Tetralin and indane derivatives and use thereof as 5-ht antagonists

FIELD: chemistry.

SUBSTANCE: described is a compound of formula

or its pharmaceutically acceptable salt, where m, p, q, Ar, R1 and R2 are as given in the description, as well as a pharmaceutical composition with selective affinity to 5-HT receptors which contains a formula (I) compound.

EFFECT: obtained compounds have selective affinity to 5-HT receptors and can be used, as expected, in treating certain central nervous system disorders.

21 cl, 1 tbl, 6 ex

 

This invention relates to compounds substituted indane and tetralin and compositions containing these compounds, their use in the preparation of drugs useful in certain disorders of the CNS (Central nervous system), and methods for their preparation.

In more detail, in the proposed invention the compounds of formula I

or their pharmaceutically acceptable salt,

where m has a value from 0 to 3;

p has a value from 1 to 3;

q is 0, 1 or 2;

Ar represents a possibly substituted aryl or possibly substituted 5 to 12-membered heteroaryl;

each R1independently represents halogeno, C1-12-alkyl, C1-12-halogenoalkane, C1-12-heteroalkyl, cyano, -S(O)q-R3, -C(=O)NRbRc, -SO2-NRbRc, -N(Rd)-C(=O)-Reor-C(=O)-Rewhere q has the value from 0 to 2, each of Ra, Rb, Rcand Rdindependently represents hydrogen or C1-12-alkyl and R6represents hydrogen, C1-12-alkyl, C1-12-alkoxy or hydroxy;

R2represents a

;

X represents-O - or-NR7-;

n has a value of 2 or 3;

each of R3and R4independently represents hydrogen or alkyl, or R3and R4vestamager to form-C(O)-;

each of R5and R6independently represents hydrogen or C1-12-alkyl, or R5and R6together with the nitrogen to which they are attached, may form a five - or six-membered ring which may include an additional heteroatom selected from O, N and S, or one of R5and R6and one of R3and R4together with the atoms to which they are attached, may form a five - or six-membered ring which may include an additional heteroatom selected from O, N and S, and

R7represents hydrogen or C1-12-alkyl.

The invention also suggested methods of preparation and methods of application of the aforementioned compounds and pharmaceutical compositions containing these compounds.

Steps 5-hydroxytryptamine (5-HT) as the major modulatory neurotransmitter in the brain is mediated by several families of receptors called 5-NT, 5-HT2, 5-NT3, 5-NT, 5-NT, 5-MT and 5-MT. Based on the high level of mRNA of the receptor 5-NT in the brain found that the receptor 5-NT may play a role in the pathology and treatment of disorders of the Central nervous system. In particular, 5-HT2-selective 5-NT-selective ligands identified as potentially useful in the treatment of certain CNS disorders such as Parkinson's disease, Huntington's disease, anxiety is, depression, manic depression, psychoses, epilepsy, obsessive compulsive disorders, mood disorders, migraine, Alzheimer's disease (enhancement of cognitive memory), sleep disorders, eating disorders such as anorexia, bulimia and obesity, panic disorder, akathisia, attention deficit disorder and hyperactivity disorder (ADHD), attention deficit disorder (add), withdrawal due to abuse of drugs, such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal cord injury and/or head injury such as hydrocephalus. It is also expected that such compounds will be useful in the treatment of certain gastrointestinal (LCD) disorders such as functional bowel disorder. See, for example, B.L.Roth et al., J. Pharmacol. Exp. Ther., 1994, 268, 1403-14120; D.R.Sibley et al., Mol. Pharmacol., 1993, 43, 320-327; A.J.Sleight et al., Neurotransmission, 1995, 11, 1-5 and A.J.Sleight et al., Serotonin ID Research Alert, 1997, 2(3), 115-8.

Although some of the modulators 5-MT and 5-NTA already described, continues to exist a need for compounds that are useful for modulating receptor 5-NT, receptor 5-NTA or both receptors.

In the proposed invention compounds substituted khinolinov, compositions containing these compounds, their use in the preparation of medicines, and that the same methods for their preparation. In specific embodiments of the invention proposed connection piperazineethanesulfonic khinolinov and pharmaceutical compositions containing these compounds, and their use in the preparation of drugs useful in the treatment of diseases of the Central nervous system (CNS) disorders of the gastrointestinal tract.

All publications cited in this description, included in or incorporated by reference in its entirety.

Unless otherwise stated, the following terms used in this application, including the description and the claims, are defined as below. It should be noted that in the context of this description and the attached claims forms singular nouns include the corresponding plural forms, unless the context clearly requires otherwise.

