UA77405C2 - Isoxazolines derivatives as antidepressants - Google Patents

Abstract

, (I) The invention concerns substituted isoxazolines derivatives according to Formula (I): wherein X = CH2, N-R7, S or O, R1, R2 and R3 are certain specific substituents, Pir is an optionally substituted piperidyl or piperazyl radical and R3 represents an optionally substituted aromatic homocyclic or heterocyclic ring system including a partially or completely hydrogenated hydrocarbon chain of maximum 6 atoms long with which the ring system is attached to the Pir radical and which may contain one or more heteroatoms selected from the group of O, N and S; a process for their preparation, pharmaceutical compositions comprising them and their use as a medicine, in particular for the treatment of depression and/of anxiety and disorders of body weight. The compounds according to the invention have surprisingly been shown to have a serotonine (5-HT) reuptake inhibitor activity in combination with additional antagonist activity and show a strong anti-depressant activity without being sedative. Compounds according to the invention are also suitable for treating patients with anxiety disorders and disorders of body weight. The invention also relates to novel combination of substituted isoxazolines derivatives having anti-depressant activity and/or anxiolytic activity and/or body weight control activity with antidepressants, anxiolytics and/or antipsychotics to improve efficacy and/or onset of action.

Description

Description of the invention

The present invention relates to substituted isoxazoline derivatives having antidepressant activity and/or 2 anxiolytic activity and/or body weight control activity, methods of their preparation, pharmaceutical compositions containing them, and their use as medicinal products, in particular, for the treatment of depression, anxiety, stress-related disorders associated with depression and/or anxiety and body weight disorders, including anorexia nervosa and bulimia nervosa.

The invention also relates to novel combinations of substituted isoxazoline derivatives having antidepressant activity and/or anxiolytic activity and/or body weight control activity with antidepressants, anxiolytics and/or antipsychotic agents.

Tetrahydronaphthalene and indane derivatives exhibiting antidepressant activity are known (from EP-361577

VI. These compounds are typical monoamine reuptake blockers with additional d»-adrenoceptor antagonist activity and exhibit antidepressant activity without a sedative effect.

The problems associated with these compounds in the prior art are that these compounds cause significant side effects such as nausea, agitation, increased heart rate and decreased sexual function. In addition, it takes a long time, in particular, 3-4 weeks, before the appropriate reaction begins.

The purpose of this invention is to create new derivative compounds that exhibit antidepressant and/or anxiolytic activity and/or body weight control activity, in particular, compounds that do not have the above-mentioned disadvantages.

The present invention relates to new isoxazoline derivatives of the general formula (I) в-Я ut () " about their pharmaceutically acceptable acid or base addition salts, their stereochemically isomeric forms and their M-oxide form, where: -B7, 5 or 0; o

B is selected from the group consisting of hydrogen, alkyl, phenyl, phenylalkyl, alkylcarbonyl, alkyloxycarbonyl, and mono- and dialkylaminocarbonyl, and the phenyl and alkyl groups are optionally substituted with one or more halogen atoms; that each of K! and K?, independently of each other, are selected from the group consisting of hydrogen, hydroxyl, 35 cyano, halide, UNO, OoOSN", phenyl, phenylalkyl, alkyloxy, alkyloxyalkyloxy, - alkyloxyalkyloxyalkyloxy, tetrahydrofuranyloxy, alkylcarbonyloxy, alkylthio, alkyloxyalkylcarbonyloxy, pyridinylcarbonyloxy , alkylcarbonyloxyalkyloxy, alkyloxycarbonyloxy, alkenyloxy, alkenylcarbonyloxy and mono- and dialkylaminoalkyloxy, and alkyl and aryl radicals are optionally substituted by one or more hydroxyls or halide atoms or amino groups; or 7 79 B" and B? can together form a bivalent radical -К!-К2-, which is selected from the group consisting of с -сн.-сн.о-о-, -0-СНо-СНо-, -0 -СНо-О-, -СН4У-О-СН" and -0-СНо-СНо-О-; :з» а and 6 are centers of asymmetry; (СНо)т denotes a linear hydrocarbon chain consisting of t carbon atoms, where t is an integer from 1 to 4; 45 y ' y y y y no -1 Horn denotes an optionally substituted radical corresponding to any of the formulas (Ia), (NAME) or (Is) sp B in Kk where: each of KZ, independently of each other, is selected from the group consisting of hydrogen, hydroxyl, amino,

HF) nitro, cyano, halide and alkyl; H denotes an integer in the interval from 1 to 5; 7 VE? selected from the group consisting of hydrogen, alkyl and formyl; and

BZ denotes an optionally substituted aromatic homocyclic or heterocyclic ring system together with an optionally substituted and partially or fully hydrogenated hydrocarbon chain of 1 to 6 atoms in length, by means of which the indicated ring system is attached to the Rig radical, and one or more of these atoms can be heteroatoms selected from 0, M and 5.

More specifically, the invention relates to compounds of the formula (I), in which K denotes a radical corresponding to any of the formulas (Ша), (ПИБ) and (Пс) b5 also (1) and zro : Z where: 710 and denotes a simple compound bond, if 7 denotes a bivalent radical selected from the group consisting of -bno-, -F(-0)-, -CH(OH)-, -C(-M-OH)-, -CH(alkyl) -, -0-, -5-, -5(-0), -МН- ; or denotes a double bond, if 7 denotes a trivalent radical of the formula -CH- or "C(alkyl)-;

A represents a 5- or b--membered aromatic homocyclic or heterocyclic ring selected from the group consisting of phenyl, pyranyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, oxadiazolyl and isoxazalyl ; p denotes an integer in the interval from 0 to 4; d denotes an integer from 0 to 7;

IN? selected from the group consisting of hydrogen, alkyl, phenyl, biphenyl, naphthyl, halide and cyano, and the alkyl and aryl radicals are optionally substituted by one or more hydroxyl or halide atoms or amino groups;

IN? is equal to B; or

In and KE? can together form a bivalent radical -K7-KU-, selected from the group consisting of -CH»o-,

ESn-, -CH.-СНо-, -СН:СН-, -О-, -МН-, M-, -5-, - СНоМ(alkyl)-, -"СНЕМ-, -СНХО- and -ОСН" at-; each of KZ, independently of each other, is selected from the group consisting of hydrogen, hydroxyl, amino, ch 29 nitro, cyano, halide, carboxyl, alkyl, phenyl, alkyloxy, phenyloxy, alkylcarbonyloxy, Ho) alkyloxycarbonyl, alkylthio, mono- and dialkylamino, alkylcarbonylamino, mono- and dialkylaminocarbonyl, mono- and dialkylaminocarbonyloxy, mono- and dialkylaminoalkyloxy, and the alkyl and aryl radicals are optionally substituted by one or more hydroxyls or halide atoms or amino groups; or two vicinal radicals BEZ can together form a bivalent radical -22-KU- selected from the group consisting of -СН 2-СН.-0О-, -0-СН.-СНо, -0-СНо-Ф( -0)-, -0-СН.-О-, -СН.-0О-СНо-, -0О-СН.-СНо-О-, («in») -сСн-сСн-сн-сСнН-, - СНАсСнН-СнНАМ-, -СНАСН-М-СН-, -СНА-М-СнНАСН-, -М-АСН-СНАСН-, -СН.-СНо-СНе-, « -bn.-Сн.-сС(50) - and -СН.-СН.-СНо-СнН»-; and

BO is selected from the group consisting of hydrogen, alkyl, phenylalkyl, and phenyl. uh-

Preferably, the invention relates to those compounds in which XO or MH; B and B? both denote alkyloxy; t:-1; Horn h- denotes a radical of formula (a), where C is hydrogen and n-4; BZ denotes a radical of the formula (IB), where 7 denotes -CH-, and is a double bond, A denotes a phenyl ring, B denotes alkyl and BO is hydrogen.

Even better, the invention relates to compounds in which XO, KE and B? both are methoxy; t-1; The horn denotes a "radical of the formula (Ia), in which KZ is hydrogen and n-4; KZ denotes a radical of the formula (IB), in which 7 denotes C 70 -CH-, and denotes a double bond, A denotes a phenyl ring, BE is methyl and KO is hydrogen. c In the framework of this application, alkyl denotes linear or branched saturated hydrocarbon radicals having from 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, butyl, 1-methylpropyl, 1,1-dimethylethyl, pentyl, hexyl ; or alkyl denotes cyclic saturated hydrocarbon radicals having from 3 to 6 carbon atoms, for example, cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Haloide (halogen) is a generic name - 15 of fluorine, chlorine, bromine and iodine. Alkyl radicals, optionally substituted by one or more halide atoms, are, for example, polyhaloalkyl radicals, for example, difluoromethyl and trifluoromethyl. It is believed that pharmaceutically acceptable salts include therapeutically active non-toxic forms of acid addition salts that the compounds of formula (I) are capable of forming. Such salts can be obtained by treating the basic form of compounds of formula (I) with appropriate acids, for example, inorganic (a) 50 acids, for example, hydrohalic acid, in particular, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; organic acids, for example, acetic acid, glycolic acid, propionic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,

HF) cyclamic acid, salicylic acid, p-aminosalicylic acid and pamoic acid.

GF Compounds of formula (I) containing acidic protons can also be converted into their therapeutically active non-toxic forms of addition salts of metals or amines by treatment with appropriate organic and inorganic bases. Suitable base salt forms include, for example, ammonium salts, alkali and alkaline earth metal salts, in particular lithium, sodium, potassium, magnesium and calcium salts, salts with organic bases, for example, benzathine, M-methyl-O-glucamine, hybramine salts and salts with amino acids such as arginine and lysine.

Conversely, the indicated salt forms can be converted to free forms by treatment with an appropriate base or acid. 65 The term "addition salt" ("addition salt") in the meaning used in this application,

also includes solvates that can form compounds of formula (I), as well as their salts. Such solvates are, for example, hydrates and alcoholates.

It is believed that M-oxide forms of compounds of formula (I) include such compounds of formula (I) in which one or more nitrogen atoms are oxidized to the so-called M-oxide, in particular, such M-oxides in which M-oxidized is one or several nitrogens of the piperazinyl radical.

The term "stereochemically isomeric forms" as used herein refers to all possible isomeric forms that compounds of formula (I) may have. Unless otherwise indicated or defined, the chemical names of the compounds refer to a mixture of all possible stereochemically isomeric forms, and said mixtures contain all 7/0 diastereomers and enantiomers of the basic molecular structure. More specifically, stereogenic centers can have

K- or 5-configuration; substituents on bivalent cyclic (partially) saturated radicals can have a cis- or trans-configuration. Compounds having double bonds can have E or 7-stereochemical forms with respect to said double bond. Stereochemically isomeric forms of the compounds of formula (I) are undoubtedly considered to be within the scope of this invention.

According to the CA5 nomenclature rules, if the molecule contains two stereogenic centers with a known absolute configuration, then the descriptor K or Z is assigned (based on the sequence rule

Kana-Ingolda-Preloga (Sapp-Ipdoid-Rgeo9)) to the chiral center with a smaller number - the support center.

The configuration of the second stereogenic center is indicated with the help of relative descriptors (KK or (K",571, where K" is always defined as a reference center and (K7,K"| denotes centers with the same chirality, and (K",5") denotes centers with different chirality.For example, if the chiral center with a lower number in the molecule has

C-configuration, and the second center is K, then the stereodescriptor will be defined as 5-(K",57). If the symbols "o" and "B" are used: the position of the senior substituent on the asymmetric carbon atom in the ring system, which has a lower number in the ring, is always denoted as " the 5'-position of the midplane defined by the ring system. The position of the senior substituent on the second asymmetric carbon atom in the ring Ha gr; system (a hydrogen atom in compounds of formula (I)) in relation to the position of the senior substituent on the supporting atom is denoted as "od" if it is on the same side of the mean plane defined by the ring system, or "B" if it is on the other side of the middle plane defined by the ring system.

