition" includes the preparation of the active ingredient with encapsulating material as a carrier to receive a capsule in which the active component (with other carriers or without them) is surrounded by carrier, which is thus associated with him. Similarly, included Sasha.

Tablets, powders, sachets and capsules can be used as solid dosage forms suitable for oral administration.

Liquid compositions include solutions, suspensions and emulsions. For example, sterile water or water propylene glycol solutions of the active compounds can be a liquid preparations suitable for parenteral administration. Liquid compositions can also be prepared in the form of a solution in an aqueous solution of polyethylene glycol.

Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, corrigentov, stabilizers and thickeners. Aqueous suspensions for oral use can be prepared by dispersing finely ground active component in water together with a viscous substance, such as natural and synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other suspen yousie agents, known in the field of pharmaceutical preparations.

Depending on the method of administration of the pharmaceutical composition preferably comprises from 0.05% to 99 wt.% (percent by weight), preferably from 0.10 to 50 wt.% compounds according to the invention, all percentages by weight based on the weight of the entire composition.

A therapeutically effective amount for the practical application of the present invention can be determined by applying the well-known criteria, including the age, weight and response of the particular patient, and interpreted in the context of the disease that cures or prevents a specialist in this field of technology.

In another aspect of the present invention, a method for producing compounds of the present invention.

In one of the embodiments of the invention, a method for obtaining compounds of formula I

including the interaction of N,N-diethyl-4-[(3-nitrophenyl)(1-piperazinil)methyl]benzamide R-CH2X or R-CHO obtaining nitro-intermediate;

restore the specified intermediate compounds suitable regenerating agent, where

R is selected from 2-ftoheia, 3-ftoheia and 4-ftoheia; and

X is selected from Cl, I, Br, -OTs (tosyl) and OMs (mesilate).

In one of the embodiments specified revitalizing agentmode to be selected from hydrogen, zinc and iron.

In yet another embodiment of the specified N,N-diethyl-4-[(3-nitrophenyl)(1-piperazinil)methyl]benzamide can be selected from N,N-diethyl-4-[(S)-(3-nitrophenyl)(1-piperazinil)methyl]benzamide and N,N-diethyl-4-[(R)-(3-nitrophenyl)(1-piperazinil)methyl]benzamide.

In another embodiment R may be a 2-forfinal; and the compound of the formula I can represent 4-[(3-AMINOPHENYL)[4-[(2-forfinal)methyl]-1-piperazinil]methyl]-N,N-diethylbenzamide.

In another embodiment R may be a 3-forfinal; and the compound of the formula I can represent 4-[(3-AMINOPHENYL)[4-[(3-forfinal)methyl]-1-piperazinil]methyl]-N,N-diethylbenzamide.

In another embodiment R may be a 4-forfinal; and the compound of the formula I can represent 4-[(3-AMINOPHENYL)[4-[(4-forfinal)methyl]-1-piperazinil]methyl]-N,N-diethylbenzamide.

More specifically, the compounds of the present invention and intermediate compounds used for their production, can be obtained in accordance with the ways of synthesis as described in schemes 1 and 2.

Scheme 1

Scheme 2

Biological assessment and property

Found that the compounds according to the invention are active against δ receptor in a warm-blooded animal such as man. In particular, we discovered that joint is according to the invention are effective ligands of the δ receptor. The in vitro demonstrated below, these unexpected activity, particularly in relation agonistic activity and efficiency, as demonstrated in the functional analysis of the rat brain. and/or functional analysis of the human δ receptor (below). This property can be associated with activity in vivo and may not correlate linearly with the binding affinity of. In these in vitro test the activity of compounds against δ receptors and receive IC50to determine the selective activity for a particular connection in relation to δ receptors. In the context of the present invention IC50in General refers to the concentration of the compound in which see 50%replacement of standard radioactive ligand δ receptor.

Activity of compounds against κ and µ receptors also measured in a similar analysis.

Models in vitro

Cell culture

Human 293S cells expressing the cloned human κ, δ and µ receptors, and resistant to neomycin, grown in suspension at 37°C and 5% CO2in shaker flasks containing calcium-free medium Needle, modified, Dulbecco (DMEM), 10% fetal bovine serum (FBS), 5% calf serum (BCS), with 0.1% Pluronic F-68 and 600 μg/ml of geneticin.

Samples of rat brain weighed and washed with chilled on ice is ideologicheskim solution buffered phosphate (PBS) containing 2.5 mm ethylenediaminetetraacetic acid (EDTA), pH 7.4). Samples of brain gomogenizirovannom using Polytron for 30 s (for rats) in chilled on ice lyse buffer (50 mm Tris, pH 7.0, 2.5 mm EDTA, with the addition of phenylmethylsulfonyl immediately before use to a concentration of 0.5 mm from the concentrated 0.5 M solution in a mixture of DMSO (dimethyl sulfoxide):ethanol).

Preparation of membranes

Cells precipitated and resuspended in lyse buffer (50 mm Tris, pH 7.0, 2.5 mm EDTA by adding phenylmethylsulfonyl (PMSF) immediately before use to 0.1 mm 0.1 M concentrated solution in ethanol), incubated on ice for 15 min, then homogenized using Polytron within 30 C. the Suspension is centrifuged at 1000 g (max) for 10 min at 4°C. the Supernatant stored on ice, and precipitation resuspended and centrifuged as before. Supernatant after both zentrifugenbau combined and centrifuged at 46000 g (max) for 30 minutes Precipitation resuspended in chilled Tris buffer (50 mm Tris/Cl, pH 7.0) and centrifuged again. The final precipitation resuspended in the buffer to membranes (50 mm Tris, of 0.32 M sucrose, pH 7.0). Aliquots (1 ml) in polypropylene tubes, frozen in a dry ice/ethanol and stored at -70°C prior to the application of the Oia. Protein concentration is determined by a modified analysis of Lowry with sodium dodecyl sulfate.

Analyses linking

Membranes are thawed at 37°C, cooled on ice (or store on ice if not used immediately), three times through the needle 25 gauge and diluted in buffer for binding (50 mm Tris, 3 mm MgCl21 mg/ml bovine serum albumin (BSA) (Sigma A-7888), pH 7.4, which is stored at 4°C. after filtration through a 0.22 mm filter, and which immediately add 5 µg/ml Aprotinin, 10 μm of bestatin, 10 μm diprolene And, if membranes prepared from tissue (rat, mouse, monkey, in the absence of dithiothreitol (DTT)). In chilled on ice polypropylene tubes size 12×75 mm containing 100 μl of each radioligand and 100 μl of test compounds at various concentrations, add aliquots of 100 μl. Total binding (OS) and nonspecific binding (NS) define respectively in the absence and in the presence of 10 μm naloxone. Tubes vortexing and incubated at 25°C for 60-75 minutes, after which the contents are subjected to rapid vacuum filtration and washed with approximately 12 ml/tube chilled on ice wash buffer (50 mm Tris, pH 7.0, 3 mm MgCl2through filters GF/B (Whatman), pre-washed for at least 2 h in 0.1%polyethylenimine. Remaining on the filter is the radioactivity (disintegrations per minute) was measured using a beta counter after exposure filters for at least 12 h in minivelo, containing 6-7 ml of scintillation fluid. If the analysis is carried out in a 96-well tablets with deep holes, filtering is performed via monofilter for 96-well plates are designed in polyethylenimine (PAYS), which was washed with 3×1 ml of the washing buffer and dried in an oven at 55°C for 2 h Filter plates are counted in a TopCount (Packard) after adding 50 μl of scintillation fluid MS-20/well. In the case of the analyses carried out in 96-well tablets with deep holes, IC50compounds estimate based on a 10-point curves of substitution in the case of the Delta, and the 5-point curves of substitution in the case of µ and κ. The analysis is carried out in 300 μl with the appropriate amount of membrane protein (2 μg, 35 μg, and 1 μg in the case of, respectively, δ, µ and κ) and 50000-80000 disintegrations / min/hole corresponding indicator (125I-Deltorphin II, 125I-FK33824, and 125I-DPDYN respectively for δ, µ and κ). The total binding and the nonspecific binding determined in the presence and absence of 10 μm naloxone.