"Agonist" refers to a compound that enhances the activity of other compounds or receptor site.

"Alkyl" means a monovalent normal or branched saturated hydrocarbon group, consisting solely of carbon atoms and hydrogen atoms, having from one to twelve carbon atoms. "Lower alkyl" refers to alkyl group containing from one to six carbon atoms (i.e., "C1-C6alkyl"). Examples of alkyl groups include methyl, ethyl, propyl, isopr the saws, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, as well as those groups which are illustrated below in the examples, the compounds according to the invention, but are not limited to them.

"Alkylene" means normal saturated divalent hydrocarbon radical containing from one to six carbon atoms, or a branched saturated divalent hydrocarbon radical containing from three to six carbon atoms, for example methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropene, butylene, pentile, as well as those groups which are illustrated below in the examples, the compounds according to the invention.

"Albaniles" means normal unsaturated divalent hydrocarbon radical containing from one to six carbon atoms, or a branched unsaturated divalent hydrocarbon radical containing from three to six carbon atoms, such as ethenylene (-CH=CH-), 2,2-dimethylethylene, propylen, 2-methylpropenyl, butylen, penttinen, as well as those groups which are illustrated below in the examples, the compounds according to the invention.

"Alkoxy" means the group-OR where R is an alkyl, as defined in this description. Examples of alkoxy groups include methoxy, ethoxy, isopropoxy, as well as those groups which are illustrated below in the examples, the compounds according to the invention, but not ogran who obtained them.

"Aminoalkyl" means a group-R-R', where R' represents amino and R is alkylene, such as defined in this description. "Aminoalkyl" includes aminomethyl, aminoethyl, 1-aminopropyl, 2-aminopropyl, and the like. Grouping amino "aminoalkyl" may be substituted once or twice by alkyl with education "acylaminoalkyl" and "dialkylaminoalkyl" respectively. "Acylaminoalkyl" includes methylaminomethyl, methylaminomethyl, methylaminopropyl, ethylaminomethyl and the like. "Dialkylaminoalkyl" includes dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, N-methyl-N-ethylaminomethyl, as well as those groups which are illustrated below in the examples, the compounds according to the invention.

"Antagonist" refers to a compound that reduces or prevents the action of another connection or receptor site.

"Aryl" means a monovalent cyclic aromatic hydrocarbon group consisting of mono-, bi - or tritsiklicheskogo aromatic ring. The aryl group may be substituted in accordance with the order, as defined in this description. Examples of aryl groups include phenyl, naphthyl, naphthalenyl, tenantry, fluorenyl, indenyl, pentalene, azulene, acidifier, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfide, diphenylsulfone, diphenylsulphide the sludge, benzodioxane, benzofuranyl, benzodioxolyl, benzopyranyl, benzoxazines, benzoxazinones, benzopyranyl, benzofurazanyl, benzopyranyl, benzomorphans, methylenedioxyphenyl, atlanticcity, as well as those groups which are illustrated below in the examples, the compounds according to the invention, including their partially hydrogenated derivatives, but not limited to.

"Allen" means a divalent aryl radical, where the aryl is as defined herein. "Allen" includes, for example, ortho-, meta - and para-phenylene (1,2-phenylene, 1,3-phenylene and 1,4-phenylene, respectively), which may be substituted in accordance with the order, as defined in this specification.

"Arylalkyl and aralkyl"that can be used interchangeably, mean a radical-R-R', where R represents alkylenes group and R' represents an aryl group, such as defined herein, for example benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, as well as those groups which are illustrated below in the examples, the compounds according to the invention, are examples of arylalkyl.

"Cycloalkyl" means a saturated carbocyclic group consisting of a mono - or bicyclic rings. Cycloalkyl can be possibly substituted by one or more substituents, where each Deputy independently represents with the battle hydroxy, alkyl, alkoxy, halogeno, halogenoalkane, amino, monoalkylamines or dialkylamino, unless specifically stated otherwise. Examples cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, as well as those groups which are illustrated below in the examples, the compounds according to the invention, including a partially unsaturated derivatives, such as cyclohexenyl, cyclopentenyl, but not limited to.

"Cycloalkenyl" means a group of the formula-R-R', where R represents alkylene and R' represents cycloalkyl, such as defined in this specification.

