Piperazinovogo connection

 

(57) Abstract:

Describes the new piperazinovogo compounds of General formula I, where one of R8and R9represents phenyl which may be substituted by one or more substituents selected from the group comprising halogen, C1- C3-alkoxy, C1-C3-alkyl and trifluoromethyl, and the other of R8and R9represents hydrogen, C1-C6-alkyl, C3- C6-cycloalkyl,3-C6alkenyl or3-C6-quinil; any two of R3, R4and R5represent methyl and the other radical is hydrogen; R6represents a hydrogen atom, a C1-C6-alkyl, C3-C6-cycloalkyl,3-C6alkenyl or3-C6-quinil; and its pharmaceutically acceptable simple, ester, salt or physiologically functional derivative. The compound of formula 1 can be used as agonist/antagonist which pairs of conjugates to monitor transduction and study the function of neurotransmitters, and they demonstrate a variety of therapeutic applications, including mediating analgesia, and the ability ispolzovanie, caused by an overdose of drugs and alcohol, pulmonary edema, depression, asthma, emphysema and asthma, cognitive disorders and diseases of the gastrointestinal tract. 3 table.

This invention relates generally compounds having diarylpyrimidine nature and finds application in therapy mainly as the receptor-binding compounds, i.e. as agonist/antagonist pairs of components conjugates, for testing/analysis of the action of receptors and neurotransmitters. Compounds provided by the present invention include substances diarylpyrimidine nature, which can be, on the one hand, used as a mu and/or Delta-opioid receptor compounds mediating the analgesia, and to find application in the treatment of pains of different nature, in the fight against drug addiction and alcoholism, in the treatment of conditions caused by overdose of drugs, mental illness, urinary incontinence, treatment of cough, pulmonary edema, diarrhea, depression, and cognitive, respiratory and gastro-intestinal disorders. The invention also relates to pharmaceutical compositions comprising such compounds, methods of treatment of some rimii opioid compounds led to the identification of a large number of different compounds of this class as endogenous, and exogenous origin. A considerable part of the research was focused on the elucidation of the mechanism of action of opioid drugs nature, particularly how they interact with the opiate receptors of the cells and differentiated tissues.

Usually medication opioid nature is classified according to the selectivity of their binding to receptors on cells and differentiated tissues, which specific kind of medication binds as a ligand. Such receptors include mu () - Delta (), Sigma () and Kappa ( ) - receptors.

Widely known narcotic opioids, such as morphine and its analogues selective for opioid mu-receptors. Mu receptors are mediators in analgesia, respiratory depression and inhibition of the passage of contents through the GI tract. Kappa-receptors mediate the analgesia and sedation. Sigma receptors mediate a variety of biological activity.

The existence of opioid Delta receptor was discovered relatively recently, following the isolation and study of characteristics of endogenous enkephalinergic peptides that are ligands for this receptor. Research poslednego the red paintings of his actions. Delta-receptors mediate the analgesia, but, apparently, are not inhibitors of intestinal transit like mu-receptors.

Usually opioid agents are characterized as agonists or antagonists. Agonists and antagonists are agents that recognize and bind to the receptors, causing (either initiating or blocking) biochemical/physiological effects; this process is known as transduction. Agonists inhibit or suppress the release of neurotransmitters in the tissue containing receptors, such as inhibition of pain responses or effects on other phenomena associated with their output. Antagonists also bind to receptors but do not inhibit the release of neurotransmitters. Thus, antagonists bind to the same receptor sites as the agonists, and block binding of the latter.

With regard to specific receptor ligands, previously the difference between the Delta receptor agonists and antagonists have been made on the basis of their activity in assays using stimulated by an electric current sperm receptacles mouse, which is usually considered as a suitable tissue for diagnosis Delta-receptors. In the anti-Christ. Noah electric current ileum of the Guinea pig.

Known only to a relatively small number obtained in pure form agents, selective for the Delta receptor. Except for the Delta-opioid receptor antagonists and agonists described in patents (U.S. patent 4,816,586; international patent application WO93/15062), all known selective for the Delta opioid receptor compounds are peptides, including endogenous enkephalins and other endorphins, as well as analogues of exogenous peptides. All previously synthesized analogs of exogenous peptides have many disadvantages in terms of their stability, possible appropriate ways to deliver them as medicinal agents and their distribution in vivo in tissues.

Studied various physiological effects known opioid peptide ligands, such as analgesia, respiratory depression, gastrointestinal effects, the impact on mental, emotional, and cognitive functional activities and mediating/modulation of other physiological processes.

(U.S. patent 4,518,711) describes the cyclic conformationally strained analogs of enkephalins. Among these compounds are agonists and antagonists delete, as compounds of the present invention, are compounds of polyaryletherketones nature, are described in the following works.

S. Goenechea etc. describes the oral administration of the compounds of polyaryletherketones nature in the study of metabolism meclozine in the human body (Goenechea S. et. al. Investigation of the biotransformation of meclozine in the human body. J. Clin. Chem. Clin. Biochem., 26(2), 105-115, (1988)).

(W. Meuldermans et. al. Plasma levels, biotransformation, and excretion of oxatomide in rats, dogs, and man. Xenobiotica, 15(6), 445-462, (1984)) held metabolic analysis of the content in the plasma, biotransformation and excretion of oxatomide.

T. Iwamoto and others (T. Iwamoto et. al. Effects of KB-2796, a new calcium antagonist, and other diphenylpiperazines on [3H]nitrendipine binding. Jpn. J. Pharmacol. , 48(2), 241-247, (1988)) describes the effects of the individual compounds of polyaryletherketones nature as a calcium antagonist.

K. Natsuka, etc. describes the racemates and enantiomers of substituted on the first position of 4-[2-(3 oksifenil)-1-phenylethyl]piperazinone derivatives (Natsuka K. et. al. Synthesis and structure-activity relationships of 1-substituted 4-(1,2-diphenylethyl)piperazine derivatives having narcotic agonist and antagonist activity. J. Med. Chem., 30(10), 1779-1787, (1987)).

(The application for the European patent N 458,160) described substituted derivatives difenilmetana used in kachestva, linking the two phenyl half of the molecules may have as a substituent at its carbon atom piperidino or piperazinilnom group.

(Patent application South Africa N 8604522) described N-substituted arylalkyl and arylalkylamine amino-heterocyclic compounds, including derivatives of piperidine, which presents useful as cardiovascular, antihistamines and antisecretory agents.

(The application for the European patent N 133,323) described some compounds diphenylbutylpiperidines nature, useful as reseating antihistamines.

The need for improved opioid compounds, especially not with harmful side effects that are inherent to traditional opiates, like morphine and pethidine, there constantly.

The present invention particularly relates to compounds of diarylpyrimidine nature, corresponding to the formula:

(I)

where one of the radicals R8and R9represents phenyl, possibly substituted by one or more substituents selected from the group comprising halogen, C1-C3alkoxy, C1-C3alkyl and trifluoromethyl, and the other was from radical the-C6alkenyl or C3-C6quinil; any two of the radicals R3, R4and R5represent methyl and the other radical represents hydrogen; and R6represents hydrogen, C1-C6alkyl, C3-C6cycloalkyl, C3-C6alkenyl or C3-C6quinil; and its pharmaceutically acceptable simple ether, ester, salt or physiologically functional derivative.

The term "alkyl" in the context of the present invention involves a broad interpretation, including both alkyl groups with non-branched chain, and alkyl groups having a branched chain structure.

By "physiologically functional derivative" refers to pharmaceutically acceptable salt, complex or simple esters or salts of these esters are compounds corresponding to the formula (I), or other connection, which is being introduced to the recipient is able to form (directly or indirectly) of the above compound of formula (I) or active metabolite or residue. Phenolic C1-C6alkalemia esters represent a subclass of physiologically functional derivatives of the compounds of formula (I).

The enantiomeric forms of the compounds,shrub, free of other enantiomers or in the form that may contain impurities (in a mixture of enantiomeric pairs and/or in a mixture of numerous varieties of enantiomers).

A subclass of compounds described by formula (I) are compounds in which R6, R8or R9represents a C1-C6alkyl or C3-C6cycloalkyl.

A subclass of compounds described by formula (I) are compounds in which R3and R5both represent methyl, and R4- hydrogen.

One of the preferred subclasses of compounds covered by this invention are compounds corresponding to the formula:

(II)

where R6, R8and R9are the same as defined above.

The following subclass of compounds described by formula (I) are compounds in which R6represents a C3-C6alkenyl or C3-C6quinil and preferably allyl group.

Another subclass of compounds described by formula (I) are compounds in which either R8or R9is a phenyl group which may be substituted by one of the following substituents: halogen atom, a Cwhether fluorine and/or group C1-C6- methoxy group.

Another subclass of compounds described by formula (I) are compounds in which one of R8and R9represents an unsubstituted phenyl group.

The following subclass of compounds described by formula (I) are compounds in which the other of R8and R9represents a hydrogen atom, a C1-C6alkyl, C3-C6cycloalkyl, or allyl group. Preferably, C3-C6the alkyl represented, for example, methyl, ethyl or through the group (including n-, ISO - and cyclo-through the group).

From the point of view of specificity and preference diarylpyrimidine derivatives described by the above formula, the compound NR8R9can be selected, for example, from the group consisting of:

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Examples benzamide compounds that meet the above General formula (I) and covered by the invention described below.

3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-(4-forfinal)-N-methylbenzamide;

3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl-N-methyl-N-phenylbenzene;

3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-dibenzyl)-N-ethyl-M-phenylbenzene;

(-) - 3 ( (R)-- ((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-phenylbenzene;

3-( ((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-methyl-N-(2-permitil)phenyl)benzamide;

3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl-N-methyl-N-(2,4,6-trichlorophenyl)benzamide;

3-( (R)-- ((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-(3-forfinal)-N-methylbenzamide;

3- ( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-phenyl-N-propylbenzamide;

3-( (R)-- (((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-(4-forfinal)-N-methylbenzamide;

3-( (R)-- (((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-(2-forfinal)-N-methylbenzamide;

3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-ethyl-N-(4-forfinal)benzamide;

3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-allyl-N-phenylbenzene;

-3-( (R)-- ((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-(cyclopropyl)methyl-N-phenylbenzene;

3-( (R)-- ((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-isopropyl-N-phenylbenzene;

3-( (R)-- ((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-cyclopropyl-N-phenylbenzene;

3-( (R)-- ((2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-(3-forfinal)-N-propylbenzamide;

3-( (R)-- ((2S, l-1-piperazinil)-3 - oxybenzyl)-N-ethyl-N-(2-forfinal)benzamide;

3-( (R)-- (2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-(4-methoxyphenyl)-N-propylbenzamide;

3-( (R)-- (2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-ethyl-(4-methoxyphenyl)-N-propylbenzamide;

3-( (R)-- (2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-ethyl-(4-methoxyphenyl)-N-benzamide;

3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-methyl-N-phenylbenzene;

3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - methoxybenzyl)-N-(3-forfinal)-N-methylbenzamide;

3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - methoxybenzyl)-N-ethyl-N-(4-forfinal)-benzamide;

3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3- (oxybenzyl)-N-(4-methoxyphenyl)-N-propylbenzamide;

3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3- (N-(3-forfinal)-N-methylcarbamoyl)benzyl)MENILMONTANT; and their pharmaceutically acceptable simple and esters, salts or physiologically functional derivatives.

Particularly preferred compounds of the above list of compounds provided by the invention are:

3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-(4-forfinal)-N-methylbenzamide;

3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-methyl-N-phenylbenzene;

the Il-1-piperazinil)-3 - oxybenzyl)-N-phenyl-N-propylbenzamide;

3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-(4-methoxyphenyl)-N-methylbenzamide;

3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-(2-forfinal)-N-methylbenzamide;

3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-(3-forfinal)-N-methylbenzamide;

3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-ethyl-N-(4-forfinal)-benzamide; and their pharmaceutically acceptable simple and esters, salts or physiologically functional derivatives.

Table 1 below shows the chemical structure of the eight above especially preferred compounds of the present invention, designated here as the connection "A", "B", "C", "D", "D", "E", "W" and "H", respectively.

Compounds described by the above General formula (I), show selectivity for binding to the receptor(s). Depending on the structure and stereospecificity compounds described particular cases of the formula (I), they are able to communicate with a particular receptor(s) from Delta receptors, mu-receptors, Kappa receptors, Sigma receptors and combinations of these receptors.

Various connections described on the other connection, to meet this same General formula, show the Delta-receptor antagonistic activity, as described more fully below. Another connection, provided by the General formula (I), show mu-receptor activity and in some cases mixed mu-receptor/Delta-receptor activity.

Examples of pharmaceutically acceptable esters described in the present invention are: (1) esters of carboxylic acids on the hydroxyl group of compounds of formula (I), in which decarbonising part of the carboxyl site of the ether group represented by the following substituents: an unbranched or branched alkyl (e.g., n-through t-butilkoi, n-butilkoi), alkoxyalkyl (for example, methoxymethyl), arylalkyl (e.g., benzyl), aryloxyalkyl (for example, phenoxymethyl) and aryl (e.g. phenyl) groups; 2) esters of amino acids (for example, L-vallina or L-isolationa group); 3) esters of dicarboxylic acids (e.g., hemisuccinate group); 4) carbonate esters (for example, ethoxycarbonyl group); 5) urethane esters (for example, dimethylaminocarbonylmethyl, (2-amino-ethyl)aminocarbonyl group); and 6) inorganic esters (e.g. etiologichesky functional derivatives are salts, formed from the respective bases of alkali metals (e.g. sodium, potassium), alkaline earth metals (e.g. calcium, magnesium), ammonium and NX4+(where X represents a C1-C4alkyl group). Pharmaceutically acceptable salts formed by the amino group include salts of organic carboxylic acids, such as acetic, lactic, tartaric, malic, lactobionic, fumaric and succinic acids; organic sulfonic acids, such as methanesulfonate, econsultancy, setinova, benzolsulfonat and p-toluensulfonate acid; and inorganic acids such as hydrochloric, Hydrobromic, sulfuric, phosphoric and sulfamic acids. Pharmaceutically acceptable salts of the compounds having hydroxyl group, consist of the anion of the above compounds in combination with a suitable cation such as Na+, NH4+or NX4+(where X represents, for example, WITH1-4alkyl group).

Used here in the description of the present invention the term "aryl" means a broad interpretation: as related to carbocyclic as well as heterocyclic aromatic groups.

For pharmaceutical which should be salts of pharmaceutically acceptable acids or bases. However, salts of acids or bases, which are not pharmaceutically acceptable may also find use, for example, upon receipt or purification of pharmaceutically acceptable compounds . All salt as formed from pharmaceutically acceptable acids and bases, and they are not covered by the present invention.

Compounds provided by the present invention are used as exogenous compounds that interact with receptors in other words, compounds that are used to link or separate receptors, such as the Delta, mu, Sigma, Kappa-receptors, or with two or more receptors of this type. Interactive connection can act as agonist/antagonist-component conjugate pairs that can be used for conducting analysis of neurotransmitter function in cellular systems, or systems of differentiated tissues. In addition to using compounds of the present invention in the receptor analysis, differential binding and special cases for cellular, histological monitoring and monitoring at the level of the organism as a whole, and for making estimates of these compounds exhibit of funds in the treatment of various physiological and pathological conditions.

Compounds provided by the present invention include species of agonists useful in the treatment of pains of different nature, diarrhea, depression, urinary incontinence, mental disorders, cough, edema, gastrointestinal disorders, spinal injury and addiction to the excessive use of drugs.

Compounds of the present invention also include the types of antagonists, which, as mentioned, are useful in studies of neurotransmitters, as well as the types of antagonists that can be used in the treatment of alcoholism, diseases caused by overdose of drugs opiate nature or drugs, representing another variation agonists.

In addition, when degradation or dysfunction of opioid receptors occurs or causes a painful condition covering fabric or separate cellular loci for diagnostics and visualization are used isotope-labeled versions of opioid compounds provided by the invention, for example, in diagnostic methods, which consists in obtaining scanogram brain using positron emissionnoi tomography (PET).

In the case of opioid means of ones nature, considered by the present invention, the nature of the manifestations of the relationship between structure and function in a range of different compounds corresponding to General formula (I), varies greatly, and even such subtle differences as changes in stereochemistry, can lead to different transduction effects. As a consequence, the formula (I) includes both types of agonists and antagonists.

As for the Delta receptor agonists, their activity is mostly set and measured using analysis of sperm receptacles mice, stimulated by an electric current.

In addition, in the practical application of the compounds of the present invention were obtained rigorous proof of the existence in the brain of subtype Delta-receptors, different from the Delta receptors sperm receptacles mouse.

Consequently, to predict activity as agonists and antagonists compounds provided by the invention, can be used and other methods of analysis of repernyh agonists mainly establish and measure on induced electric current ileum of the Guinea pig.

Compounds a, B, C, D, e, F, G and H are a variety of highly selective opioid receptor ligands. They all are very effective tools for mediating analgesia. In General, the range of applicability of the compounds of diarylpyrimidine nature provided by the invention, as painkillers can be easily found by simple tests by binding to receptors without excessive experimental work. From this point of view, and only as an illustration, the compounds of diarylpyrimidine nature, provided by the present invention, which mainly are agonists of mu-receptors, can be used, for example for mediating analgesia in surgery. Provided by the invention compounds of diarylpyrimidine nature, which is mainly agonist Delta-receptors, can be used for epidural anesthesia, and connections, which represents a mixed mu/Delta opioid agonists, i.e., compounds a, B, C, D, e, F, G and H - for example for surgical and/or post-operative analgesia.

Mixed mu/Delta receptor nature of the compounds covered by this what soedineniya, currently used for pain relief.

The vast majority of currently used high-performance painkillers, including morphine, fentanyl, meperidine, Sufentanil and codeine, are compounds that bind to the mu-receptors. It is well known that these compounds effectively Uporaba the analgesia, cause side effects such as loss of coordination, loss of visual perception, muscle rigidity and respiratory depression, and can cause nausea, vomiting, fever, and fainting. Such side effects are usually absent or, at least, not as strong when used for mediating analgesia compounds that bind to the Delta receptors. Accordingly, the use of mixed mu/Delta receptor compounds of the present invention may reduce or even eliminate the side effects normally associated action mu-rezeptionsgeschichte connections.

For use in pharmaceuticals and diagnostics compounds according to the invention it is desirable that they were obtained in substantially pure in terms of the enantiomeric composition; such enantiomeric purity (enantiomeric excess, EI) the nutrient value of EI is at least 99%. The value of the enantiomeric excess is a quantitative measure of the abundance of the main isomer over minor present with him, and can be easily measured appropriate for this purpose by methods well known in the art, such as high performance liquid chromatography (VGH), gas chromatography (GC), nuclear magnetic resonance (NMR) using reagents that cause chiral chemical shift, etc.

Compounds a, B, C, D, e, F, G and H are enantiomerically pure analgesic agents who agonism both mu-and Delta-receptors. In tests on rodents, for example, these compounds demonstrate analgesia comparable with the analgesia induced by morphine, but to a much lesser extent, enhance muscle rigidity and respiratory depression. In addition, tests on rodents have shown that these compounds do not cause seizures, as it happens in cases of structural net Delta agonists.

Although at first glance it may seem that all connections according to the invention are agonists of the Delta-receptors, will exhibit similar properties in vivo activity of the corresponding measured in experiments on sperm se the present invention, include compounds that can serve as an important tool for receptor analysis (rat brain), among these compounds, preferably active against one or the other Delta-receptor subtypes, and compounds with mu-receptor or a mixed mu-receptor/Delta-receptor activity.

The results of the analysis of binding and test analgesia show that the compounds of the present invention differently mediate the analgesia in relation to a variety of stimuli and physiological disorders. This, in turn, serves as a proof of the high level of complexity of the actions of neurotransmitters and responses caused by stimuli associated with different opioid receptors, including mu-receptors, Delta-receptors and receptor Delta subtypes.

A series of compounds of the present invention described by formula (I) or their precursors (which are also in many ways represent new connections and thus are considered as subject matter) find, in addition to opioid activity or other biological activity, including biological activity, which consists in the of eBet from the discussion above, compounds of the present invention find wide use for the treatment of a large number of diverse physiological conditions and disorders. The invention thus involves the use of such compounds in the production of pharmaceuticals for the treatment or prevention of these physiological States and disorders. In addition to those already mentioned possible therapeutic applications of other possible applications of the compounds provided by the present invention include the treatment of bronchial disorders such as asthma, emphysema and shortness of breath.