The compounds of the formula (I) and some of the intermediate compounds have in their structure at least two stereogenic centers, which are respectively denoted a and p in the formula (IM. Due to the synthesis route by which the synthesis of 30 tricyclic systems is carried out, the configuration of these two asymmetric centers a and 5 is predetermined in such a way that the relative configuration of the center a is 57, and the center p-K". o

The invention also includes derivative compounds (which are usually called "prodrugs") of pharmacologically active compounds according to the invention, which degrade ip mimo with the formation of compounds according to the invention. Prodrugs usually (but not always) have lower activity at the target receptor than the compounds to which they are degraded. Prodrugs are particularly useful when the desired compound has chemical or physical properties that make its administration difficult or ineffective. For example, the desired compound may be poorly soluble, it may not be well tolerated across the mucosal epithelium, or it may have an undesirably short plasma half-life. An additional discussion of antidotes can be found in EigeiiMa, M.). ei ai., "Rgodgadz", YuOgid Oeiimegu Zuvietv, 1985, pp. 112-176, and YuOgidv, « 1985, 29, pp. 455-47 3). 40 The pharmacologically active compounds of the invention in the form of prodrugs will generally be compounds of formula (I), their pharmaceutically acceptable acid or base addition salts, their stereochemically isomeric forms a and their M-oxide forms having an esterified or amidated acid group. Such esterified acid groups are groups of the formula -SOOKX, where EX denotes C. c-alkyl, phenyl, benzyl or one of the following groups: he; B 45 and Sh Y 4

Amidated groups include groups of the formula - SOMKUKA-, where KU denotes H, C-6-alkyl, phenyl or benzyl and K- and denotes -OH, H, C-6-alkyl, phenyl or benzyl. o 20 Compounds of the invention having an amino group can be derivatized with a ketone or aldehyde such as formaldehyde to form a Mannich base. This base will hydrolyze in aqueous solution with first-order kinetics.

Compounds of formula (I), obtained by the methods described below, can be synthesized in the form of racemic mixtures of enantiomers, which can be separated from each other using separation procedures known to specialists. Racemic compounds of formula (I) can be converted to the corresponding diastereomeric salt forms

F! by reaction with a suitable chiral acid. These diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization, and enantiomers are released from them with the help of alkalis. An alternative method of separation of enantiomeric forms of compounds of formula (I) includes liquid chromatography using a chiral stationary phase. The indicated pure stereochemically isomeric forms can also be obtained from the corresponding pure stereochemically isomeric forms of the corresponding starting materials, provided that the reaction occurs stereospecifically. If a specific stereoisomer is required, then the indicated compound will preferably be synthesized by stereospecific synthesis methods. In these methods, it is better to use enantiomerically pure starting materials.

It was surprisingly shown that the compounds of the invention have selective serotonin (5-HT) reuptake inhibitor activity in combination with additional β-adrenoceptor antagonist activity and exhibit potent antidepressant and/or anxiolytic and/or weight control activity without sedation. effect In addition, taking into account their activity as a selective inhibitor of reuptake of serotonin (5-HT), as well as an antagonist of α-adrenoceptors, the compounds of the invention are also suitable for the treatment and/or prevention of diseases in which any one of the activities or a combination these activities may have therapeutic applications. In particular, the compounds according to the invention may be suitable for the treatment and/or prevention of the following diseases: n« disorders of the central nervous system, including: - mood disorders, including especially major depressive disorder, depression with psychotic features, 7/0 Kcatatonic features, melancholic features, with or without atypical signs of postpartum seizures and, in the case of recurrent episodes, with or without seasonal manifestations, dysthymic disorder, bipolar disorder type I, bipolar disorder type II, cyclothymic disorder, recurrent brief depressive disorder, mixed affective disorder, bipolar disorder , not otherwise specified, mood disorder due to a general medical condition, substance-induced mood disorder, mood disorder not otherwise specified /5, seasonal affective disorder and premenstrual dysphoric disorder, - anxiety disorders, including panic attack, agoraphobia, panic disorder without agoraphobia, agoraphobia without a history of panic disorder, spec physical phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder and anxiety disorder not otherwise specified, - stress-related disorders associated with depression and/or anxiety, including acute stress reaction, regulated disorders (brief depressive reaction, prolonged depressive reaction, mixed anxiety and depressive reaction, regulated disorder with predominant disturbance of other emotions, regulated disorder with predominant behavioral disturbance, regulated disorder with mixed emotional and behavioral disturbances, s.v. regulated disorders with other specified predominant symptoms) and other reactions to severe stress, - dementia, amnesic disorders and cognitive disorders not otherwise specified, especially (8) dementia caused by degenerative disorders, injuries, injuries, infections, vascular disorders, toxins, anoxia, vitaminosis or endocrine disorders, or amnesic disorders caused by alcohol or other causes of thiamine deficiency, bilateral right temporal lobe damage due to encephalitis caused by Negrez vitriech and other limbic encephalitis, loss of neurons due to anoxia / hypoglycemia / severe convulsions and surgery, degenerative disorders, vascular disorders or atrioventricular pathology of the IP type, "g - disorders of cognitive ability due to impairment of cognitive ability caused by other medical conditions, personality disorders, including paranoid personality disorder, schizoid personality disorder, schizotypal personality disorder, antisocial personality disorder, borderline personality disorder, hysterical personality disorder, narcissistic personality disorder, avoidant personality disorder, dependent personality disorder, obsessive-compulsive personality disorder, and personality disorder not otherwise specified, isoaffective disorders arising from various causes, including schizoaffective disorders of the manic type, depressive type, mixed type, paranoid, unsystematized, catatonic, undifferentiated and 7-3 s residual schizophrenia, schizophrenia-like disorder, schizoaffective disorder, delusional disorder, short

And psychotic disorder, split psychotic disorder, substance-induced psychotic disorder and psychotic disorder not otherwise specified - akinesia, akinetic-rigidity syndromes, dyskinesia and drug-induced parkinsonism, Gilles de la Tourette syndrome and its symptoms, tremor, chorea, myoclonus, twitching and dystonia, -I - attention deficit/hyperactivity disorder (ADHD), - Parkinson's disease, drug-induced parkinsonism, post-encephalitic parkinsonism, sh- progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, their parkinsonism complex - dementia due to amyotrophic lateral sclerosis (A! 5) and calcification of the basal nuclei, - dementia of the Alzheimer type, with early or late onset, with a depressed mood, o - behavioral disorders and behavioral disorders in persons with dementia and the mentally retarded, including dysphoria sp and agitation, - extrapyramidal movement disorders, - Down syndrome, - akathisia, - eating disorders, incl. including anorexia nervosa, atypical anorexia nervosa,

F) neurogenic bulimia, atypical neurogenic bulimia, overeating associated with other psychological disorders, vomiting associated with other psychological disorders, and nonspecific eating disorders, AIDS-associated dementia, chronic pain conditions, including neuropathic pain, inflammatory pain , cancer pain and postoperative pain after surgery, including dental surgery. These indications may also include acute pain, skeletal muscle pain, low back pain, upper extremity pain, fibromyalgia and myofascial pain syndromes, orofascial pain, abdominal pain, phantom pain; trigeminal neuralgia and 65 atypical facial pain, nerve root damage and arachnoiditis, geriatric pain, central pain and inflammatory pain,

"- neurodegenerative diseases, including Alzheimer's disease, Huntington's disease,

Creutzfeldt-Jakob disease, Pick's disease, demyelinating disorders such as multiple sclerosis and amyotrophic lateral sclerosis (A! 5), other neuropathies and neuralgia, multiple sclerosis, amyotrophic lateral sclerosis, stroke and head injury, "addiction disorders, including: - dependence on substances or substance abuse with or without physiological dependence, especially when the substance refers to alcohol, amphetamines, amphetamine-like substances, caffeine, marijuana, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, phencyclidine-like compounds , 70 sedative-hypnotic agents, benzodiazepines and/or other substances, especially suitable for the treatment of withdrawal from the above-mentioned substances and delirium due to the cessation of alcohol consumption, - mood disorders induced, in particular, by alcohol, amphetamines, caffeine, marijuana, cocaine, hallucinogens , inhalation agents, nicotine, opioids, phencyclidine, sedatives, hypnotics, anxiolytics, etc. and other substances - anxiety disorders induced, in particular, by alcohol, amphetamines, caffeine, marijuana, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics, anxiolytics and other substances and regulated anxiety disorders, " smoking cessation, n" body weight control, including obesity, "" sleep disorders and disorders, including: - dyssomnias and/or parasomnias, such as primary sleep disorders, sleep disorders associated with another mental disorder, sleep disorders due to general medical condition and substance-induced sleep disorder, circadian rhythm disorders, improvement of sleep quality, "- sexual dysfunction, including sexual desire disorders, sexual arousal disorders, c.o. Orgasmic disorders, sexual pain disorders, sexual dysfunction due to a general medical condition, substance-induced sexual dysfunction and sexual dysfunction not otherwise specified. and)

Thus, the present invention also relates to the compounds of formula (I) defined above, their pharmaceutically acceptable acid or base addition salts, their stereochemically isomeric forms, their M-oxide form, and their prodrugs suitable for use as a medicament. In addition, the present invention also relates to the use of the compound of formula (1), its pharmaceutically acceptable acid or base addition salts, its stereochemically isomeric forms, its M-oxide form, as well as its prodrugs for the production of a medicinal agent for the treatment of depression, anxiety and body weight disorders or any of the above diseases in general. "Mr

The compounds of the invention may also be suitable for use as adjunctive treatment and/or prophylaxis in the above-mentioned diseases in combination with antidepressants, anxiolytics and/or antipsychotics currently known or currently being developed or emerging in the future. cha to improve efficiency and/or onset of action. This is evaluated in rodent models for which antidepressant, anxiolytic and/or antipsychotic activity has been demonstrated. For example, the compounds are evaluated in combination with antidepressants, anxiolytics, and/or antipsychotics to alleviate stress-induced hyperthermia. "

Thus, the invention also relates to a pharmaceutical composition including the compounds according to the invention and sv) with one or more other compounds selected from the group consisting of antidepressants, anxiolytics and antipsychotic agents, as well as the use of such a composition for the production of a medicinal product;" intended to improve the effectiveness and/or onset of action in the treatment of depression and/or anxiety.

To evaluate these compounds according to the indicators of their antagonistic activity against OO-adrenoceptors and the activity of inhibiting the reuptake of serotonin (5-HT), studies of binding of receptors and neurotransmitter transporters and signal transduction can be used. As indicators of central penetration and effectiveness in blocking o-adrenoceptors and serotonin transporters, respectively, the determination of ex mimo occupation of o-adrenoceptors and serotonin transporters can be used. As an indicator of ip

In addition to its antagonism of ao-adrenoceptors, reversal of the loss of the righting reflex, which is observed in rats after subcutaneous injection or oral administration of a dose of the compound before intravenous administration of medetomidine to rats (medetomidine test), can be used. Inhibition of head twitching and excitement in rats, which is observed after subcutaneous injection or oral administration of a dose of the compound before subcutaneous administration of p-chloroamphetamine to rats (pCA-test), can be used as an indicator of the activity of inhibiting the reuptake of serotonin (5-HT).

The invention also relates to a composition comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound of the invention. The compounds of the invention or any subgroup thereof can be included in the formulations of various pharmaceutical forms for the purpose of administration. All compositions that are usually used for systemic administration of drugs can be named as appropriate compositions. For the manufacture of pharmaceutical compositions of the present invention, an effective amount of a particular compound, 60% optionally, in the form of an additive salt as the active ingredient, is thoroughly mixed to a homogeneous state with a pharmaceutically acceptable carrier, which may take a variety of forms, depending on the desired form of administration drug These pharmaceutical compositions are preferably produced as dosage forms suitable, in particular, for administration orally, rectally, subcutaneously, by parenteral injection or inhalation. For example, in the preparation of compositions in the form of dosage forms for oral administration, any conventional pharmaceutical medium can be used, such as, for example, water, glycols, oils, alcohols, and the like. in the case of liquid preparations for oral administration, such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrants, etc., in the case of powders, pills, capsules and tablets. Due to the ease of administration, tablets and capsules are the best dosage forms for oral administration, for which, of course,

Solid pharmaceutical carriers are used. For parenteral compositions, the vehicle will usually include sterile water, at least predominantly, although other ingredients may be included, for example to improve solubility. For example, solutions for injections can be prepared in which the carrier includes a saline solution, a glucose solution, or a mixture of saline and glucose solutions. Injectable suspensions can also be prepared, in which suitable liquid carriers, suspending agents, etc. can be used. Also included are preparations in the form of solid forms, which are intended to be converted, shortly before use, into preparations in liquid form. In compositions suitable for subcutaneous administration, the carrier optionally includes a penetration-enhancing agent and/or a suitable wetting agent, optionally in combination with a small amount of suitable impurities of any nature which do not exhibit a significant deleterious effect on the skin.

These additives may facilitate dermal delivery and/or may be useful in the preparation of the desired compositions. These compositions can be introduced in different ways, for example, as a transdermal patch, as a point patch, as an ointment.

It is especially preferable to prepare the above-mentioned pharmaceutical compositions in the form of dosage forms for ease of administration and uniformity of doses. Dosage forms, as used herein, refer to physically separate portions suitable for administration as single doses, each portion containing a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect, in combination with the desired pharmaceutical carrier. Examples of such dosage forms are tablets (including score tablets or coated tablets), capsules, pills, sachet powders, wafers, suppositories, injectable solutions or suspensions, and the like, and discrete multiples thereof.