Functional tests

Agonistic activity of the compounds is measured by determining the extent to which the complex compound and the receptor activates the binding of GTP-independent (GTP) with G-proteins, which are associated receptors. In the analysis of binding GTP combine GTP[γ]35S with the test compound and the membranes of cells HEK-293S, Express the respective cloned human opioid receptors, or from homogenized brain samples rat or mouse. Agonists stimulate the binding of GTP[γ]35S in these membranes. Values EU50and Emaxcompounds determined from curves dose-response. The right shift of the curve dose-response Delta-agonist by naltrindole carried out to confirm that the agonistic activity mediated by Delta-receptors. For functional analyses of the human δ-receptors EC50(low) measured when the human δ-receptors used in the analysis, expressed lower levels than those used to determine EC50(high). The values of Emaxdetermined relative to the standard δ-agonist SNC80, i.e. a value greater than 100%, corresponds to the compound which has the best performance compared with SNC80.

Procedure for GTP in the brain of the rat

Membranes of rat brain was thawed at 37°C, three times through the needle 25-gauge blunt-end and diluted in the buffer for the binding of GTPγS (50 mm HEPES, 20 mm NaOH, 100 NaCl, 1 mm EDTA, 5 mm MgCl2, pH 7.4, add freshly prepared 1 mm DTT, 0.1% BSA). In cultivation membranes add the final concentration of 120 μm guanozintrifosfata (GDP). EC50and Emaxcompounds evaluated according to 10-point curves dose-response in 300 μl with the appropriate number of membrane proteins is (20 μg/well) and 100000-130000 disintegrations per minute GTP[γ] 35S per well (0,11-0,14 nm). Base and maximum stimulated binding determined in the absence and presence of 3 μm SNC80. The analysis carried out on the cells of SOME 293S, stably expressing the cloned Delta receptor is carried out in a slightly different buffer (50 mm Hepes, 20 mm NaOH, 200 mm NaCl, 1 mm EDTA, 5 mm MgCl2pH to 7.4, add freshly prepared: 0.5% BSA without DTT) and the final concentration of 3 μm GDP.

Data analysis

Specific binding (SS) was calculated as OS-NS and SS in the presence of various test compounds is expressed as the percentage of control of the SS. The values of the IC50and hill coefficient (nHfor substitution of the ligand specifically bound peroxidase of radioligand was calculated by logarithmic graphs or programs fit curves, such as Ligand, GraphPad Prism, SigmaPlot, or ReceptorFit. The values of the inhibition constants (Ki) was calculated according to the equation of Cheng-Prusoff. Mean values±standard error of the mean (SOS) for IC50, Kiand nHprovided for the ligands tested at least three curves replacement.

Table 1 shows some biological data for several compounds according to the invention, measured using the above tests.

IC50hdIC50hkIC50hmEC50h (low)EC50h (low) EmaxEC50h (h)EC50h (h) EmaxEC50rbEC50rb Emax
0,587552471520,63for 95.34,18to 103.822,82130,3
8,80more than 100003316N/ON/O100,389,09465,966,32

0,7177258226248.10 per 89,96N/ON/ON/ON/O
1,085767273677,4284,44N/ON/ON/ON/O

N/O - not available

Experiments with saturation of the receptor

The values of Kδ for radioligand determined by analysis of the binding on cell membranes with the appropriate radio at concentrations in the range of 0.2 to 5 times relative to the preset δ (up to 10 times if the required number of radioligand are valid). Specific binding of radioligand expressed as pmol/mg of membrane protein. Values δ and Bmaxfor individual experiments are derived from the nonlinear adjustments specifically associated (In) relative to the nm of free (F) radioligand for the individual in accordance with one model.

Determination of the mechanical allodynia using test von Frey

Testing is performed in the period from 08:00 to 16:00 h using the method described in Chaplan et al. (1994). Rats is amemait in containers made of plexiglass on the surface of wire mesh, enabling access to the foot, and leave for addiction within 10-15 minutes the Test area represents the middle of the sole of the left hind legs, avoiding less sensitive paw pads. Before the feet touch the series of 8 hairs von Frey with logarithmically incremental stiffness(0,41, 0,69, 1,20, 2,04, 3,63, 5,50, 8,51 and 15,14 g; Stoelting, III, USA). Hair von Frey applied from under the mesh floor perpendicular to the surface of the sole with sufficient force to cause weak deflection of the legs and hold for about 6-8 seconds. A positive reaction record in the case, if the paw pulls sharply. Wince directly when removing hair is also considered as a positive reaction. The movement is considered as uncertain reaction and in such cases, the stimulus is repeated.

The test Protocol

Animals in the group treated with complete adjuvant's adjuvant (FCA), test the next day after surgery. 50%threshold of otdergivanija determined using the method of "up-down" Dixon (Dixon, 1980). Testing begins with hair 2,04 g in the middle of the series. Incentives are always consistently ascending or descending. In the absence of reaction in the form of otdergivanija paws on the source selected hairs are stronger stimulus; in the case of otdergivanija lapislazuli choose a weaker stimulus. For optimal calculation of the threshold level with the use of this method requires 6 reactions in the immediate vicinity of the 50%threshold, and counting these 6 reaction begins when the first change occurs in the reaction, for example, for the first time crossed the threshold level. In cases when the threshold levels are outside stimuli, respectively assign values to 15, 14 (normal sensitivity) or 0,41 (maximum allodynia). The resulting picture of the positive and negative reactions tabularium using the rules X = no otdergivanija; O = OTDELENIE, and 50%threshold of otdergivanija interpolate using the formula

50%g threshold = 10(Xf+κδ)/10000

where Xf = the value of the last used hair von Frey (logarithmic units); κ = - valued (Chaplan et al. (1994)) for a picture of the positive/negative reactions; and δ = mean difference between stimuli (logarithmic units). Here δ=0,224.

Threshold von Frey turn in percentage of maximum possible effect (% PHE) in accordance with Chaplan et al. 1994. To calculate % PHE using the following equation:

The introduction of the test substance

Rats injected (subcutaneously, intraperitoneally, intravenously or orally) those who together with the substance before the test von Frey, the time between the introduction of the test compounds and test von Frey varies depending on the nature of the tested compounds.

Test with cramps

Acetic acid causes abdominal reduction intraperitoneal injection to rats. This then leads to typical pulling their bodies. With the introduction of anesthetics described movement watch with less frequency and the drug is chosen as a potential good candidate.

Full and typical reflex cramps considered only when the following items are included: the animal is not in motion; lower back slightly weakened; watching the soles of both feet. In this assay, compounds of the present invention demonstrate significant inhibition reactions in the form of cramps after oral dose of 1-100 µmol/kg

(1) Preparation of solutions

Acetic acid (Asón): 120 µl of acetic acid is added to a fall of 19.88 ml of distilled water to obtain a final volume of 20 ml with a final concentration of 0.6% Asón. The solution is then mixed (vortex) and prepared for injection.

Connection (medicine): Each connection is prepared and dissolved in a suitable diluent in accordance with standard methods.

(2) infusion

Compound (drug is medium) is injected oral, intraperitoneally (V.B.), subcutaneously (P.K.) or intravenously (I.V) at a concentration of 10 ml/kg (based on average body weight of a mouse) for 20, 30 or 40 minutes (in accordance with the connection class and its characteristics) before testing. When the compound is administered centrally: intraventricular (IVC) or vnutriobolochechnoe (V.O.)injected volume of 5 ál.

Asón injected intraperitoneally (V.B.) in two areas at a concentration of 10 ml/kg (based on average body weight of a mouse) directly before testing.

(3) Testing

For the animals (mice) observed for 20 minutes and the number of events (reflex cramps) record and accumulate at the end of the experiment. Mice are kept in individual cells of type "box for shoes" attached to the litter. Usually at the same time watching 4 mice: one control and three doses of the drug.

For alarm and similar alarm indications evaluate the effectiveness in conflict test Geller-Seifter in rats.

For evidence of functional gastrointestinal disorders efficiency can be evaluated on rats in the analysis described Coutinho SV, et al., in the American Journal of discrimination - Gastrointestinal&Liver discrimination. 282 (2):G307-16, Feb 2002.

Additional testing protocols in vivo

Objects and content

Not treated male rats Sprague Dawley (175-200 g) kept in groups of 5 pieces in the room to the controlled temperature (22°C, humidity 40-70%, 12-hour light/dark period). Experiments conducted during the light phase of the cycle. Animals get food and water without restrictions and kill them immediately upon receipt of the data.

Sample

Tested in respect of compounds (drugs) groups of rats include groups that do not undergo any processing, and the group that is treated with lipopolysaccharide (LPS) of E. coli. For the experiment with the processing of FSC four groups injected LPS, one of the four groups is then treated with media, while three other groups injected the drug together with a carrier. The second ongoing series of experiments include five groups of rats, all of which are not treated with LPS. The group not treated, do not enter any compound (drug), nor the media; the other four groups treated with media containing drug or without him. These experiments are carried out to determine the anxiolytic or sedative drugs that may contribute to the reduction of the USV.