"Heteroalkyl" means an alkyl radical, as defined herein, where one, two or three hydrogen atoms replaced by Deputy, is independently selected from the group consisting of-ORa, -NRbRcand-S(O)nRd(where n is an integer from 0 to 2), taking into account the fact that the accession heteroalkyl radical is through a carbon atom, where Rarepresents hydrogen, acyl, alkyl, cycloalkyl or cycloalkenyl; Rband Rcindependently of one another represent hydrogen, acyl, alkyl, cycloalkyl or cycloalkenyl and when n is 0, Rdrepresents hydrogen, alkyl, cycloalkyl or cycloalkenyl and, when n is 1 or 2, Rdrepresents and the keel, cycloalkyl, cycloalkenyl, amino, acylamino, monoalkylamines or dialkylamino. Typical examples include methoxy, ethoxy, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-hydroxy-1-hydroxymethylation, 2,3-dihydroxypropyl, 1-hydroxymethylation, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-amino-ethyl, 3-aminopropyl, 2-methylsulfonylmethyl, aminocarbonylmethyl, aminosulfonyl, aminosulfonyl, methylaminoethanol, methylaminomethyl, methylaminoethanol, as well as those groups which are illustrated below in the examples, the compounds according to the invention, but are not limited to them.

"Heteroaryl" means a monocyclic or bicyclic monovalent radical containing from 5 to 12 ring atoms having at least one aromatic ring containing one, two or three ring heteroatoms selected from N, O or S, the remaining ring atoms are C, taking into account the fact that the attachment point heteroaryl radical will be on an aromatic ring. Heteroaryl ring can be substituted in accordance with the order, as defined in this description. Examples of heteroaryl groups include imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothiazyl, type the sludge, furanyl, pyranyl, pyridyl, pyridinyl, pyridil, pyrrolyl, pyrazolyl, pyrimidyl, chinoline, ethenolysis, benzofuran, benzothiophene, benzothiophene, benzimidazole, benzoxazole, benzoxadiazole, benzothiazolyl, benzotriazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, honokalani, purinol, hintline, hemolysins, naphthyridine, pteridine, carbazole, azepine, diazepine, acridine and the like, including partially hydrogenated derivatives, but are not limited to them. The above-mentioned heteroaryl groups may be partially saturated. Accordingly, heteroaryl" includes "imidazoline", "tetrahydropyrimidines", as well as those groups which are illustrated below in the examples, the compounds according to the invention.

"Heteroaryl" means a divalent heteroaryl radical, where heteroaryl is such as defined in this description. "Heteroaryl" may be substituted in accordance with the order, as defined in this description. "Heteroaryl" includes, for example, indoline, pyrimidinyl, as well as those groups which are illustrated below in the examples, the compounds according to the invention.

The terms "halogen" and "halogen", which can be used interchangeably, refer to the Deputy fluorine, chlorine, bromine or iodine.

"Halogenated" means alkyl, such as determining what about this description, in which one or more hydrogen atoms substituted by identical or different halogen atoms. Typical halogenoalkane include-CH2Cl, -CH2CF3, -CH2Cl3, perfluoroalkyl (for example-CF3), as well as those groups which are illustrated below in the examples, the compounds according to the invention.

"Heterocyclimamines" means a saturated ring, where at least one ring atom is a N, NH or N-alkyl, and the remaining ring atoms form alkylenes group.

"Heterocyclyl" means a monovalent saturated group consisting of rings in the amount of from one to three, with one, two, or three, or four heteroatoms (chosen from nitrogen, oxygen or sulfur). Ring heterocyclyl may be substituted in accordance with the order, as defined in this description. Examples of groups heterocyclyl include piperidinyl, piperazinil, homopiperazine, azepine, pyrrolidinyl, pyrazolidine, imidazoline, imidazolidine, pyridinyl, pyridazinyl, oxazolidinyl, isoxazolidine, morpholine, thiazolidine, isothiazolinones, hinokitiol, chinoline, ethenolysis, benzimidazolyl, diazolidinyl, benzothiazolyl, benzoxazolyl, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, thiomorpholine, themorphological, themorphological, digit chinoline, dihydroisoquinolines, tetrahydroquinoline, tetrahydroisoquinoline, as well as those groups which are illustrated below in the examples, the compounds according to the invention, including a partially unsaturated derivatives, but not limited to.