The compounds of the invention can generally be prepared using a sequence of stages, each of which is known to those skilled in the art.

In particular, compounds of the formula (I) with the Rig-radical of the formula (Pa) can be obtained by carrying out i) a reaction of nucleophilic substitution of an intermediate compound of the formula (IM) with a substituted piperazine of the formula (M). These reactions can be carried out in a solvent inert to the reaction, such as dioxane, methyl isobutyl ketone or

M,M'-dimethylformamide, in the presence of a suitable base, such as potassium carbonate, sodium carbonate or isotriethylamine, or even without a base, using in this latter case an excess of the reagent of formula (M). A convenient range of reaction temperatures is from 1002C to 15026. o and -

In the compound (IM), Y represents any suitable reactive leaving group, in particular, a halide such as chlorine, bromine or iodine, or a sulfonyloxy group such as methylsulfonyloxy or 4-methylbenzenesulfonyloxy. "

Compounds of the formula (I) with the Rig-radical of the formula (Pa) can also be obtained according to the 2-stage reaction scheme, in which the intermediate compound of the formula (IM) is first introduced into the reaction with a substituted piperazine of the formula - c (MI), after which the molecule introduce the radical KZ. The reaction conditions are similar to those described above for compound h of formula (MI). "» o en» -K» shn, hand -I and nki. y t 7 ni iz In the compound (IM), Y represents any suitable reactive leaving group, in particular, a halide such as chlorine, bromine or iodine, or a sulfonyloxy group, such as methylsulfonyloxy or 4-methylbenzenesulfonyloxy.(ab) 50 In the intermediate compound (MI), one of the nitrogen functions may also be protected, for example, by a t-butyloxycarbonyl group.

Tire o p a v

In compound (IX), Y represents any suitable reactive leaving group, in particular, a halide such as chlorine, bromine or iodine, or a sulfonyloxy group such as methylsulfonyloxy or 4-methylbenzenesulfonyloxy. As a compound (ХХ) can also be used В?ХНО. for Compounds of the formula (I) with the Ri-radical of the formula (Pa) can also be obtained according to a 2-stage reaction scheme, in which the intermediate compound of the formula (MI) is introduced into the reaction with the acid of the formula (X), followed by the restoration of the carbonyl function of the intermediate compound (XI). Step 1 reactions can be carried out in a reaction inert solvent such as chloroform, dichloromethane, tetrahydrofuran, dimethylformamide, or a mixture thereof, using any method known to those skilled in the art, using condensation reagents such as 1.1" -carbonyldiimidazole, M,M'-dicyclohexylcarbodiimide or by preconversion of the carboxylic acid of formula (X) into its corresponding chloride anhydride.The reactions depicted in step 2 can be carried out using a suitable reducing agent such as lithium aluminum hydride or aluminum hydride, in a suitable solvent, for example, tetrahydrofuran. In general, these reactions are carried out in the temperature range from -202C to room temperature.

Bk and nah sne y

In intermediate compounds (XI) and (XII), group A denotes an optionally substituted aromatic homocyclic or heterocyclic ring system, including a partially or fully hydrogenated hydrocarbon chain of not more than 5 atoms in length, of which one or more carbon atoms may be replaced by one or by several atoms selected from the group consisting of oxygen, nitrogen and sulfur, by means of which the ring system is attached to the radical Rig, which was defined above.

Substitutes B! and B? may be substituted or converted into one another by methods well known to those skilled in the art, 720 such as demethylation, acylation, esterification, amination, and amidation.

The starting materials and some of the intermediate compounds are compounds that can be purchased on the market or can be obtained by conventional methods of carrying out reactions well known to those skilled in the art. For example, intermediate compounds of the formula (IM) in which X-O can be obtained according to the following reaction scheme (Scheme 1):

Vanni, and sch with Z sk. no: coda Ya sob and o higher ev

IS) zo In the intermediate (CM), Y represents any suitable reactive leaving group, in particular, a halide such as chlorine, bromine or iodine, or a sulfonyloxy group such as methylsulfonyloxy or 4-methylbenzenesulfonyloxy. In addition, АЙК in the intermediate compound (ХМ) denotes any С.4.в-alkyl group, in particular, an ethyl group, and t is defined in formula (1).

Intermediate compounds of the formula (IM), in which X-MH, can also be obtained in a way equivalent to stage 1 c. c5 Above, provided that the intermediate compound (XII) is replaced by its aminated analog (KHMI), better, with an amino group protected by it, for example, by the СОСЕ group. The alkylation step can be carried out in a solvent inert to the reaction, such as tetrahydrofuran or dimethylformamide, in the presence of a strong base such as sodium or potassium hydride, and with the addition of a crown ether such as 18-crown-b or 15-crown-5 . The range of reaction temperatures from room temperature to 6026 is convenient. sh. full

B. nuts Intermediate compounds of the formula (CHMI) are converted to oximes of the formula (CHMI) using methods known in the art, such as using hydroxylammonium chloride in the presence of MANSO with or pyridine in a solvent inert to the reaction, for example, ethanol. The intermediate compound (CHMIII) is oxidized to its nitrile oxide and then undergoes intramolecular cycloaddition to form the compound of formula (XIX). This oxidation can be carried out using a solution of sodium hypochlorite in the presence of triethylamine in an inert solvent such as dichloromethane at room temperature. Oxidation can also be carried out with 595 using chloramine T (sodium salt of M-chloro-4-methylbenzenesulfonamide), with stirring and heating

HF) in a solvent such as refluxing ethanol. At this stage, two of the stereocenters a and 5 of the compound of formula (1) are formed. I'm sorry

The preparation of the compound of formula (XX) can be carried out using methods known in the art, for example, by reduction of the carbonyl compound of formula (XIX) in the presence of a suitable reducing agent, for example, sodium borohydride, in a suitable solvent, such as water, alcohol, tetrahydrofuran or their derivatives the mixture, of course, at room temperature.

An intermediate compound of formula (IM) can be prepared from an intermediate compound of formula (XX) using standard methods. Thus, the reaction with methanesulfonyl chloride or 4-methylbenzenesulfonyl chloride in the presence of a base, such as triethylamine, in a solvent inert to the reaction, for example, dichloromethane, at 70 reaction temperature in the range from 09 to room temperature, gives the corresponding sulfonyl oxide derivative of the intermediate compound (IM). The corresponding halogenated derivative can also be prepared, for example, by treating the intermediate compound of formula (XX) with triphenylphosphine in the presence of tetrachloromethane in a solvent inert to the reaction, such as tetrahydrofuran, with stirring and refluxing the mixture. yad tyu tu fstediv Yar

It will be understood that in the reactions above and below, the reaction products can be isolated from the reaction medium and, if necessary, further purified by methods known in the art, such as extraction, crystallization and chromatography. In addition, it is clear that reaction products that exist in more than one enantiomeric form can be separated from their mixture by known methods, in particular, preparative chromatography, such as preparative HPLC. Typically, the intermediate compounds (IM) and final compounds of formula (I) can easily be resolved into their enantiomeric forms.

Compounds according to the invention, in which X-CH 5", can be obtained in accordance with the following reaction scheme (o) (Scheme 2), in which the intermediate compound of the formula (M) is first M-alkylated with a dihalide derivative of the formula (XX) using standard methods, in the presence or absence of a base and in a solvent inert to the reaction, such as chloroform, dichloromethane or 1,2-dichloropentane, and at a reaction temperature in the range from room temperature to 20°C to 802C, obtaining an intermediate compound of formula (XXI). An aldehyde of formula (XXII) is reacted with tert-butylamine in an aprotic solvent such as toluene, with stirring and heating to reflux while removing water using a standard device such as a trap

Dean-Stark, receiving the name of the formula (XXIM). C-alkylation of the intermediate compound of the formula (XXIM) by the intermediate compound of the formula (XXI) can be carried out in the presence of an alkyllithium derivative, such as n-butyllithium, under in an inert atmosphere and in a dry inert solvent, such as tetrahydrofuran, at low temperatures in the range from -782C to 02C, to obtain an intermediate compound of the formula (XXM). An intermediate of formula (XXMI) can be prepared by reacting a compound of formula (XXM) with hydroxylamine in the presence of a base such as sodium bicarbonate in a solvent such as a lower alkyl alcohol such as ethanol, of course at room temperature. Finally, the oxidation of the oxime derivative of the formula (XXMI) to its nitrile oxide and subsequent cycloaddition to form the compound of the formula (XXMI) can be carried out by similar standard methods as those described above for the intermediate of the formula (XXMI), with by the formation of compounds of formula (XIX). ;"

Ky p o i einn -1 food vka vkvy VO zn -- SOYA ia zhi day oson n teklo yu he siniy nki nnny i still 60 days

The given seyei and piece b5 are not required

It is clear that the reaction steps disclosed above can be adapted to specific reaction products.

The described reaction stages can be carried out in any manner known to those skilled in the art, including reactions in solution or solid-phase reactions, in which the reaction products are bound to the resin material and - in the final cleavage stage - are released from the resin material. Examples of such embodiments and improvements are described as Examples later in this application.

Compound 3,Za,4,5-tetrahydronaphtho|1,2-cisoxazole-Z-acetic acid (formula (IM), in which each of B" and B? denotes H, m-O, X-CHNO and I-COOH ) was disclosed in Zupipeis Sottipisaiopv, 27(16), 2733-2742 (1997) as an intermediate for the synthesis of anti-inflammatory, analgesic and antipyretic compounds and excluded from patent protection.

The following examples illustrate the present invention without limiting it.

Experimental part

The numbering system of the carbon ring of the compound of formula (I) used in this application is as follows: mon: she she she

For some compounds, the absolute stereochemical configuration of the stereogenic carbon atom(s) was not determined experimentally. In these cases, the stereochemically isomeric form that was isolated first is designated as "A" and the second as "B", without further reference to the true stereochemical configuration. However, the indicated isomeric forms "A" and "B" can be unambiguously characterized by a person skilled in the art using methods known in the art, such as, for example, X-ray diffraction. Stereogenic centers a and 6 in formula (I) have, respectively, ring numbers За and 3. с

Hereinafter, "DMF" refers to M,M-dimethylformamide, "OIRE" refers to diisopropyl ether, and "THF" refers to tetrahydrofuran.

Preparation of intermediate compounds

An example of JSC. and

Obtaining intermediate compound 1 is) r sya vch | "c) she m and M

A solution of the methyl ester of 4-bromo-2-butenoic acid (0.1647 mol) in DMF (BOml) is added dropwise to a mixture of 2-hydroxy-4,5-dimethoxy-benzaldehyde (0.08233 mol) and KSO" (0. 1647 mol) in DMF (200 ml).

The reaction mixture is stirred for 2 hours at room temperature, filtered and the filtrate is evaporated to a dry residue. The residue is washed in 1095% Mahon's aqueous solution, and then extracted with CHClCl. The separated organic layer is dried (Ma»ZO)), filtered and the solvent is evaporated. The residue is washed with diethyl ether and then dried. Obtained: 20 g of intermediate compound 1 (8795). t s Example A1.5 h» Preparation of intermediate compound 2 n more than 1 g Hydroxylamine (0.045 mol) is added to a solution of intermediate compound 1 (0.041 mol) in ethanol (15 Oml). Add pyridine (57 ml). The reaction mixture is stirred for 2 hours at room temperature, and then poured into water and acidified with concentrated HCl. This mixture is extracted by СНоСИИ». The separated organic layer is dried (Ma»3O), filtered and the solvent is evaporated. Obtained: 11.7g (9695, yield of crude substance).

The sample (2 g) is purified by high-performance liquid chromatography on silica gel (eluent: СНХСИО/СНЗОН 95/5).

Pure fractions are collected and the solvent is evaporated. The residue is washed with diethyl ether and then dried.

Obtained: 0.9 g of intermediate compound 2.

Example of AT.s

F, Preparation of intermediate compound Z

And you are not

Mmaosi, 595 (13Oml) was added dropwise to a mixture of intermediate compound 2 (0.037mol) and EZM (Iml) in CHCl (220ml). The reaction mixture is stirred for 4 hours at room temperature, and then washed with water, dried (Ma»5O), filtered and the filtrate is evaporated. The residue is purified by chromatography on a short open column with silica gel (eluent: СНоSiO/2-propanone 100/0 and 95/5). The required fractions are collected and the solvent 65 is evaporated. Received: 5.8g (5495, used at the next stage of the chain without additional purification).

The sample (2g) is recrystallized from E(OAc). The precipitate is separated on a filter and dried. 1.7g of intermediate compound 3 is obtained.