Introduction LPS

Rats given the opportunity to settle in the experimental laboratory for 15-20 min before processing. Inflammation cause by the introduction of LPS (endotoxin of gram-negative bacteria E. coli, with serotype 0111:B4 (Sigma). FSC (2.4 μg) intracerebroventricular (ICV) is injected in a volume of 10 µl using standard stereotactic surgical methods with isoflurane anesthesia. The skin between the ears kljuvovidno retard and make a longitudinal incision approximately 1 cm to exposure of the surface of the skull. The area of the puncture is determined by coordinates: 0.8 mm back from bregma, 1.5 mm lateral (left) from lambda (sagittal suture), and 5 mm below the surface of the skull (vertically) in the lateral ventricle. LPS is injected through a sterile needle stainless steel (26-G 3/8) with a length of 5 mm, attached to a Hamilton syringe with a volume of 100 μl through a polyethylene tube (RE; 10-15 cm). On top place a tube with a diameter of 4 mm, made of cut needle (20-G), and attach it to the needle 26-G using a silicone adhesive to obtain a desired depth of 5 mm.

After LPS injection needle is left in place for another 10 to allow for diffusion connection, and then removed. The incision is closed and the rat return to the original cell and leave at least 3.5 hours before testing.

Experiment to stimulation by blowing air

Rats leave in the experimental laboratory after the injection of LPS and the introduction of compounds (drugs). At the time of testing, all rats recovered and placed outside La the oratorio. Rats one contribute to the laboratory for testing and placed in a transparent box (9×9×18 cm), which is then placed in a ventilated sound-absorbing booth size 62 (width) × 35 (depth) × 46 (h) cm (BRS/LVE, Div. Tech-Serv Inc). Blowing air through the air nozzle 0,32 cm control system (AirStim, San Diego Intruments), is able to inject the air with fixed duration (0.2 s) and fixed intensity with a frequency of 1 injection of 10 C. Perform a maximum of 10 dowani or as possible before the first vocalizations, whichever comes first. First, the injection of air indicates the start of registration.

Experiment design for ultrasonic reception

Vocalizations recorded for 10 minutes using a microphone (G.R.A.S. sound and vibrations, Vedbaek, Denmark)placed inside each booth, and control using software laboratory information management system (LMS CADA-X V, Data Acquisition Monitor, Troy, Michigan). Register frequency from 0 to 32000 Hz, preserve and analyze using the same software (LMS CADA-X 3.5 In, Time Data Processing Monitor and UPA (programming by the user and the analysis)).

Compounds (drug)

the pH for all compounds (drugs) is brought to a value of 6.5 to 7.5 and enter them in volume 4 ml/kg After administration of the compound (drug what about tools), the animals are returned to their original cells before testing.

Analysis

The registration is carried out using a series of statistical analysis and Fourier analysis filtering (20-24 kHz) and to calculate the parameters of interest. Data expressed as mean value ± SOS. Statistical significance is assessed using a T-test for comparison between rats not treated, and rats treated with LPS, and one-way ANOVA (analysis of variance) followed by the test multiple comparisons Dunnett (post-hoc) for the efficacy of drugs. The difference between groups is considered as significant when the minimum value of p is not more than 0,05. Experiments repeated at least twice.

Determination of thermal hyperalgesia using the plantar test Hiraiwa (Hargreave)

The introduction of the FCA or carrageenan

Full beta-blockers (FCA): SIGMA cat. No. F 5881, Mycobacterium tuberculosis (H37Ra, ATCC 25177), 1 mg/ml, inactively warm, dried, 0,85 ml of paraffin, 0.15 ml of monooleate manned. Or carrageenan type IV Lambda (Cg): SIGMA cat. Number C-3889, (gelatin, vegetable; Irish moss), (1.0% solution) NaCl.

Injections are carried out using a Hamilton syringe with the amount of sterile needles 26G5/8”. Rats are selected and placed in the camera for anesthesia with isoflurane. When the desired actions rats recovered and placed in a supine position on the belly (sternal position). Rear left leg clamp the needle is injected subcutaneously, ventrally, between the fingertips #2 and #3 to find the middle of the feet (metatarsal area). Finally, a volume of 100 μl of a solution FCA or 100 μl of a solution of carrageenan slowly injected into the paw and a small pressure is applied within 3-4 seconds after removing the needle.

If the animals are awake during the procedure, their return to the inhalation chamber to achieve the desired actions.

After injection into the sole animals provide an opportunity to Wake up under the supervision of his cage.

When processing FCA rats leave for 48 hours for the development of inflammation. When processed by carrageenan in rats leave for 3 hours for the development of inflammation. In the morning on the day of testing, rats are placed in a laboratory (in their cages). Give them a chance to settle into the room within 30 minutes.

The test area

A thermal stimulus is applied to the center of the surface of the sole between the pads. The test area must be in contact with the glass, and between the sole and the glass should not be urine or faeces to ensure proper heat transfer characteristics from the glass to the skin.

Apparatus for plantar test consists of a box with a glass top/platform, the temperature of the glass surface maintained at 30°C in a feedback mechanism. Below this glass platform is lamp, attached keychain, four button is slow to the mobile rack the mirror is located below in order to give the opportunity to direct the light on the paw of the rat. When turning on the lamp it shines through a hole diameter of approximately 2 mm, the Experimenter turns on the light, and automatic sensors turn lights off when the paw pulls from the surface; an interrupt at the time 20,48 seconds provides the guarantee that will not happen tissue damage if the rat will not hold out a paw. The experimenter can also turn off the lights at any time. The timer records the period of time during which light is enabled.

Fluxmeter: measures the amount of flow/cm2when turn on the light. It must be supported approximately 97-98; the flow can be modified by adjusting apparatus for plantar test, but must never be altered in the middle of the experiment.

Period of time

The experiment can be conducted through different periods of time after the initiation of inflammation. Hyperalgesia is measured after 48 h after injection of FCA or 3 h after injection of carrageenan.

The test procedure

Rats not subjected to treatment: curve dose-response as a control share the same group of 7 rats; they are subjected to anesthesia along with the rest of 28 rats, but the injection is not carried out. Testing non-exposed group can be carried out before what achalam or directly after the experiment with the minimum possible stress rats are placed in individual Plexiglas boxes (14×21×9 cm) on the surface of the device for plantar test; give them a chance to settle for 30 minutes. When the animals are ready for testing, the light is placed directly beneath the test area and include and record the length of time before otdergivanija paws. After a period of time 5-8 minutes to allow the skin temperature to return to normal, perform a second check, rats, then remove and put into their cells.

Base value: the Remaining 28 rats (divided into 4 groups), which were injected with FCA (or carrageenan), placed in individual boxes on the device and allow to settle for 30 minutes. The experimenter must assess the degree of inflammation of the paws and test, did not change its color. A thermal stimulus is placed under the test area and record the length of time before otdergivanija feet; by two Desk as before. Compare these baseline values with baseline values for animals, not subjected to processing that allows you to determine whether hyperalgesia.

Testing after administration of the drug: once established the presence of hyperalgesia, rats injected interesting connection. Each connection is prepared and dissolved the most appropriate media in accordance with standard methods. The route of administration, dose, volume, and time of testing after injection connection-specific (or class of compounds). When the connection test after 20-30 minutes after the injection, such as centuries or P.K. injection, rats are placed in the apparatus for plantar test and give you the opportunity to get used to it, until the drug exerts its action. When the connection test in 60 minutes or more after injection, rats are placed back in their cages with their rugs. Rats will always be placed back in their cages with their original litter to minimize stress recovery of social structure within a group of rats. After 30 min the rats are placed in the apparatus for plantar test and provide an opportunity for 30 minutes to get used to the device for testing. Testing is carried out in accordance with previously described. Have two registration.

Test criteria

The animal must be calm and quiet, already ready and in the correct position, in the absence of urine or faeces between the skin of the legs and the glass surface of the device. The animal should not be tested if:

- the animal is in locomotion, including Obrucheva, cleaning and inspection;

- animal sleeps;

animal shows obvious signs of stress (tonic nepodvizhno the ü, vocalizations, pinned ears), unless they are a possible result of side effects connection and cannot be avoided;

- the animal is located so that the paw is not in direct contact with the glass (paw lies on the surface of the tail);

the paw of the animal acquires a blue color as a result of poor injection. In this case, the animal is completely excluded from the experiment (in the beginning).