In addition, in connection with various CNS disorders, such as compulsive behavior, depression, psychosis, etc. were found endogenous opioids, such as enkephalins and endorphins, and their neurological system, and varieties of agonists or antagonists covered by formula (I) of the present invention find application in the fight against such diseases.

Different varieties as agonists and antagonists include compounds of formula (I) are also used in the treatment of conditions associated with abuse/addiction to drugs (opioid/narcotic nature), and therefore clicks the s programs, that traditional medicines have side effects or have other defects that act as contraindications or restricting their use.

With regard to the treatment of addiction to drugs with a wide range of effective compounds covered by the present invention, it is noted that methadone is a mu-opiate receptor with action similar to morphine, i.e., the use of methadone entails addiction and abuse. Methadone is used as an agent for therapy maintenance" drug addicts, allowing such individuals to maintain functional status in period to eliminate their addiction to drugs safe and non-criminal way. In this respect, the compounds provided by the invention, can be used instead of or together with traditionally used means to treat conditions of addiction to drugs such as naltrexone, methadone, clonidine etc.

Some compounds covered by the present invention, as mentioned above, are used as local anesthetics, such as analgesia on the spine, as well as compounds according to the invention mo, nedosmotreli the present invention include various compounds, which are Delta-opioid receptor agonists on the Delta subtype sperm receptacles mouse, as well as compounds that are antagonists such subtype Delta-receptors. In addition, they include compounds representing agonists and antagonists of Delta receptors in the brain, which, as was shown experimentally, belong to the subtype of Delta receptors different from those of the sperm-vessels of the mouse. A significant number of compounds described by the above formula (I) of the present invention, has both agonistic and antagonistic activity against both subtypes of Delta receptors. A number of these compounds have high activity with respect to mu-opioid receptors, being either pure mu-receptormediated compounds, or mixed mu/Delta-receptormediated, and other compounds covered by this invention have significant affinity to Sigma receptors.

In tests in vitro for activity as an agonist/antagonist, such as tests on the affinity to the receptor, and in tests on inhibition of C is depending on the specific compound in the range from nanomolar to micromolar concentrations.

Compounds of the present invention have pharmaceutical activity, including, inter alia, analgetic activity, and applied to mammals, for example humans, in conditions when you need pain relief.

The method of obtaining analgesic response in vulnerable subjects, is the introduction of the animal required for pain relief amount of the compounds of formula (I).

In addition, various compounds of the present invention, which finds therapeutic use, can be successfully used to treat conditions such as drug addiction and chronic alcoholism, excessive use of drugs and alcohol; mental, emotional, and cognitive disorders; cough; pulmonary edema; gastrointestinal diseases. Accordingly, the present invention involves a method of treating animal subjects in this condition(s) in need of such treatment, which consists in the introduction of such animals required number of compounds of the present invention, a therapeutically effective for the above condition.

Subjects in the treatment which can be applied to the methods provided by the present invention, on asomewhat mammals, and especially predominantly, people.

Depending on the specifics of the cure state of the compounds of formula (I) may be introduced at any suitable therapeutically effective and safe dose, without undue experimentation may be determined by a specialist.

In General, while the effective therapeutic dose of the compounds provided by the invention can vary widely depending on the specific application, status or nature of the disease that is easily identified by experts in the field, appropriate therapeutic doses of the compounds of formula (I) for each species compositions described herein and to achieve a therapeutic benefit in the treatment of any of these States will be in the range of 1 microgram (μg) to 100 milligrams (mg) per kilogram of live weight of the recipient per day, preferably in the range from 5 μg to 75 mg, and most preferably in the range from 10 μg to 50 mg per kilogram of body weight per day. The required dose is divided mainly into two, three, four, five, six or more podos entered at appropriate intervals of time during the day. These padosi can be administered as separate dosage forms, most of all, preferably from 50 μg to 10 mg of the active ingredient in the dosage form. Alternatively, if required by the state of the patient, the dose can be given by continuous infusion.

The route of administration and type of dosage forms without a doubt will have an impact on the definition of a therapeutic amount of the compounds necessary and effective for this therapeutic use.

For example, oral input dose at least twice, namely in 2-10 times higher than doses used in parenteral method of administration, for the same active ingredient. The order of the doses of the compounds according to the invention having affinity to the mu-receptors, with the introduction of oral way for pain is from 5 to 200 mg per 70 kg of body weight per day. Level doses when using capsules totaling about 10% of the level of injecting. For dosage forms as tablets typical procedure level dose of the active ingredient sufficient for pain relief, is 10-100 mg per pill.

The compounds of formula (I) can be used per se, as well as in the form of their pharmaceutically acceptable esters and ethers, salts, and other physiologically functional derivatives.

The present izobreteniya, which comprise as the active agent one or more compound(s) according to the invention, and a pharmaceutically acceptable carrier. The invention also encompasses the use of compounds according to the invention, such as compounds covered videosurgery formulas (I) and (II), in the production of pharmaceuticals for the treatment and prevention of conditions and disorders, it is widely described.

In such manufacturing technologies pharmaceuticals active agent is primarily used in conjunction with one or more pharmaceutically acceptable carrier(s), and can also be used with other therapeutic ingredients. The carrier(s) must be pharmaceutically acceptable in the sense that it is compatible with other ingredients of the medicinal product and safety for the recipient. The active agent is introduced, as described above, in amounts to ensure the effective achievement of the desired pharmacological effect and the required daily dose.

Medicines include means suitable for parenteral and non-parenteral use, and specific methods of their administration are oral, rectal, local, nuclearmedicine, podruchnogo, bronchial, lymphatic, and intra-uterine administration. Preferred drugs are those suitable for parenteral administration.

In cases where the active agent used in the composition of the liquid drug, such means conveniently enter parenteral. When the drug is a suspension or a powder mixed with a biocompatible carrier, for its introduction is convenient to use oral, rectal or bronchial ways.

When using directly the active agent in the form of a powdered solid material, it is convenient to introduce orally. Alternatively it can be entered by bronchial spray powder in gas-carrier for the formation of gas dispersion, which, with the use of special equipment for inhalation (suitable spray device is inhaled by the patient.

In some cases it may be useful to use an active agent in vector form, for example, encapsulating it in a liposome or other suitable encapsulating environment or locking of the active agent using, for example, covalent bonding, chelation, or tx2">

A suitable form of medicines, including an active agent provided by the present invention are single dose dosage forms that can be prepared with well-known pharmaceutical methods. Such methods typically include the step of combining the active compound(s) with the carrier comprising one or more additional ingredient. In a typical case, the drug is prepared by uniform and homogeneous Association the active compound(s) with a liquid carrier, a finely powdered solid carrier, or both types of these media, followed, if necessary, shaping the product form desired medicines.

Drugs of the present invention suitable for oral administration may be in the form of a single drug, such as gelatin and starch capsules, tablets or lozenges, each containing a certain amount of active ingredient in the form of a powder or granules; or a suspension in water or non-aqueous liquid in the form of a syrup, elixir, emulsion, or to be a liquid medication.

A tablet may be prepared presso who should produce, using the right equipment, by applying the active compounds in the form of powder or granules which may be mixed with a binder, shredder, lubricant, inert diluent, surface active agent or output agent. Molded tablets, consisting of a mixture of the powdered active compound with a suitable carrier may be made by molding in a suitable equipment.

The syrup can be obtained by adding the active compound to a concentrated aqueous solution of sugar, for example sucrose, to which may be added an additional ingredient(s).

This additional ingredient(s) may include flavorings, suitable preservative agents, retarding the crystallization of the sugar, and agents that increase the solubility of any other ingredient, such as polyhydroxyethyl, for example glycerol or sorbitol.

Medicines for parenteral administration are typically sterile aqueous preparation of the active compounds, mainly isotonic with the blood of the recipient (e.g., saline solution). Such drugs may include suspendresume and thickening agent or more bodies. Medicines can be prepared in the form of a single or multiple dose form.

Medicines for nasal applications include purified aqueous solutions of the active compounds with preservative agents and agents that provide isotonicity. The pH and isotonic condition of such medicines should preferably be set equal to those for the mucous membrane of the nasal cavity.

Medicines for rectal injection can be a suppository with a suitable carrier, such as coconut oil, saturated fats or saturated fatty carboxylic acid.

Eye medicines can be prepared by the same method as nasal solution, except that the pH and isotonic factor in this case should be close to those in the eyes.

Medicines for local use include active compound dissolved or suspended in one or more environments, such as mineral oil, petroleum, polyhydroxystearic or other bases used for the preparation of drugs for local application agent or thixotropic gel-like media, such as the media based on cellulose, such as methylcellulose or acetylcellulose, sticking received the drug in the device, providing a reliable contact with the skin when worn.

In addition to the aforementioned ingredients of the medicinal product provided by the present invention may also include one or more additional ingredient(s) from among the solvents, buffer solutions, flavouring agents, binders, shredders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.

The present invention also involves a method of obtaining certain of the above compounds of formula (I) and its pharmaceutically acceptable esters and ethers, salt or other physiologically functional derivative, with the specified method includes the method of synthesis, selected from the following methods (A), (B) and (C):

(A) alkylation of a piperazine of formula (IV) alkylating agent of the formula (III),

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where the substituents from R3to R6and R8and R9defined as in any of the previous descriptions, P predstavil R6is hydrogen may alkylation of the compounds of formula (I) alkylating agent of formula R6-X1where R6is C1-C6the alkyl, C3-C6cycloalkyl, C3-C6alkenyl or C3-C6the quinil; and X1represents a leaving group, or perhaps the alkylation of the compounds of formula (I) by reductive amination of C1-C6aldehyde in the presence of a reducing agent;

(B) interaction of the compounds of formula (V),

(V)

where the substituents from R3to R6and P are defined as previously, and suitable as a substituent Z can be bromine atoms, iodine or triftormetilfullerenov group,

(a) in the case when Z is a bromine atom, or iodine; an alkyl metal or a suitable reactive metal, the result of which can be substitution on the transition metal in the formed containing the metal connection with the formation of other metal-containing compound; the interaction of the obtained metal-containing compound with carbon dioxide by conversion of the resulting carboxylic acid into the corresponding chloride, anhydride or complex R9defined as before, or the interaction of the obtained metal-containing compound with aminocarbonylmethyl formula ClCONR8R9where R8and R9defined as before; or

(b) in the case when Z is a bromine atom, iodine or triftormetilfullerenov group; tianyoude reagent by hydrolysis of the resulting nitrile alkali or an aqueous solution of mineral acid, conversion of the resulting carboxylic acid into the corresponding chloride, anhydride or ester and the interaction of the resulting chloride, anhydride or ester with an amine of the formula HNR8R9where R8and R9defined as before; or

(C) in the case when Z is a bromine atom, iodine or triftormetilfullerenov group; an excess of amine of the formula HNR8R9where R8and R9defined as before, and carbon monoxide in the presence of a catalyst in the form of the transition metal with the formation of the compounds of formula (I), where R8and R9defined as before; or

(C) the interaction of the compounds of formula (VI) with phenylethylenediamine compound of formula (VII):

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where the substituents from R3to R6and R8and R9defined as before, P is an atom of the GP; (A. R. Katritzky, K. Yannakopoulou, P. Lue, Rasala D., Urogdi L. J. Chem. Soc. , Perkin Trans. 1, 1139, (1989); D. Seebach, Betcart S., Schiess, M. Helv. Chim. Acta, 67, 1593, (1984)) and, when P is hydroxylamino group, removing protection from a hydroxyl group; if necessary, the conversion of the compounds of formula (I) into its pharmaceutically acceptable simple and esters or salt or physiologically functional derivative.

Methods AND

The reaction between the alkylating agent of formula (III) and piperazine of formula (IV) can be carried out in a solvent such as toluene or acetonitrile.

Alkylating agents of the formula R6-X1commercially available or can be obtained using the literature methods. Alternatively, alkylation with alkylating agent of formula R6-X1can be applied the method of reductive amination, in which suitable, commercially available C1-C6aldehyde restore regenerating agent, such as Lamborgini sodium in solvents such as alcohols or ethers.

Method B

(a) Compound of formula (I) can be obtained from compounds of formula (V) in which Z is a bromine atom, or iodine, and P - hydroxylamin) exchange of reactive halogen in organometallics reagent, such as n-utility, or the activated form of metal, such as lithium or magnesium, leading to the formation of an intermediate metal-containing compound followed by reaction with carbon dioxide, which results in the formation of carboxylic acid in anhydrous solvent such as tetrahydrofuran, in the atmosphere of inert gas (e.g. nitrogen). The carboxylic acid may then be converted into carboxamide formula (I) by the methods described below.

Alternative intermediate metallsoderjasimi connection formed from the compounds of formula (V) can be treated with a suitable carbamoylation (ClCONR8R9to obtain compounds of formula (I).

(b) a Compound of formula (I) can also be obtained from compounds of formula (V) in which Z is an atom of bromine, iodine or triflate (triftormetilfullerenov) group by processing tianyoude reagent, such as copper cyanide, in a suitable solvent, such as dimethylformamide or N-organic, leading to the corresponding compounds of formula (V) in which Z represents a nitrile group, which can then be hydrolyzed with alkali or an aqueous solution of mineral sour formula (I) various well-known in the art methods, such as education chloride (for example, using thionylchloride or oxalylamino), or the formation of a mixed anhydride (for example, using isobutylphthalate), or the formation of an activated ester by conventional peptide synthesis reagents (for example, dicyclohexylcarbodiimide or hexaphosphate benzotriazol-1 yloxy-Tris(dimethylamino)phosphonium), and any of these intermediate compounds can be converted into the desired carboxamide formulas (I) through reaction with the corresponding amine (HNR8R9) in a suitable solvent such as dichloromethane or dimethylformamide.

(C) a Compound of formula (I) can also be obtained from compounds of formula (V) in which Z is an atom of bromine, iodine or triflate group by treatment in the presence of a transition metal catalyst, such as tetrakis(triphenylphosphine)palladium, excess amine or carbon monoxide in a solvent such as tetrahydrofuran or acetonitrile.

Method IN

The compound of formula (VI) can be obtained as a reactive intermediate compounds by combination of the aldehyde of formula (VIII) with a piperazine of formula (IV),

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in which the substituents from R3to RLa in a suitable solvent, such as toluene or dichloromethane, or for the intermediate compounds of formula (VI) in which W represents benzotryazolyl group, if necessary, the active intermediate compound may be isolated by crystallization or other suitable methods.

The compound of formula (I) can be obtained in the form of one enantiomeric form by classical separation using enantiomerically pure acids, such as almond, or by education easily separated diastereomers using enantiomerically pure derivatizing agent, or by chromatographic separation, or by using the enzymatic separation of the compounds of formula (I) or a suitable derivative, or by obtaining the compounds of formula (I) of the enantiomerically pure precursors, which can themselves be obtained in the form of single enantiomers in a similar way.

The compounds of formula (III) can be obtained from the appropriate alcohols of the formula (IX), in which the phenol is protected with a suitable protecting group P by methods such as halogenoalkane using thionyl chloride or tetrabromide triphenylphosphine/carbon or reaction with methylsulfonylamino or toluensulfonyl and can be obtained using the literature methods or their modifications, in which R6changed by the appropriate alkylation agent R6-X1.

The compounds of formula (V) can be obtained by alkylation of the piperazine of formula (IV) alkylating agent of the formula (X) is the same as described above for the case of alkylation of piperazine. Alkylating agents of the formula (X) is similarly obtained from alcohols of formula (XI) by methods similar to those described above for compounds of formula (III).

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Alcohols of formula (IX) or (XI) can be obtained by adding at low temperature (for example, -60oC to -78oC) substituted arylmethylidene compounds prepared from compounds of formula (XII) in which Z represents a reactive halogen atom (e.g., iodine or bromine), replaced benzaldehyde formula (XIII) using the methods described above.

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Conversely, the compounds of formula (IX) or (XI) may also be formed in a similar reaction, mentioned previously substituted phenylethanolamine compounds (VII) with benzaldehyde formula (VIII).

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Compounds (VII), (VIII), (XII) and (XIII) and their corresponding substituted derivatives can be obtained from commercially available materials using standard described in the bodice reaction with a suitable agent, for example, acid halide or anhydride. The compound of formula (I), including its esters can be converted common ways in its pharmaceutically acceptable salts, for example by treatment with a suitable acid. Ester or salt of the compounds of formula (I) can be transformed into the original connection, for example by hydrolysis. Phenolic esters of the compounds of formula (I) in which P represents a C1-C6alkyl group, can be prepared in the same manner as has been described here previously.

On the basis of the above, and General concerns regarding the ways of synthesis, it should be clear that to obtain diarylpyrimidine compounds of the present invention can be useful in a variety of methods of synthesis that should be obvious even for specialists of medium qualification. Illustrative methods for the synthesis of compounds related to the vast field of the compounds covered by the present invention is described below by way of examples; it becomes apparent that the compounds provided by the invention, can be produced using other, different methods and ways of synthesis known in the art, the following illustrative must be clear, what new types of compounds of the present invention include various new types of intermediates, precursors, Pro-drugs, analogs and derivatives of the compounds referred here to the field of invention.

In those cases when the application of the methods of synthesis of compounds provided by the invention, as an intermediate reaction products obtained racemic mixtures, they can be separated using well-known and accepted in this field of methods and tools, such as the formation of diastereomeric salts with enantiomerically pure carboxylic acids, chromatographic separation of stereoisomers, enzymatic separation and other suitable conventional methods.

Below is an illustrative schematic of the synthesis of racemic ()-3-( (R*)-- ((2S*,5R*)-4-allyl-2,5-dimethyl-1 - piperazinil)-3-oxybenzyl)-N,N-diethylbenzamide, hereinafter designated as Compound (a)-1, which can be obtained in the form of its constituent enantiomers by classical separation or stereoselective methods for the synthesis of final products or a suitable intermediate connections. Such methods additionally proillyustriroval, called here the Connection I, which is described in more detail in (reference) example 1. An illustrative scheme of the synthesis and methodology division, described later, can be similarly used for the synthesis and separation of compounds provided by the invention, and in contrast, other methodologies of synthesis and/or separation can be used for this purpose experts in this field.

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As for the previous scheme of the synthesis, the original benzhydrylamine alcohol can be obtained from 3-(t-butyldimethylsilyloxy)bromine benzol according to the following scheme:

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The intermediate compound can also be obtained through the benzophenone, which in turn can be synthesized by adding organometallics connection to 4-bromobenzonitrile:

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Other ways to obtain the intermediate compounds include the condensation of the appropriate substituted piperazine with a carbonyl compound. Condensation with benzaldehyde can give the imine salt, which in the presence of argillite can form benzhydrylpiperazine compounds in which X = CONEt2Y = CH2CH = CH2or X = Br, Y = CH2CH = CH2in the form of mixtures of their Diaz is vitellinae amination of a suitable benzophenone corresponding piperazine can lead to direct obtaining the desired compounds.

Similarly, "disguised imine" connection, in which Z is a suitable leaving group (for example, benzotryazolyl group or trichlorides of oxititan), can be processed arylmethylidene compounds (for example, abilities or bromide ariline),

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then benzylpiperazine can dissociate with the formation of the desired imine ion in situ.

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Similarly reductive amination of a suitable benzien appropriate amarasena can directly lead to the desired compounds.

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Connection ()-1 can also be synthesized by alternative synthesis below.

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TRANS-1-allyl-2,5-dimethylpiperazine reagent used in the above scheme of the synthesis, can be formed respectively in the following synthesis process.

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Racemic TRANS-1-allyl-2,5-dimethylpiperazine can be divided into its constituent enantiomers by the classical method of separation using enantiomerically pure carboxylic acids, resulting in a chiral intermediate compound (2R, 5S)-1-allyl-2,5-dimethylpiperazine, poluce in enatiomers pure form using illustrative path synthesis, below.

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When enantiomerically pure (2R,5S)-1-allyl-2,5-dimethylpiperazine handle the racemic benzhydrylamine, the resulting product is a mixture of two enantiomerically pure diastereomers that can be separated by conventional methods such as chromatography or selective crystallization.

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In addition to the above, Compound I or ()-1 can be synthesized via nitrile path synthesis using copper cyanide as tianyoude agent, as shown below.

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An alternative scheme for the synthesis of Compound I from the corresponding halogenated compounds is shown below.

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The above illustrative material showed examples of methods of synthesis, which can be useful for the formation of compounds such as Compound I or ()-1, as well as compounds of benzhydrylpiperazine nature, provided by the present invention, using the relevant or similar reagents.

Features and advantages of the present invention are more fully shown in the following not limitiruyuscaya chemical syntheses, described in the next paragraph.