Example of AT.a

Obtaining intermediate compound 4 9 women

Mavn,y (0.043mol) was added in portions to a solution of intermediate compound C (0.017mol) in THF (50ml) and H2O (ml), stirred and cooled in an ice bath. The resulting reaction mixture is stirred for 2 hours at room temperature. Add 2-propanone with stirring during ЗОхв. The reaction mixture is washed with water and extracted with СНоСі". The separated organic layer is washed with brine, dried (MA»50Od), filtered and the solvent is evaporated. The residue is purified by chromatography on a short open column with silica gel (eluent: СНоСИЛ/СНЗОН 95/5) and high performance liquid chromatography on silica gel (eluent: СНОСИ/СНЗОН 98/2). Pure fractions are collected and the solvent is evaporated. The sample (1.8 g) is treated with diethyl ether and then dried. Obtained: 1.2 g of intermediate compound 4 (5996).

An example of JSC. is

Preparation of intermediate compound 5:

EBM (0.01 bmol) was added to a solution of intermediate compound 4 (obtained according to AZ) (0.0109 mol) in CHClCl (bOml). The mixture is cooled in an ice bath. Methanesulfonyl chloride (0.012 mol) was added and the resulting reaction mixture was stirred for 30 minutes. Then the mixture is washed with water, dried (Ma 2504), filtered and the solvent is evaporated. Obtained: 3.5 g of intermediate compound 5 (8296, used in the next step of the reaction without (5) additional purification).

Example A1./

Obtaining the intermediate compound 6 is the first step

The reaction under the atmosphere of M". VVgz (0.04368 mol) is added dropwise to a stirred solution of intermediate compound 5 (obtained according to At.e) (0.0087 mol) in СНоСИ» (100 ml), cooled to -782С. The reaction mixture is allowed to warm up to -402C and stirring is continued for 2 hours at -402C. Then the mixture is poured into a river with ice water, and СНоСи is extracted." The separated organic layer is dried (Mo5O,), filtered and the solvent is evaporated. The residue is purified by flash chromatography on a silica gel column (eluent:

SnOSiOSZON 97/3), and then HPLC (eluent: SNSO»/SNZON 99.5/0.5 to 90/10). Collect two groups of fractions with the product and evaporate the solvent. Yield: 0.750 g of intermediate compound 6 (2696).

Example A1.9 - c Preparation of an intermediate compound of 7 g» pH. -I A mixture of intermediate compound 5 (obtained according to A1.4) (0.0422 mol) and piperazine (0.1267 mol) in 1,4-dioxane (15 ml) is stirred for 2 hours at 1002С. The solvent is evaporated. The residue is washed with water and extracted with СНоСи». The separated organic layer is dried (Ma»ZO), filtered and the solvent is evaporated. at 20 Obtain: 13g of intermediate compound 7 (NMR: 8596).

Example AT.p sl Preparation of intermediate compound 8 »

GF) about: and be. | | and

Intermediate compound 5 (obtained according to AtT.e) (200g, 0.58mol) is separated into its enantiomers by the method of chiral chromatography on a YIS110-2 column with a stationary phase SNIKAI RAK-AO (2000g, packing pressure: 45bar, detection range: 2 ,56, wavelength: 240nm, temperature: 302С; injected solution: 200g in 4L of SZSM; then add 19.bl of methanol (4295 ethanol) and filter; volume for injection: 70Oml; eluent:

SNZON/SNUSM 70/30 )ob./06.)). Collect two groups of product fractions and evaporate the solvent. Yield: 95 g of intermediate compound 8.

Example A1.i

Preparation of intermediate compound 9 b5 i

What's up and what's up and what's up

A mixture of intermediate compound 8 (obtained according to A1.n) (0.0728 mol) and 1-(tert-butyloxycarbonyl)piperazine (0.087 mol) in dioxane (5000 ml) is stirred and refluxed for 48 hours.

The solvent is evaporated and SN0Si is added." NiO and MaonN (5095) are also added and the mixture is extracted with SneoSi.

The separated organic layer is dried (Mo95O) and the solvent is evaporated under vacuum. Intermediate compound 9 is obtained.

Example A1.)

Obtaining an intermediate compound of 10 ev

A mixture of intermediate compound 9 (0.00318 mol) and 2,2,2-trifluoroacetic acid (189 ml) in СНоSiO» (500 ml) was stirred for 1 hour at room temperature. The solvent is evaporated and the residue is dissolved in

СНоБСИ". Mahon (5095) is added and the mixture is extracted. The separated organic layer is dried (Ma5zo)), filtered and the solvent is evaporated under vacuum. The residue is purified by chromatography on a short column with silica gel (eluent: СНоСИ»(Meon/mН») 100/0; 95/5). Pure fractions are collected and the solvent is evaporated. Yield: 14.32 g of intermediate compound 10 (59965).

Example of AT.K

Preparation of intermediate compound 11 from the mixture of intermediate compound 10 (0.00599 mol), 1-chloro-2-propanone (0.00599 mol) and KSO" (0.01199 mol) in

DMF (200 ml) was stirred for 24 hours at room temperature. The solvent is evaporated. The residue (ав) is dissolved in СН 2Си». The organic solution is washed with water, dried (Ma950O4), filtered and the solvent is evaporated under vacuum. Yield: (quantitative yield) of intermediate 11.

Example A1.I -

Preparation of intermediate compound 12 der r and U chn

Reaction under an atmosphere of M 5. A mixture of 3,4-dihydro-2-naphthalenecarboxylic acid (0.004 mol) and 1,1"-carbonylbis(1H-imidazole) (0.0047 mol) in dry SNCI" is stirred for one hour at room temperature. "» temperature. A solution of intermediate compound 7 (obtained according to Ai.4) (0.004 mol) in dry СНоСі» is added and the resulting reaction solution is stirred for about 24 hours at room temperature. The solution is washed with water and then extracted with СНоСі". Separated the organic layer is dried (Ma»50)), filtered and the solvent is evaporated. The residue is purified by chromatography on a short open column with silica gel (eluent: СНоСиИг/СНЗзОНН 97/3). Pure fractions are collected and the solvent is evaporated. Yield: 0.4g - And intermediate compound 12 (2296).

Example AT.t ve Obtaining an intermediate compound 13 svo sp sn ЧО ш я. ovi in C and o Ethenyltriphenylphosphonium bromide (0.0025 mol) is added to a solution of intermediate compound 7 (obtained according to

A1.9) (O0.00Zmol) in SNS" (20ml). The reaction mixture was stirred for 4 hours at room temperature. ime) The solvent is evaporated under reduced pressure. Yield: 2.2 g of intermediate compound 13, used in the next step of the reaction without additional purification. 60 Example of AT.p

Preparation of intermediate compound 14 b5 vel Ya

To a solution of (E)-3-iodo-2-methylpropenoic acid (0.009 mol) in dry СНоСи» (100 ml) at room temperature in a stream of Mo is added 1,1'-carbonylbis|1H-imidazole| (0.0099 mol). The mixture is stirred for 1 hour, and then intermediate compound 7 (obtained according to A1.9) (0.009 mol) is added. The reaction mixture was stirred at room temperature for 16 hours, washed with HO and brine, dried (Ma»5O)) and the solvent was evaporated under reduced pressure. The residue (white foam) is purified by chromatography on a short open column with silica gel (eluent: СНХСИ./Меон 99/1). Pure fractions are collected and the solvent is evaporated. Yield: 3.82 g of intermediate 14 (white solid, 8196).

Example AT.o 70 Preparation of intermediate compound 15 leg

A solution of GAIIN,y, 1.0M/1GF (0.00848mol) in THF (100ml) is stirred with irrigation in a flow of Mo at -2096.

Add one portion of AlIISi3 (0.009С3mol) and the resulting mixture is stirred at -2029С7 for 10 minutes.

A solution of intermediate compound 14 (obtained according to AT.p) (0.0077 mol) in THF (100 ml) was added dropwise and the resulting mixture was stirred at -202C for 1 hour. A saturated 2095 solution of MH SI is added dropwise at -102C and the reaction mixture is allowed to warm to room temperature. HO is added to the suspension and extracted

SNOSI". The separated organic layer is dried (Ma»5O)) and the solvent is evaporated under reduced pressure.

The residue is treated with ESO and dried. Yield: 3.7 g of intermediate 15 (white solid, 9496). Ge

Example AT1.r (5)

Preparation of the intermediate compound 16 - p

A mixture of intermediate compound 7 (obtained according to A1.9) (0.015 mol), 1-chloro-2-propanone (0.015 mol) and CoCO»z o (0.03 mol) in SNUSM (bOml) is stirred for 24 hours at room temperature . The solvent is evaporated. "

The remainder is divided between water and the CH axis." The separated organic layer is dried (MA»3O), filtered and the solvent is evaporated. The residue is purified by chromatography on a short open column with silica gel (eluent: - z5 SNSILSNZON 95/5). Pure fractions are collected and the solvent is evaporated. Yield: 4.79 g of intermediate compound 16 (8295). uh-

Example AT.4

Preparation of intermediate compound 17 and Mavn., (0.0128 mol) is added in portions to a solution of intermediate compound 16 (obtained according to AT1.r) "" (0.0051 mol) and HO (3.2 ml) in THF (40.5 ml) at 02S. The reaction mixture is stirred overnight at room temperature, and then treated with 1095 aq. solution of MN SI. This mixture is extracted by СНоСИИ». The separated organic layer is dried, filtered and the solvent is evaporated. The residue is purified by chromatography on a short -I open column with silica gel (eluent: СНоСиЛ/СНЗОН 97/3). The required fractions are collected and the solvent is evaporated. Yield: 1.6 bg of intermediate 17 (8095).

Example AT.g "g" Preparation of an intermediate compound 18 20 pi in sl Yoan

Intermediate compound 7 (obtained according to AshI.94) (0.0 mol) is dissolved in CH 3CM (200 ml) and K»CO3 (0.27 ml) is added. Add oxirane methanol (0.27 mol) and stir the reaction mixture over the weekend at 60 2C.

The solvent is evaporated under vacuum. The remainder is divided between water and СНоСи». The organic layer is separated, (F. dried (Ma»3O)), filtered and the solvent is evaporated under reduced pressure. The residue is purified by preparative HPLC ((1) eluent: СНоСИАСНЗОН/МН») 95/5, then (2) eluent: СНОСИЛ/СНЗОН 90/10). The product fractions are collected and the solvent is evaporated. Yield: 7.5 g (6195) of pure intermediate compound 18 and 3.5 g of a mixture of starting material/target compound 1/1.

Example A1.5

Preparation of intermediate compound 19

AND

Intermediate compound 18 (obtained according to A1.g) (0.0012 mol) is dissolved in CHCl (20 ml). Add a solution of the sodium salt of periodic acid (0.0024 mol) in MansSoU/NoO (a sufficient amount (4.5.)). The resulting reaction mixture is vigorously stirred for 2 hours. The mixture is divided between water and CH 25Si". The separated organic layer is washed with brine, dried (Ma»zZO)), filtered and the solvent is evaporated under vacuum.

Yield: 0.430 g of intermediate compound 19 (quantitative yield; used in the next step of the reaction without additional purification).

Example Aha

Preparation of intermediate compound 20 and zhi

The reaction under the atmosphere of M". A solution of 2,2,2-trifluoro-M-(2-formylphenyl)-acetamide (0.1869 mol) in DMF (375 mL) was added dropwise to Mann (0.2055 mol) in DMF (375 mL). The mixture is stirred for ЗОхв. at room temperature. A solution of methyl ester of 4-bromo-3-butenoic acid (0.280 3 mol) in DMF (200 ml) is added dropwise. Then add 18-crown-b (catalytic amount). The resulting reaction mixture is stirred for 2 hours at 60 9C, and then overnight at room temperature. The solvent is evaporated. The residue is washed in water and extracted with СНоСи». The separated organic layer is dried (Ma»53O)), filtered and the solvent is evaporated. The residue is purified by chromatography on an open column with silica gel (eluent: СНоСио/hexane 90/10, 100/0 and СНоСИ/2-propanone 96/4, 90/10 and 80/20). Pure fractions are collected and the solvent is evaporated. Obtained: 44.37 g of intermediate compound 20 (7595, used in the next "M" stage of the reaction without additional purification). at

Example A2.r

Preparation of intermediate compound 21 and c. Zetsenov Yu

B i she i i shko | "in)

Hydroxylamine (0.169 mol) and pyridine (0.21 mol) were added to a solution of intermediate compound 20 (obtained according to A2.a) (0.1407 mol) in ethanol (450 ml) and the resulting reaction mixture was stirred for 3 hours at - room temperature. The mixture is washed with 1095 citric acid solution, and then extracted with CH.