When present in urine or faeces, animal extract, the glass surface is wiped clean, and then the animal is placed back. When the animal is asleep or demonstrates toxic immobility, the experimenter can gently move the box or to wave a hand in front of the box in order to cause short-term attention. In the test should be carried out a detailed observation of the behavior of the animal.

Repeated tests

At any time during the experiment, if the experimenter is not sure that OTDELENIE paws is not a response to a thermal stimulus, the animal can be tested again after 5-8 minutes. This may be the result of a sudden movement of the animal or urination, or defecation in the application of the stimulus.

Acceptable reaction

Any of the following reactions is considered as a response to a thermal stimulus:

- uderjivauschiy movement of the legs from the article is KLA (often followed by licking paws);

- the lateral movement of the body (contralateral relative to the stimulated paw);

fingers otdelyvayutsya from glass;

- Centralnaya part (mid-foot) inflamed paws pulls from the glass.

Analysis

Data expressed as mean value ± SOS. Statistical significance is assessed using a T-test for comparison of rats not exposed to, with rats with inflammation, and one-way ANOVA with subsequent test of multiple comparisons Dunnett (post-hoc) for the effectiveness of the drug. The difference between groups is considered as significant when the minimum value of p is not more than 0,05.

The drug metabolism and pharmacokinetic properties

Unexpectedly, it was found that one or more than one metabolic and pharmacokinetic property of the compounds is improved by the fluorescent-substitution on the lower benzyl benzylpiperazine grouping of the formula I. In one of the embodiments discovered that certain reactive metabolites reduced or eliminated for compounds of the present invention. In yet another embodiment, some compounds of the present invention provide improved bioavailability, which may be a result of their weak affinity with 2D6 and 3A4 cytochrome P450. Following Ana is the vermehren demonstrate one or more of these unexpected properties of these compounds.

Incubation with microsomes

The compound of the present invention (10 μm nominal initial concentration) individually incubated with liver microsomes of rats (0.5 mg/ml protein) in 0.1 M buffer KH2PO4(pH 7.4) with 5 mm MgCl2and 5 mm detection reagent (glutathione (GSH), N-acetylcysteine (NAC) or CH3ONH2) for 60 min at 37°C. the Reaction initiated by adding the restored adenine dinucleotide phosphate NADPH (1 mm) and stopped by adding to the incubation mixture of equal amount of acidifier (with 0.1%formic acid in acetonitrile).

Incubation with hepatocytes

The compound of the present invention (nominal initial concentration 10 μm) for 1 h at pH 7.4 and 37°C individually incubated with freshly isolated hepatocytes of rats (Sprague Dawley) and stored at cryogenic temperatures hepatocytes dogs (Beagle) (1×106cells/ml). The incubation mixture with hepatocytes containing environment, Williams E, supplemented with 25 mm HEPES, 1% ITS-G solution (Life Technologies, cat. No. 41400-045), 10 mm HEPES (pH of 7.4) and 2 mm L-glutamine. Incubation was stopped by adding to the incubation mixture of equal volume of acidified with 0.1% formic acid) acetonitrile.

Analysis by liquid chromatography/mass spectrometry (LC-MS)

After deposition of protein supernatant samples were analyzed from the Oseni metabolites using LC-MS in full scan. Information about the molecular weight was obtained for each detected metabolite. Picture of fragmentation as a result of additional experiments LC-MS/MS were analyzed in order to help identify patterns of primary metabolites.

Devices
HPLCSystem HPLC HP 1100 (Hewlett Packard, D-76337 Waldbronn, Germany)
MSLCQ (Finnigan Corporation, 355 River Oaks Parkway, San Jose, CA)
Conditions MS (LCQ)
The voltage source4,5 kV
Capillary temperature180°C
The gas flow in the casing80
Additional gas flow5
Source typeEPI
The mode of ionizationPositive
Conditions of HPLC
ColumnPhenomenex Synergi MAX-RP, 4 μm to 2.0×150 mm (Phenomenex, Torrance, CA)

The mobile phaseA=0,1% formic acid in water, B=CAN (acetonitrile)
The flow velocity0.2 ml/min
Temperature45°C
DetectionMass spectrometer LCQ
Gradient method
TimeAndB
09010
304060
30,11090
331090
33,19010
409010

Test results

The primary route of biotransformation detected for compounds, pre whom were returned an N-desetilirovania, N-dealkylation and hydroxylation. For compounds of the present invention, having a fluoro-substituted benzyl-piperazinilnom group, incubated rat hepatocytes have not found a glutathione adduct benzene. On the contrary, a certain amount of glutathione adduct on the ring found in incubated rat hepatocytes for similar compounds without fluoro-substituted benzyl rings.

How were synthesized in vivo

Way

Rats randomly assigned to eight groups for processing:

media-calm, media, stress, drug-calm, drug-stress. Probes were synthesized (CMA/12, the length of the membrane 4 mm for mPFC) are implanted in the brain for 2 hours before the experiment and perfusion artificial cerebrospinal fluid (CSF) (aCSF, CMA Microdialysis AB) with a flow rate of 1.1 ml/min for 2 h to stabilize the base value. Three samples taken after 20 min to determine the base value, animal VB. injected carrier or connection and the sampling is carried out in the next 5 hours Program procedures stress begin within 20 minutes after administration of the compounds. Samples immediately (interactively) is injected into the system high-performance liquid chromatography (HPLC) for analysis of concentrations of monoamines. The concentration of neurotransmitters in 3 clicks is Zach, selected before the introduction connections/media, average and determine the base value (100%). The concentration of neurotransmitters in the subsequent microdialysate then expressed as a percentage of base levels.

The procedure of stress

To stress use standard boxes for passive avoidance, equipped with lights, sound signals and shockers (Med Associates Inc.). The boxes are placed in a sound-proof chamber. The model of stress is carried out in one day. Animals will have acclimatised in the cells for 2 hours, then within 6 minutes is exposed to a series of flashing lights with subsequent electric foot shocks (duration 0.5 s, the intensity of 1.5 mA, a total of 10 shocks). "Quiet" group exposed in the camera exposure to light, but without shock. After 40 minutes the light sequence in the latter animals was repeated, but without shock.

Introduction of medicines

All compounds are dissolved in sterile distilled water (carrier) and injected intraperitoneally (V.B.) for 20 min before stress.

HPLC and electrochemical detection

The HPLC system consists of a pump 5041, detector model A Coulochem II, speakers MD-150 3×150 mm, amperometric cell model 5041 (all from ESA Inc) and injector online (from BAS Inc.). The mobile phase represents the t a: 75 mm Na 2HPO4, 25 mm EDTA, 1.7 mm 1-octanesulfonic acid, 100 μl/l triethylamine, 10% acetonitrile, pH 3.0. The potential set at the level to +0.65 V, the rate of flow is maintained at the level of 0.3 ml/min, Data are collected using the system information/analysis on the basis of personal computer (PC) (computer 501 and the software A/D Software, ESA, Inc.), integrated and transferred into a spreadsheet/graphics software for further analysis.

When groups of 6-8 rats prepared with intracerebral the probes were synthesized, placed in the middle prefrontal the cerebral cortex (where the neurochemical signal is strongest), is exposed to the model described above, in animals treated with diluent, find the increase in the concentration of norepinephrine (ne) and dopamine. Some compounds according to the invention block long increase in the concentration of ne and dopamine.

Model alarm Geller-Seifter (Geller-Siefter)

In a conflict test the hungry animals are trained to press a lever for admission feed in a standard operant chamber under two conditions. In the first condition, called "unrepressed component, the feed is delivered on average after 17 taps on the arm (also called the "scheme VR17 gain"). In the second condition, called the "depressed whom onent", which signalisiert flashes of light inside the operant chamber, the feed also comes in average after 17 presses the lever, but to the bottom of the cage additionally supplied electric shock in a separate schema VR17. Afternoon sessions consist of 5 interleaved presentations of each of the components: suppressed (duration 3 minutes) and unrepressed (duration 3 minutes). The number of clicks on the lever caused in a depressed component, is clearly lower compared with unrepressed component. Anti-anxiety agents such as diazepam, increasing the number of taps on the pedal, which animal produces in a depressed component over a range of doses, without changing the number of taps on the arm, which animal produces unrepressed component. Some compounds according to the invention in this way appear as anxiolytic drug.