Melting points were measured using the apparatus of Thomas-Hoover and was not adjusted. All chemicals, unless specified, were purchased from Aldrich Chemical Company, Milwaukee, Wisconsin. Commercial solvents were used without further purification with the exception of tetrahydrofuran, which was distilled over metallic potassium. The spectra of nuclear magnetic resonance (NMR) were obtained using a spectrometer models Perkin-Elmer R-24, Varian XL-200 or XL-300. VIH-analyses was performed using liquid chromatography system firms Waters, equipped spectral system 700 Satellite WISP, the controller 600 crystal and photodiode detector 991, using either column Cyclobond I (4,6 250 mm Advanced Separations Technologies, Whippany, New Jersey) or column Bondapak C-18 (125 A, 3,9 300 mm, Waters Chromatography Division, Millipore Corporation, Milford, Massachusetts) with a flow rate of 1 ml/min Analytical gas chromatography was carried out on the device Series II Hewlett-Packard (model 5890), using a flame ionization detector and helium as the carrier gas (the temperature of the injector 225oC, detector temperature 250oC). Optical rotation was measured on a polarimeter 241 Perkin-Elmer. Macc-spectrometric measurements were performed Oneida Rese thin-layer chromatography was performed on glass plates firms Analtech, coated with silica gel GF (250 μm), and preparative thin-layer chromatography on plates Uniplate the same firm, covered with silica gel GF (1000 and 2000 µm). Analysis elemental composition performed Atlantic Microlab, Norcross, Georgia.

(Reference) Example 1

(+)-3-( - ((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinil) -3-oxybenzyl)-N, N-diethylbenzamide

3-Iodobenzoyl acid (55,5 g, 0,224 mol) was dissolved in tetrahydrofuran (220 ml) and oxanilide (22 ml, 0,252 mol). After adding 4 drops of dimethylformamide as catalyst the solution was stirred for 1 hour at room temperature and the solvent was removed under vacuum. The residue was dissolved in 220 ml of petroleum ether (boiling range 35-60oC) and cooled in an ice bath to 0oC. Then was added dropwise diethylamine (55 ml, 0,532 mol) over 15 minutes. The reaction mixture was stirred in the ice bath for an additional 15 minutes, then was diluted with ethyl acetate (100 ml) and washed with saturated solution of sodium chloride (50 ml). The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo to achieve approximately half the initial volume. Then the solution was filtered through a small padding of silica gel using ethyl acetate to wash the stuffing. In the-iodobenzene in the form of oil amber color. NMR (300 MHz, CDCl3): (R)-- 1,11 (br s, 3H); to 1.21 (br s, 3H); 3,23 (br s, 2H); 3,51 (br s, 2H); 7,13 (ddd, J1= 0.8 Hz, J2= 7,6 Hz, J3= 7,6 Hz, 1H); to 7.32 (ddd, J1= 1.3 Hz, J2= 1.3 Hz, J3= 7.5 Hz, 1H); 7,71 (d, J = 1.2 Hz, 1H); 7,72 (ddd, J1= 1.3 Hz, J2= 1.3 Hz, J3= approximately 8,0 Hz (partially blocked), 1H). Mass spectrum (Cl-CH4) m/e 304 (MM1, 100%). Est. for C11H14NOI: C, 43,58; H, 4,56; N, 4,62; I, 41,86. Found: C, 43,68; H, With 4.64; N, With 4.64; I, 41,92.

To 250 ml of dimethylformamide was added 3-oxybenzaldehyde (70 g of 0.57 mol), tert-butyldimethylsilyloxy (92 g, and 0.61 mol) and imidazole (92 g of 1.35 mol). The resulting mixture was stirred in nitrogen atmosphere for 1 hour. The solution was poured into water (1.5 l) and was extracted with petroleum ether (2 500 ml, boiling range 35-60oC). The organic phase was washed with a saturated solution of sodium chloride (100 ml), dried over magnesium sulfate, treated with silica gel (20 g), filtered and concentrated in vacuo. The residue was further dried under high vacuum, receiving 126,6 g (94%) sensitive to the action of air and light 3-((tert-butyldimethylsilyl)oxy)benzaldehyde in the form of oil amber color. NMR (300 MHz, CDCl3): 0,22 (s, 6N); 0,99 (s, 9H); 7,10 (ddd, J1= 1.2 Hz, J2= 2,5 Hz, J3= 7.9 Hz, 1H); to 7.32 (dd, J1= 1.5 Hz, J2= 2,4 Hz, 137 (M+1, 100%). Calculated for C13H20O2Si: C, 66,05; H, 8,53. Found: C, 65,95; H, 8,56.

n-Utility in hexane (280 ml of 2.5 M solution) was added via a dropping funnel to 1.4 l of tetrahydrofuran at a temperature of -78oC in nitrogen atmosphere. After cooling a solution of n-utility to -78oC to it slowly for 20 minutes was added a solution of N,N-diethyl-3-iodobenzene (106 g of 0.35 mol) in tetrahydrofuran (350 ml). During the addition the internal temperature rose to -65oC. Upon completion of addition the solution was stirred 10 minutes and it slowly over 7 minutes was added a solution of 3-((tert-butyldimethylsilyl)oxy)benzaldehyde (88 g, and 0.37 mol) in tetrahydrofuran (90 ml). The reaction mixture was stirred an additional 5 minutes at -78oC and left to warm to -10oC. the Mixture was poured in 875 ml of petroleum ether (boiling range 35-60oC) and a solution of dibasic sodium phosphate (300 ml of a 2M solution) was shaken and separated the organic phase. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in a mixture of ethyl acetate:petroleum ether (1:3, 90 ml), was applied on a column of silica gel (1 kg) and washed with a mixture of ethyl acetate: petroleum is 5.9 grams(80%) 3-(3-((tert-butyldimethylsilyl)oxy) -oxybenzyl)-N, N-diethylbenzamide in the form of a viscous amber oil painting. NMR (300 MHz, DMCO-d6): -- of 0.13 (s, 6N); to 0.92 (s, 9H); 0,98 (br s, 3H); 1,11 (br s, 3H); 3,10 (br s, 2H); 3,39 (br s, 2H); 5,69 (d, J = 4,1 Hz, 1H); 5,96 (d, J = 4,2 Hz, 1H); of 6.68 (dd, J1= 1.9 Hz, J2= 7.7 Hz, 1H); at 6.84 (s, 1H); 6,97 (d, J = 7.7 Hz, 1H); 7,16 (d, J = approximately 8 Hz (partially hidden), 1H); 7,17 (t, J = 7.7 Hz, 1H); 7,28 (s, 1H); to 7.35 (t, J = 7.8 Hz, 1H); 7,42 (d, J = 7,6 Hz, 1H). Mass spectrum (Cl-CH4) m/e 414 (M+1, 11%), 178 (32%). Est. for C24H35NO3Si: C, 69,69; H, 8,53; N, 3,39. Found: C, 69,65; H, 8,56; N, 3.40 In.

Three-neck round bottom flask with a volume of 12 liters was filled with TRANS-2,5-dimethylpiperazine (767 g, 6,72 mol), recrystallized from toluene (melting point 115-119oC), and 600 ml of water. The flask was cooled in an ice bath and its contents slowly with stirring solution was added methanesulfonic acid (1290 g of 13.4 mol) in 600 ml of water, keeping the temperature below 40oC. the Solution was cooled to 20oC and to it was added 800 ml of ethanol. Additional funnel 500 ml was filled with 60% aqueous potassium acetate solution of 2-liter tank with this solution and the potassium acetate was added to the reaction mixture until the pH is 4.0. The second additional funnel was filled with a solution of ethylchloride (642 ml of 6.71 mol) in 360 ml tetrahydrofur the population so in order to maintain in the reaction mixture the pH 4,0 0,1, if necessary, cooling the reaction vessel and providing a temperature of 25oC. after adding ethylchloride the reaction mixture was stirred for 1 hour, continuing to add the potassium acetate solution to maintain the pH is 4.0. Organic solvents drove under vacuum. The remaining aqueous solution was washed with 1500 ml of ethyl acetate to remove impurities bis-carbamate. An ethyl acetate wash was extracted with two portions of 500 ml of 1M hydrochloric acid for separation of the product. The acid extracts were combined with the original aqueous solution and adding 10M sodium hydroxide solution, brought to pH to a value of 11 with simultaneous cooling to maintain the temperature below 40oC. the Aqueous solution was extracted with two portions of ethyl acetate in 1500 ml), the combined extracts were dried over magnesium sulfate and the solvent was removed, getting 927 g (74%) of ethyl-TRANS-2,5-dimethyl-1-piperidinecarboxylate in the form of a yellow oil.

A mixture of ethyl-TRANS-2,5-dimethyl-1-piperidinecarboxylate (643 g of 3.45 mol), allylbromide (328 ml of 3.80 mol) and sodium carbonate (440 g, 4,15 mol) in 2500 ml of acetonitrile was heated under reflux for is under vacuum. The residue was dissolved in 4000 ml of dichloromethane and washed with two portions of 500 ml of 1M sodium hydroxide. The dichloromethane solution was dried over magnesium sulfate and the solvent was removed, getting 630 g (81%) of ethyl TRANS-4-allyl-2,5-dimethyl-1-piperidinecarboxylate in the form of butter.

Ethyl TRANS-4-allyl-2,5-dimethyl-1-piperidinecarboxylate (630 g, 2,78 mol) was added to 87% solution of granulated potassium hydroxide (2970 g, 46 mol) in 4300 ml of 95% ethanol and boiled under reflux for 1.5 hours. Within the first 0.5 to 1 hour of heating observed the emission of carbon dioxide. The reaction mixture was cooled to a temperature below the boiling point, after which it was carefully added 2000 ml of toluene. The ethanol was removed by azeotropic distillation at 105oC, adding additional 4000 ml of toluene in a reaction vessel for distillation. After collecting 9000 ml of distillate, the reaction mixture was cooled to 100oC and to it was carefully added to 1000 ml of toluene. The solution was slowly cooled to 5oC and kept at this temperature for 30 minutes. After this, the solution was filtered, washing otfiltrovana precipitate additional 1500 ml of toluene. The filtrate is washed with 1000 ml of water, dried over magnesium sulfate and the solvent was removed, J = 6.3 Hz, 3H); to 0.92 (d, J = 6.3 Hz, 3H); and 1.63 (t, J = 11 Hz, 1H); is 2.05 (m, 1H); 2,30 (t, J = 11 Hz, 1H); 2,6-2,8 (m, 4H); to 3.33 (dd, J1= 5 Hz, J2= 14 Hz, 1H); 5,09 (d, J = 8.7 Hz, 1H); 5,13 (d, J = 14 Hz, 1H); 5,8 (m, 1H).

Di-p-toluoyl-D-tartaric acid (Schweizerhall, Inc., South Plainfield, New Jersey) (1.25 kg, and 3.2 mol) was dissolved in hot (about 60oC) 95% ethanol (16 l) and to the solution several techniques were added racemic TRANS-1-allyl-2,5-dimethylpiperazine (500 g, 3,2 mol) (caution: exothermic reaction). In a hot solution was added seed crystals diastereoisomers pure salt (obtained in preliminary small-scale separation) and the solution was cooled to room temperature for 2-3 hours. The solution was slowly stirred for two days at room temperature. The resulting salt was collected by filtration, washed twice with 95% ethanol and dried in vacuum, obtaining 826,5 g solid white (47%). Repeat the process with the second portion of the di-p-toluoyl-D-tartaric acid and racemic TRANS-1-allyl-2,5-dimethylpiperazine gave 869 g (50%) of the substance.

All the obtained Sol (1695) was divided into three portions, each of which was recrystallized twice described later. The salt was dissolved in boiling 95% ethanol (about 2.7 liters per 100 grams of salt) in a flask with a return x the Noe mixing of the solution during the distillation in order to avoid crystallization on the walls of the vessel). In a hot solution was added a seed crystal diastereoisomers pure salt, cooled to room temperature slowly and was stirred for 2 days before collecting the salt by filtration. (Note: subsequent experiment showed that the time of crystallization can be reduced from 2 days to 8 hours). The total yield of the product was 1151, Salt was dissolved in 3 l of 2 M aqueous sodium hydroxide solution and the aqueous solution was extracted with four portions of dichloromethane, 1 l each. The organic extracts were combined, dried over sodium sulfate and the solvent was removed with a rotary evaporator at a temperature of less than 20oC, getting 293 g (29% based on racemic weight) of (2R,5S)-1-allyl-2,5-dimethylpiperazine in the form of a clear oil. =-55,1o(abs. ethanol, C= 1,2). Trifurcated product obtained by triperoxonane anhydride and analyzed by capillary gas chromatography (column 20 m 0.32 mm, Chiraldex B-PH, Advanced Separation Technologies Inc. , Whippany, NJ, 120oC) showed stereocilia more than 99% of the time delays of the desired enantiomer of 11.7 min; the other enantiomer of 10.7 min).

3-(3-((tert-Butyldimethylsilyl)oxy) []2D0-oxybenzyl)-N, N-diethylbenzamide ethylbenzamide (115,9 g is La noticeably exothermic. The mixture was stirred for 15 minutes and then concentrated in vacuo (carefully in the beginning of the process because of the rapid gas evolution). After removal of all volatile components of the crude 3-(3-tert-butyldimethylsilyl)oxy)- -- Chlorobenzyl)-N, N-diethylbenzamide was dissolved in acetonitrile (560 ml). To the solution was added sodium iodide (42 g, 0,280 mol), diisopropylethylamine (73 ml of 0.42 mol) and (2R,5S)-1-allyl-2,5-dimethylpiperazine (52,5 g, 0,280 mol). The mixture was boiled under reflux in a nitrogen atmosphere with stirring for 2.5 hours. The acetonitrile was removed by distillation in a nitrogen atmosphere with a duration of several hours. After cooling, the reaction mixture was poured into ethyl acetate (1.1 l) and potassium carbonate solution (350 ml of 2 M aqueous solution) and shaken. The organic phase was separated, dried over solid potassium carbonate and concentrated in vacuo. The residue was dissolved in a mixture of ethyl acetate:petroleum ether (1:1, 150 ml) and applied on a column of silica gel (3 kg). Elution with a mixture of ethyl acetate:petroleum ether (1: 1) gave the desired isomer from the first two eluruumid of epimeres. The solution of the eluate was concentrated to small volume and left for 12 hours. The precipitated crystalline impurity was removed by filtration and the filtrate was concentrated to dryness.

Example 2

3-( ((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinil) -3-oxybenzyl)-N-methyl-N-phenylbenzene

A mixture consisting of 1400 g (8,1 mole) 3-bromophenol, 1218 g (8,1 mole) of tert-butylcholinesterase and 1376 g (20,2 mole) of imidazole in 1600 ml of N,N-dimethylformamide was stirred at room temperature under nitrogen atmosphere for 18 hours. The reaction mixture was poured into aqueous buffer solution of pH 8 and extracted with diethyl ether. The ether extracts were washed with water and saline Bromphenol-tert-butyldimethylsilyl ester as orange oil. NMR (CDCl3200 MHz) d: 0,2 (s, 6H); of 0.95 (s, 9H); to 6.8 (m, 1H); to 7.0, and 7.1 (m, 3H).

Silloway ether (1771, 6,17 mol) was dissolved in 4 l of dry tetrahydrofuran, optionally dried over molecular sieves, was transferred to a 12 l reaction flask in a nitrogen atmosphere and cooled to -78oC. In the flask under stirring in nitrogen atmosphere was added n-utility (2400 ml of 1.6 M solution in hexane) with such a rate as to maintain the temperature of the reaction mixture below -70oC. Stirring at -78oC was continued for 2 hours. To the mixture was added a solution of 3-bromobenzaldehyde (1119, 6,05 mol) in 600 ml of dry tetrahydrofuran with speed, providing the temperature of the reaction mixture below -70oC. After stirring at a temperature of -78oC for 2 hours the reaction was stopped with 1400 ml of a saturated aqueous solution of ammonium chloride and the reaction mixture was left to warm to room temperature. The mixture was filtered to remove solid particles and produced the separation of the layers. The organic phase is washed with saline, dried over sodium sulfate and evaporated, receiving 2500 g of the crude (R)-- (3-bromophenyl)-3-(tert-butyldimethylsilyloxy)benzyl alcohol in the form of a yellow oil. is from 90:10 to 75:25 with subsequent replacement of the solvent to dichloromethane:ethyl acetate/90:10) gave 692,3 g - (3-bromophenyl)-3- (tert-butyldimethylsilyloxy)benzyl alcohol in the form of a yellow oil. NMR (CDCl3, 200 MHz) - 0,2 (s, 6N); of 0.95 (s, N); 2,3 (br s, 1H) ; 5,7 (s, 1H); 6.75 in (d, J = 8 Hz, 1H); 6.8 cm (s, 1H); 6,9 (d, J = 8 Hz, 1H); to 7.2 (m, 2H); and 7.3 (d, J = 8 Hz, 1H); 7,4 (d, J = 8 Hz, 1H); 7.5 (a s, 1H).

To a solution of benzhydryl alcohol (160 g of 0.41 mol) in 1 l of dichloromethane was added dropwise thionyl chloride (38 ml, of 0.51 mol) and the resulting mixture was stirred over night at room temperature. The solvent was removed under vacuum, the residue pererestorani in toluene, after which the solvent again drove under vacuum to remove excess thionyl chloride, receiving untreated : (3-bromophenyl)-3-(tert-butyldimethylsilyloxy)benzylchloride in the form of a brown oil. NMR (CDCl3, 200 MHz) to 0.2 (s, 6H); of 0.95 (s, 9H); 6,0 (s, 1H); 6,8-7,0 (m, 3H); 7,2-7,6 (m, 5H).

A mixture of benzhydrylamine and (-)-(2R, 5S)-1-allyl-2,5-dimethylpiperazine (137, 6mm g of 0.89 mol of example 1, infra) in 1500 ml of acetonitrile was heated under reflux for 48 hours, concentrated in vacuo and the residue was dissolved in ethyl acetate. The mixture was washed with 0.25 M aqueous solution of sodium hydroxide, dried over sodium sulfate and concentrated in vacuo, getting 202,6 g butter dark color, which was dissolved in acetonitrile (1 l) and mixed with dwwhu the solvent was removed under vacuum. The residue was dissolved in dichloromethane (2 l), washed with buffer solution with pH 8, was dried over sodium sulfate and concentrated to a dark oil painting, which was stirred in acetonitrile (700 ml) at 25oC within 72 hours of receiving the precipitate reddish-brown color. Recrystallization from acetonitrile (2 l) gave to 35.3 g of a single diastereoisomer: 3-( : ((2S,5R)-4-allyl-2,5-dimethyl-1 - piperazinil)-3-bromobenzyl)phenol in the form of a solid white color. NMR (DMCO-d6, 200 MHz) (R)-- of 0.95 (d, J=6 Hz, 3H); of 1.03 (d, J = 6 Hz, 3H); 1.8 m (dd, J1= 6 Hz, J2= 10 Hz, 1H); 2,1 (dd, J1= 6 Hz, J2= 10 Hz, 1H); 2,4-2,6 (m, 3H); 2,7 (d, J = 11 Hz, 1H); 2,8 (dd, J1= 7 Hz, J2= 14 Hz, 1H); 3,2 (dd, J1= 6 Hz, J2= 13 Hz, 1H) and 4.9 (s, 1H); 5,1 (d, J = 10 Hz, 1H); 5,2 (d, J=18 Hz, 1H); 5,7-5,9 (m, 1H); 6,6-6,8 (m, 3H); 7,0-7,4 (m, 4H); at 7.55 (s, 1H); 9,35 (s, 1H). The mother liquid was evaporated, getting 127 g solid brown color. Part (11 g) of this material was purified by chromatography on silica gel in the solvent system dichloromethane:ethanol (0-2,5%). Collected first eluruumis with speakers isomer, getting 2,32 g 3( : ((2S,5R)-4-allyl-2,5-dimethyl-1 - piperazinil)-3-bromobenzyl)phenol in the form of a solid light-yellow substance. NMR (DMCO-d6, 200 MHz) (S)-- of 0.95 (d, J=6 Hz, 3H); of 1.05 (d, J=6 Hz, 3H); 1.85 to (dd, J1=7 Hz, J2= 9 Hz, 1H); ,1 (dd, J1=5 Hz, J2= 9 Hz, 1H); 4,95 (s, 1H); 5,1 (d, J=10 Hz, 1H); 5,2 (d, J=17 Hz, 1H); 5,8 (m; 1H); 6,6 (d, J=8 Hz, 1H); to 6.8 (m, 2H); 7,1 (t, J=8 Hz, 1H); and 7.3 (m, 2H); 7,5 (m, 2H); and 9.3 (s, 1H).