The separated organic layer is dried (Ma»5O)), filtered and the solvent is evaporated. Obtained: 45.76 bg of intermediate compound 21 (9895, used in the next stage of the reaction without additional purification). "

Example A2.p

Preparation of intermediate compound 22 - s fo (Zh siy b

A mixture of intermediate compound 21 (obtained according to A2.B) (000658 mol) and the sodium salt of N-chloro-4-methylbenzenesulfonamide (0.0658 mol) in ethanol (5000 ml) was stirred and refluxed for 2 hours. The mixture is concentrated under vacuum, filtered through dicalite, and the filtrate is washed with water and brine, and then extracted with СНоСі. The separated organic layer is dried (4 (Ma»53O)), filtered and the solvent is evaporated. The residue is purified by chromatography on an open column with silica gel (eluent: СНоSiO/2-propanone 100/0, 96/4, 90/10 and 80/20). The required fractions are collected and the solvent is evaporated.

The residue (syrup) is crystallized from hexane, and then washed with BIRE and dried. Obtained: 12.32 g of intermediate compound 22 (5796). (Ф, Example A2g.a) Preparation of intermediate compound 23 bo

Mavn., (0.0289mol) was added in portions to a mixture of intermediate compound 22 (obtained according to A2.c) in5 (0.0116bmol) in THF (81ml) and H-O (6.8ml), stirred and cooled in an ice bath. The resulting reaction mixture is stirred overnight at room temperature. The mixture is treated with a saturated aqueous solution

MNaCl, and then extracted with EtOAc. The separated organic layer was dried (Ma»3O4), filtered and the solvent was evaporated. The residue was washed with NaCl, and then recrystallized from EtOAc. The precipitate was separated on a filter and dried. Obtained: 0.9 g of intermediate compound 23 (38965).

Example A2.e

Preparation of intermediate compound 24 (w

A mixture of intermediate compound 23 (obtained according to A2.a) (0.001468 mol) and triphenylphosphine (0.001909 mol) in tetrachloromethane (30 ml) and THF (20 ml) is stirred and refluxed for 3 hours.

The solvent is evaporated to a dry residue. The residue is purified by chromatography on a short open column with silica gel (eluent: СНоСиг/hexane 90/10, then 100/0). The required fractions are collected and the solvent is evaporated. 72 The residue is crystallized from methanol. The sediment is separated on a filter and dried. Obtained: 2.6 g of intermediate compound 24 (7996).

Example of AZ.a

Preparation of intermediate compound 25 and 1,1-Dimethylethyl-1-piperazinecarboxylate (0.02 mol) were added in portions to a solution of 1,4-dichloro-2-butene (0.025 mol) in CHO" (bOml). The reaction mixture was stirred for 24 hours at room temperature, and then stirred and refluxed for 24 hours. The reaction is quenched with saturated aqueous d) Manso solution, dried (Ma»zO)), filtered and the solvent is evaporated. The residue is purified by chromatography on a short open column with silica gel (eluent: СНоСИЛ/EOАс). Pure fractions are collected and the solvent is evaporated. Obtained: 2.2 g of intermediate compound 25 (4096).

Example AZ.r that)

Obtaining intermediate compound 26 about

And her" and shcha and ek, and what - and in her-

The reaction is carried out in flow M". A mixture of Mann, 6095, (0.0579 mol) and 18-crown-b (cat. quantity) in THF (25 ml) is cooled. A mixture of 2-amino-4,5-dimethoxybenzaldehyde (0.0579 mol) in THF (5 Oml) is added in portions. The reaction is stirred at room temperature for 30 minutes. A mixture of intermediate compound 25 " (obtained according to AZ.a) (0.038 bmol) in THF (5 Oml) is added in portions. The mixture is stirred at room temperature for 3 days, and then treated with MN SI (1095). The mixture is extracted by SNSI. The organic layer is separated, dried, filtered and the solvent is evaporated to a dry residue. The residue is purified by chromatography on a short open column (eluent: СНо.СИ./СНЗОнН 99/1 and 98/2). Pure fractions are collected and the solvent is evaporated. Yield: 5.5 g of intermediate compound 26 (2396).

Example of AZ.s

Preparation of intermediate compound 27

Le Zh. -k zhkka STILL 7 z o i, sp The reaction is carried out in a flow of Mo. A mixture of intermediate compound 26 (obtained according to A2.5) (0.02 mol) in THF (8d8Oml) and 18-crown-b (cat. number) is added in portions to a mixture of Mann, 6095, (0.0Zmol) in THF (20ml ). The mixture is stirred at room temperature for 20 min. and trifluoroacetic anhydride (0.022 mol) is added in portions. The mixture is stirred at room temperature for 3 hours, treated with a solution of МН СИ 59 (2090), and then СНоСи» is extracted and the solvent is evaporated to a dry residue. The residue is cleaned

HF) by chromatography on a short open column with silica gel (СНоСиИ»/СНЗОНН 99/1 and 98/2). Clean fractions 7 are collected and the solvent is evaporated. Yield: 5.3 g of intermediate compound 27 (5890).

Example AZ.a in Preparation of intermediate compound 28 65 p

A mixture of intermediate compound 27 (obtained according to AZ.c) (0.0115 mol), hydroxylamine (0.012 bmol) and ManSO»z (0.0233 mol) in abs. ethanol (bOml) is stirred at room temperature for 24 hours, filtered and the solvent is evaporated to a dry residue. Yield: 5.8 g of intermediate compound 28 (9596).

Example of AZ.e

Preparation of intermediate compound 29 rhein 1-Chloro-2,5-pyrrolidinedione (0.0272 mol) was added in portions to a solution of intermediate compound 28 (obtained according to AZ.a) (0.0109 mol) in CHClCl (100 ml). The mixture is stirred at room temperature for 2 hours. Add 75 drops of ESHZM (0.0272 mol). The mixture is stirred at room temperature overnight, quenched with 1095% CosSO solution, and then extracted and the solvent evaporated to a dry residue. Yield: intermediate compound 29.

Example of ASIA

Preparation of intermediate compound 30 as i and a va

A mixture of intermediate compound 29 (obtained according to AZ.e) (0.0109 mol) and GION (0.0119 mol) in HO (17.5 ml) and 1,4-dioxane (7/0 ml) was stirred at room temperature for 3 hours. The mixture is treated with a solution of Mmason i) (2H), and then extracted with СНоСі». The solvent is evaporated to a dry residue. The residue is purified by chromatography on a short open column (eluent: SN.SIL/SNZON 98/2). Pure fractions are collected and the solvent is evaporated.

Yield: 2.07 g of intermediate 30 (4595). yu zo Example AZ.Ya

Preparation of intermediate compound 31 o shu m

Trifluoroacetic acid (7.9 ml) was added dropwise to a solution of intermediate compound 30 (0.0047 mol) in CHClCl (33 ml). The mixture is stirred at room temperature for 3 hours, cooled and basified with 5095 Mahon solution. The mixture is extracted and the solvent is evaporated to a dry residue. Yield: 1.bg of compound 31 (10095). "

Example A4.a statement Also -

Preparation of the intermediate compound 32 with the boards; p ily and s a ak y Still o s ne - 45 e 1,4-Dichloro-2-butene (0.033 mol) is added to a mixture of 1-(2-naphthylmethyl)piperazine (0.025 mole) and Mansoz

Sh- (0.025 mol) in SNS" (75 ml). The reaction mixture was stirred for 24 hours at room temperature. Their solid matter is collected on a filter, washed with an additional amount of СНоСи» and the organic solution is washed with 1095 5 g of a solution of MagSO»z, dried (Ma»ZO)), filtered and the solvent is evaporated. The residue is purified by chromatography on a short open column with silica gel (eluent: СНоСИЛ/Е(Ac/2-propanone). Pure fractions are collected and the solvent is evaporated. Yield: 3.4 g of intermediate compound 32 (43905).

Example A4.r

Preparation of intermediate compound 33 o i

GI I per r

A solution of M (0.054 bmol) and tert-butylamine (0.09833 mol) in toluene (/bml) was stirred and refluxed for 24 h using a Dean-Stark trap. The solvent is evaporated.

The residue is purified by distillation (boiling point at 0.5 mmHg: 7592). Obtained: 8.1 g of intermediate compound 33 (7295).

Example A4.p

Preparation of intermediate compound 34 b5

Shevouvnoya

The reaction under Mo atmosphere. To a solution of intermediate compound 33 (obtained according to A4.a) (0.0125 mmol) and 2,2,6,6-tetramethylpiperidine (0.0012 mol) in dry THF (25 ml) add dropwise H-Vy and (0.014 mol) , stir at -782C. The mixture is stirred for 3 hours at -10 C. A solution of intermediate compound 32 (obtained according to A4.5) (0.008 mol) in dry THF (25 ml) is added in portions at -1092 C. The reaction mixture is stirred for 24 hours at room temperature, then quenched with MH SI (1095) and the organic layer is separated. The aqueous layer is extracted with СНоСи». The combined organic layers are dried (Ma»5O4), filtered and the solvent is evaporated. Obtained: 5.6 bg of intermediate compound 34 (10090).

Example A4.a

Obtaining intermediate compound 35 5000 is clearly AI

Manso" (0.015 mol) and hydroxylamine (0.0125 mol) are added to a solution of intermediate compound 34 (obtained according to A4.c) (0.008 mol) in abs. ethanol (HOml). The reaction mixture was stirred for 24 hours at room temperature. Add СНоСи» and the solid substance is collected on a filter and washed with СНоССи».

The solvent is evaporated. The residue is diluted with CHCl and washed with 1095% NaCl and brine. The organic layer is separated, dried (Ma»3O)), filtered and the solvent is evaporated. The residue is purified by chromatography on a short open column with silica gel (eluent: СНоСИ/ЕАС/2-propanone). The required fractions are collected and the solvent is evaporated. Obtained: 0.9 g of intermediate compound C5 (2496).

Example Ab5.a Ha

Obtaining intermediate compound 36 about mA yu

A mixture of A (0.029 mol) and intermediate compound 5 (obtained according to AtT.e) (0.0058 mol) in 1,4-dioxane (bml) is stirred for 2 hours at 100°C. The solvent is evaporated. The residue is purified by chromatography on a short open column with silica gel (eluent: СНоСИО/СНЗОН 98/2-97/3). The product fractions are collected and the solvent is evaporated. Output: Z,Zg of intermediate compound 36. i-

Example A5B.r

Preparation of intermediate compound 37 - «

Trifluoroacetic acid (11.7 ml) is added dropwise to a solution of intermediate compound 36 (obtained according to AB. (0.0071 mol) in CHCl3 (5 bml) and the resulting reaction mixture is stirred for 3 hours at -10260. h. The reaction mixture is cooled, and then additionally basified with 5095 Mah. This mixture is extracted and the solvent is evaporated from the extract. Yield: 2.5 g of intermediate compound 37 (quantitative yield; used in the next step of the reaction without further purification).

A. Preparation of final compounds - and Example B1I1.а -1 Preparation of compound 1 not in ей ШЕ sp Mixture of intermediate compound 5 (obtained according to At.e) (0.029 mol) and 1-(3-phenyl-2-propenyl)piperazine (0.0582 mol) is heated for 2 hours at 1002. The crude reaction mixture is washed with water and extracted

SNOSI". The separated organic layer is dried (Ma»ZO)), filtered and the solvent is evaporated. Remainder

It is purified by chromatography on a short open column with silica gel (eluent: СНоСи»/СНЗОН 95/5) and HPLC on silica gel (eluent: СНоСиИ»/СНЗзОН 80/20). Pure fractions are collected and the solvent is evaporated. This fraction (F) is separated into its optical enantiomers by the method of chiral chromatography on a Spigairak AO column (eluent:

GI SonNBONN/SNUSM 90/10). (8)-Enantiomeric fractions are collected and the solvent is evaporated. The residue is dissolved in methanol and converted into a salt of hydrochloric acid (1:2). The precipitate is separated on a filter and dried. Obtained: 2.47 g of compound 1.

Example B1.r

Obtaining the compound 2 m V 65 s

A mixture of intermediate compound 5 (obtained according to At.e) (0.0044 mol) and (3-phenyl-2-propenyl)piperazine

(0.0087mol) is stirred for 2 hours at 1002С. The reaction mixture is purified by chromatography on a short open column with silica gel (eluent: СНоСИг/СНзЗОНН 95/5), and then by high-performance liquid chromatography on silica gel (eluent: СНОСИЛ/СНЗОН 96/4). Pure fractions are collected and the solvent is evaporated.