EXAMPLES

The invention is additionally described in detail using the following examples, which describe the ways in which the compounds of the present invention can be obtained, purified, analyzed and subjected to biological testing, and are not considered as limiting the invention.

INTERMEDIATE COMPOUND 1: 4-Iodine-N,N-diethylbenzamide

To a mixture of 4-identified (75 g) in 500 ml of CH2Cl2at 0°C is obavljale mix Et 3N (50 ml) and Et2NH (100 ml). After adding the resulting reaction mixture was heated to room temperature within 1 h and then washed with saturated ammonium chloride. The organic extract was dried (Na2SO4), filtered and evaporated. The residue was recrystallized from hexanol to obtain 80 g of INTERMEDIATE COMPOUND 1.

INTERMEDIATE COMPOUND 2: 4-[hydroxy(3-nitrophenyl)methyl]-N,N-diethylbenzamide

N,N-Diethyl-4-itbased (5.0 g, 16 mmol) was dissolved in THF (150 ml) and cooled to -78°C. in atmosphere nitrogen. Dropwise within 10 minutes at a temperature of from -65°C to -78°C was added n-BuLi (15 ml, 1.07 M solution in hexane, 16 mmol). The solution was then Coulibaly 3-nitrobenzaldehyde (2.4 g, 16 mmol) in a mixture of toluene/THF (tetrahydrofuran) (approx. 1:1, 100 ml) at -78°C. After 30 min was added NH4Cl (aq). After evaporation in vacuo, extraction with a mixture of EtOAc/water, drying (MgSO4) and evaporation of the organic phase the residue was purified by chromatography on silica (0-75% EtOAc/heptane) to give the INTERMEDIATE COMPOUND 2 (2.6 g, 50%).

1H NMR (400 MHz, CDCl3) δn1.0-1.3 (m, 6H), 3.2 (m, 2H), 3.5 (m, 2H), 5.90 (s, 1H), 7.30-7.40 (m, 4H), 7.50 (m, 1H), 7.70 (d, J=8 Hz, 1H), 8.12 (m, 1H), 8.28 (m, 1H).

INTERMEDIATE COMPOUND 3: N,N-diethyl-4-[(3-nitrophenyl)(1-piperazinil)methyl]benzamide

To a solution of INTERMEDIATE COMPOUND 2 in the form of alcohol (of 10.01 g, 30,mmol) in dichloromethane (200 ml) was added thienylboronic (2,58 ml, 33.6 mmol). After one hour at room temperature the reaction mixture was washed with saturated aqueous sodium bicarbonate (100 ml) and the organic layer was separated. The aqueous layer was washed with dichloromethane (3×100 ml) and the combined organic extracts were dried (Na2SO4), filtered and evaporated.

The crude benzylbromide was dissolved in acetonitrile (350 ml) was added piperazine (10.5 g, 122 mmol). After heating the reaction mixture for one hour at 65°C. the reaction mixture was washed with a mixture of saturated ammonium chloride/ethyl acetate and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3×100 ml) and the combined organic extracts were dried (Na2SO4), filtered and evaporated to obtain racemic INTERMEDIATE COMPOUND 3.

INTERMEDIATE COMPOUND 4B: N,N-diethyl-4-[(R)-(3-nitrophenyl)(1-piperazinil)methyl]benzamide

Racemic INTERMEDIATE COMPOUND 3 was dissolved in stanol (150 ml) was added di-para-toluoyl-D-tartaric acid (to 11.79 g, 1 equivalent). The product was besieged within 12 hours. The solid product was collected by filtration and pererestorani in boiling under reflux ethanol to dissolve all solids (approximately 1200 ml of ethanol). After cooling, the solid was collected by filtration and recrystallization was repeated. Solid substances is about was collected by filtration and was treated with aqueous sodium hydroxide (2 M) and was extracted with ethyl acetate. The organic extract was then dried (Na2SO4), filtered and evaporated to obtain 1,986 g of INTERMEDIATE COMPOUND 4B.

1H NMR (400 MHz, CDCl3) δH1.11 (Shir. s, 3H), 1.25 (Shir. s, 3H), 2.37 (Shir. s, 4H), 2.91 (t, J=5 Hz, 4H), 3.23 (Shir. s, 2H), 3.52 (Shir. s, 2H), 4.38 (s, 1H), 7.31-7.33 (m, 2H), 7.41-7.43 (m, 2H), 7.47 (t, J=8 Hz, 1H), 7.75-7.79 (m, 1H), 8.06-8.09 (m, 1H), 8.30-8.32 (m, 1H).

Chiral purity was determined by HPLC using the following conditions:

Column Chiralpack AD (Daicel Chemical Industries)

The low rate of 1 ml/min

The analysis time of 30 minutes at 25°C.

Isocratic 15% ethanol (containing 0.1% vol./about. diethylamino) 85% hexane (containing 0.1% vol./about. diethylamino)

The retention time of a molecule = 20 minutes.

INTERMEDIATE COMPOUND 4A: N,N-diethyl-4-[(S)-(3-nitrophenyl)(1-piperazinil)methyl]benzamide

(S) Enantiomer of INTERMEDIATE COMPOUNDS 4A can be obtained by implementing the above procedure division using di-para-toluoyl-L-tartaric acid.

CONNECTION 1: 4{(S)-(3-AMINOPHENYL)[4-(4-terbisil)piperazine-1-yl]methyl-N,N-diethylbenzamide

To a solution of INTERMEDIATE 4A (467 mg) in 1,2-dichloroethane (13 ml) was added 4-forbindelse (252 μl, 2 EQ.) and triacetoxyborohydride sodium (498 mg; 2 equiv.). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 18 hours and evaporated. Added acadeny sodium bicarbonate and the aqueous solution was extracted with three portions of dichloromethane and the combined organic substance was dried over anhydrous sodium sulfate, was filtered and evaporated. The compound was dissolved in a mixture of ethanol, tetrahydrofuran, water and saturated ammonium chloride (4 ml; the ratio of 4:2:1:1 vol./vol.). Added iron nanoparticles (3 times on the tip of a spatula) and the solution was heated at 150°C for 10 minutes under the influence of microwaves. The resulting mixture was cooled, filtered through celite and evaporated. The residue was purified by flash chromatography on silica gel, elwira gradient from 1% to 5% Meon in dichloromethane. The obtained product was dissolved in dichloromethane to which was added 1.2 ml of 1 M HCl in diethyl ether. The solvent was removed and the product was isolated as hydrochloride salt with obtaining COMPOUND 1 (164 mg, 30%yield) as a colorless solid. Purity (HPLC): more than 99%; optical purity (chiral HPLC): more than 99%;

1H NMR (400 MHz, CD3OD), 1.08 (t, J=6.5 Hz, 3H), 1.21 (t, J=6.5 Hz, 3H), 3.20-3.26 (m, 4H), 3.51-3.54 (m, 6H), 4.43 (s, 2H), 7.19-7.23 (m, 2H), 7.34 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.54-7.63 (m, 3H), 7.70-7.82 (m, 4H). Found: C, 54,63; N, Of 6.49; N, 8,68. C29H36N4OF × 4,1 HCl × 0,8 H2O × 0.1 s4H10About have, 57,67; N, 6,51; N, 8,67%.

COMPOUND 2: 4-{(R)-(3-AMINOPHENYL)[4-(4-terbisil)piperazine-1-yl]methyl}-N,N-diethylbenzamide

To a solution of INTERMEDIATE 4B (5,790 g, 14.6 mmol) in 1,2-dichloroethane (60 ml) was added 4-forbindelse (2,04 ml, 19.0 mmol) and triacet sybolized sodium (as 4.02 g, 19.0 mmol). After 20 hours at room temperature, the reaction mixture was extinguished aqueous sodium bicarbonate and the organic layer was separated. The aqueous layer was extracted with dichloromethane (3×100 ml) and the combined organic extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography elwira 30-50% acetone in hexano obtaining a colorless foam (5,285 g, 71%), which represents a nitro intermediate connection. The nitro intermediate connection (5,285 g, 10.4 mmol) was dissolved in a mixture of ethanol, tetrahydrofuran, water and aqueous saturated ammonium chloride (ratio 4:2:1:1 vol./about.) (100 ml) was added iron nuggets (0,63 mg, 11.5 mmol). The reaction mixture was heated to the temperature of reflux distilled and was periodically added to the additional amount of iron granules. After 24 hours boiling under reflux (90°C.) the reaction mixture was cooled to room temperature and filtered through celite and evaporated. To the residue was added aqueous sodium bicarbonate and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×100 ml) and the combined organic extracts were dried (Na2SO4), filtered and evaporated. The residue was purified on silica gel, elwira 1-5% methanol in dichloromethane to obtain COMPOUND 2 (3,505 g) as a dark yellow foam. The crude substance updat the Executive was obtained by the above flash chromatography and was re-purified by a second flash chromatography elwira from 100% ethyl acetate to 5% methanol in ethyl acetate to obtain more 0,949 g of COMPOUND 2. Received combined substance: 4,454 g (yield 90%). Purity (HPLC): more than 99%; optical purity (chiral HPLC): more than 99%;1H NMR (400 MHz, CD3OD) 1.08 (t, J=6.5 Hz, 3H), 1.21 (t, J=6.5 Hz, 3H), 3.20-3.26 (m, 4H), 3.51-3.54 (m, 6H), 4.43 (s, 2H), 7.19-7.23 (m, 2H), 7.34 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.54-7.63 (m, 3H), 7.70-7.82 (m, 4H). Found: C, 54,00; N, 6,34; N, Of 8.47. C29H35FN4O × 4,7 HCl × 0.2 s4H10About × 0,1 H2O has, 54,02; N, 6,37; N, 8,46%.