The term "possibly substituted", when used in combination with "aryl", phenyl", "heteroaryl" or "heterocyclyl", means an aryl, phenyl, heteroaryl or heterocyclyl, which may independently substituted by substituents in the amount of from one to four, preferably one or two substituents selected from alkyl, cycloalkyl, cycloalkenyl, heteroalkyl, hydroxyalkyl, halogen (for example F), nitro, cyano, hydroxy, alkoxy, amino, acylamino, monoalkylamines, dialkylamines, halogenoalkane, halogenoalkane, heteroalkyl, -COR (where R represents hydrogen, alkyl, phenyl or phenylalkyl), -(CR'R")n-COOR (where n is an integer from 0 to 5, R' and R" independently represent hydrogen or alkyl and R represents hydrogen, alkyl, cycloalkyl, cycloalkenyl, phenyl or phenylalkyl) or(CR'R")n-CONRaRb(where n is an integer from 0 to 5, R' and R" independently represent hydrogen or alkyl, and Raand Rbindependently from each other, represent hydrogen, alkyl, cycloalkyl, cycloalkenyl, phenyl or phenylalkyl)

The term "leaving group" has the meaning which is usually associated with him in the chemistry of organic synthesis, i.e. means an atom or a group substitutable in terms of substitution reactions. Examples of leaving groups include halogen, alkane - or arensulfonic, such as methanesulfonate, econsultancy, thiomethyl, benzosulfimide, tosyloxy, titilate, dehalogenation, possibly substituted benzyloxy, isopropoxy, acyloxy, as well as those groups which are illustrated below in the examples, the compounds according to the invention, but are not limited to them.

"Modulator" means a molecule that interacts with the target. These interactions include agonist, antagonist, and the like, such as defined herein, but not limited to.

The term "probable" or "possible" means that further describes the event or condition may not necessarily take place and that the description includes instances where the event or condition occurs and instances where it does not occur.

"A painful condition" means any disease, condition, symptom or indication.

"Inert organic solvent" or "inert solvent" means that the solvent is inert under the reaction conditions described in connection therewith, and includes, for example, benzene, toluene, acetonitrile, tetrahedr is furan, N,N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine and the like. Unless otherwise stated to the contrary, the solvents used in the reactions according to the present invention are inert solvents.

"Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and is not undesirable neither biologically nor otherwise, and includes that which is acceptable for veterinary and medical pharmaceutical applications.

The term "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable in accordance with the order, as defined herein, and which possess the desired pharmacological activity of the parent compound. Such salts include:

salt accession acid, formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or formed with organic acids such as acetic acid, benzolsulfonat acid, benzoic acid, camphor AlfaNova acid, citric acid, econsultancy acid, fumaric acid, glucoheptonate acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonate acid, Mukanova acid, 2-naphthalenesulfonate acid, propionic acid, salicylic acid, succinic acid, tartaric acid, para-toluensulfonate acid, trimethylarsine acid and the like, or

salts formed as a result of either replacement of the acidic proton present in the original compound, a metal ion, for example an alkali metal ion, alkali earth metal ion or an aluminum ion, or its interaction with organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

Preferred pharmaceutically acceptable salts are salts formed with acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, maleic acid, phosphoric acid, wine is Oh acid, citric acid, sodium, potassium, calcium, zinc and magnesium.

It should be clear that all references to pharmaceutically acceptable salts include forms accession solvent (solvate) or crystal forms (polymorphs), such as defined in the present description, the above-mentioned salt accession acid.

The terms "Pro-drug" and "prodrug", which in this description can be used interchangeably, refers to any compound which releases an active source drug according to formula I in vivo when such prodrug is administered to a subject is a mammal. Prodrugs of the compounds of formula I are prepared by modifying one or more functional groups present in the compound of formula I, so that this(s) modification(s) could(I) lead to cleavage in vivo to release the parent compound. Prodrugs include compounds of formula I where the group hydroxy, amino or sulfhydryl in the compound of formula I is associated with any group that can be chipped off in vivo recovery of free hydroxyl groups, amino or sulfhydryl respectively. Examples of prodrugs include esters (for example, derivatives of acetate, formate and benzoate), carbamates (for example, N,N-dimethylaminoethyl) hydroxyl functional groups in the compounds fo the mules I, N-acyl derivatives (e.g. N-acetyl) N-maniowy bases, Schiff bases and enaminones functional amino groups, oximes, acetals, ketals and enol esters of ketone and aldehyde functional groups in compounds of formula I and the like, but not limited to, see Bundegaard, H. "Design of Prodrugs" R.1-92, Elsevier, New York-Oxford (1985), and the like.