The residue (1.4 g) is treated with diethyl ether and then dried. Obtained: 1.2 g of compound 2 (60965).

Example of VI.s

Obtaining compound Z 70 as well as

A mixture of intermediate compound b (0.00227mol), (E)-1--2-methyl-3-phenyl-2-propenyl)piperazine (0.0027Zmol) and

Mmanso" (0.00455 mol) in dioxane (0 ml) is stirred and refluxed for 48 hours. The solvent is evaporated. The residue is dissolved in СНоС. The organic solution is washed with water, dried (Ma5O), filtered and the solvent is evaporated. The residue is purified by chromatography on a short open column with silica gel (eluent: СНоОССИНЗОН/МНЗ) 99/1), followed by HPLC (eluent: СНОСИ»/СНЗОН 99.5/0.5 to 98/2).

The required fractions are collected and the solvent is evaporated. Yield: 0.17 g of compound 3.

Example VI1.a

Preparation of compound 4 to where С ka

KI ben vka

The amount of food 8 (Her zgi A1.p) (0.0058 ) (0.0116 ) is a mixture of the intermediate compound obtained according to A1. ; mol) and iodine, mol) in dioxane (MOml) are stirred and refluxed for 8 h, then stirred overnight at room temperature, then stirred and refluxed for 18 h. The mixture is treated with H 20 and extracted with СНоСі". The solvent of the separated organic layer is evaporated. The residue is purified by chromatography on a short open column (eluent: СНоСИ»/Meon 97/3). at

The desired fractions are collected and the solvent is evaporated. The residue is treated with diethyl ether and then dried.

Yield: 0.9 g of compound 4 (3395). "

Example VI1.e them-

Preparation of the compound 5 m. in. "

A mixture of intermediate compound 10 (obtained according to A1.i) (0.0029 mol), (0.0058 mol), ASON o Sh0Y "z (0.48 g) and (AcO)5VNMa (0.4 g) in 1,2-dichloropentane (2O0ml) are stirred and refluxed overnight. The mixture is treated with HO and extracted. The solvent of the separated organic layer is evaporated.

The residue is purified by chromatography on a short column with silica gel (eluent: SNSO/Meon 97/3). The required fractions are collected and the solvent is evaporated. The residue is treated with diethyl ether and then dried. Yield: 1.07 g of compound 5 (8296). -1 Example B1./

Obtaining the compound 6 sh» 20 zn p Viche o doti o HA sl «ai

A mixture of compound C (obtained according to Pr. B1) (0.0002 mol), acetyl chloride (0.00024 mol) and EBM 29 (0.00061 mol) in chloroform (100 ml) was stirred at room temperature for 2 hours. Water is added and this (FI mixture is extracted with СНоСі". The separated organic layer is dried (М9504), filtered and the solvent is evaporated under vacuum. The residue is purified by column chromatography / TLC (ССО-ТИ С) on Spgotaiigop (eluent: SNOSIL/СНЗОН 97/ 3; then 99/1). The required fractions are collected and the solvent is evaporated. Yield: 0.022 g of compound 6. bo Example B1.9

Preparation of compound 7

Preparation of compound 8 to KO shk v

Compound 2 (obtained according to B1.B5) (0.0022 mol) is isolated and separated into its optical enantiomers by chiral chromatography on a Spigairak AO column (eluent: SoHnNBONH/SNZUSM 90/10). Collect two groups of fractions and evaporate the solvent. Receive: -1.5g of fraction 1 (purity of ISI: »99.590) and -1.5g of fraction 2 (purity

CPI: 299.595). Fraction 1 is crystallized by treatment with hexane with stirring overnight. The sediment is separated on a filter and dried. Obtained: 1.08 g of compound 7 (fatty solid). Fraction 2 was crystallized by treatment with E(Ac) with stirring overnight. The precipitate was separated on a filter and dried. Obtained: 0.54 g of 8 (fatty solid).

Example B2.a

Obtaining the compound 9 baths in!

A mixture of intermediate compound 24 (obtained according to Ag.e) (0.0022 mol), 1-(2-naphthalenylmethyl)piperazine, (0.0044 mol) and KI (catalytic amount) in 1,4-dioxane (2.5 ml) is stirred and reflux overnight. The reaction mixture is washed with water and this mixture is extracted with CHCl. The residue is purified by chromatography on a short open column with silica gel (eluent: СНСИ./СНЗОН 98/2), and then

VERH (eluent: СНоСИ.СНЗОН/МН») 96/4). Pure fractions are collected and the solvent is evaporated. The remainder is processed by

VIRE, collected on a filter and dried. Yield: 0.3 g of compound 9 (3096).

Example B2.r i)

Preparation of compound 10 from Ai o och «

The reaction under the atmosphere of M". A solution of compound 9 (obtained according to B2.a) (0.0012 mol) in dry THF (3 mL) and 18-crown-6 (catalytic amount) was slowly added to a solution of Mann, 6095, (0.0018 mol) in dry THF (2 mL ). in

The reaction mixture is stirred for ЗОхв. at room temperature, acetyl chloride (0.00133 mol) is added dropwise and the reaction mixture is stirred for 3 hours at room temperature. The reaction mixture is treated with aqueous MN SI and CNOSi is extracted." The separated organic layer is dried, filtered and the solvent is evaporated. The residue is purified by chromatography on a short open column with silica gel (eluent:

SnOSILSZONE 98/2), and then HPLC (eluent: SNSOSILSZONE/MN») 98/2). Pure fractions are collected and the solvent « 70 is evaporated. Yield: 0.26 g of compound 10 (5295). 8 s Example VZ.a and Preparation of compound 11 and? -i Mixture of intermediate compound 31 (obtained according to AZ.4a) (0.0045 mol), (E)-(3-chloro-2-methyl-1-propenyl)benzene (0.0037 mol) and KSO" (0. 0037mol) in DMF (15ml) is stirred at 702C for 2 hours. The mixture is washed with 500 ml of water, and then CNOSi is extracted. The organic layer is separated, dried, filtered and the solvent is evaporated. The residue is purified by chromatography on a short column with silica gel (eluent: СНХСОО/СНЗООН с 98/2). The required fractions are collected and the solvent is evaporated. The residue is again purified by HPLC (eluent:

СНоСИСНЗОН/МН») 98/2). Pure fractions are collected and the solvent is evaporated. The remainder is processed by OIRE. The sediment is separated on a filter and dried. Yield: 0.34 g of compound 11 (2095).

Example B3.r

Preparation of compound 12

F) because and:

Preparation of compound 13 65 Compound 11 (obtained according to VZ.a) (0.00605 mol) is purified by high-performance liquid chromatography on Spigaise! 0.) (eluent: hexane/Meon/geH 20/24/56). The required fractions are collected and the solvent is evaporated. Entrance:

fractions A and B. Fraction A is purified by high-performance liquid chromatography on KR VO5 SIV (eluent: (0.590

MNAOAc in HO/SNZSM (9010UMeOnH 70/30). Pure fractions are collected and the organic solvent is evaporated. The aqueous layer is extracted with СНоСи». The separated organic layer is dried (Ma5O), filtered and the solvent is evaporated.

The residue is stirred in hexane and the precipitate is filtered off. Yield: 0.69 g of compound 12. Fraction B is purified by high-performance liquid chromatography on KR VO C18 (eluent: (0.595 MNAOAc in NoOO/СНСМ (901043uMeon 70/30). Pure fractions are collected and the organic solvent is evaporated. The aqueous layer is extracted

SNOSI". The separated organic layer is dried (Ma5O)), filtered and the solvent is evaporated. The residue is stirred in hexane and the precipitate is filtered off. Yield: 0.67 g of compound 13. 70 Example 4

Obtaining a compound of 14 t SA

The reaction is carried out in the solid phase using the Ocevi 210 synthesizer (Aghdopatsi Tesppoiodiyev, Zap

Sapovz, BOTH). M,M-Diisopropylethylamine (0.003 bmol) is added to the suspension of I; that (0.000 bmol) in acetonitrile (4 mL). Add 1-(2-chlorophenylmethyl)piperazine (0.0012 mol) and the resulting reaction mixture is stirred for 20 hours at 802. After that, each reaction vessel is filtered and the filtrate is evaporated. The residue is purified by HPLC. Pure fractions are collected and the solvent is evaporated. Yield: 0.102 g of compound 14.

Example В5.а sch

Obtaining the compound 15 Ge)

She in; Io) c

A mixture of intermediate compound 7 (obtained according to A1.9) (0.003 bmol), 2-(bromomethyl)naphthalene (0.0055 mol) and KSO" (0.0055 mol) in MIC (15 ml) was stirred for -24 hours at 1002С. The crude reaction mixture is "washed with water, and then extracted with СНоСі". The separated organic layer is dried (Ma»50)), filtered and the solvent is evaporated. The residue is purified by high-performance liquid chromatography on -

With silica gel (2x) (I) eluent: SNSIL/SNZON 95/5; (II) eluent: СНоСИБ(СНЗОН/МН») 98/2). Pure fractions are collected by Kk. and the solvent is evaporated. Obtained: 0.2 g of compound 15(1196).

Example B5.r

Preparation of compound 16 "c Y soy i "c Preparation of compound 17.

In the same way. And I ! che c) - Compound 15 (obtained according to B5.a) (0.010 bmol) is separated into its enantiomers by chromatography on a -i column (eluent: hexane/SoNBOH, gradient from 30/70 to 0/100; column: SNIVAG RAK AO 1000 And 20μm OIASEG). Two clean fractions are collected and the solvent is evaporated from them. The residue is dissolved in CH ZOH and converted into a salt of hydrochloric acid (1:2). The sediment is separated on a filter and dried. Obtained: 2.08 g of compound 16

OO 070 (36965) and 2.19 g of compound 17 (3896).

Example Bb sl Preparation of compound 18 o Mixture of intermediate compound 7 (obtained according to A1.9) (0.0045 mol), 2-methyl-3-(3-thienyl)-2-propenal ime) (0.00675 mol), Mavn( OAc)z (0.00675 mol) and HOAc (2 drops) in 1,2-dichloroethane (3 mL) were stirred overnight at room temperature. Add a saturated aqueous solution of МНАСИ and this mixture is extracted with СНоССи". The separated organic layer is dried (M950), filtered and the solvent is evaporated under vacuum. The residue is purified by flash chromatography on a silica gel column (eluent: СНоСИСН3ЗОН/МН») 9773), followed by HPLC (eluent: СНоСИЛИДСНЗОН/МН») 99/1 to 98/2). The product fractions are collected and the solvent is evaporated. Yield: 0.965 g of compound 18 (4695; also contains 390 isomer (2)).

Example B7 bB Preparation of compound 19

95 A mixture of intermediate compound 10 (obtained according to A1.)) (0.00 mol), 4-chlorobenzaldehyde (0.0045 mol) and (AcO)zVNMa (0.0045 mol) in 1,2-dichloropentane (30 mL) is stirred with irrigation for 2 hours at room temperature. A saturated aqueous solution of МНАСИ is added and the mixture is extracted with СНоСи». The separated organic layer is dried (Mo950O)), filtered and the solvent is evaporated under vacuum. The residue is purified by chromatography on a short open column with silica gel (eluent: CHNOCl(Meon/mMmH”) 97/3). The required fractions are collected and then the solvent is evaporated. The residue is precipitated from OIRE. Yield: 1.180 g of compound 19 (5795).

Example B8

Preparation of the compound 20 kyu A "5 2 VYMY

A mixture of GU (0.0003bmol), 2-methylbenzaldehyde (0.00108mol) and MaOSNz, 3096 in xia bin

SNZON, (0.00108 mol) in dry SNZON (8 ml) is stirred for 16 hours at 652 (the reaction is carried out in the solid phase using the Ocevi 210 synthesizer (Agdopatsi Tesppoiodiegz, Zap Sagpovz, OBA)). The mixtures are filtered and the filtrate is purified by HPLC (eluent: СНоСИЛСНЗОН/МН») 98/2). The required fractions (8) are collected and the solvent is evaporated. Yield: 0.032 g of compound 20.

Example B9

Obtaining the compound 21 yu dream dream

The reaction under the atmosphere of M". A solution of GiIAIN;, 1M/THF (0O, vml) is stirred at -2020. Add in one portion -

AISIz (0.0009 mol). The resulting solution is stirred for 10 minutes. at -202C. A solution of intermediate compound 12 (obtained according to A1.I) (0.0008 mol) in dry THF (5 ml) is added dropwise and the resulting reaction mixture is stirred for one hour at -202C. Then carefully add a saturated aqueous solution of MNASI.