COMPOUND 3: 4-[(R)-(3-AMINOPHENYL)[4-[(2-forfinal)methyl]-1-piperazinil]methyl] - N,N-diethylbenzamide

To a solution of INTERMEDIATE 4B (298 mg, 0,752 mmol) in 1,2-dichloroethane (8.5 ml) was added 2-forbindelse (160 mg, 1,503 mmol, 2 EQ.) and triacetoxyborohydride sodium (319 mg, 1,503 mmol, 2 EQ.). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 18 hours and evaporated. Was added saturated sodium bicarbonate and the aqueous solution was extracted with three portions of dichloromethane and the combined organic substance was dried over anhydrous sodium sulfate, filtered and evaporated. The compound was dissolved in a mixture of ethanol, tetrahydrofuran, water and saturated ammonium chloride (3 ml; the ratio of 4:2:1:1 vol./vol.). Added iron nanoparticles (3 times on the tip of a spatula) and the solution was heated Ave is 150°C for 10 minutes under the influence of microwaves. The resulting mixture was cooled, filtered through celite and evaporated. The crude substance was dissolved in CH2Cl2and washed with water. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried (Na2SO4), filtered and evaporated. The product was purified by reverse-phase HPLC (gradient 5-50% CH3CN in H2O containing 0.1% TFU) to obtain COMPOUND 3 (0.28 g, yield 46%) as a salt TFU. Substance liofilizirovanny of CH3CN/H2O obtaining dark yellow powder.1H NMR (400 MHz, CD3OD) 1.08 (t, J=6.6 Hz, 3H), 1.22 (t, J=6.6 Hz, 3H), 2.39 (Shir. s, 2H), 3.02 (Shir. s, 2H), 3.18-3.38 (m, 4H), 3.43 (Shir. s, 2H), 3.52 (q, J=6,8 Hz, 2H), 4.43 (s, 2H), 4.53 (s, 1H), 7.09 (dt, J=2,3, 6,8 Hz, 1H), 7.24-7.30 (m, 1H), 7.30-7.41 (m, 6H), 7.52-7.60 (m, 4H). Anal. the expect. for C29H35FN4O × 2,8 TFU × 0,4 H2ABOUT: WITH, 51,88; N, A 4.86; N, 6,99. Found: C, 51.89ˆ; N, 4,89; N, 6,97%. MS (expect.): 475,3 (MN+), MS (detection.): 475,2 (MH+). HPLC: k': 2,35; purity: more than 99% (215 nm), more than 99% (254 nm), more than 99% (280 nm). The HPLC conditions: Bond C-18, gradient 10-95% B, flow rate: 1 ml/min, 25°C: 0,1% TFU in H2O, B: 0.1% OF TFU in N.

Rotation: [α]16D=-8,91 (c=1,179, Meon).

COMPOUND 4: 4-[(R)-(3-AMINOPHENYL)[4-[(3-forfinal)methyl]-1-piperazinil]methyl]-N,N-diethylbenzamide

To a solution of INTERMEDIATE 4B (281 mg, 0,709 mmol) in 1,2-dichloroethane (8 ml) is obavljale 2-forbindelse (180 mg, 1,417 mmol, 2 EQ.) and triacetoxyborohydride sodium (300 mg, 1,417 mmol, 2 EQ.). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 18 hours and evaporated. Was added saturated sodium bicarbonate and the aqueous solution was extracted with three portions of dichloromethane and the combined organic substance was dried over anhydrous sodium sulfate, filtered and evaporated. The product was dissolved in a mixture of ethanol, tetrahydrofuran, water and saturated ammonium chloride (3 ml; the ratio of 4:2:1:1 vol./vol.). Added iron nanoparticles (3 times on the tip of a spatula) and the solution was heated at 150°C for 10 minutes under the influence of microwaves. The resulting mixture was cooled, filtered through celite and evaporated. The resulting product was dissolved in CH2Cl2and washed with water. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried (Na2SO4), filtered and evaporated. The product was purified by reverse-phase HPLC (gradient 5-50% CH3CN in H2O containing 0.1% TFU) to obtain COMPOUND 4 (0.375 g, yield 65%) as a salt TFU. This substance liofilizirovanny of CH3CN/N2About obtaining a dark yellow powder.1H NMR (400 MHz, CD3OD) 1.08 (t, J=6.4 Hz, 3H), 1.21 (t, J=6.8 Hz, 3H), 2.38 (Shir. s, 2H), 3.00 (Shir. s, 2H), 3.16-3.28 (m, 4H), 3.40 (Shir. s, 2H), 3.51 (q, J=6,8 Hz, 2H), 4.37 (s, 2H), 4.56 (s, 1H), 7.18 (ddd, J=1,2, 2,3, 7,8 Hz, 1H), 7.24 (ddd, J=1,0, 2,7, 8,8 Hz, 1H), 7.28-7.38 (m, 4H), 7.55 (d, J=8,2 Hz, 2H).

Anal. the expect. for C29H35FN4O × 2,7 TFU × 1,1 H2O: C, 51,50; N, FREE 5.01; N, 6,98. Found: C, 51,52; N, Free 5.01; N, 6,87%. MS (expect.): 475,3 (MN+), MS (detection.): 475,2 (MH+). HPLC: k': 2,43; purity: more than 99% (215 nm), more than 99% (254 nm), more than 99% (280 nm). The HPLC conditions: Bond C-18, gradient 10-95% B, flow rate: 1 ml/min, 25°C: 0,1% TFU in H2O, B: 0.1% OF TFU in MeCN. Rotation: [α]16D=-8,94 (C=1.04 million, the Meon).

1. Diphenylbutylpiperidine compound of the formula

its pharmaceutically acceptable salt or their mixture.

2. Enantiomerically pure 4-{(R)-(3-AMINOPHENYL)[4-(4-terbisil)piperazine-1-yl]methyl}-N,N-diethylbenzamide or its pharmaceutically acceptable salt.

3. The method of treatment of anxiety in a warm-blooded animal, including the introduction of a specified animal in need of such therapy, the compounds according to claim 1 or 2, or its pharmaceutically acceptable salt in an amount effective for such treatment.

4. The method of treatment of pain in a warm-blooded animal, including the introduction of a specified animal in need of such therapy, the compounds according to claim 1 or 2, or its pharmaceutically acceptable salt in an amount effective for such treatment.

5. Method of treating depression in a warm-blooded animal, including the introduction of a specified animal needs is usemouse in such therapy, compounds according to claim 1 or 2, or its pharmaceutically acceptable salt in an amount effective for such treatment.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention refers to benzamide 4-(phenyl-piperazin-methyl) derivatives of the general formula I in which R1 - aryl, heteroaryl, selected from the group which includes difuryl, pyridyl and thienyl; R2 - hydrogen or C1-12 alkyl. The methods of preparation of the compounds, pharmaceutical composition on their basis and application while preparing medicines are described.

EFFECT: compounds can be applied to treatment of pain and functional gastroenteric upset.

8 cl, 1 ex

Casr antagonist // 2315036

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel compound represented by the following formula (1) , its pharmaceutically acceptable salts or optically active isomers wherein each symbol is given in the invention description. Proposed compound possesses antagonistic effect with respect to calcium-sensitive receptor (CASR). Also, invention relates to a therapeutically medicinal agent used in treatment of osteoporosis based on this compound, to a method for treatment of osteoporosis, calcium receptor antagonist and to agent promoting secretion of parathyroid hormone (PTH).