3-( : ((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinil)- 3-bromobenzyl)phenol (147,3 g, 0,355 mol) was dissolved in 1 l of N-methyl-2-pyrrolidone with copper cyanide (63,6 g of 0.71 mol) and the reaction mixture was placed on 170oC for 30 hours. After cooling to room temperature the contents of the reaction mixture was poured into 7 l of aqueous 14% solution of sodium cyanide. The mixture was stirred overnight and extracted with ethyl acetate. An ethyl acetate extracts were combined, washed with water, dried over sodium sulfate and concentrated in vacuo, getting 133,3 g solid brown color. Chromatography on silica gel with ethanol (2-7%) in dichloromethane gave of 97.8 g of the crude 3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)benzonitrile. After recrystallization from acetonitrile, there was obtained 74,2 g (58%) of pure 3-( (R)-- ((2S,5R)-4-allyl - 2,5-dimethyl-1-piperazinil)-3-oxybenzyl)benzonitrile in a solid white color.

Benzonitrile (78,8 g and 0.22 mole) was combined with 60 g of granular sodium hydroxide in 1 liter of 95% ethanol and boiled under reflux for 72 hours. To remove a acid to a value of 5. The solvent was removed in vacuo, getting 138,8 g 3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-oxybenzyl)benzoic acid in a mixture with sodium chloride. A portion (5.0 g) of the crude acid was mixed with 50 ml of water. The resulting suspension was filtered, washed solid material on the filter with three portions of water and dried in vacuum for three hours, getting 2,02 g 3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)benzoic acid in the form of a solid light beige color. NMR (DMCO-d6,200 MHz) (R)-- of 0.95 (d, J=6 Hz, 3H); 1,1 (d, J=6 Hz, 3H); 1,9 (ddd, J1=3 Hz, J2=7 Hz, J3=10 Hz, 1H); 2,1 (dd, J1=8 Hz, J2=10 Hz, 1H); 2,5 (m, 2H); 2,7-2,9 (m, 2H); 3,2 (m, 2H); of 5.05 (d, J=12 Hz, 1H); 5,2 (d, J=18 Hz, 1H); 5,8 (m, 1H); 6,7 (m, 3H); 7,1 (t, J=8 Hz, 1H); 7,4 (t, J=8 Hz, 1H); the 7.65 (d, J=8 Hz, 1H); 7,8 (d, J=8 Hz, 1H); 8.0 a (s, 1H); and 9.4 (s, 1H). = +4,1o(0.1 M aqueous sodium hydroxide, with=1,09). Est. for C23H28N2O30,75 H2O: C, 70,12; H, AT 7.55; N, 7,11. Found: C, 70,23; H, 7,35; N, 7,10. Mass spectrum (Cl-CH4) m/e 381 (M+1, 35%); 380 (M, 2%); 227 (28%); 155 (100%); 153 (83%).

3-( []2D0((2S, 5R)-4-Allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)benzoic acid (25,9 g of 50% by weight of the mixture with sodium chloride, 34,0 mmole) was dissolved in 40 ml of dimethylformamide containing 12.8 g (84,9 mmole) of tert-butylcholinesterase and 11.5 g (ml ice water and was extracted with 500 ml of diethyl ether. The ether extract was washed twice with 250 ml of water and then 125 ml of saturated solution of sodium chloride, then dried over sodium sulfate and solvent was removed, getting to 20.8 g of crude tert-butyldimethylsilyl 3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3- (tert-butyldimethylsilyloxy)benzyl)-benzoate.

Untreated silyl ether-silloway ester (20.7 g, to 33.9 mmole on the basis of previous reaction) was dissolved in 60 ml of dichloromethane and cooled in nitrogen atmosphere to 0oC. To the solution was added dropwise oxalicacid (3,7 ml, 42,4 mmole). Maintaining the temperature of the mixture at 0oC, and to it was slowly added 10 drops of dimethylformamide as catalyst. During the addition of dimethylformamide was observed gas evolution. The temperature of the mixture was maintained equal to 0oC for 30 minutes, after which the mixture was left to warm to room temperature. The solution was stirred at room temperature under nitrogen atmosphere for 24 hours. All volatile compounds were removed by evaporation under reduced pressure, getting 29,76 g of the crude 3-( (R)-- ((2S, 5R)- 4-allyl-2,5-dimethyl-1-piperazinil)-3-(tert-butyldimethylsilyloxy) benzyl)benzoyl chloride in the form of a solid yellow-brown color. Paul is Lil-2,5-dimethyl-1-piperazinil)-3 - tert-butyldimethylsilyloxy)benzyl)benzoyl chloride (2,33 g crude, approximately 1.44 g of the basic substance, of 2.81 mmole, based on 3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-oxybenzyl) benzoic acid) was dissolved in 12 ml of dichloromethane at room temperature under nitrogen atmosphere. To the solution was added 0.5 ml of triethylamine. Next was added dropwise N-methylaniline (and 0.46 ml, 4.3 mmole) (reaction is exothermic) and the reaction mixture was stirred over night at room temperature. All volatile compounds were removed by evaporation under reduced pressure, obtaining a solid resinous substance brown.

The crude solid was dissolved in acetonitrile (8 ml) under nitrogen atmosphere at room temperature. To the solution was added fluoride of tetraethylammonium hydrate (1.19 g, 6.42 per mmole) and the solution was stirred at room temperature for 1 hour. After removal of solvent the residue was purified by chromatography on silica gel (4 cm 12 cm) in the solvent system of 0.5 - 2% ethanol in dichloromethane, getting 0,368 g (28% over 4 steps from 3-( (R)-- ((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-oxybenzyl)benzoic acid 3-( (R)-- ((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3- (oxybenzyl)-N-methyl-N-phenylbenzene in the form of a solid light-yellow color. NMR (300 MHz, DMCO-d6): (R)-- to 0.89 (d, J=6.0 Hz, 3H); to 0.96 (d, J=6.0 Hz, 3H); 111,0 HZ, 1H); 2,82 (dd, J1=7,0 Hz, J2=a 13.9 Hz, 1H); 3,17 (dd, J1=4,8 Hz, J2=a 13.9 Hz, 1H); to 3.34 (s, 3H); of 4.77 (s, 1H); 5,10(d, J=10.1 Hz, 1H); 5,16 (d, J=17.3 Hz, 1H); 5,70 -5,82 (m, 1H); 6,41 (d, J=7,4 Hz, 1H); is 6.54 (s, 1H); only 6.64 (d, J=8.0 Hz, 1H); 7,05-7,26 (m, 10H); 9,31 (s, 1H). Mass spectrum (Cl-CH4) m/e 470 (M+1, 100%), 376 (81%), 316 (45%), 153 (97%). = +12,3o(ethanol, C=1,2). The free amine (0,339 g) was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH 3.0, followed by precipitation with diethyl ether from dichloromethane, getting 0,321 g (88% yield) of monohydrochloride in the form of a hygroscopic powder light yellow color. Est. for C30H35N3O2HCl H2O: C, 68.75 Kilopascals; H, 7,31; N, 8,02; Cl, 6,76. Found: C, 68,86; H, 7,42; N, 8,00; Cl, 6,84.

Example 3

3-( []2D0((2S, 5R) -4-Allyl-2,5-dimethyl-1-piperazinil) -3-oxybenzyl)-N-(4-forfinal)-N-methylbenzamide

Following the General method of reductive alkylation described in the literature (Krishnamurty, S. Tetrahedron Lett., 23, 3315, (1982)), acetic-formic anhydride was obtained by slow addition of formic acid (7.5 ml) of acetic anhydride at 0oC. After stirring for 5 minutes at 0oC the mixture was heated to 55oC and kept at this temperature under nitrogen atmosphere for 1.75 hours. The mixture was cooled to 0ooC. To the solution was added dropwise borane in tetrahydrofuran (40 ml, 1.0 M solution). During the first half of the process of adding watched the evolution of gas. At the end of the process of adding the solution was boiled under reflux for 3 hours. The solution was cooled to 0oC and to it was carefully added 10 ml of methanol. After stirring for 10 minutes to the reaction mixture was added an ethanolic solution of hydrogen chloride (7 ml 7.1 M solution) and the mixture was stirred over night. After removal of all volatile compounds in vacuo received the crude N-methyl-4-ftoranila in the form of a solid light purple color. NMR (200 MHz, DMCO-d6): (R)-- to 2.65 (s, 3H); 5,54 (s, 1H); 6,51 (dd, J1=4,7 Hz, J2=8,8 Hz, 2H); 6,93 (dd, J1=a 8.9 Hz, J2= 8,8 Hz, 2H).

3-( ((2S, 5R)-4-Allyl-2,5-dimethyl-1-piperazinil)-3-tert - butyldimethylsilyloxy)benzyl)benzoyl chloride (Example 2, infra, 2,03 g untreated, approximately 1.29 g is the notes) was dissolved in 8 ml of dichloromethane at room temperature under nitrogen atmosphere. To the solution was added 0.5 ml of triethylamine. Next was added dropwise 4-fluoro-N-methylaniline (0,478 mg, 3,82 mmole) in dichloromethane (5 ml) (exothermic reaction) and the reaction mixture was stirred over night at room temperature. All volatile compounds were removed by evaporation under reduced pressure, obtaining a solid resinous substance yellow-brown color.

The crude solid was dissolved in acetonitrile (8 ml) under nitrogen atmosphere at room temperature. To the solution was added fluoride of tetraethylammonium hydrate (1.06 g, 5.7 mmole) and the solution was stirred at room temperature overnight. After removal of solvent the residue was purified by chromatography on silica gel (4 cm 14 cm) in the solvent system 0,25-3,5% ethanol in dichloromethane, getting 0,419 g (34% over 4 steps from 3-( (R)-- ((2S, 5R)-4-allyl-2,5 - dimethyl-1-piperazinil)-3-oxybenzyl) benzoic acid 3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3- (oxybenzyl)-N-(4-forfinal)-N-methylbenzamide in the form of a yellow powder. NMR (300 MHz, DMCO-d6): (R)-- to 0.88 (d, J=6.0 Hz, 3H); to 0.96 (d, J=6.0 Hz, 3H); 1,68 (dd, J1= 7.7 Hz, J2= to 10.8 Hz, 1H); 2,02 (dd, J1=7,1 Hz, J2=to 10.7 Hz, 1H); 2,28 (br d, J=10,7 Hz, 1H); 2,35-2,52 (m, 2H); 2.66 per (br d, J=a 10.6 Hz, 1H); 2.82 from (dd, J1= 7,4 Hz, J2=a 13.9 Hz, 1H); and 3.16 (dd, J1=4,6 Hz, J2=1 9H); 9,31 (s, 1H). Mass spectrum (Cl-CH4) m/e 488 (M+1, 100%), 334 (11%), 153 (68%). +6,9o(ethanol, C=1,6). The free amine (0,390 g) was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH of 3.3, followed by precipitation with diethyl ether from dichloromethane, getting 0,327 g (78% yield) of monohydrochloride in the form of a hygroscopic powder light yellow color. Est. for C30H34N3O22F HCl H2O: C, 66,47; H, To 6.88; N, 7,75; F, 3,50; Cl, 6,54. Found: C, Collected 66.36; H, 6,74; N, 7,82; F, 3,27; Cl, 6,62.

Example 4

3-( []2D0= ((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinil)-3-oxybenzyl-N- (4-chlorophenyl)-N-methylbenzamide

4-Chloro-N-methylamine was obtained from 4-Chloroaniline, coupled with 3-( (R)-- ((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-(tert - butyldimethylsilyloxy)benzyl)benzoyl chloride, removed the protective group and purified using the methods described in example 3, obtaining 3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-oxybenzyl-N- (4-chlorophenyl)-N-methylbenzamide in the form of powder light yellow color. NMR (300 MHz, DMCO-d6): (R)-- to 0.89 (d, J= 6.2 Hz, 3H); 0,93 (d, J=6,1 Hz, 3H); 1,65 (dd, J1=7,6 Hz, J2=to 10.8 Hz, 1H); for 2.01 (dd, J1=7,6 Hz, J2=10.4 Hz, 1H); and 2.27 (dd, J1=1.5 Hz, J2= to 11.4 Hz, 1H); 2,35-2,52 (m, 2H); to 2.65 (br d, J =10,8 Hz, 1H); 2,82 dd, J1=7,6 Hz, J2=13.5 Hz, 1H); and 3.16 (dd, J1=C, 1H);? 7.04 baby mortality-7,25 (m, 5H); 7,13 (d, J= 8.5 Hz, 2H); 7,29 (d, J=8.5 Hz, 2H); 9,31 (s, 1H). Mass spectrum (Cl-CH4) m/e 504 (35Cl, M+1, 86%), 350 (28%), 153 (100%). = +10,2o(ethanol, c = 1,6). Monohydrochloride was prepared as in example 3, receiving hygroscopic powder light yellow color. Est. for C30H34N3O2Cl HCl 0,75 H2O: C, 65,04; H, Only 6.64; N, 7,58; Cl, 12,80. Found: C,6504; H, Of 6.71; N 7,49; Cl, 12,83.

Example 5

3-([]2D0((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinil)-3-oxybenzyl)-N-ethyl-N - phenylbenzene

3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3- (tertBUTYLPEROXY)benzyl)benzoyl chloride (example 2, infra, of 2.81 g of untreated, approximately 1,74 g of the basic substance, 3,39 mmole, based on 3-( (R)-- ((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-oxybenzyl)benzoic acid) was dissolved in 10 ml of dichloromethane at room temperature under nitrogen atmosphere. To the solution was added 0.5 ml of triethylamine. Next was added dropwise N-ethylaniline (0,780 ml, 6.2 mmole) (reaction is exothermic) and the reaction mixture was stirred over night at room temperature. All volatile compounds were removed by evaporation under reduced pressure, obtaining a thick brown oil.

The crude oil was dissolved in acetonitrile (10 ml) in an atmosphere etheremadivaru at room temperature for 1 hour. After removal of solvent the residue was purified by chromatography on silica gel (4 cm to 15 cm) in the solvent system of 0.5 - 3% ethanol in dichloromethane, getting 0,508 g (31% over 4 steps from 3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1 - piperazinil)-3-oxybenzyl)benzoic acid 3-( (R)-- ((2S, 5R)-4 - allyl-2,5-dimethyl-1-piperazinil)-3-oxybenzyl)N-ethyl-N-phenylbenzene in a solid white color. NMR (300 MHz, DMCO-d6): (R)-- to 0.89 (d, J=6,1 Hz, 3H); to 0.96 (d, J=6,1 Hz, 3H); of 1.07 (t, J=7.0 Hz, 3H); 1,67 (dd, J1=7,4 Hz, J2=10.4 Hz, 1H); 2,02 (dd, J1=7,4 Hz, J2=to 10.6 Hz, 1H); and 2.27 (dd, J1=1.4 Hz, J2=to 10.6 Hz, 1H); 2,36-2,52 (m, 2H); 2.66 per (br d, J= 10.4 Hz, 1H); 2.82 from (dd, J1=7.8 Hz, J2=13.5 Hz, 1H); and 3.16 (dd, J1=4.0 Hz, J2= a 13.9 Hz, 1H); 3,83 (q, J=7,0 Hz, 2H); 4.75 V (s, 1H); 5,09 (d, J=9.9 Hz, 1H); 5,16 (d, J=and 17.2 Hz, 1H); 5,70 of 5.84 (m, 1H); 6,41 (d, J=7,6 Hz, 1H); is 6.54 (s, 1H); 6,63 (d, J=8,2 Hz, 1H); 7.03 is-7,29 (m, 10H); of 9.30 (s, 1H). Mass spectrum (Cl-CH4) m/e 484 (M+1, 100%), 330 (57%), 153 (66%). +10,4o(ethanol, c= 1,2). Monohydrochloride was prepared from 0,473 g of the free amine as in example 3, receiving 0,389 g (76% yield) of a hygroscopic white powder. Est. for C27H37N3O2HCl H2O: C, 66,19; H, 7,49; N, 7,81; Cl, 6,59. Found: C, 69,41; H, 7,52; N, 7,73; Cl, 6,48.

Example 6

(-)-3-( []2D0= ((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinil)-3 - oxobenzo)-N-phenylbenzene

Ametal-1-piperazinil)-3-(t-butyldimethylsilyloxy) benzyl)benzoyl chloride (example 2, infra) using the method of obtaining benzamide as described in example 2. NMR (200 MHz, DMCO-d6): (R)-- 0,99 (d, J=5.7 Hz, 3H); 1,10 (d, J=5.8 Hz, 3H); at 1.91 (dd, J1= 7,0 Hz, J2= 10.5 Hz, 1H); and 2.14 (dd, J1=6,0 Hz, J2=10.4 Hz, 1H); of 2.51-of 2.81 (m, 2H); is 2.88 (dd, J1=6,8 Hz, J2=a 13.9 Hz, 1H); 3,18 (dd, J1=5.4 Hz, J2=to 13.8 Hz, 1H); of 5.06 (d, J=15.6 Hz, 1H); 5,14 (s, 1H); 5,19 (d, J=18,1 Hz, 1H); of 5.75 (m, 1H); 6.73 x (m, 3H); 7,10 (d, J=7.8 Hz, 1H); 7,17 (d, J=8.0 Hz, 1H); 7,30-to 7.59 (m, 3H); the 7.65 (d, J=7,6 Hz, 1H); 7,71-7,83 (m, 3H); to 7.93 (s, 1H); 9,37 (s, 1H); of 10.21 (s, 1H). Mass spectrum (Cl-CH4) m/e 456 (M+1, 100%), 302 (41%), 153 (77%); . -4,44o(ethanol, c=1,4). Monohydrochloride was prepared as in example 2, receiving hygroscopic powder light yellow color. Est. for C29H33N3O2HCl 0,75 H2O: C, 68,90; H, Was 7.08; N, 8,31; Cl, 7,01. Found: C, 69,00; H, 7,06; N, 8,32; Cl, 6,95.

Example 7

3-( []2D0= ((2S, 5R)-4-Allyl-2,5-dimethyl-1-piperazinil)-3 - oxobenzo-N-(3-forfinal)-N-methylbenzamide

1-(3-Fluoro-)-N-methylaniline was obtained from 3-foronline using a modified method of reductive amination. In the first phase was obtained 1-oxidativestress by adding 37% aqueous formaldehyde to benzotriazole at 40oC in the ratio of 1:1 and cooled to room temperature to precipitate the reaction product. After Phil is ol and 3-ftoranila (92,2 g). Water was removed in the form of an azeotropic mixture using a trap Dean-Stark. After three hours of boiling, the mixture was cooled to room temperature, then put a few hours in the fridge for complete precipitation. The solid is in the form of white crystals were collected by filtration, getting 174,2 g (86,6%) 1-(3-ftoranila)methyl-1H-benzotriazole.

1-((3-Ftoranila)methyl-1H-benzotriazol (173,9 g) suspended in anhydrous tetrahydrofuran. To the mixture at room temperature portions was added sodium borohydride (32,5 g). At the end of the addition the mixture was heated under reflux for 4 hours. The solution was cooled and slowly poured into 400 ml of 5 M hydrochloric acid with ice and stirred for 1 hour at room temperature. the pH of the solution was brought down to 9 to 10 with 10 M sodium hydroxide solution. The product was extracted with diethyl ether. The ether extracts are successively washed with 1 M sodium hydroxide solution, a saturated solution of sodium chloride and water. The organic phase was dried over sodium sulfate, evaporated under reduced pressure, obtaining of 87.5 g (97%) of 3-fluoro-N-methylaniline in the form of a colorless oil. [NMR (200 MHz, DMCO-d6): (R)-- was 2.76 (s, 2H); to 3.41 (br s, 1H); 6,59-6,92 (m, 3H); 7,27 (q, J=8.0 Hz, 1H)].

3-Carboxyl is, supplied with potassium chloride tube to trap moisture. The reaction vessel was placed in an oil bath and heated, keeping the bath temperature below 100oC. the Mixture was boiled under reflux to obtain a clear solution and for an additional 5-10 minutes before cooling to room temperature. The solution was diluted with anhydrous toluene and all volatile compounds were removed under vacuum.