The reaction mixture is washed with water, and then extracted with СНоСі". The separated organic layer is dried ((Ma»5zO)), filtered and the solvent is evaporated. The residue is treated with ether. The residue (0.13 g) is purified with the help of SS-TI S Spgotaiogop (eluent: SNSI./SNZON 97/3). Pure fractions are collected and the solvent is evaporated. From c Yield: 0.09 g of compound 21 (3095). "» Example B10 " Preparation of compound 22 » tni DY ay

Reaction in the stream M". A mixture of intermediate compound 13 (obtained according to At) (0.00 mol) in dry SNH2O (200 ml) is stirred at room temperature. Add MaOsCH»ez, 30956, in SNHSO (0.002 mol). 50 g of 5-indancarboxaldehyde (0.002 mol) was added and the resulting reaction mixture was stirred and refluxed for 16 hours. The reaction mixture is allowed to cool to room temperature. Add 2090 ml of MNASI and this mixture is extracted with СНоСи». The separated organic layer is washed with water, brine, dried (MA»ZO)), filtered and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on a short open column and SO-TI C (eluent: СНСИ./СНЗОН 98/2). The product fractions are collected and the solvent is evaporated. Yield: 0.035g of compound 22 (7.295, light brown solid).

GF! Example 811

Preparation of compound 23 is called) in some of the C І ee

A mixture of intermediate compound 15 (obtained according to As. o) (0.0013 bmol), 2-(trimethylstannyl)pyridine (0.0027 mol) and RY(PPH3), (0.0001 mol) in toluene (20 ml) is heated to 1002. The reaction the mixture is stirred for 16 hours and allowed to cool to room temperature. HO is added and the mixture is extracted with СНоСи». The separated organic layer is collected, washed with NaO and brine, dried (Ma»5O4) and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on a short open column with silica gel (eluent: SNSI./Meon 98/2). The pure fraction is collected and the solvent is evaporated. The resulting residue is purified by SS-TI C methods on Spgotaiigop (eluent: СН.СИ./Ммеон 98/2). Pure fractions are collected and the solvent is evaporated. Yield: 0.044 g of compound 23 (light brown solid, 796).

Example 812

Obtaining compound 24 potai HT 0 ey

The reaction under the atmosphere of M". n-Vigy, 2.5M/hexanes (0.0062mol) was added dropwise to a stirred solution of (p-fluorobenzyl)triphenylphosphonium chloride (0.0062mol) in THF (20ml). The mixture is stirred for 15 minutes. A solution of intermediate compound 11 (obtained according to A1.K) (0.00514 mol) in THF (20 Oml) was added dropwise.

The reaction mixture is stirred for 16 hours at 50 9C. Water is added and this mixture is extracted with ESO.

The separated organic layer is dried (Maoa5O)), filtered and the solvent is evaporated under vacuum. The residue is purified by chromatography on a short open column with silica gel (eluent: SNSIL/SNZON 97/3), and then

HPLC (eluent: SNYOSIL(SNZON/MH") 99/1) for separation of (E)7) isomers. Collect two groups of product fractions and evaporate the solvent from them. Yield: 0.651 g of compound 24 (26906, (E)).

Example B1Z3

Preparation of compound 25

I will eat resin. (0.0016 bmol; 1.5 mmol/g) is suspended in THF. Add 1.6 M Viyi (0.0015 mol) and stir the mixture for 15 minutes. The mixture is filtered and the residue on the filter (resin) is washed with anhydrous THF (Zh). at

The resin is resuspended in THF (bBml). Intermediate compound 19 (obtained according to A1.5) (0.0004 mol) is added and the same reaction mixture is stirred overnight at 1002C. The mixture is cooled, filtered and the filtrate is evaporated under vacuum. The residue is purified by preparative HPLC (eluent: SNHSISZON/MH» 97/3). The product fractions are collected and the solvent is evaporated. Yield: 0.168 g of compound 25. -

Example 814

Preparation of compound 26 h A mixture of intermediate compound 16 (obtained according to A1.r) (0.0025 mol), benzeneamine (0.0028 mol) and Mavna i? y : o : - (0.0028 mol) in HOAc (5 Oml) is stirred for 2 hours at room temperature. Add an aqueous solution

MNAON This mixture is extracted by СНоСи». The separated organic layer is dried (M950), filtered and the solvent is evaporated under vacuum. The residue is purified by chromatography on a short open column with - silica gel (eluent: СНоСИгСНЗОН/МНЗ) 99/1), and then by flash chromatography on a column with silica gel -1 (eluent: СНСЊ(СНЗОН/МН») 98/2). The product fractions are collected and the solvent is evaporated. Yield: 0.181 g of compound 26 (1596). Example B15 o 50 Preparation of compound 27 sl ks NE NK an Z | Y Y

Add I in (0.0018 mol) dropwise to a solution of intermediate compound 17 (obtained according to the description of AtT.a) (0.0012 mol), 3-fluorophenol (0.0018 mol) and PP3, swarm. (0.0024mol) in dry THF (1Oml) under Mo atmosphere. The reaction mixture was stirred overnight at room temperature. The mixture is filtered, 60 is washed with СНоСіі» and СНЗОН and the solvent is evaporated. The residue is purified by chromatography on a short open silica gel column (eluent: CHNOSIL/E(OAc 2/1 and CHCl/CHZON 96/4), followed by flash chromatography on a silica gel column (eluent: CHNOSIL/CHZON 97/3). Fractions the product was collected and the solvent was evaporated to yield 0.29 g of compound 27 (5096).

Example B16. Preparation of compound 28 of mass (495) (0.005 mol) is added to a solution of intermediate compound 35 (obtained according to A4.a) (0.002 mol) in

SNІІІ" (10 ml). The reaction mixture was stirred for 4 hours at room temperature. Add Ei ZM (0.004 mol) and the reaction mixture is stirred for 24 hours at room temperature. The organic layer is separated, washed with Ma»5O» (1095), dried (Ma»3O)), filtered and the solvent is evaporated. The residue 70 is purified by chromatography on a short open column with silica gel (eluent: EUAs and SNCI/SNZON 95/5).

The required fractions are collected and the solvent is evaporated. The residue is diluted with diethyl ether, and then filtered through decalite and the filtrate is evaporated. The residue is dissolved in diethyl ether and converted into a salt of hydrochloric acid (1:2). The precipitate is separated on a filter, washed with 2-propanone and diethyl ether and dried. Yield: 0.15 g of compound 28 (1596).

Example B17

Preparation of compound 29 ve and z

A mixture of intermediate 37 (prepared according to AB5.9) (O0.00bmol) and 2-(bromomethyl)naphthalene (0.00Zmol) in dioxane (400ml) was stirred at 1002 for b hours and then overnight at room temperature.

The reaction mixture is treated with 1095 K 2CO3 aqueous solution, and then СНоСиИ is extracted. The separated organic layer is evaporated. The residue is purified by chromatography on a short, open column with silica gel C (eluent: SNHCI./SNHZON 95/5 and 90/10 and SNOSIL(SNHZON/MH»U) 95/5). The product fractions are collected and the solvent is evaporated. The residue (1.49 g) was treated with diethyl ether and then dried. Yield: 0.8 g of compound 29 (53965).

The following tables (Tables 1-5) list a number of compounds that have been prepared according to any of

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I walk outside her; her:

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Ko eV shi A i i: te; and here I am

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F) ko bo b5

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Sho seh her sha sh she - zo SHY Sh shi i 7 - s p i MO p horse YN st -1 zh vei shi shi shi sht s Dn shin (F) kobo b5 nin ny nn nin s y yu shi shi sho her : AI | Yi shi she Yi i; y pe y 5 DYNY shk as We NN, na shi she shi sha S shi y Motya Yaku nya sec Y SHY NI odym Io) zada i Ide shi p o i SHY OA still G donya renvn v ne y | klbh those! ; « du raise she -v

In v and I and. an v: y oi Vit nyy - she z sho ;" "she pa sh ;

Shi ni nyny m - and her shi shi a EH, oh" in. !

She r i and ope I, : še | y SHY E (av) ny v na t zhov kn v v V sp S. Pharmacological examples

Example SI: Experiments on binding o-adrenergic receptors and 5-HT transporter

General Information

The interaction of the compounds of formula (I) with p2-receptors and p5-HT transporters was assessed using IP migo experiments on radioligand binding. In general, a low concentration of a radioligand with high affinity i) binding to a specific receptor or transporter is incubated with a sample of a tissue preparation enriched in i) a specific receptor or transporter, or with a preparation of cells expressing cloned human receptors, in a buffered medium. During incubation, the radioligand binds to the receptor or transporter. After reaching binding equilibrium, the receptor-bound radioactivity is separated from the unbound radioactivity and the receptor- or transporter-bound activity is calculated. The interaction of test compounds with the receptor is assessed using competitive binding experiments. Different concentrations of the test compound are added to the incubation mixture containing the receptor or transporter preparation and the radioligand. The test compound inhibits radioligand binding in proportion to its binding affinity and its concentration. IZNI-rauvolscine was used as a radioligand for binding Pood, Poov and Poos receptors, and IZNI|-paroxetine was used for the P5-HT transporter.

Cell culture and membrane preparation

Chinese hamster ovary cells (CHO), stably transfected with cDNA of adrenergic /-ood-; oov- or human oos-receptor, cultured on Dulbecco's modified Eagle's medium (OMEMU mixture

Nutrients Napt'z E12 (ratio 1:1) (Birso, Sepi-Weidisht) with the addition of 1095 heat-inactivated fetal bovine serum (Iie ThesppoIodiez, MegeIreKe-Weidiit) and antibiotics (100 IU/ml penicillin 0, 10Omkg/ml streptomycin sulfate, 11Omkg/ ml of pyruvic acid and 100 μg/ml of I-glutamine). One day before harvesting, cells were induced with 5 mM sodium butyrate. At a degree of confluence of 80-9095, the cells are scraped in a phosphate-salt buffer without Ca? and Md? and collected by centrifugation at 1500 x 9 for 10 min. Cells 70 are homogenized in Tris-HCI 50mM using an OIKhaishtakh homogenizer and centrifuged for 1 hour. at 23500x9. The sediment is washed once by resuspension and rehomogenization and the final sediment is resuspended in

Tris-HCl, divided into aliquots of 1 ml and stored at -7026.

Experiments on the binding of subtypes of oo-adrenergic receptors

Membranes are thawed and rehomogenized in incubation buffer (glycylglycine 25 mM, pH 0). In a total volume of 75 μl, 2-10 μg of protein are incubated with (Nirauvolscin (MET-722) (Mem/Epdiapia Misieag, OZA) (final concentration 1NM) with or without a competitive agent for 10 min at 25 °C followed by by rapid filtration through a SOB/B filter using a Rineptayeyub harvester (RasKaga, Megidep, ST). The filters are washed with a large amount of ice-cooled washing buffer (Tris-HCl, 5 ΩMM, pH 4). The radioactivity bound on the filter is determined using scintillation of the counter in the device Torsoshpi (RaskKaga, 20 Megidep, ST) and the results are expressed in pulses per minute (srt). Nonspecific binding is determined in the presence of 1 μM oxymetazoline for Pozd and poov receptors and 1 μM spiroxatrin for Pozos receptors.

Experiments on 5-HT transporter binding

Membranes of human platelets (Oseapih Viozsiepsez Sogrogayop, Napomeg, MO, OA) are thawed, diluted with a buffer (Tris-HCI 500 mM, 120 mM Mass and 5 mM KS) and quickly (max. 3s) homogenized using a 25 s Shigaishtakh homogenizer. In a total volume of 25 μl, 50-100 μg of protein is incubated with IZNIparoxetine (o) (MET-869) (Mem Epdiapa Misieag, OA) (final concentration of 0.5 nM) with or without a competitive agent for two minutes. at 252C. Incubation is stopped by rapid filtration of the incubated mixture through OR/B filters, pre-moistened with 0.196 polyethylene amine, with the help of a Riyeptaiyu9b harvester (RasKkaga, Megidep, ST). Filters are washed with a large amount of ice-cooled buffer and the radioactivity on the filter is counted using a Torsotspi liquid scintillation counter (RasKaga, Megidep, ST). Data are expressed in pulses per minute (srt). To determine non-specific binding, use imipramine (in the final concentration of µm).