EFFECT: valuable medicinal properties of antagonist.

33 cl, 66 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to R-2-aminoarylpropionic acid amides and pharmaceutical composition comprising thereof that can be used for prophylaxis and inhibition of recruiting and activation of leukocytes, and in treatment of pathologies directly dependent on indicated activation. Invention proposes compound of the general formula (1): wherein A, q, Ph and R have corresponding values, or its pharmaceutically acceptable salt. Also, invention describes a method for preparing amide of the formula (1) and pharmaceutical composition used in prophylaxis of leukocytes activation. Invention provides the development of pharmaceutical composition that can be used for prophylaxis and treatment of damaged tissues caused by enhancing activation of neutrophile granulocytes (polymorphonuclear leukocytes) in inflammation foci. Also, the invention relates to R-enantiomers 2-(aminoaryl)-propionylamides of the formula (1) that can be used for suppression of neutrophyles hemotaxis caused by IL-8. Also, compounds of this invention can be sued in treatment of psoriasis, ulcerous colitis, glomerulonephritis, acute respiratory insufficiency and rheumatic arthritis.

EFFECT: valuable medicinal properties of compounds.

8 cl, 16 ex

The invention relates to pharmaceutically acceptable salts of the compounds of formula (I) or solvate specified salts in which the compound of formula (I) is in the form of (R)-enantiomer, (S)-enantiomer or the racemate

The invention relates to derivatives of N-(4-carbamimidoyl) glycinamide formula (I), where E denotes hydrogen or HE, Q denotes hydrogen or alkyl, R is aryl, cycloalkyl or alkyl substituted radicals R1, R2, R3, R1denotes hydrogen, COOH, COO-alkyl or aryl, R2denotes hydrogen, aryl, cycloalkyl or heteroaryl, R3denotes hydrogen, aryl or HE (in any position other thanposition relative to the nitrogen atom is attached to an alkyl group R) or optional substituted by an amino group, three of the radicals X1-X4denote the group of C(Ra), C(Rb) or C(Rc), and the fourth represents C(Rd), Ra-Rddenote H, HE, NO2dialkylamino, halogen, alkyl, alkoxy, aryloxy, aralkylated, heteroarylboronic, geterotsiklicheskikh, COOH, COO-alkyl, NH-SO2-alkyl, NH-SO2-aryl, two adjacent groups Ra-Rbdenote alkylenedioxy, G1and G2denote hydrogen, HE, the invention relates to intermediate compounds of the formula (IV), (V), (VI) used in the methods of making compounds of formula (I), and are in взаимодействCN, the nitrile of formula (IV) is transformed into amidinopropane C(N-G1)NH-G2

The invention relates to new compounds of the formula (I), where R1is hydrogen or a fragment of ester, E is hydrogen or hydroxy, three of X1-X4denote the group of C(Ra), C(Rb) or C(Rc), and the fourth represents C(Rdor N, where Ra-Rdis hydrogen, alkenyl, quinil, alkenylacyl, alkoxy, alkylamino, alkoxyalkyl, alkoxyalkanols, alkoxycarbonylmethyl, alkoxycarbonylmethyl, alkoxycarbonylmethyl, alkyl, alkoxycarbonylmethyl, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl, allylurea, allylthiourea, alkylsulfonamides, alkylsulfonyl, aminoethoxy, arylalkyl, Allakaket, arylalkyl, arylalkylamine, arylcarboxylic, arylcarboxamide, aryloxy, aryloxyalkyl, arylsulfonyl, arylsulfonamides, carboxy, carboxylic, substituted alkyl, substituted amino, halogen, substituted halogen, cycloalkyl, substituted cycloalkyl, hydroxy, substituted hydroxy, heterocycle, substituted heterocycle, or two adjacent groups of Ra-Rdtogether form the fragment condensed di - or monooxygenase ring or aryl ring

The invention relates to new derivatives of 1,2,3,4-tetrahydronaphthalene formula (I) as (R)-enantiomers, (S)-enantiomers or racemates, in the form of free base or pharmaceutically acceptable salt or solvate, where X is N or CH; Y is NR2-CH2, NR2-CO or CO-NR2; R2represents N or C1-C6-alkyl; R1represents N or C1-C6-alkyl; R3represents phenyl which may be mono - or Disaese4; R4represents H, halogen, CN, CF3WITH1-C6-alkoxy, optionally substituted heterocyclic ring containing one or two heteroatoms selected from N, O, or COR8; R8represents a heterocyclic ring containing one or two heteroatoms selected from N, O; R9is1-C6-alkyl, ОСНF2HE, halogen, C1-C6-alkoxy, C1-C6-alkoxy - C1-C6-alkyl

The invention relates to new derivatives of 4-(1-piperazinil)benzoic acid of formula I in which Ar represents a mono-, di - or tricyclic aryl having from 6 to 14 carbon atoms, while Ar may have from 1 to 3 substituents selected from the group comprising (C1-C8)alkyl, (C1-C8)alkoxy, halogen, trifluoromethyl; R1selected from the group comprising a hydrogen atom, cycloalkyl containing from 3 to 8 carbon atoms, (C6-C14)aryl, heteroaryl(C1-C6)alkyl, and heteroaryl selected from the group comprising furyl; R2and R3is hydrogen, a solvate and a pharmaceutically acceptable salt

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) and formula (II), their tautomers and pharmaceutically acceptable salts. In formula (I) and in formula (II), X - S; R1 - H; R2 - NR5R6; R3 - 5-6-member heteroaryl with 1 heteroatom, selected from N and S, or phenyl, optionally substituted with one or two substituents, selected from halogen, amino, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-halogenalkyl and C1-C6-halogenalkoxy; R4 - H, C1-C6 alkyl, C1-C6 alkoxy or XR3, where X and R3 are determined above; R5 - H; R6 - H; L - N or CR7, where R7 - H; M - S. Invention also relates to pharmaceutical composition, containing as active component invention compound, to method of inhibiting activity of caseinkinase lε and to method of obtaining compounds of formula (I) or formula (II).

EFFECT: compounds of claimed invention possess properties of casein kinase lε inhibitors.

13 cl, 5 tbl, 44 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmaceutical chemistry, namely to manufacturing anti-depression mianserin hydrochloride-base medication. Medication is made in form of tablets and contains mianserin hydrochloride, calcium diphosphatedihydrate, potato starch, methylcellulose, aerosil, magnesium stearate with film coating on the basis of hydroxypropylmethylcellulose. In accordance with method of manufacturing, mianserin hydrochloride, calcium diphosphatedihydrate, 60% of potato starch mass and 40% of aerosol mass are mixed, after which mass is moisturised with methylcellulose, preliminarily dissolved in water and heated to temperature 45-55°C, obtained wet mass is dried to residual humidity 2.5-3.0%, granulated through sieve with hole diametre 1-1.5 mm and is mixed with the remaining 40% of starch and 60% of aerosol, magnesium stearate is added, by means of pressing obtained are tablets-nuclei, onto which film coating based on hydroxypropylmethylcellulose is applied. Also determined is crystal structure of preparation.

EFFECT: invention ensures obtaining of tablets with sufficient strength and time of dissolution within 15-20 minutes.

6 cl, 3 dwg, 12 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to field of pharmaceutics and medicine and concerns application of trans-5-chlor-2-methyl-2,3,3a, 12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole for production of pharmaceutical preparation for treatment of bipolar disorder in mammal, method of treating bipolar disorder and set for application in treatment of bipolar disorders.

EFFECT: invention ensures high treatment efficiency.

16 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 2-alkylamino-3-sulfonyl-pyrazolo[1,5-a]pyrimidines, their pharmaceutically acceptable salts and/or hydrates which have serotonin 5-HT6 receptor antagonist properties and can be used in treating or preventing development of various central nervous system diseases, whose pathogenesis is related to 5-HT6 receptors, particularly Alzheimer's disease, Parkinson's disease, Huntington disease, schizophrenia, other neurodegenerative diseases, cognitive and anxiety disorders and obesity. In general formula (I):

R1 and R3 independently denote optionally identical C1-C3alkyl, R2 is a -(CH2)nX group or R1 and R3 independently denote different substitutes selected from C1-C3 alkyl or a -(CH2)nX group, and R2 is a hydrogen atom or C1-C3alkyl; R4 is C1-C3alkyl; Ri5 is a hydrogen atom, one or two identical or different halogen atoms, C1-C3alkyl; i is equal to 0, 1 or 2; n is equal to 0, 1, 2 or 3; X is a carboxyl CO2H, C1-C3alkyloxycarbonyl, aminocarbonyl CONR6R7 or a NR6R7 amino group; R6 and R7 denote optionally identical hydrogen atom, optionally substituted C1-C3 alkyl, C3-C7cycloalkyl or an optionally substituted 5-7-member azaheterocyclyl containing 1-2 nitrogen atoms in the ring, where the substitutes are selected from C1-C3alkyl; or R6 and R7 together with the nitrogen atom to which they are bonded form an optionally substituted 5-6-member azaheterocyclyl containing 1-2 nitrogen atoms in the ring, where the substitutes are selected from C1-C3alkyl.