The crude chloride was dissolved in dichloromethane and cooled in a water bath with ice. To the solution from the dropping funnel was added first 6 ml of triethylamine, and then to 1.83 g of N-methyl-3-foronline in dichloromethane. A cloudy solution was left for 1 hour to heat to room temperature. To the solution was added water and the product was extracted with dichloromethane. The organic layer was washed with water and saturated sodium chloride solution, dried over sodium sulfate and the solvent was removed under vacuum. N-(3-Forfinal)-3-formyl-N-methylbenzamide (3,20 g) was obtained as oil light Golden color (93% yield without chromatography). [NMR (300 MHz, DMCO-d6): to 3.38 (s, 3H); 6,94-7,02 (m, 2H); 7.18 in-7,29 (m, 2H); 7,46 (t, J=7.7 Hz, 1H); at 7.55 (d, J=7,6 Hz, 1H); 7,81 (m, 2H); for 9.90 (s, 1H)].

In a 12 liter 3-neck round bottom flask was placed TRANS-2,5-DIMET ml of water. The flask was cooled in an ice bath and its contents slowly with stirring and cooling to maintain the temperature below 40oC solution was added methanesulfonic acid (1290 g of 13.4 mol) in 600 ml of water. The solution was cooled to 20oC and to it was added 800 ml of ethanol. Addition funnel 500 ml was filled with 60% aqueous potassium acetate solution of 2 l tank with this solution and the potassium acetate was added to the reaction vessel to bring the pH to 4.0. The second addition funnel was filled with a solution of ethylchloride (642 ml of 6.71 mol) in 360 ml of tetrahydrofuran. Solutions ethylchloride and potassium acetate were simultaneously added dropwise to an agreed rate to maintain the pH value of the reaction solution is 4.0 to 0.1 if necessary cooling to maintain the temperature of 25oC. after adding ethylchloride the reaction mixture was stirred for 1 hour, continuing to add the potassium acetate solution to maintain a pH of 4.0. Organic solvents were removed by distillation under vacuum. The remaining aqueous solution was washed with 1500 ml of ethyl acetate to remove all bis-urethane impurities. An ethyl acetate wash was extracted with two portions of 500 ml of 1 M hydrochloric acid, extracting p is sodium cooled to maintain the temperature below 40oC. the Aqueous solution was extracted with two 1500 ml portions of ethyl acetate, the combined extracts were dried over magnesium sulfate and the solvent was removed, getting 927 g (74%) of ethyl-TRANS-2,5-dimethyl-1-piperidinecarboxylate in the form of a yellow oil.

A mixture of ethyl-TRANS-2,5-dimethyl-1-piperidinecarboxylate (643 g of 3.45 mol), allylbromide (328 ml of 3.80 mol) and sodium carbonate (440 g, 4,15 mol) in 2500 ml of acetonitrile was heated under reflux for 1.5 hours. The reaction mixture was cooled to room temperature, filtered and the solvent was removed under vacuum. The residue was dissolved in 4000 ml of dichloromethane and washed with two portions of 500 ml of 1 M sodium hydroxide solution. The dichloromethane solution was dried over magnesium sulfate and the solvent was removed, getting 630 g (81%) of ethyl TRANS-4-allyl-2,5-dimethyl-1-piperidinecarboxylate in the form of butter.

Ethyl TRANS-4-allyl-2,5-dimethyl-1-piperidinecarboxylate (630 g, 2,78 mol) was added to a solution of 87% of granulated potassium hydroxide (2970 g, 46 moles) in 4300 ml of 95% ethanol and boiled under reflux for 1.5 hours. During the first 0.5 - 1 hour watched the allocation of carbon dioxide. The reaction mixture was cooled to a temperature below the boiling point and to her neatly dobavljaci additional 4000 ml of toluene in a reaction vessel. After collecting 9000 ml of distillate, the reaction mixture was cooled to a temperature of 100oC and to it was carefully added to 1000 ml of toluene. The solution was slowly cooled to 5oC and kept at this temperature for 30 minutes. The solution was filtered and the filter cake washed with an additional 1500 ml of toluene. The filtrate was washed with water (1000 ml), dried over magnesium sulfate and the solvent was removed, getting 296 g (69%) of TRANS-1-allyl-2,5-dimethylpiperazine as a dark liquid. NMR (300 MHz, DMCO-d6): of 0.87 (d, J=6.3 Hz, 3H); to 0.92 (d, J=6.3 Hz, 3H); and 1.63 (t, J= 11 Hz, 1H); is 2.05 (m, 1H); 2,30 (t, J=11 Hz, 1H); 2,6-2,8 (m, 4H); to 3.33 (dd, J1= 5 Hz, J2=14 Hz, 1H); 5,09 (d, J=8.7 Hz, 1H); 5,13 (d, J=14 Hz, 1H); 5,8 (m, 1H).

Di-p-toluene-D-tartaric acid (Schweizerhall, Inc., South Plainfield, New Jersey) (1.25 kg, and 3.2 mol) was dissolved in hot (about 60oC) 95% ethanol (16 l) and to the solution several techniques were added racemic TRANS-1-allyl-2,5-dimethylpiperazine (500 g, 3,2 mol) (caution: exothermic reaction). In a hot solution was added seed crystals diastereoisomers pure salt (obtained in preliminary small-scale separation) and the solution was cooled to room temperature for 2 to 3 hours. The solution was slowly stirred for two days at room temperature. Abrazovivaetsa white (47%). Repeat the process with the second portion of the di-p-toluene-D-tartaric acid and racemic TRANS-1-allyl-2,5-dimethylpiperazine gave 869 g (80%) of the substance.

All the obtained Sol (1695) was divided into three portions, each of which was recrystallized twice described later. The salt was dissolved in boiling 95% ethanol (about 2.7 liters per 100 grams of salt) in a flask with reflux condenser and approximately half volume of ethanol was removed by distillation. (Note: you will need a vigorous stirring of the solution during the distillation in order to avoid crystallization on the walls of the vessel). In a hot solution was added a seed crystal diastereoisomers pure salt, cooled to room temperature slowly and was stirred for 2 days collecting salt by filtration. (Note: subsequent experiment showed that the time of crystallization can be reduced from 2 days to 8 hours). The total yield of the product was 1151, Salt was dissolved in 3 l of 2 M aqueous sodium hydroxide solution and the aqueous solution was extracted with four portions of dichloromethane, 1 l each. The organic extracts were combined, dried over sodium sulfate and the solvent was removed with a rotary evaporator at a temperature of less than 20oC, getting 293 g of ethanol, c= 1,2). Trifurcated product obtained by triperoxonane anhydride and analyzed by capillary gas chromatography (column 20 M 0.32 mm, Chiraldex B-PH, Advanced Separation Technolohies Inc. , Whippany, NJ, 120oC) showed stereocilia more than 99% of the time delays of the desired enantiomer of 11.7 min; the other enantiomer of 10.7 min).

(2R, 5S)-1-allyl-2,5-dimethylpiperazine (6,13 g), benzotriazole (4,79 g) and N-(3-forfinal)-3-formyl-N-methylbenzamide (10,23 g) was stirred in anhydrous toluene containing one drop of triethylamine. The mixture was placed in an oil bath with a temperature of 140oC (bath temperature). The flask was connected to a trap Dean-Stark for azeotropic removal of water in a stream of nitrogen. The mixture was boiled under reflux for 2-3 hours and most of the toluene under reduced pressure. The crude adduct can be isolated at this stage crystallization, giving 3-(((2R, 5S)-4-allyl-2,5-dimethyl-1-piperazinil)-3-(1H-benzotriazol-1 - yl)methyl)-N-(3-forfinal)-N-methylbenzamide in the form of a mixture of epimeres, but because of its sensitivity to water, as a rule, it is convenient to use in subsequent reactions without purification. (The reaction mixture in toluene is usually suitable for further stages).

A solution of 3-bromophenol (500 g, 2,89 mol), tert-Buti and at room temperature. The reaction solution was poured into 3000 ml of water and was extracted with two portions of 2000 ml of diethyl ether. The combined extracts were dried over sodium sulfate and solvent was removed, getting 846 g of 3-(bromophenoxy)-tert-butyldimethylsiloxy in the form of a pale yellow liquid. NMR (300 MHz, CDCl3): []2D0of 0.2 (s, 6H); and 1.0 (s, 9H); to 6.75 (m, 1H); 7,0 (br s, 1H); and 7.1 (m, 2H).

3-(Bromophenoxy)-tert-butyldimethylsilyl (17,12 g) was dissolved in anhydrous tetrahydrofuran (150 ml) and cooled to -78oC in nitrogen atmosphere. To the solution slowly with a syringe was added n-utility in hexane (23,88 ml of 2.5 M solution). In the process stirring for 40 minutes at -78oC the solution became white and partly cloudy. The solution was transferred by means of a bifurcated needle into the flask containing etherate magnesium bromide (16.5 g) in tetrahydrofuran (150 ml) and stirred at room temperature for 1 hour. Untreated benzotriazole adduct with the previous phase, containing mainly 3-(((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinil)-3-(1H-benzotriazol-1 - yl)methyl-N-(3-forfinal)-N-methylbenzamide, was dissolved in tetrahydrofuran and added to freshly prepared reagent bromide ariline. The solution was gently heated in the process of adding and purchase the oru carefully added 0.5 M aqueous solution of hydrochloric acid until until its pH reached a value equal to 6. The product was extracted with 250 ml ethyl acetate and the solvent was removed under vacuum.

Tert-butylmethacrylate protective group was removed by dissolving the residue in 175 ml of tetrahydrofuran and adding 85 ml of aqueous HCl at room temperature. The solution was heated adding acid. The mixture was stirred for 40 minutes at room temperature. After adding diethyl ether gave the Department of aqueous acid layer. The aqueous layer was washed a second time in diethyl ether and brought it pH to a value of 8-9, using an aqueous solution of sodium hydroxide. The product was extracted with ethyl acetate. An ethyl acetate extract were combined and washed with dilute sodium hydroxide solution to remove the remaining benzotriazole. After that, the organic layer was washed with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated under reduced pressure. Product (10,85 g, 56%) was obtained as a mixture of two diastereomers in a ratio of 91:9 in favor of the desired diastereoisomer, as determined using VIH analysis. WICH was performed on a column-Bondapak C-18 (125 A, 3,9 300 mm, Waters Chromatohraphy Division, Millipore Corparation, Milford, MA) using 60% methanol and 40% 0.1 M in the ATA/hexane, getting 3-( ((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-oxybenzyl)-N- (3-forfinal)-N-methylbenzamide in the form of a solid crystalline substance white (so pl. 144 - 145oC) purity relative to the isomeric composition of 99% (according to VGH). NMR (200 MHz, DMCO-d6): (R)-- 0,84 (d, J=6.0 Hz, 3H); 0,97 (d, J= 5,9 Hz, 3H); 1.69 in (dd, J1=7.7 Hz, J2=to 10.7 Hz, 1H); for 2.01 (dd, J1=7,4 Hz, J2=to 10.7 Hz, 1H); 2,28 (br d, J=8,3 Hz, 1H); 2.40 a-2,52 (m, 2H); to 2.67 (br d, J=10.5 Hz, 1H); 2.82 from (dd, J1=7,6 Hz, J2=13,2 Hz, 1H); 3,17 (br d, J=14,0 Hz, 1H); to 3.34 (s, 3H); 4.80 to (s, 1H); 5,10 (d, J=10.1 Hz, 1H); to 5.17 (d, J= 17.3 Hz, 1H); 5,70 of 5.84 (m, 1H); 6.42 per (d, J=7,1 Hz, 1H); 6,56 (s, 1H); of 6.65 (d, J= 8,3 Hz, 1H); 6,90-to 7.32 (m, 9H); 9,31 (s, 1H). Mass spectrum (Cl-CH4) m/e 488 (m+1, 100%), 334 (39%), 153 (87%). = +4,9o(abs. ethanol, C= 1,2). The free amine was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH of 3.7, followed by precipitation with diethyl ether from dichloromethane, getting monohydrochloride in the form of a hygroscopic powder whitish color. Est. for C30H34N3O2F HCl 1,25 H2O: C, 65,92; H, 6,92; N, 7,69; Cl, Of 6.49. Found: C, 66,07; H, Of 6.95; N, 7,53; Cl, 6,54.

Example 8

3-( []2D0((2S,5R)-4-Allyl=2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-methyl-N-(2,4,6-trichlorophenyl)benzamide

N-Methyl-2,4,6-trichloroaniline [NMR (200 MHz, CDCl3): (R is inyl)-3-(tert-butyldimethylsilyloxy) benzyl)benzoyl chloride, filmed protective group and was purified by the methods described in example 3, obtaining 3-( ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-methyl-N-(2,4,6-trichlorophenyl)benzamide in the form of a whitish powder coating. NMR (200 MHz, DMCO-d6): (R)-- of 0.90 (d, J= 6,1 Hz, 3H); and 0.98 (d, J=6.0 Hz, 3H); 1,65 (dd, J1=7,4 Hz, J2=to 10.6 Hz, 1H); 2,03 (dd, J1=7.5 Hz, J2=10,2 Hz, 1H); 2,35 (d, J=11.7 Hz, 1H); 2,38 is 2.51 (m, 2H); to 2.65 (br d, J=a 10.6 Hz, 1H); 2,80 (dd, J1=7,0 Hz, J2=13.3 Hz, 1H); of 3.12 (m, 1H); 3,18 (s, 3H); 4.80 to (s, 1H); 5,11 (d, J=11.0 cm Hz, 1H); by 5.18 (d, J= 16,8 Hz, 1H); 5,66-by 5.87 (m, 1H); 6.48 in (d, J=8,4 Hz, 1H); 6,56 (s, 1H); only 6.64 (d, J=8.6 Hz, 1H); 7,16 (t, J=8.0 Hz, 1H); 7,22-7,28 (m, 3H); 7,38 (s, 1H); of 7.69 (d, J= 2.2 Hz, 1H); 7,72 (d, J=2.2 Hz, 1H); 9,31 (s, 1H). Mass spectrum (Cl-CH4) m/e: 572 (M+1, 14%), 153 (100%).

Example 9

3-( ((2S, 5R)-4-Allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-methyl-N-(2-(trifluoromethyl)phenyl)benzamide

N-Methyl-2-(trifluoromethyl)aniline [NMR (200 MHz, DMCO-d6): (R)-- a 2.75 (S, 3H); 3.40 in (S, 1H); 6,70 (t, J=8.0 Hz, 1H); 6,94-7,16 (br m, 2H); 7,38 (d, J= 7,3 Hz, 1H)] was obtained from 2-(trifluoromethyl)aniline, was associated with 3-( ((2S, 5R)-4-allyl-2,5 - dimethyl-1-piperazinil)-3-(tert-butyldimethylsilyloxy)benzyl) benzoyl chloride, filmed protective group and was purified by the methods described in example 3, obtaining 3-( (R)-- ((2S,5R)-4-allyl - 2,5-dimethyl-1-piperazinil)-3-oxybenzyl)-N-methyl-N-(2-Cryptor - methyl)phenyl)benzamide in the form of a yellow powder. NMR (200 (s, 3H); 4,79 (s, 1H); 5,11 d, J=10,2 Hz, 1H); by 5.18 (d, J=17,0 Hz, 1H); 5,70-of 5.82 (m, 1H); 6.42 per (d, J=7,6 Hz, 1H); of 6.65 (d, J=7.7 Hz, 1H); to 6.67 (s, 1H);? 7.04 baby mortality-7,83 (m, 9H); to 9.32 (s, 1H). Mass spectrum (Cl-CH4) m/e 538 (M+1, 82%), 384 (13%), 153 (100%).

Example 10

3-( ((2S,5R)-allyl-2,5-dimethyl-1-piperazinil)-3-oxybenzyl) -N-methyl-N-phenylbenzene

3-( (S)-- ((2S, 5R)-4-Allyl-2,5-dimethyl-1-piperazinil)-3 - bromobenzyl)phenol (2.30 g, 5.5 mmole, example 2, infra) was mixed with tert-butylimidazolium (1,67 g, 11 mmol) and imidazole (0,94 g of 13.8 mmole) in 30 ml of dimethylformamide at room temperature over night under nitrogen atmosphere. The reaction mixture was poured into ice water and was extracted with diethyl ether. The ether layers were washed with water and brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by chromatography on silica gel in the solvent system hexane:ethyl acetate (0-50%), receiving a 2.36 g salelologa ester as a yellow oil.

Silloway ester (2.25 g, 4.2 mmole) was dissolved in 80 ml of dry tetrahydrofuran, optionally dried over molecular sieves, was transferred to a reaction flask in a nitrogen atmosphere and cooled to -78oC. In the flask under stirring in nitrogen atmosphere was added n-utility (2,6 ml of 1.6 M solution in hexane) with such speed that padiatrie 2-3 minutes. The mixture was heated to room temperature with constant stirring to maintain the degassing of dissolved carbon dioxide. The solvent was evaporated, the residue pererestorani in toluene, and then again under vacuum, removed the solvent, removing all n-rambutan. The residue was dissolved in dichloromethane (50 ml), was added thionyl chloride (0,46 ml, 6.3 mmole) and the mixture was stirred at room temperature for 40 minutes. After this was added triethylamine (2.3 ml, is 16.8 mmole) and N-methylaniline (0.5 ml, 4.6 mmole) and stirring at room temperature was continued overnight. The reaction mixture was washed with water, dried over sodium sulfate and the solvent was removed under vacuum, obtaining of 2.68 g of brown oil. The crude product was dissolved in acetonitrile and subjected to the action of 1.2 g (6.3 mmole) of fluoride tetraethylammonium dihydrate for 10 minutes at room temperature. The solvent was evaporated and the residue was purified by chromatography on silica gel in the solvent system dichloromethane:ethanol (0-3,5%), getting to 0.92 g of 3-( (S)-- ((2S, 5R)-4-allyl-2,5-dimethyl - 1-piperazinil)-3-oxybenzyl)-N-methyl-N-phenylbenzene in the form of a solid light beige color. NMR (DMCO-d6, 200 MHz): (S)-- of 0.9 (d, J=6 Hz, 3H); of 0.95 (d, J=6 Hz, 3H); 1.7 to (dd, J1=6 Hz, J=7 Hz, J2=15 Hz, 1H); 3,4 (s, 3H); 4.7 in (s, 1H); 5,1 (d, J=10 Hz, 1H); 5,2 (d, J=17 Hz, 1H); 5,8 (m, 1H); and 6.6 (m, 2H); at 6.8 (s, 1H); 7,0 (t, J=8 Hz, 1H); 7,1 - 7,3 (m, N); and 9.4 (s, 1H). = +4o(abs. ethanol, C=2,7). The product was dissolved in absolute ethanol and titrated with ethanolic hydrogen chloride to pH 3. The solution was concentrated and thereto was added diethyl ether in order to precipitate monohydrochloride, which was dried under vacuum, obtaining 0,617 g powder light beige color. Est. for C30H35N3O2HCl 0,70 H2O: C, 69,47; H, 7,27; N, 8,10; Cl, 6,84. Found: C, 69,76; H, 7,27; N, 7,74; Cl, 6,60.

Example 11

3-( []2D0) ((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-phenyl-N-propylbenzamide

N-Propylaniline were obtained from aniline and propionic anhydride, was associated with 3-( (R)-- (2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-(tert - butyldimethylsilyloxy)benzylchloride, removed the protective group and was purified by the methods described in example 3, obtaining 3-( (R)-- ((2S,5R)-allyl-2,5-dimethyl-1-piperazinil)-3-oxybenzyl)-N-phenyl-N - propylbenzamide in the form of powder light yellow color. NMR (200 MHz, DMCO-d6): (R)-- of 0.87 (t, J=7.4 Hz, 3H); of 0.91 (d, J=5,9 Hz, 3H); and 0.98 (d, J=6.0 Hz, 3H); is 1.51 (m, 2H); 1.69 in (dd, J1= 7,2 Hz, J2=10,9 Hz, 1H); to 2.06 (dd, J1=7,0 Hz, J2=10.5 Hz, 1H); 2,30 (d, J= 10.3 Hz, 1H); 2,39 -2,54 (m, 2H); 2,65 (bH); 5,12 (d, J=10,2 Hz, 1H); by 5.18 (d, J=16.0 Hz, 1H); 5,71 of 5.84 (m, 1H); to 6.43 (d, J=7,6 Hz, 1H); to 6.57 (s, 1H); only 6.64 (d, J=8.0 Hz, 1H); 7,02-7,33 (m, 10H); to 9.32 (s, 1H). Mass spectrum (Cl-CH4) m/e 498 (M+1, 100%), 344 (23%), 153 (80%). +8,9o(ethanol, C=1,1). The free amine (0,585 g) was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH 4.0 with subsequent precipitation with diethyl ether from dichloromethane, getting 0,479 g monohydrochloride in the form of a hygroscopic powder whitish color. Est. for C32H39N3O2HCl 0,75 H2O: C, 70,18; H, Of 7.64; N, To 7.67; Cl, 6,47. Found: C, 70,16; H, 7,73; N, To 7.59; Cl, 6,51.