Data analysis and results in. 35 The data of the analyzes in the presence of the compound are calculated as a percentage of the total binding measured in the absence of the test compound. Inhibition curves, which are plots of the proportion of total binding versus the logarithmic value of the concentration of the test compound, were generated automatically, and sigmoidal inhibition curves were approximated by nonlinear regression. The riC values of 50 test compounds are calculated from the individual curves. " 20 All compounds of the formula (I) caused more than 50905 inhibition (riC o) of at least the weather site (but often also of the Noov and Poos sites) and simultaneously of the 5-HT transporter site at the tested concentrations in the range from 109M to 109M in concentration-dependent method. For a number of selected compounds, covering most of the different variants of the formula (I), the results of studies of ip miigo are given in Table 6. sp v |ta ve vv o yu 6 vav voi left vo 5 vav |ve v? lv z |vlo khvo vshcho bo 43 bo | 719686 7.80 -daA-

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Example C2: IP mimo experiments to determine the antagonism of the OO-adrenoceptor and the inhibitory activity of the reuptake of serotonin (5-HT) that)

A. Medetomidine test o

Onset and termination of medetomidine-induced (0.1Omg/kg, intravenous (i.m.)) loss of the righting reflex were recorded in overnight fasted Uuid male rats (200-250g). The intensity of "loss of righting reflex" was evaluated in points: 0- normal behavior, 1- mild ataxia, 2- severe ataxia, 3- loss of righting reflex for a period of "5 min., 4- loss of righting reflex for a period of "5 min. By

Under standard conditions, the test compound or solvent was administered (subcutaneously (5.s.) or orally (r.o.)) per hour. - medetomidine. Criteria of drug-induced antagonism: (1) antagonism of loss of righting reflex: duration -Ochv. (1,490 false positive control; p-74) (2) reversal of ataxia: score "2 (095 false positive results). Criterion of drug-induced potentiation: "loss of righting reflex for more than 120 minutes. (095 false positives).

Antagonists of OO-adrenoceptors or stimulators of behavior of central action antagonize the loss of the righting reflex; compounds with a sedative effect can lead to an increase in duration. The following observations were made: the beginning of the loss of the righting reflex (min), the end of the loss of the righting reflex (min) and the intensity of the loss of the righting reflex (in points, 0-4). Observations were carried out after 1 hour. after subcutaneous (5.s.) (solutions) or oral (r.o.) (suspension) administration, respectively. The starting dose was 1 µg/kg (Ref: Wegdeg, O.M., Sggappa, K., Moijmeg, M.E., Ehr. Meygoi. 103, 111-115 (1989); and Eshieg, K.M/., Retu, K.M/., Moisu, V.V. Eitsg. U. Rnaptasoi. 33, 119-124 (1975); and Iavzvzep, V.,., -I Reausporpagtasoi. 57, 151-153 (1978)) .

B. pSA test Male UUida rats (body weight: 200-20g) were used. One hour after the introduction of the test (α) 50 compound or solvent, a subcutaneous injection of pSA solution (5mg/kg; TOml/kg) was made. Forty-five minutes after the injection of pSA, head twitches (NTM/) are counted and evaluated in arousal points (EHS) during three consecutive 5-minute time intervals. (starting 45, 50 and 55 minutes after the introduction of rsCA). The score was determined by a trained observer according to the following scale of intensity: 0- absent or doubtful, 1- present, 2- expressed, 3- maximum. For statistical analysis, head twitches counted within 15 minutes are summed up. 59 observations. For other phenomena, the average value for three 5-minute time intervals is used.

GF) Standard observations are carried out every hour. after subcutaneous (8.s.) or oral (r.o.) administration. t The initial dose is usually 1Omg/kg. First, doses are administered to 2 animals. If both animals showed activity in at least one of the observed indicators, the compound was considered active and testing was repeated at a 4-fold reduced dose. If activity was observed in only one of the two animals, 60 testing was performed on an additional animal. If activity was detected in this additional animal, the compound was also considered active and testing was repeated at a 4-fold reduced dose. In all other cases, the compound was considered inactive for this time-route-dose combination (Reference: dapzzep, RA)., Mietedeegv,

S.0.,E., Amzhmotsiege, B., Zspepekep5e, K.N.Y., Medepz, A.A.N.R., Meepy, T.R. 9. Adaptations. Ex. TPegar. 244, 685-693 (1988). because Results

A large number of compounds according to the invention show central activity (minimum effective dose) both in the medetomidine test and in the pCA test at 1 Ωg/kg and less.

Example CZ3: Binding analysis (55 TRUZ

Membranes of a Chinese hamster ovary (CHO) cell line expressing weather-adrenergic receptor are thawed and rehomogenized in 20 mM Nerez buffer. The incubation medium consists of: 20 mM Nerez buffer, pHn7.5, 1 mM COR, ZMM Mosi", 100 mM mass, 0.25 nM |55|STRUBZ and 10 μg of protein per well in a 96-well plate.

Antagonists and reference agonist noradrenaline (ZpM) are added after 20 min. to (25|STRUZ. Incubation (2Ochv., 372) is finished by rapid filtration through SBR/B filters and binding is quantified using a liquid 70 scintillation counter.

The results

All compounds of the invention tested in the STRUuvb binding assay showed no significant increase in binding | 255|STRU5 with Nood receptor In concentrations up to 1O0μM. All compounds tested by this method 75 were able to inhibit the norepinephrine-induced increase in binding | 5|STRUZ, which confirms their antagonistic nature with respect to this receptor.

Claims (14)

The formula of the invention 1. The compound of the general formula (I) is a compound of the general formula (I), its pharmaceutically acceptable addition salts of acids or bases, its stereochemically isomeric forms and its The M-oxide form, where: X means CH", M-B7, 8 or 0, and 30 B is selected from the group consisting of hydrogen, alkyl, phenyl, phenylalkyl, alkylcarbonyl, lower alkyloxycarbonyl and mono- and dialkylaminocarbonyl, and phenyl and alkyl groups are optionally substituted by one or more halide atoms, in each of EK" and K?, independently of each other, selected from the group consisting of hydrogen, hydroxy, - 35 cyano, halide, UNO, OoOSN" , phenyl, phenylalkyl, alkyloxy, alkyloxyalkyloxy, m alkyloxyalkyloxyalkyloxy, tetrahydrofuranyloxy, alkylcarbonyloxy, alkylthio, alkyloxyalkylcarbonyloxy, pyridinylcarbonyloxy, alkylcarbonyloxyalkyloxy, alkyloxycarbonyloxy, alkenyloxy, alkenylcarbonyloxy and mono- and dialkylaminoalkyloxy radicals are optionally substituted by one or more hydroxyls or halide atoms or amino groups, or "B" and B? can together form a bivalent radical -К-К2-, which is selected from the group consisting of -о с -сн.-СсСн.-о-, -0-СНо-СНо-, -0-СНо-О-, -СН .-О-СНо- and -0-СНо-СНо-О-, а and 6 are centers of asymmetry, with (СНо)т means a linear hydrocarbon chain of t carbon atoms, where т is an integer in the range from 1 to 4, The horn means an optionally substituted radical of any of the formulas (Pa), (NAME) or (Ps) ron Boni (a), p I Still 'lezh. tysia IN (1) - shEOyaO vne SHK In NYA i MU NEUZHTykh her RYAEY KITAYEM TENY - their PIK nim ert sha "Va t "t. ra o 50 her ev yav sl M what where: each of KZ, independently of each other, is selected from the group consisting of hydrogen, hydroxy, amino, 29 nitro, cyano, halide and alkyl, n means an integer from 1 to 5 , GF) VE? is chosen from the group consisting of hydrogen, alkyl and formyl, and GI VZ means a radical according to any of the formulas (III) and NN | pyati, that orvy Bk " ek M p zho er bo tek nya: She ya NN ze Iv yatAZ TT rak Z that Du MiEYah Y sovu MY yah Ne ra 65 Not yet where: a means a simple bond, and 7 means a bivalent radical , selected from the group consisting of -CH 5-, -sh(-0)-, -CH(OH)-, -C(-M-OH)-, -CH(alkyl)-, -0О-, - 5-, -5(50)-, -МН-, or a means a double bond, and 7 means a trivalent radical of the formula -CH- or -C(alkyl)-, A means 5- or b--len aromatic homocyclic or a heterocyclic ring selected from the group consisting of phenyl, pyranyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, oxadiazolyl and isoxazolyl, p is an integer from 0 to 4.70 d means an integer from 0 to 7, B" is selected from the group consisting of hydrogen, alkyl, phenyl, biphenyl, naphthyl, halide and cyano, wherein the alkyl and aryl radicals are optionally substituted with one or more hydroxyl or halide atoms or amino groups , In? is equal to B, or B" and EE? can together form a bivalent radical -B-B-, which is selected from the group consisting of -Сно-, -СН-, -СН.-СНно-, -СН-СН-, - О-, -МН-, -М-, -5-, -СНоМ(-alkyl)-, -"СНЕМ-, -СН2О- and -ОСН"-, each of KZ, independently of each other, is selected from the group, consisting of hydrogen, hydroxyl, amino, nitro, cyano, halide, carboxyl, alkyl, phenyl, alkyloxy, phenyloxy, alkylcarbonyloxy, alkyloxycarbonyl, alkylthio, mono- and dialkylamino, alkylcarbonylamino, mono- and dialkylaminocarbonyl, mono- and dialkylaminocarbonyloxy, mono- and dialkylaminoalkyloxy, and the alkyl and aryl radicals are optionally substituted by one or more hydroxyls or halogen atoms or amino groups, or two vicinal KU radicals can together form a bivalent radical -К92-К6-, which is selected from the group consisting of -СН 5 -СН.-О-, -0-СНо-СНо-, -0О-СНо-С(-20)-, -0-СНо-О-, -СНО-О-СНо, -0О-СНО-СНо-О -, -сн-сн-сн-снН-, -СНАсСнН-СнНАМ-, -СНАСН-М-СН-, -СНА-М-СнНАСН-, -М-АСН -СНАСН-, -СН.-СНо-СНе-, с 29 -сНО-СНо-С(0)- and -СНо-СНо-СНо-СНо-, and o BO is selected from the group consisting of hydrogen, alkyl, phenylalkyl and phenyl. 2. The compound according to claim 1, which differs in that X is O or MH, B and B? both mean alkyloxy, t - 1, Rg means a radical of the formula (Ia), in which BZ means hydrogen and n - 4, BZ means a radical of the formula (PIB), in which y 7 means "CH-, and means a double bond, A means phenyl ring, EB means alkyl, KO is hydrogen. 3. The compound according to any of claims 1-2, intended for use as a medicinal product. at 4. A pharmaceutical composition containing a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound according to any one of claims 1-2. 5. The method of obtaining a pharmaceutical composition according to claim 4, which differs in that the compound according to any of claims 1-2 and a pharmaceutically acceptable carrier are mixed. Cha 6. Use of the compound according to any one of claims 1-2 for the production of a medicinal product for the treatment of depression, anxiety and body weight disorders. 7. A pharmaceutical composition containing a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound according to any one of claims 1-2 and one or more other compounds selected from group 70 consisting of antidepressants, anxiolytics and antipsychotics means - with 8. Application of the pharmaceutical composition according to claim 7 for the production of a medicinal product designed to improve the effectiveness and/or onset of action in the treatment of depression, anxiety and body weight disorders. "» 9. A method of treating depression, anxiety and body weight disorders, in which a therapeutically effective amount of a compound according to any one of claims 1-2 and one or more other compounds selected from the group consisting of 75 antidepressants, anxiolytics and antipsychotics together is administered or sequentially and in any order. -AND 10. Application of the pharmaceutical composition according to claim 7 in the treatment of depression, anxiety and body weight disorders. 11. The method of obtaining a pharmaceutical composition according to claim 7, which is characterized by mixing a compound according to any one of claims 1-2 and a compound selected from the group consisting of antidepressants, anxiolytics and "" antipsychotics, and a pharmaceutically acceptable carrier . 12. The method of obtaining a compound according to any of claims 1-2, which differs in that the reaction of the compound of the formula (IM) with the compound of the formula (M) with shcha m) Y Sh chech z or formulas (MY) b5 ram (M) MB. where B", 82, 23, 28, X, t and n have the values defined in clause 1, and Y means the leaving group. 13. The compound of the general formula (IM) ZD (M) EX stevia uh ne LEV Be ne VEK chai CHEKY dnih Ma de VK", 2, X and t have the values indicated in point 1, and It is selected from the group consisting of 19 ОО.СНАСН,У), ООСН», СИ, Вг and |, with the exception of З,За,4,5-tetrahydronaphtho|1,2-cisoxazole-3-acetic acid. 14. Compound of the general formula (MI!) yasa ID. SO poh shk Mania EE Se in zt J -. Cache Men no sh va o de B", B, X, t, VZ and p have the values specified in clause 1. Official bulletin "Industrial property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2006, M 12, 15.12.2006. The State Department of Intellectual Property of the Ministry of Education of the Ministry of Education and Science of Ukraine. o "cha m. shi s z -I -I sh" o 50 sl F) ime) 60 b5