EFFECT: obtaining new biologically active compounds.

26 cl, 12 dwg, 4 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of the formula (I) where: A is an aryl or a 5-member heteroaryl containing a S heteroatom, possibly substituted with one or two substitutes selected from a group consisting of halogen, C1-6-alkyl or C1-6-alkoxy; n equals 1 or 2; p equals 1, 2, 3 or 4; q equals 1; r equals 0 or 1; R1 is C2-6-alkynyl substituted with aryl, or C1-6-alkyl possibly substituted with one-five substitutes selected from a group consisting of halogen, hydroxy, C1-6-alkyl, C1-6-halogenoalkyl, -OC(O)-C1-6-alkyl, C3-10-cycloalkyl, C1-6-alkoxy, possibly substituted with one, two or three halogens or aryl, aryl which is possibly substituted with a halogen or C1-6-alkoxy, 5-9-member heteroaryl, one, two or three ring atoms of which are heteroatoms selected from N or O, and the rest of the ring atoms are C atoms, possibly substituted with C1-6-alkyl, and phenoxyl, or is C1-6-alkoxy, or is C3-10-cycloalkyl which is possibly substituted with one or more Ra, or is a 5- or 6-member heterocycloalkyl containing one, two or three heteroatoms selected from nitrogen, oxygen or sulphur, possibly substituted with one or more Ra, or is an aryl possibly substituted with one or more Ra, or is a 5-10-member heteraryl, one, two or three ring atoms of which are heteroatoms selected from N, O and S, and the rest of the ring atoms are C atoms, possibly substituted with one or more Ra, or is -NRbRc, where Rb is H or C1-6-alkyl and where Rc is H, C1-6-alkyl or aryl, possibly substituted with one or more Ra, where Ra is selected from: halogen, cyano, oxo, hydroxy, halogenobenzenesulfonyl, C1-6-alkyl, possibly substituted with one, two or three substitutes selected from a group consisting of 5-10-member heterocycloalkyl and aryl, which is possibly substituted with halogen or C1-6-alkoxy, C1-6-halogenoalkyl, C1-6-halogenoalkoxy, C1-6-alkoxy, possibly substituted with aryl or 5-10-member heteroaryl, one, two or three ring atoms of which are heteroatoms selected from N, O and S, and the rest of the ring atoms are C atoms, which is possibly substituted with C1-6-alkyl, aryloxy, -NH(CO)-C1-6-alkyl, -O(CO)-C1-6-alkyl, C1-6-alkylsulfonyl, aryl, 4-6-member heterocycloalkyl containing one, two or three heteroatoms selected from nitrogen, oxygen or sulphur, possibly substituted with hydroxy, C1-6-alkyl or oxo, 5-10-member heteroaryl,one, two or three ring atoms of which are heteroatoms selected from N and O, and the rest of the ring atoms are C atoms, possibly substituted with C1-6-alkyl or oxo, and di(C1-6)alkylamino; R2 is H, OH, C1-6-alkyl or halogen; as well as their pharmaceutically acceptable salts. The invention also relates to medicine and to use of the compounds in any of paragraphs 1-24.

EFFECT: obtaining novel biologically active compounds with affinity to dopamine D3 receptor and to serotonin 5- HT2a receptor.

27 cl, 86 ex

FIELD: medicine.

SUBSTANCE: invention relates to pharmaceutical industry, in particular to composition for treatment of depression. Pharmaceutical composition for depression treatment which includes one of initial material compositions, taken in defined quantity: ginseng and licorice root; water extract of ginseng or ethanol extract of ginseng and water extract of licorice or ethanol extract of licorice; ginseng and water extract of licorice or ethanol extract of licorice; water extract of ginseng or ethanol extract of ginseng and licorice root. Pharmaceutical composition for treatment of depression, which contains water extract of ginseng or ethanol extract of ginseng and acid relative to glycyrrhizic acid. Method of obtaining pharmaceutical composition for treatment of depression, which includes drawing of ginseng in ethanol solution of with obtaining of first extract; purification of first extract with obtaining of second extract; drawing licorice root in water with obtaining of third extract; its drying, and mixing and filtering of second and third extracts. Method of obtaining pharmaceutical composition, which includes mixing of ginseng extract with acid, relative to glycyrrhizic acid.

EFFECT: compositions are effective for treatment of depression.

18 cl, 3 dwg, 1 tbl, 10 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 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

FIELD: medicine.

SUBSTANCE: invention refers to compounds having anxiolytic and antidepressant activity, which are derivatives of the formula 1 (a-b), or formula 2 (a-b) at that compounds of formula 2 (a-b) are intermediate products in synthesis of compounds of the formula , where R-Cl is a compound 1a or R'=COOC2H5 - compound 1b, , where R=COOC2H5 and R'=C1 - compound 2a; R=R-COOC2H5 - compound 2b.

EFFECT: obtaining new biologically active compounds that differ from analogues as intended in low toxicity and lack of side effects.

5 cl, 3 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of general formula 1, their pharmaceutically acceptable salts and/or hydrates having serotonin 5-HT6 receptor antagonist properties. In general formula 1 , R1 and R3 independently denote optionally identical C1-C3 alkyl, and R2 is a -(CH2)nX group or R1 and R3 independently denote different substitutes selected from C1-C3 alkyl or a -(CH2)nX group, and R2 is a hydrogen atom or C1-C3 alkyl; R4 is C1-C3 alkyl; Ri5 is a hydrogen atom, one or two identical or different halogen atoms, C1-C3 alkyl; equals 0, 1 or 2; n equals 0, 1, 2 or 3; X is a carboxyl CO2H, C1-C3 alkyloxycarbonyl, aminocarbonyl CONR6R7 or amino group NR6R7; except compounds in which R3 is a -(CH2)nX group, where X is an amino group NR6R7 and n equals 0; R6 and R7 are optionally identical and denote a hydrogen atom, optionally substituted C1-C5 alkyl or R6 and R7 together with the nitrogen atom with which they are bonded form an optionally substituted 6-member azaheterocyclyl containing 1-2 nitrogen atoms in the ring, where the substitute is selected from C1-C3 alkyl.

EFFECT: obtaining compounds which can be used in treating diseases of the central nervous system during prevention or treatment of cognitive disorders, neurodegenerative diseases, psychiatric disorders, have anxiolytic and nootropic effect and can be used to prevent and treat anxiety disorders and enhance mental capacity.

25 cl, 2 tbl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I , where: R1, R2, R3 and R4 independently from each other mean hydrogen, F, CI, Br, I; R5 designates hydrogen, alkyl with 1, 2, 3, 4, 5 or 6 C atoms, or cycloalkyl with 3, 4, 5 or 6 C atoms; R6 designates hydrogen; R7 and R8 independently from each other mean hydrogen, W means CrH2r or CsH2S-2; and one or more CH2-groups in C2H2r and CsH2s-2 can be substituted with NR17, oxygen or S; R17 means hydrogen, alkyl with 1, 2, 3 or 4 C atoms; r means 1, 2, 3, 4, 5 or 6; s means 2, 3 or 4; X designates-with C(O)- or -S(O)2-; Z means -C(O)- or a bond; and also to their pharmaceutically acceptable salts and trifluoroacetates. The invention also concerns application of the compounds of formula I, and also to a pharmaceutical composition.

EFFECT: preparation of new biologically active compounds exhibiting NHE3 inhibiting activity.

16 cl, 64 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly to pharmacology and concerns application of derivatives of gamma-aminobutyric acid in the form of 4-amino-3-phenyl butane acid salts of general formula

as an anxiolytic and cerebroprotective agent reducing inclination to alcohol.

EFFECT: preparation of the agent with reduced by-effects.

2 cl, 10 tbl, 14 ex

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