Example 12

(+)-3-( []2D0((2S, 5R)-4-Allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-ethyl-N-(4-forfinal)benzamide

4-Fluoro-N-ethylaniline [NMR (200 MHz, D-d6): a 1.25 (t, J = 7,1 Hz, 3H); of 3.12 (q, J = 7,1 Hz, 2H); 3.24 in (br s, 1H); to 6.57 (dd, J1= 4.5 Hz, J2= 9,0 Hz, 2H); 6.90 to (t, J = 8,9 Hz, 2H)] was prepared from 4-foronline and acetic anhydride by methods described in example 3. For the synthesis of N-(4-forfinal)-3-formyl-N-ethylbenzamide [NMR (200 MHz, D-d6): a 1.11 (t, J = 7.0 Hz, 3H): 3,88 (q, J = 7,0 Hz, 2H); 7,10 (t, J = 8.6 Hz, 2H); 7,21-7,35 (m, 2H); 7,46 (q, J = 7,4 Hz, 1H); 7,56 (d, J = 7.2 Hz, 1H); 7,83 (m, 2H); to 9.93 (s, 1H)] was used aniline and the methods described in example 7. (+)-3- ( ((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinil)-3-oxybenzyl)-N-ethyl-N- (4-tarfilename through the crude 3-(((2R, 5S)-4-allyl-2,5-dimethyl-1-piperazinil)-3-(1H-benzotriazol - 1-yl)methyl)-N-ethyl-N-(4-forfinal)benzamide using the procedures described in example 7. Final recrystallization produced from acetonitrile. NMR (200 MHz, D-d6): (R)-- of 0.91 (d, J = 6,1 Hz, 3H); and 0.98 (d, J = 6.0 Hz, 3H); 1,08 (t, J = 7.0 Hz, 3H); 1,71 (dd, J1= 7,0 Hz, J2= 11.3 Hz, 1H); 2,05 (dd, J1= 7,2 Hz, J2= to 10.8 Hz, 1H); 2,31 (d, J = 11,4 Hz, 1H); 2,36-to 2.57 (m, 2H); 2,69 (dd, J1= 2.2 Hz, J2= to 10.7 Hz, 1H); 2,85 (dd, J1= 7,0 Hz, J2= a 13.9 Hz, 1H); 3,18 (dd, J1= 5.3 Hz, J2= a 13.9 Hz, 1H); of 3.84 (q, J = 7,0 Hz, 2H); 4,78 (s, 1H); 5,11 (d, J = 10.0 Hz, 1H); by 5.18 (d, J = 16.4 Hz, 1H); 5,65-to 5.58 (m, 1H); 6,46 (d, J = 7,4 Hz, 1H); to 6.58 (s, 1H); of 6.65 (d, J = 8,1 Hz, 1H); 7,01-7,27 (m, 9H); was 9.33 (s, 1H). Mass spectrum (Cl-CH4) m/e 502 (M+1, 90%), 348 (15%), 153 (100%). = +6,30o(abs. ethanol, c = 1,1).

The free amine (0,313 g) was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH of 3.95 with subsequent precipitation with diethyl ether from dichloromethane, getting to 0.263 g monohydrochloride in the form of a hygroscopic white powder. Est. for C31H36N3O2F HCl H2O: C, 66,95; H, 7,07; N, 7,56; Cl, 6,38. Found: C, 66,97; H, 7,10; N, 7,47; Cl, 6,41.

Example 13.

(+)-3-( []2D0((2S, 5R)-4-Allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-(4-methoxyphenyl)-N-methylbenzylidene)benzyl)benzoyl chloride, filmed protective group and was purified by the methods described in example 3, obtaining (+)-3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-oxybenzyl)-N- (4-methoxyphenyl)-N-methylbenzamide in the form of powder, light purple color, NMR (200 MHz, D-d6): (R)-- to 0.89 (d, J = 6.0 Hz, 3H); to 0.96 (d, J = 6,1 Hz, 3H); of 1.66 (dd, J1= 6,5 Hz, J2= to 11.0 Hz, 1H); 2,00 (dd, J1= 7,1 Hz, J2= 10.4 Hz, 1H); and 2.27 (br d, J = 11,4 Hz, 1H); 2,36-of 2.54 (m, 2H); of 2.64 (d, J = 11,6 Hz, 1H); 2.82 from (dd, J1= 6,9 Hz, J2= to 13.6 Hz, 1H); 3,18 (dd, J1= 5.4 Hz, J2= to 12.8 Hz, 1H); 3,30 (b, 3H); 3,68 (s, 3H); was 4.76 (s, 1H); 5,11 (d, J = a 10.6 Hz, 1H); by 5.18 (d, J = 17,1 Hz, 1H); 5,66-5,88 (m, 1H); 6.42 per (d, J = 7,4 Hz, 1H); to 6.58 (s, 1H); 6,63 (d, J = 7,4 Hz, 1H); is 6.78 (d, J = 8,8 Hz, 2H); 6,97-7,24 (m, 7H); 9,34 (s, 1H). Mass spectrum (Cl-CH4) m/e 500 (M+1, 79%(, 346 (49%), 153 (100%). = + 96o(abs. ethanol, c = 1,0). The free amine was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH 4.0 with subsequent precipitation with diethyl ether from dichloromethane, getting monohydrochloride in the form of a hygroscopic powder light purple color. Est. for C31H37N3O3HCl H2O: C, 67,19; H, 7,28; N, 7,58; Cl, 6,40. Found: C, 67,01; H 7,30; N, 7,53; Cl, 6.42 Per.

Example 14

(+)-3-( []2D0((2S, 5R)-4-Allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-(2-forfinal)-N-methylbenzamide

2-Fluoro-N-metranil the 2S,5R)-4-allyl - 2,5-dimethyl-1-piperazinil)-3-(tert-butyldimethylsilyloxy)benzyl) benzoyl chloride, filmed protective group and was purified by the methods described in example 3, obtaining 3-( (R)-- ((2S,5R)-4-allyl-2,5 - dimethyl-1-piperazinil)-3-oxybenzyl)-N-(2-forfinal)-N-methylbenzamide in the form of a whitish powder coating. NMR (200 MHz, D-d6): (R)-- to 0.92 (d, J = 6,1 Hz, 3H); 0,99 (d, J = 6,1 Hz. 3H); 1.69 in (dd, J1= 6,7 Hz, J2= to 10.8 Hz, 1H); 2,05 (dd, J1= 7,6 Hz, J2= to 11.1 Hz, 1H); 2,30 (br d, J = 11.5 Hz, 1H); 2,41-2,52 (m, 2H); 2,68 (br d, J = 10.4 Hz, 1H); and 2.83 (dd, J1= 7,2 Hz, J2= to 13.8 Hz, 1H); 3,20 (dd, J1= 6,1 Hz, J2= to 14.2 Hz, 1H); 3,30 (s, 3H); 4,82 (s, 1H); 5,12 (d, J = 9.7 Hz, 1H); by 5.18 (d, J = 15,8 Hz, 1H); 5,72 and 5.86 (m, 1H); 6,45 (d, J = 7,4 Hz, 1H); 6,56 (s, 1H); 6,66 (d, J = 8.0 Hz, 1H); 7,05-7,38 (m, 9H); was 9.33 (s, 1H). Mass spectrum (Cl-CH4) m/e 488 (M+1, 100%), 334 (45%), 153 (86%). = +2,02o(abs. ethanol, C = 1,1). The free amine was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH 4.0 with subsequent precipitation with diethyl ether from dichloromethane, getting monohydrochloride in the form of a hygroscopic white powder. Est. for C30H34N3O2F HCl 0,75 H2O: C, 67,03; H At 6.84; N, 7,82; Cl, 6,59. Found: C, 67,05; H, 6,86; N, To 7.77; Cl, 6,67.

Example 15

3-( []2D0((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinil) -3-oxiranyl)-N-allyl-N-phenylbenzene

N-Allylamines [NMR (200 MHz, DMCO-d6): (R)-- 3,68 (t, J=5,2 Hz, 2H); 5,10 (d, J=10,2 Hz, 1H); 5,23 of bromide through triptoreline using General method, described in (Harland P. A., Hodge P., W. Maughan , E. Wildsmith Synthesis, 941, (1984).

N-Allylamines was associated with 3-( ((2S,5R)-4-allyl-2,5-dimethyl-1 - piperazinil)-3-(tert-butyldimethylsilyloxy)benzyl) benzoyl chloride, removed the protective group and was purified by the methods described in example 3, obtaining 3-( (R)-- ((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-allyl-N-phenylbenzene in the form of a whitish powder coating. NMR (200 MHz, DMCO-d6): (R)-- of 0.91 (d, J=6.3 Hz, 3H); 0,97 (d, J=5.8 Hz, 3H); 1,67 (dd, J1=6,7 Hz, J2= to 10.6 Hz, 1H); 2,03 (dd, J1=7,0 Hz, J2=10.3 Hz, 1H); to 2.29 (d, J=11,9 Hz, 1H); 2,39 of $ 2.53 (m, 2H); to 2.67 (br d, J=11.2 Hz, 1H); and 2.83 (dd, J1=6,8 Hz, J2= 14.4 Hz, 1H); 3,17 (dd, J1=5,2 Hz, J2=14,0 Hz, 1H); of 4.45 (d, J=5.5 Hz, 2H); 4,78 (s, 1H); 5,11 (d, J=7,4 Hz, 1H); 5,12 (d, J=8.5 Hz, 1H); to 5.17 (d, J= 11,9 Hz, 1H); by 5.18 (d, J=15.3 Hz, 1H); 5,71 is 5.98 (m, 2H); 6.42 per (d, J=7,6 Hz, 1H); 6,56 (s, 1H); of 6.65 (d, J=7.8 Hz, 1H); 7,02-7,33 (m, 10H); was 9.33 (s, 1H). Mass spectrum (Cl-CH4) m/e 496 (M+1, 45%), 342 (22%), 153 (100%). +6,0o(abs. ethanol, C=1,1). The free amine was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH of 3.8 with subsequent precipitation with diethyl ether from dichloromethane, getting monohydrochloride in the form of a hygroscopic white powder. Est. for C32H37N3O2HCl H2O: C, 69,86; H, 7,33; N, Of 7.64; Cl, 6,44. Found: C, 69,94; H, 7,24; N, 7.62mm; Cl, 6,52.

N-(Cyclopropyl)methylaniline was associated with 3-( ((2S,5R)-4-allyl - 2,5-dimethyl-1-piperazinil)-3-(tert-butyldimethylsilyloxy)benzyl) benzoyl chloride, removed the protective group and was purified by the methods described in example 3, obtaining 3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl - 1-piperazinil)-3-oxybenzyl)-N-(cyclopropyl)methyl-N-phenylbenzene in the form of a powder whitish color.

NMR (200 MHz, DMCO-d6): (R)-- 0,09 (m, 2H); 0,39 (m, 2H); to 0.92 (d, J= 6.3 Hz, 3H); to 0.96 (d, J=6.2 Hz, 3H); 1.28 (in m, 1H); 1.69 in (dd, J1=7,4 Hz, J2= 11.5 Hz, 1H); 2,04 (dd, J1=6,6 Hz, J2=to 11.0 Hz, 1H); 2,30 (br d, J1=12.1 Hz, 1H); 2.40 a-to 2.54 (m, 2H); to 2.67 (br d, J=9.8 Hz, 1H); 2,85 (dd, J1=7,4 Hz, J2= to 13.7 Hz, 1H); and 3.16 (dd, J1=4.5 Hz, J2=to 14.7 Hz, 1H); and 3.72 (d, J=7,0 Hz, 2H); of 4.77 (s, 1H); 5,12 (d, J=10.0 Hz, 1H); by 5.18 (d, J=15.6 Hz, 1H); 5,70-to 5.85 (m, 1H); 6,44 (d, J=7,3 Hz, 1H); to 6.57 (s, 1H); of 6.65 (d, J=8,0 1H); 7,02-7,33 (m, 10H); was 9.33 (s, 1H). Mass spectrum (Cl-CH4) m/e 510 (M+1, 61%), 356 (42%), 153 (100%). = +8,9o(abs. ethanol, c=1,1). the free amine was dissolved in ethanol and titrated e is oratane, getting monohydrochloride in the form of a hygroscopic white powder. Est. for C33H39N3O2HCl 1,25 H2O: C, 69,70; H, 7,53; N 7,39; Cl, 6,23. Found: C, 69,82; H 7,52; N Of 7.36; Cl, 6,28.

Example 17

3-( []2D0((2S, 5R)-4-Allyl-2,5-dimethyl-1-piperazinil)-3-oxybenzyl)- N-isopropyl-N-phenylbenzene

N-isopropylaniline [NMR (200 MHz, DMCO-d6): (R)-- of 1.13 (d, J=6.3 Hz, 6N); to 3.58 (m, 1H); and 5.30 (d, J=8.0 Hz, 1H); of 6.49 (t, J=7.2 Hz, 1H); 6,55 (d, J= 7.8 Hz, 2H); 7,06 (t, J=7,6, 2H)] was prepared from aniline and acetone using reductive amination according to the General method described in (Schellenberg, K. A. J. Org. Chem., 28., 3259, (1963)).

N-Isopropylaniline tied then with 3-( ((2S,5R)-4 - allyl-2,5-dimethyl-1-piperazinil)-3-(tert-butyldimethylsilyloxy)benzyl) benzoyl chloride, removed the protective group and was purified by the methods described in example 3, obtaining 3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-oxybenzyl)- N-isopropyl-N-phenylbenzene in the form of a whitish powder coating. NMR (200 MHz, DMCO-d6): (R)-- to 0.92 (d, J=6,1 Hz, 3H); 0,99 (d, J=5,9 Hz, 3H); 1,11 (d, J=6.9 Hz,6H); 1.70 to (dd, J1=7,2 Hz, J2=to 11.1 Hz, 1H); 2,07 (dd, J1=7,6 Hz, J2= to 10.6 Hz, 1H); 2,33 (br d, J=9.9 Hz, 1H); 2,42-of 2.54 (m, 2H); 2,68 ( br d, J= 10.4 Hz, 1H); 2,85 (dd, J1=6,5 Hz, J2=a 13.9 Hz, 1H); and 3.16 (dd, J1=4,9 Hz, J2= 14.1 Hz, 1H); 4.75 V (s, 1H); 4, the range (Cl-CH4) m/e 498 (M+1, 100%), 344 (43%), 153 (76%). = +6,4o(abs. ethanol, C= 1,4). The free amine was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH 4.0 with subsequent precipitation with diethyl ether from dichloromethane, getting monohydrochloride in the form of a hygroscopic white powder. Est. for C32H39N3O2HCl 0.5 H2O : C, 70,76; H, To 7.61; N, 7,74; Cl, 6,53. Found: C, 71,01; H 7,83; N, 7,49; Cl, 6,41.

Example 18

3-( []2D0((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinil)-3-oxybenzyl) -N-cyclopropyl-N-phenylbenzene

N-Cyclopropylamine was obtained using the approach of Burton for arilirovaniya amines (Darton D. H., Finet, J.-P., Khamsi J. Tetrahedron Lett., 28, 887, (1987)). Cyclopropylamine (1.0 g, of 17.5 mmole) was added to the triphenylbismuth (9,25 g, 21,0 mmole) and copper acetate (1.6 g, is 8.75 mmole) in dichloromethane (30 ml) at room temperature under nitrogen atmosphere. The mixture was stirred for 18 hours, filtered to remove all insoluble material through the gasket from Celica low altitude and was purified by chromatography on a column of silica gel (4 cm to 10 cm) by elution with the solvent system hexane/ethyl acetate (95/5). To obtain the N-cyclopropylalanine (0.8 g) from the fraction containing the product was removed under the d, J=8,2 Hz, 2H); to 7.09 (t, J= 7.8 Hz, 2H).

N-Cyclopropylamine tied then with 3-( ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3- (tert-butyldimethylsilyloxy)benzyl)benzoyl chloride, removed the protective group and was purified by the methods described in example 3, obtaining 3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-oxybenzyl)- N-cyclopropyl-N-phenylbenzene in the form of a yellow powder. NMR (200 MHz, DMCO-d6): (R)-- of 0.44 (m, 2H); 0,70 (m, 2H); 0,93 (d, J=6,1 Hz, 3H); 1,01 (d, J=5.7 Hz, 3H); 1,74 (dd, J1=7.7 Hz, J2=11.8 Hz, 1H); 2,05 (dd, J1= 6,8 Hz, J2=to 11.1 Hz, 1H); 2,39 (br d, J=10.5 Hz, 1H); 2,41-of 2.54 (m, 2H); 2,69 (br d, J=11.8 Hz, 1H); and 2.83 (dd, J1=6,6 Hz, J2=to 13.6 Hz, 1H); 3,5-on 3.36 (m, 2H); a 4.83 (s, 1H); 5,10 (d, J=9.8 Hz, 1H); to 5.17 (d, J= 17,4 Hz, 1H); 5,70 and 5.86 (m, 1H); to 6.57 (d, J=7,1 Hz, 1H); 6,63 (s, 1H); of 6.65 (d, J= 8,2 Hz, 1H); 7.03 is-7,38 (m, 10H); 9,34 (s, 1H). Mass spectrum (Cl-CH4) m/e 496 (M+1, 100%), 342 (45%), 153 (90%). +7,1o(abs. ethanol, C=1,1). The free amine was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH of 3.95 with subsequent precipitation with diethyl ether from dichloromethane, getting monohydrochloride in the form of a hygroscopic orange powder. Est. for C32H37N3O2HCl 1,50 H2O: C, 68,74; H, 7,39; N, 7,51; Cl, 6,34. Found: C, 68,56; H, 7,49; N 7,26; Cl, 6,37.

Example 19 3-( []2D0= ((2S,5R)-4-Allyl-2,5-dimethyl-1-Pipera, 3H); 3,02 (dq, J1= 7,2 Hz, J2=7.2 Hz, 2H); 5,86 (br m, 1H); 6,24-6.42 per (m, 3H); 7,07 (q, J=7.8 Hz, 1H)] was prepared from 3-foronline and acetic anhydride, was associated with 3-( ((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3- (tert-butyldimethylsilyloxy)benzyl)benzoyl chloride, removed the protective group and was purified by the methods described in example 3, obtaining 3-( (R)-- ((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-oxybenzyl) -N-ethyl-N-(3-forfinal)benzamide in a solid white color. NMR (200 MHz, DMCO-d6): (R)-- to 0.92 (d, J=6 Hz, 3H); to 0.96 (d, J=6 Hz, 3H); of 1.05 (t, J=7 Hz, 3H); 1,7 (m, 1H); is 2.05 (m, 1H); 2,3 (m, 1H); 2,5 (m, 2H); to 2.7 (m, 1H); 2,9 (m, 1H); 3,2 (m, 1H); 3.9 to (q, J=7 Hz, 2H); and 4.8 (s, 1H); 5,1 (d, J=10 Hz, 1H); 5,2 (d, J=16 Hz, 1H); 5,8 (m, 1H); 6,45 (d, J=8 Hz, 1H); and 6.6 (s, 1H); of 6.65 (d, J= 8 Hz, 1H); 6,9 (d, J=8 Hz, 1H); 7,0 - 7,2 (m, 3H); 7,2-7,4 (m, 5H); a 9.35 (s, 1H). = +4,3o(abs. ethanol, C=3,9). Est. for C31H36FN3O2HCl 0.5 H2O: C, 68,06; J, 7,00; N, 7.68 Per; Cl, 6,48. Found: C, 68,10; H,? 7.04 Baby Mortality; N, 7,63; Cl, 6.42 Per. Mass spectrum (Cl-CH4) m/e 502 (M+1, 39%), 501 (M, 9%), 348 (29%), 153 (100%).

Example 20

3-( []2D0((2S, 5R)-4-Allyl-2,5-dimethyl-1-piperazinil) -3-oxybenzyl)-N-(2-forfinal)-N-propylbenzamide

2-Fluoro-N-propylaniline [NMR (DMCO-d6, 200 MHz): (R)-- of 0.93 (t, J=7.4 Hz, 3H); to 1.59 (m, 2H); 3.04 from (q, J=6.5 Hz, 2H); 5,33 (br m, 1H); 6,47 return of 6.58 (m, 1H); 6,70 (t, J=8,1 Hz, 1H); 6,93-7,05 (m, 2H)] was prepared from 2-foronline and propionic anhydride, tied the local group and purified by methods described in example 3, obtaining ( 3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-oxybenzyl)- N-(2-forfinal)-N-propylbenzamide in a solid white color. NMR (DMCO-d6, 200 MHz): (R)-- 0,9-1,05 (m, 9H); 1,5 (m, 2H); 1,7 (m, 1H); is 2.05 (m, 1H); 2,3 (m, 1H); 2,5 (m, 2H); to 2.7 (m, 1H); to 2.85 (m, 1H); 3,2 (m, 1H); 3,7 (m, 2H); and 4.8 (br s, 1H); 5,1 (d, J=10 Hz, 1H); 5,2 (d, J=16 Hz, 1H); 5,8 (m, 1H); 6,5 (d, J=8 Hz, 1H); and 6.6 (s, 1H); of 6.65 (d, J=8 Hz, 1H); 7,0-7,4 (m, 9H); and 9.3 (s, 1H). = +1.8Vo(abs. ethanol, C=2,8). Est. for C32H38FN3O2HCl 0,25 H2O: C, 69,05; H, 7,15; N, 7,55; Cl, 6,37. Found: C, 68,94; H, 7,19; N, EUR 7.57; Cl, 6,41. Mass spectrum (Cl-CH4) m/e 516 (M+1, 93%), 515 (M, 29%), 362 (26%), 153 (100%).

Example 21

3-( []2D0((2S, 5R)-4-Allyl-2,5-dimethyl-1-piperazinil) -3-oxybenzyl)-N-ethyl-N-(2-forfinal)benzamide

2-Fluoro-N-ethylaniline [NMR (DMCO-d6, 200 MHz): (R)-- to 1.16 (t, J=7,1 Hz, 3H); 3,11 (dq, J1= 7,2 Hz, J2=6,5 Hz, 2H); and 5.30 (br m, 1H); 6.48 in-6,59 (m, 1H); 6,70 (t, J=8.5 Hz, 1H); 6,92-7,06 (m, 2H))] was prepared from 2-foronline and acetic anhydride, was associated with 3-( ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3- (tert-butyldimethylsilyloxy)benzyl)benzoyl chloride, removed the protective group and purified by methods described in example 3 receiving 3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-oxybenzyl)-N-ethyl-N- (2-forfinal)benzamide in the form of wax light-yellow color. NMR (DMCO-d6, 200 MHz): ( 1H); 5,2 (d, J=17 Hz, 1H); 5,8 (m, 1H); 6,45 (m, 1H); of 6.5 (s, 1H); of 6.65 (m, 1H); 7,0-7,4 (m, N); a 9.35 (s, 1H). = + 3,4o(abs. ethanol, C=2,04). Est. for C31H36FN3O2HCl H2O: C, 66,95; H, 7,07; N, 7,56; Cl, 6,38. Found: C, 66,61; H, 7,14; N, 7,53; Cl, 6,40. Mass spectrum (Cl-CH4) m/e 502 (M+1, 89%), 501 (M, 17%), 348 (36%), 153 (100%).

Example 22

3-( []2D0 ((2S, 5R)-4-Allyl-2,5-dimethyl-1-piperazinil) -3-oxybenzyl)-N-(3-forfinal)-N-propylbenzamide

3-Fluoro-N-propylaniline [NMR (DMCO-d6, 200 MHz): (R)-- to 0.96 (t, J=7,3 Hz, 3H); and 1.56 (m, 2H); of 2.97 (q, J=6.9 Hz, 2H); to 5.93 (br m, 1H); from 6.22 to 6.43 (m, 3H); 7,06 (q, J=7.8 Hz, 1H)] was prepared from 3-foronline and propionic anhydride, was associated with 3-( ((2S,5R)- 4-allyl-2,5-dimethyl-1-piperazinil)-3-(tert-butyldimethylsilyloxy) benzyl)benzoyl chloride, removed the protective group and was purified by the methods described in example 3, obtaining 3-( (R)-- ((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-oxybenzyl)-N-(3 - forfinal)-N-propylbenzamide in the form of a solid light beige color. NMR (DMCO-d6, 200 MHz): (R)-- 0,9-1,05 (m, 9H); 1,5 (m, 2H); 1,7 (m, 1H); is 2.05 (m, 1H); 2,3 (m, 1H); 2,5 (m, 2H); to 2.7 (m, 1H); to 2.85 (m, 1H); and 3.8 (m, 2H); and 4.8 (s, 1H); 5,1 (d, J=10 Hz, 1H); 5,2 (d, J=16 Hz, 1H); 5,8 (m, 1H); 6,45 (d, J= 8 Hz, 1H); and 6.6 (s, 1H); 6,7 (d, J=8 Hz, 1H); 6,9 (d, J=8 Hz, 1H); 7,0-7,4 (m, 9H); and 9.3 (s, 1H). = +4,3o(abs. ethanol, with or=1.5). Est. for C32H38FN3O2HCl 0,75 H2O: C, 67,95; H, 7,22; N, 7,43; Cl, 6,27. Found ewusie compounds can be prepared by synthesis of the appropriate substituted aniline (which can be obtained from the original aniline and the appropriate carboxylic acid anhydride as well as described in example 3), binding to 3-(( []2D0((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3- (tert-butyldimethylsilyloxy)benzyl)benzoyl chloride, removing the protective groups and purification methods described in example 3. Monohydrochloride, as in example 3, can be obtained using ethanol solution of hydrogen chloride.

3-( (R)-- ((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-(4-methoxyphenyl)-N-propylbenzamide

3-( (R)-- ((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-ethyl-N-(4-methoxyphenyl)benzamide

Example 25

3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - N-ethyl-(3-forfinal)-N-methylcarbamoyl)benzyl)MENILMONTANT 3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - oxybenzyl)-N-(3-forfinal)-N-methylbenzamide (example 7, 0.05 g of 1.03 mmole) was dissolved in dry pyridine (8 ml) under nitrogen atmosphere. The solution was cooled to -10oC in a bath containing methanol with ice. To the cold solution was slowly added 394 mg phosphorylchloride. The reaction mixture was left to warm to room temperature and was stirred overnight under nitrogen atmosphere.

To the solution was added dropwise 2 ml of water. The solution was stirred for fifteen minutes and all volatile compounds dalaly the balance mainly represents 3-( (R)-- ((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-(N-forfinal)- N-methylcarbamoyl)benzyl)MENILMONTANT. (ISMS M+H peak = 568,1). Phosphate can be isolated in the form of monoammonium salts by ion-exchange chromatography.

Example 26

3-((R)-- ((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinil)-3-methoxybenzyl)- N-(3-forfinal)-N-methylbenzamide

The crude 3-(((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinil)-3- (1H-benzotriazol-1-yl)methyl)-N-(3-forfinal)-N-methylbenzamide was obtained from (2R,5S)-1-allyl-2,5-dimethylpiperazine (1.89 g), benzotriazole (1.39 g) and N-(3-forfinal)-3-formyl-N-methylbenzamide (3.0 g) in toluene as well as described in example 7.

3-Bromoanisole (4,36 g) was dissolved in dry tetrahydrofuran (40 ml) and cooled under nitrogen atmosphere to -78oC. To the solution slowly with a syringe was added n-utility in hexane (9,2 ml of 2.5 M solution). In the process of mixing for 25 minutes at -78oC the solution became white and partly cloudy. The solution was transferred by means of a bifurcated needle into the flask containing bromide etherate magnesium (of 6.02 g) in tetrahydrofuran (60 ml) and stirred at room temperature for 1 hour. The crude 3-(((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinil)-3-(1H-benzotriazol-1 - yl)methyl)-N-(3-forfinal)-N-methylbenzamide in toluene was added to the freshly prepared reagent - bromide ariline. The solution was gently heated in the process is Uchenie 2.5 hours the solution was carefully added 0.5 M aqueous solution of hydrochloric acid until until its pH reached a value of 5. The product was extracted with 100 ml ethyl acetate and the solvent was removed under vacuum. The residue was dissolved in 25 ml of 3 H of an aqueous solution of hydrochloric acid at room temperature, was added diethyl ether and the separated acidic aqueous layer. The aqueous layer was washed a second time in diethyl ether and brought its pH to a value of 10 using aqueous sodium hydroxide solution. The product was extracted with ethyl acetate. An ethyl acetate portions were combined, washed with dilute sodium hydroxide solution to remove all traces of benzotriazole, washed with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by chromatography on a column of silica gel using 1% ethanol in dichloromethane as eluent and receiving 1,71 g 3-(( (R)-- ((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-methoxybenzyl)-N- (3-forfinal)-N-methylbenzamide in the form of a solid crystalline substance white with purity relative to the isomeric composition of greater than 98% (according to VGH, carried out on a column of m-Bondapak C-18 (125 A, 3,9 300 mm, Waters Chromatography Division, Millipore Corporation, Milford, Vassachusetts), using 70% methanol and 30% of 0.1 M aqueous ACE
=7,1 Hz, J2=to 11.0 Hz, 1H); 2,05 (dd, J1= 7.5 Hz, J2=11,0 1H); 2,31 (br d, J=9,3 Hz, 1H); 2,42 of $ 2.53 (m, 2H); 2,69 (br d, J=11.2 Hz, 1H); 2,85 (dd, J1-7,0 Hz, J2=14,1 1H); 3,18 (dd, J1= 5.5 Hz, J2=13.5 Hz, 1H); 3,37 (s, 3H); 3,74 (s, 3H); 4,88 (s, 1H); 5,12 (d, J= 10.0 Hz, 1H); by 5.18 (d, J=15.7 Hz, 1H); 5,70 -5,83 (m, 1H); to 6.58 (d, J=7,6 Hz, 1H); 6,70 (s, 1H); at 6.84 (d, J=8,2 Hz, 1H); 6,94 (t, J=7.8 Hz, 1H); 7,02-7,14 (m, 2H); 7.18 in-7,14 (m, 6H); 9,31 (s, 1H). Mass spectrum (Cl-CH4) m/e 502 (m+1, 100%), 348 (81%), 153 (12%). = +7,73o(abs. ethanol, C=1,1). The free amine was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH 4.0 with subsequent precipitation with diethyl ether from dichloromethane, getting monohydrochloride in the form of a hygroscopic powder light yellow color. Est. for C13H36N3O2F HCl 0.5 H2O: C, 68,06; H; 7,00; N, 7.68 Per; Cl, 6,48. Found: C, 68,13; H, 7,12; N, 7,55; Cl, 6,35.

Example 27

3-( []20D/((2S,5R)-allyl-2,5-dimethyl-1-piperazinil) -3-methoxybenzyl)-N-ethyl-N-(4-forfinal)benzamide

The connection was obtained from the crude 3-(((2R,5S)-4-allyl-2,5 - dimethyl-1-piperazinil)-3-(1H-benzotriazol-1-yl)methyl)-N-ethyl-N- (4-forfinal)benzamide (example 12, infra) and 3-bromoanisole using the methods described in example 7. NMR (200 MHz, DMCO-d6): (R)-- of 0.91 (d, J=6.2 Hz, 3H); 0,99 (d, J=6.3 Hz, 3H); 1,08(t, J=7.0 Hz, 3H); 1,71 (dd, J1=7,0 Hz, J2=11,1 Hz B>=a 13.9 Hz, 1H); 3,17 (dd, J1=5.5 Hz, J2=a 13.9 Hz, 1H); 3,74 (s, 3H); 3,83 (q, J=7,0 Hz, 2H); a 4.83 (s, 1H); 5,11 (d, J=10,2 Hz, 1H); by 5.18 (d, J=16.4 Hz, 1H); 5,63-to 5.85 (m, 1H); 6,60 (d, J=7,4 Hz, 1H); of 6.71 (s, 1H); at 6.84 (d, J=8,2 Hz, 1H); 7,02-7,28 (m, 9H). Mass spectrum (Cl-CH4) m/e 516 (M+1, 38%), 362 (100%), 153 (16%).

Example 28

Individual compounds provided by the present invention, identified below, with links to examples of their synthesis, were evaluated for their opioid receptor activity in vitro in different receptor systems, including the Delta receptor agonism on the vessel sperm duct mouse Sperm receptacle mouse ED50and mu-receptor agonism on the ileum of the Guinea pig (the Ileum of the Guinea pig ED50).

Analysis methods used in the course of such definitions receptor activity are presented below.

The in vitro bioassays: Sperm vessel was removed from the mouse and suspended between platinum electrodes with a tension of 0.5 g in body-washed cells, buffer containing modified Krebs solution with the following composition (millimolar): NaCl, 118; KCl, 4.75 V; CaCl2, 2,6; KH2PO4, 1,20; NaHCO3, 24.5 g and glucose, 11. Buffer solution was saturated with a mixture of 95% O2/5% CO2and thermostatically 400 MS; the interval between the series - 10 seconds; pulse duration of 0.5 msec. The intact ileum (approximately 3 cm) was removed from the Guinea-pig and hung with a tension of 1 g in lapped by the camera in the same way as described for sperm receptacle. Modified buffered Krebs solution additionally contained in this case MgSO4(1.20 mm). Intestine stimulated electric rectangular wave pulses with a frequency of 0.1 Hz, a duration of 0.5 MS at high voltage. Determined the percentage of inhibition of electricity induced muscle contraction at different values of the concentrations of the compounds provided by the invention. The magnitude of the ED50found by extrapolating the curves representing the dependence of the response on the dose concentration (Lord J. A. H., Waterfield, A. A., Hughes, J., Kosterlitz, H. W. Nature, 267, 495 (1977)).

The results are shown below in table a (see below).

Example 29

Analgetic activity was measured using analysis to infringe on the tail of rats (male line Spraque-Dawley CD, weighing approximately 300 g) after intravenous injection in the tail vein. A group of 6-8 animals intravenously injected with a compound provided by the invention, in concentrace end was placed on a short period of time (maximum 20 seconds) arterial clamp (Fisher Scientific Co., self-closing arterial clamp catalogue number # 08-905), calling by squeezing pain. Nociceptive response was evaluated by signs expressing discomfort, such as running, squeak or torsion in place in order to bite the clip. For each of the compounds provided by the invention, curve built according to response the dose of the injected compounds. Analgetic activity (half-maximal effective dose, ED50) was defined as the dose, with the introduction of which half of the animals did not show any nociceptive response to the introduction of 20 seconds of arterial clamping. Antinociceptive ED50dose was 0.03 mg/kg for the compounds of examples 7 and 12.

Pharmaceutical

In the following examples, the compounds of preparations, the term "Active ingredient" may mean any of the compounds according to the invention, for example compound corresponding to formula (I) and (II).

Example 30

The drug comes in pill form

Preparations a, B and C (see recipes at the end of the description) were prepared by wet granulation of the ingredients with a solution of povidone followed by the addition of magnesium stearate and stamping.

The following drugs letku

Active ingredient - 100

Pregelatinization starch NF15 - 50/150

Formula D - mg/per pill

Active ingredient - 100

Lactose - 150

Avicel - 100/350

Formulation E (controlled time of selection)

The drug was prepared by wet granulation of the following ingredients with a solution of povidone followed by the addition of magnesium stearate and punching. mg/per pill

(a) Active ingredient: 500

(b) Hypromellose (Methocel K4M Premium - 112

(C) Lactose C. R. - 53

(d) Povidone C. R. C. - 28

(d) magnesium Stearate - 7/500

The drug released in 6-8 hours and completely the allocation process is completed after 12 hours.

Example 31

Pharmaceutical preparation in the form of capsules

Recipe AND

The drug in capsule form is prepared by mixing the ingredients described above drug G from example 30 and filling them two-part hard gelatin capsules.

Formulation B - mg/capsule

(a) Active ingredient - 100

(b) Lactose C. R. - 143

(b) Sodium salt glycolate starch - 25

(d) magnesium Stearate - 2/270

Capsules are prepared by mixing the above IG/capsule

(a) Active ingredient - 100

(b) a Macrogel 4000 BP - 350/450

Capsules are prepared by fusion of a Macrogel 4000 BP, dispersing the active ingredient in the resulting melt and fill the molten two-part hard gelatin capsules.

Formula G - mg/capsule

(a) Active ingredient - 100

(b) Lecithin - 100

(C) Peanut butter - 100/300

Capsules are prepared by dispersing the active ingredient in the lecithin and peanut oil, and filling, obtained by dispersion of a soft, elastic gelatin capsules.

Formulation D (capsule with controlled selection time)

The following medicinal product in the form of a capsule with controlled breeding is prepared by extrusion of the ingredients (a), (b) and (C) using the extruder with subsequent acquisition of the extrudate spherical shape and its drying. The dried beads are covered with a membrane (g) controlling the release and fill them two-part hard gelatin capsule. mg/capsule

(a) Active ingredient 250

(b) Microcrystalline cellulose - 125

(C) Lactose C. R. - 125

(d) Ethylcellulose - 13/513

Example 32

Policiesto, necessary to bring the pH in the range 4,0 - 7,0

The sodium hydroxide solution, 0.1 M - the amount needed to bring the pH in the range 4,0-7,0

Sterile water up to 10 ml

The active ingredient is dissolved in most of the water (35-40oC) and bring the pH of a solution is in the range from 4.0 to 7.0 using hydrochloric acid or sodium hydroxide. The mixture was adjusted with water to the desired volume value and filtered through a sterile micropore filter into sterile vials yellow glass with a capacity of 10 ml, sealed sterile tubes and top seal lids.

Formulation B

Active ingredient - 12.5 mg

Sterile pyrogen-free phosphate buffer solution, pH 7 to 25 ml

Example 33

Preparation for intramuscular injection

Active ingredient - 4.0 mg

Benzyl alcohol - 0.1 g

Glycoluril 75 - 1.45 g

Water for injection to 4.00 ml

The active ingredient is dissolved in glycoluril. Then add and dissolve benzyl alcohol and the solution was adjusted with water to a volume of 4 ml of the resulting mixture was filtered through a sterile Millipore filter and sealed in sterile vials yellow glass.

Example 34

Syrup:

The active ingredient 17.42.3169 - of 0.0125 ml

Purified water - up to 5.00 ml

The active ingredient is dissolved in a mixture of glycerin and most of purified water. Then to the solution was added an aqueous solution of sodium benzoate followed by the addition of sorbitol solution and the flavoring. The mixture was adjusted with purified water to the desired volume and mix well.

Example 35

Suppository: mg/suppository

Active ingredient - 30

Hard fat, BP (Witepsol H15 - Dynamite Nobel) - 1970/2000

One-fifth of Witepsol n melt in the vessel jacketed for steam at temperatures of up to 45oC. the Active ingredient is sifted through a 200-mm sieve and add to the melted base, mixing using a Silverson fitted with a cutting head, until, until a homogeneous dispersion. Continuing to maintain the temperature of the mixture at 45oC, add the remainder of Witepsol n and stirred to obtain a homogeneous mixture. The prepared suspension is passed through a 250 mm sieve stainless steel and cooled with constant stirring to 40oC. At a temperature of from 38oC to 40oC 2 g of the mixture injected into suitable plastic moulds volume of 2 ml Suppositories leave to cool before comatonse least one of diarylpyrimidine compounds of the present invention.

Pessaries: mg/pessary

Active ingredient - 30

Anhydrous dextrose - 490

Potato starch - 473

Magnesium stearate - 7/1000

The above ingredients are mixed directly and from the mixture obtained by direct stamping receive pessaries.

Example 37

The following are additional examples of drugs that can be useful compounds provided by the invention, including controlled drugs in the form of suspensions for oral administration, suspensions for injection, spray suspensions, drugs in the form of aerosols, in the form of powders for inhalation in the form of nasal drops.

Tablet: - 25.0 mg

The compound of formula (I) 25.0 mg

Lactose BP is 48.5 mg

Microcrystalline cellulose BP (Avicel pH 101") - 10.0 mg

Poorly substituted oxypropylation BP (LHHC LH-11") - 10.0 mg

Sodium salt of glycolate starch BP ("Explotab") - 3.0 mg

Povidone BP (K 30") - 3.0 mg

Magnesium stearate BP 0.5 mg - 100.0 mg

Suspension for oral administration:

The compound of formula (I) - 50.0 mg

Avicel RC 591 - 75,0 mg

Sugar syrup - 3.5 ml

Methoxybenzoate - 5.0 mg

The dye is 0.01%, V/o

The cherry flavor is 0.1% about/on

Tween 80 and 0.2% of the n (PVP) 170,0 mg

Tween 80 and 0.2% about/on

Methoxybenzoate - 0.1%/about

Water for injection up to 3.0 ml

The drug in capsule form:

The compound of formula (I) 1.5 mg

Starch 1500 - 150,0 mg

Magnesium stearate 2.5 mg

Fill the above drug capsule of solid gelatin.

Suspension for nebulization:

The compound of formula (I), sterile - 1.0 mg

Water for injection to 10.0 ml

Dispersivity compound of formula (I) in water for injection, pre-sterilized in a sterile container. Fill the mixture into sterile glass vials (10 ml per vial) and Zaplata each of the vials.

The drug is in the form of an aerosol:

The compound of formula (I), chopped - 1.0 mg

Aerosol dispersant - to 5.0 ml

Suspend chopped micron mill compound of formula (I) in an aerosol dispenser. Fill in the suspension under pressure prepared aerosol cans (5 ml per canister) through the hole in the faucet.

Powder for inhalation:

The compound of formula (I), chopped - 1.0 mg

Lactose - 29.0 mg

Grind into powder and mix chopped micron mill compound of formula (I) and lactose. Fill the floor of the Compound of formula (I) 20.0 mg

Methoxybenzoate - 10.0 mg

Water for injection to 10.0 ml

Dispersivity compound of formula (I) and methoxybenzoate in water for injection. Fill in the obtained suspension suitable bottle with dropper (10 ml per bottle) and close, connecting the dropper with bottle cap.

Example 38

Following preparation containing as active ingredient at least one of the compounds provided by the invention can be applied to microinfusion infusion.

Preparation for microinfusion infusion

The active ingredient 10.0 mg

Sodium chloride - 16.0 g

The hydrochloric acid solution, 0.1 M - the amount needed to bring the pH in the range from 4.0 to 7.0

The sodium hydroxide solution, 0.1 M - the amount needed to bring the pH in the range from 4.0 to 7.0

Sterile water to 20 ml

The active ingredient and the sodium chloride is dissolved in most of the water (35-40oC) and bring the pH of a solution is in the range from 4.0 to 7.0 using hydrochloric acid or sodium hydroxide. The mixture was adjusted with water to the desired volume and filtered through a sterile micropore filter into sterile vials yellow glass with a capacity of 20 ml, sealed sterilin the ava, containing as active ingredient the compounds of formula (I), can be used for transdermal administration, such as transdermal patches.

Plasters, impregnated, coated or bearing any other way drugs for transdermal application is placed on the body so that they remained in contact with the patient's skin over a long period of time.

These patches contain the active ingredient (1) in optimally buffered aqueous solution, (2) dissolved and/or dispersed in a binder, providing adhesion, or (3) dispergirovannom in the polymer.

A suitable concentration of active ingredient is from about 1% to 35%, preferably from 3% to 15%.

One example may be the introduction of active connections with patch by electrotransport or iontophoresis, as described in General terms in the literature (Pharmaceutical Research, 3(6), 318, (1986)).

Example 40

A separate example of the preparation containing the compound conforming to the invention for transdermal application is given below.

Drug for transdermal application

Active ingredient - 200.0 mg

Alcohol US gel, which form a device for the transdermal injection with a surface area of 10 cm2.

Example 41

(+)-3-( ((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - hydroxybenzyl)-N-benzyl-N-methylbenzamide

This compound is obtained from 3-( (R)-- ((2S,5R)-4-allyl-2,5 - dimethyl-1-piperazinil)-3-(tert-butyldimethylsilyloxy)benzyl) benzoyl chloride and N-benzyl-N-methylamine (getter) benzamide as described in example 2. NMR (300 MHz, D-d6, 121oC): d of 0.93 (d, J = 6.2 Hz, 3H); of 1.06 (d, J = 6.2 Hz, 3H); 1,96 (dd, J1= 6,7 Hz, J2= to 11.0 Hz, 1H); 2,12 (dd, J1= 7,0 Hz, J2= to 11.0 Hz, 1H); of 2.58 (dd, J1= 2,9 Hz, J2= to 11.0 Hz, 1H); 2,67-2,84 (m, 3H); of 2.86 (s, 3H); 2,89 (dd, J1= 6,6 Hz, J2= 13.5 Hz, 1H); 3,18 (dd, J1= 4.0 Hz, J2= 14.1 Hz, 1H); 4,58 (s, 2H); to 4.98 (s, 1H); to 5.08 (d, J = 10,2 Hz, 1H); 5,16 (d, J = 17.3 Hz, 1H); 5,74-of 5.89 (m, 1H); 6,62-6,74 (m, 3H); 7,10 (t, J = 7.8 Hz, 1H); 7,21-to 7.50 (m, 9H); 8,76 (s, 1H). Mass spectrum (Cl-CH4) m/e 484 (M+1,88%), 330 (33%), 153 (100%). (R)-- = +14.3o(ethanol, c = 1,25). The free amine was dissolved in ethanol and ethanol titrated with hcl to pH of 3.4, and then precipitated in diethyl ether from dichloromethane to obtain(+)-3-( []2D0(2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-hydroxybenzyl)-N - benzyl-N-methylbenzamide of monohydrochloride in the form of a hygroscopic pale yellow powder. CLASS="ptx2">

Example 42

(+)-3-( (R)-- (2S,5R)-4-n-propyl-2,5-dimethyl-1-piperazinil)-3 - hydroxybenzyl)-N-(3-forfinal)-N-methylbenzamide

This compound is obtained by catalytic hydrogenation of the compound from example 7 in an atmosphere of hydrogen in the presence of a catalyst of Lindley (Lindler's) in a toluene solvent environment.

Example 43

(+)-3-( (R)-- (2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - hydroxybenzyl)-N-(3,4,5-tryptophanyl)-N-methylbenzamide

This compound is produced by the method of example 7, but using 3,4,5-triptorelin instead of 3-foranyone.

Example 44

(+)-3-( (R)-- (2S,5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3 - hydroxybenzyl)-N-(3,5-differenl)-N-methylbenzamide

This compound is produced by the method of example 7, but using 3,5-diferencia instead of 3-foranyone.

Example 45

Individual compounds provided by the present invention, identified below, with links to examples of their synthesis, were evaluated for their opioid receptor activity in vitro in different receptor systems, including the Delta receptor agonism on the vessel sperm duct mouse sperm receptacle mouse ED50and mu-receptor agonism on the ileum of the Guinea pig (the response to receptor activity, described below.

The in vitro bioassays: Sperm vessel was removed from the mouse and suspended between platinum electrodes with a tension of 0.5 g in body-washed cells, buffer containing modified Krebs solution with the following composition (millimolar): NaCl, 118; KCl, 4.75 V; CaCl2, 2,6; KH2PO4, 1,20; NaHCO3and 24.5 and glucose, 11. Buffer solution was saturated with a mixture of 95% O2/5% CO2and thermostatically at 37oC. Tissue stimulated high voltage in the form of a series of pulses with a frequency of 10 Hz with a duration of 400 msec, the interval between the parts 10 seconds; pulse duration of 0.5 msec. The intact ileum (approximately 3 cm) was removed from the Guinea-pig and hung with a tension of 1 g in lapped by the camera in the same way as described for sperm receptacle. Modified buffered Krebs solution additionally contained in this case MgSO4(1.20 mm). Intestine stimulated electric rectangular wave pulses with a frequency of 0.1 Hz, a duration of 0.5 seconds at high voltage. Determined the percentage of inhibition of electricity induced muscle contraction at different values of cumulative concentrations. The magnitude of the ED50found put the ghes, H. W. Kosterlitz, Nature 267, 495, (1977)).

The results are shown below in Table B. experiments.

Example 46

Analgetic activity was measured using analysis to infringe on the tail of rats (male strain Sprague-Dawley CD, weight about 300 g) after subcutaneous injection. A group of 6-8 animals were subcutaneously injected with the compound at a concentration of 1-5 mg/ml in sterile 5% dextrose. Five minutes after injection in the tail about 1 inch from its end was placed on a short period of time (maximum 20 seconds) arterial clamp (Fisher Scientific Co., self-closing arterial clamp. Catalogue number # 08-905), calling by squeezing pain. Nociceptive response was evaluated by signs expressing discomfort, such as running, squeak or torsion in place in order to bite the clip.

Results

The compounds of examples 2, 3 and 5 have produced a strong analgesic effect after subcutaneous injection in a dose of 5 mg/kg of body weight.

Example 47

The procedure of example 46 is repeated with the compound of example 41 with the exception that do not subcutaneous, and intravenous injection. Analgesic activity (premaxilla effective dose, ED50) oanie arterial clamp for 20 seconds. Antinociceptive ED50dose of 0.12 mg/kg for the compound of example 41.

Ways of carrying out the invention

Preferred method of carrying out the invention includes the synthesis and use of preferred compounds according to the invention (made by any suitable method of synthesis, such as described above benzotryazolyl path synthesis), for example, compounds from the group comprising compounds denoted by a, B, C, D, e, F, G and H, and pharmaceutically acceptable esters, salts and other physiological relevant derivatives for the treatment of such conditions and disorders: physiological pain, diarrhea, incontinence, mental illness, chronic alcoholism and addiction to the excessive use of drugs, pulmonary edema, depression, asthma, emphysema and asthma, cognitive and gastrointestinal disorders.

Under the previous presentation of a typical method of carrying out the invention in terms of its use of the compounds according to the invention is their introduction in a pharmaceutically safe and effective dose and suitable dose form objects animal, such as man, with the purpose of inducing such objects analgoidea W, 3-( (R)-- ((2S,5R)-4-allyl - 2,5-dimethyl-1-piperazinil)-3-oxybenzyl)-N-(3-forfinal)- N-methylbenzamide.

Industrial applicability

Compounds of the present invention are compounds with high selectivity to bind to the opioid receptors that are useful in this capacity, such as agonist/antagonist pairs of components conjugates for review/analysis of the actions of receptors and neurotransmitters.

Compounds provided by the invention include benzhydrylpiperazine compounds that can be used as promoting analgesia, as well as compounds that can find application in the treatment of conditions such as addiction to the excessive use of drugs, chronic alcoholism, overdose of drugs, mental illness, urinary incontinence, diarrhea, pulmonary edema, cough and respiratory disorders.

The most preferred compound in the present invention, 3-( (R)-- ((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-oxybenzyl)-N- (3-forfinal)-N-methylbenzamide, is a mixed Delta/mu opioid agonist with a significant advantage over various well-known mu-receptor compounds in which B>8
and R9represents phenyl, possibly substituted by one or more substituents selected from the group comprising halogen, C1-C3-alkoxy, C1-C3-alkyl and trifluoromethyl, and the other of the radicals R8and R9represents hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl,3-C6alkenyl or3-C6-quinil;

any two of the radicals R3, R4and R5represent methyl and the other radical represents hydrogen;

R6represents hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl,3-C6alkenyl or3-C6-quinil;

or its pharmaceutically acceptable simple ether, ester, salt or physiologically functional derivative.

2. Connection on p. 1, wherein R3and R5both represent a methyl group, and R4- the hydrogen atom.

3. Connection on p. 2, characterized in that it has the isomeric configuration corresponding to the formula II

< / BR>
where R8, R9and R6defined in paragraph 1.

4. Connection on p. 1, characterized in that it is selected from the group including

(+)-3-((R)--((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-hydroxybenzyl)-N-methyl-N-phenylbenzene;

(+)-3-((R)--((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-hydroxybenzyl)-N-(4-chlorophenyl)-N-methylbenzamide;

(+)-3-((R)--((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-hydroxybenzyl)-N-ethyl-N-phenylbenzene;

(-)-3-((R)--((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-hydroxybenzyl)-N-phenylbenzene;

3-((R)--((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-hydroxybenzyl)-N-methyl-N-(2-(trifluoromethyl)phenyl)benzamide;

3-((R)--((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-hydroxybenzyl)-N-methyl-N-(2,4,6-trichlorophenyl)benzamide;

3-((R)--((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-hydroxybenzyl)-N-(3-forfinal)-N-methylbenzamide;

(+)-3-((R)--((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-(hydroxybenzyl)-N-phenyl-N-propylbenzamide;

(+)-3-((R)--((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-(hydroxybenzyl)-N-(4-methoxyphenyl)-N-methylbenzamide;

(+)-3-((R)--((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-hydroxybenzyl)-N-(2-forfinal)-N-methylbenzamide;

(+)-3-((R)--((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-hydroxybenzyl)-N-ethyl-N-(4-forfinal)benzamide;

(+)-3-((R)--(2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-hydroxybenzyl)-N-allyl-N-phenylbenzene;

(+)-3-((R)--((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-hydroxybenzoyl-N-phenylbenzene;

3-((R)--((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-hydroxybenzyl)-N-cyclopropyl-N-phenylbenzene;

3-((R)--((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-hydroxybenzyl)-N-(3-forfinal)-N-propylbenzamide;

3-((R)--((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-hydroxybenzyl)-N-ethyl-N-(3-forfinal)benzamide;

3-((R)--((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-hydroxybenzyl)-N-(2-forfinal)-N-propylbenzamide;

3-((R)--((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-hydroxybenzyl)-N-ethyl-N-(2-forfinal)benzamide;

3-((R)--((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-hydroxybenzyl)-N-(4-methoxyphenyl)-N-propylbenzamide;

3-((R)--((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-hydroxybenzyl)-N-ethyl-N-(4-methoxyphenyl)benzamide;

(+)-3-((S)--((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-(hydroxybenzyl)-N-methyl-N-phenylbenzene;

(+)-3-((R)--((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-methoxybenzyl)-N-(3-forfinal)-N-methylbenzamide;

(+)-3-((R)--((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-methoxybenzyl)-N-ethyl-N-(4-forfinal)benzamide;

3-((R)--((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-(hydroxybenzyl)-N-(4-methoxyphenyl)-N-propylbenzamide;

3-((R)--((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-(N-(3-forfinal)-N-methylcarbamoyl)benzyl)MENILMONTANT,

or its pharmaceutically acceptable prop. 1, characterized in that it is a (+)-3-((R)--((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinil)-3-hydroxybenzyl)-N-(3-forfinal)-N-methylbenzamide, or its pharmaceutically acceptable simple ether, ester, salt or physiologically functional derivative.

Priority points:

30.07.93 - all claims;

17.12.93 - priority application materials used in the description.

 

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1 ex, 5 tbl

FIELD: medicine, cardiology.

SUBSTANCE: it is suggested to apply cortisol antagonists in addition to clonidine while manufacturing preparation to treat heart failure. Moreover, one should introduce cortisol antagonist or a product that includes cortisol antagonist along with the second medicinal preparation being a combined preparation to be applied either simultaneously, separately or successively. The present innovation provides decreased symptoms of heart failure at decreasing cardiac muscle's fibrosis and heart sizes due to preferable impact upon glucocorticoid receptors in patient's heart and/or kidneys.

EFFECT: higher efficiency of application.

12 cl, 2 ex

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with medicinal preparations designed as solution and indicated for therapeutic needs. Eye drops contain ciprofloxacin hydrochloride monohydrate being equivalent to 0.3% free foundation, a buffer system that keeps pH within 3.5-5.5 interval, as a conserving agent - benzalconium chloride and a s a stabilizer - the salt of disodium ethylenediamine tetraacetic acid, moreover, their range of osmolality values correspond to 150-450 mM/kg H2O. Eye drops should be obtained by preparing buffer system in which mannitol should be dissolved followed by the salt of disodium ethylenediamine tetraacetic acid, benzalconium chloride, ciprofloxacin hydrochloride. Then one should perform the control for the quality of obtained solution to be then filtered by applying sterilizing elements and packed. This innovation provides treatment of eyes at creating the pressure in an eye and at certain desired osmolality.

EFFECT: higher efficiency of therapy.

4 cl, 1 ex

Endoparasitic agent // 2250779

FIELD: medicine.

SUBSTANCE: invention relates to endoparasitic agent containing cyclic depsipeptide of general formula 1 and piperazine of formula 2 .

EFFECT: endoparasitic agent with synergetic agent.

6 cl, 7 ex, 7 tbl

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating oncological diseases. It is suggested to apply bisdioxopiperazine (previously known as cardioprotector) to either treat or prevent tissue lesions caused due to sporadic transudation of cytotoxic poison for topoisomerase II (represented by anthracyclines, etoposide, teniposide, mitoxantrone daunorubicin, doxorubicin, etc.), medicinal remedies and pharmaceutical set of the same indication. It is, also, suggested to apply the method to treat or prevent tissue lesions caused by sporadic transudation of topoisomerase II poison. BisdioxopiperazineICRF-187 has impact due to catalytic inhibiting topo II. Signs for possible transudation of topoisomerase II poison (of local toxicity) usually include the availability of acute pain, erythema, development of ulcerations in area of transudation; due to the action of ICRF-187 the quantity of wounds is reduced, or the development of side effects is not observed.

EFFECT: higher efficiency of therapy.

59 cl, 12 dwg, 13 ex, 10 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of adamantane of the general formula:

wherein m = 1 or 2; each R1 represents independently hydrogen atom; A represents C(O)NH or NHC(O); Ar represents the group:

or

wherein X represents a bond, oxygen atom or group CO, (CH2)1-6, CH=, O(CH2)1-6, O(CH2)2-6O, O(CH2)2-3O(CH2)1-3, CR'(OH), NR5, (CH2)1-6NR5, CONR5, S(O)n, S(O)nCH2, CH2S(O)n wherein n = 0, 1 or 2; R' represents hydrogen atom; one of R2 and R3 represents halogen atom, nitro-group, (C1-C6)-alkyl; and another is taken among R2 and R3 and represents hydrogen or halogen atom; either R4 represents 3-9-membered saturated or unsaturated aliphatic heterocyclic ring system comprising one or two nitrogen atoms and oxygen atom optionally being heterocyclic ring system is substituted optionally with one or more substitutes taken independently among hydroxyl atoms, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, -NR6R7, -(CH2)rNR6R7; or R4 represents 3-8-membered saturated carbocyclic ring system substituted with one or more substitutes taken independently among -NR6R7, -(CH2)NR6R7 wherein r = 1; R5 represents hydrogen atom; R6 and R7 each represents independently hydrogen atom or (C1-C6)-alkyl, or (C2-C6)-hydroxyalkyl group eliciting antagonistic effect with respect to R2X7-receptors. Also, invention describes a method for their preparing, pharmaceutical composition comprising thereof, a method for preparing the pharmaceutical composition and their applying in therapy for treatment of rheumatic arthritis and obstructive diseases of respiratory ways.

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

13 cl, 88 ex

FIELD: medicine.

SUBSTANCE: at performing curative endoscopy one should apply pneumoapplication of granulated sorbent - diovine at the quantity of 0.2 g, the pressure being 15 atm. at the distance of 1.5 cm against the defect onto the surface of bleeding rupture of gastric mucosa. Diovine's coarse-grained structure enables to keep the integrity of mucous-bicarbonate barrier due to providing normal vapor exchange and moisture medium in the defect. Moreover, diovine's antimicrobial action helps to suppress gram-positive and gram-negative microflora that enables to shorten terms for defects healing and decrease the frequency of repeated hemorrhages.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a medicinal formulation consisting of a core and the stomach-dissolving envelope. The core comprises trimetazidine dihydrochloride as an active component, and starch, mannitol, povidone, magnesium stearate, croscarmelose and microcrystalline cellulose as accessory substances. The envelope comprises hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide, magnesium stearate and acid red as a dye. Also, invention describes a method for making the trimetazidine medicinal formulation. Trimetazidine tablets show high mechanical strength in the low pressing strength (3.5-5 kH). The composition of the medicinal formulation provides releasing 80% of trimetazidine for 30 min.

EFFECT: improved and valuable properties of formulation.

3 cl, 1 tbl, 1 ex

FIELD: medicine, neurology, pharmacy.

SUBSTANCE: invention proposes using levetiracetam and the corresponding levetiracetam-base pharmaceutical composition used in treatment of bipolar disorders, mania and migraine. Also, invention relates to a pharmaceutical composition based on levetiracetam and at least one inhibitor of GABA type A neuronal receptors that is used in treatment of epilepsy, alcohol withdrawal syndrome, tremor, bipolar disorders, obsessive-compulsive disorder, panic state, depression, headache, pain, ischemia and head trauma, to corresponding methods for treatment, to a method for selective enhancing the therapeutic effect of inhibitors of GABA type A neuronal receptors, to a method for treatment of patient with inhibitor of GABA type A neuronal receptors involving the combined administration of indicated inhibitor of GABA type A neuronal receptors with levetiracetam. Invention shows the possibility for using levetiracetam for treatment of chronic and neuropathic pain in lower doses as compared with doses causing secondary effects, and shows its property to enhance activity of inhibitor of GABA type A neuronal receptors.

EFFECT: improved and valuable medicinal properties of agent.

18 cl, 18 tbl, 7 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

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