"Protective group" or "protecting group" means a group which selectively blocks one reactive site in a multifunctional compound, so that a chemical reaction can be performed selectively at another unprotected reactive site, in the sense that is usually connected with him in chemistry synthesis. Some of the ways in which this invention is based on the use of protective groups, which can block the reactive nitrogen atoms and/or oxygen present in the reagents. For example, the terms "amino-protecting group" and "nitrogen protecting group" herein used interchangeably and refer to those organic groups intended to protect nitrogen atom against undesirable reactions during execution of the methods of synthesis. Typical nitrogen-protecting groups include TRIFLUOROACETYL, acetamido, benzyl (Bn), benzyloxycarbonyl (carbobenzoxy, CBZ), para-methoxybenzeneboronic, para-nitrobenzenesulfonyl, tert-buto is dicarbonyl (BOC) and the like, but not limited to. Specialists in the art knows how to select a group that is easy to remove, and which is able to protect against subsequent reactions.

The term "solvate" means the form of accession of the solvent, which contain either stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to keep solvent molecules in the crystalline solid state so that they are present in a fixed molar ratio, thus forming a MES. If the solvent is water, formed MES is a hydrate, when the solvent is alcohol, educated MES represents an anion. Hydrates are formed by combining one or more water molecules with one of the substances in which the water retains its molecular state in the form of H2O, where this combination is capable of forming one or more hydrates.

"Subject" means a mammal and namecapital. Mammal means any representative of the class of mammals, including humans; primates, non-human, such as chimpanzees and other apes and monkeys; farm animals such as cattle, horses, sheep, goats and swine; domestic animals such as rabbits, dogs, and cats; laboratory who's animals including rodents, such as rats, mice and Guinea pigs, and the like, but not limited by them. Examples of memleketim include birds and the like, but are not limited to them. The term "subject" does not indicate a specific age or gender.

"Therapeutically effective amount" means an amount of compound that when administered to a subject to treat painful conditions is sufficient to carry out such a treatment of this painful condition. "Therapeutically effective amount" generally vary depending on the compound, the disease condition to be treated, the severity of the disease to be treated, the age and relative health of the subject, the route and form of administration, the opinion of the attending physician or veterinarian, and other factors.

The terms defined above and identified in this description," when they refer to a variable, incorporate by reference the broad definition of this variable, as well as preferred, more preferred and most preferred definitions, if any.

"Treating" or "treatment" of the disease condition includes:

(1) preventing the disease condition, i.e. the impact of not allowing clinical symptoms of painful conditions develop in a subject that may be under Ergen painful condition or predisposed thereto, but have yet to experience or do not show symptoms of the disease condition;

(2) inhibiting the disease condition, that is, stopping the development of a pathological state or its clinical symptoms, or

(3) relief of painful conditions, i.e. the temporary or permanent remission of the disease condition or its clinical symptoms.

The terms "treatment", "bringing into contact" and "interaction"when they refer to a chemical reaction, means adding or mixing two or more reagents under appropriate conditions with the receipt and/or the desired product. You should take into account the fact that the reaction, which gives the specified and/or the desired product may not necessarily result directly join the two reagents that were originally added, there may exist one or more intermediate compounds, which are formed in the mixture, which, ultimately, leads to the formation of the specified and/or the desired product.

In General, the nomenclature used in this application is based on AUTONOM™ v.4.0, a computerized system of the Beilstein Institute for education IUPAC systematic nomenclature.

Chemical structures shown herein, were obtained using ISIS® version 2.2. Any open of valentinos is, present at the carbon atom, oxygen or nitrogen in the structures shown herein, indicates the presence of hydrogen.

It should be clear that the scope of the present invention includes not only the various isomers that can exist, but also various mixtures of isomers that can be formed. In addition, the scope of the present invention also includes a solvate, and salts of compounds of the formula I:

or their pharmaceutically acceptable salt,

where m has a value from 0 to 3;

p has a value from 1 to 3;

q is 0, 1 or 2;

Ar represents a possibly substituted aryl or possibly substituted 5 to 12-membered heteroaryl;

each R1independently represents halogeno, C1-12-alkyl, C1-12-halogenoalkane, C1-12-heteroalkyl, cyano, -S(O)q-Ra-C(=O)-NRbRc, -SO2-NRbRc, -N(Rd)-C(=O)-Reor-C(=O)-Rewhere q has the value from 0 to 2, each of Ra, Rb, Rcand Rdindependently represents hydrogen or C1-12-alkyl and Rerepresents hydrogen, C1-12-alkyl, C1-12-alkoxy or hydroxy;

R2represents a

;

X represents-O - or-NR7-;

n has a value of 2 or 3;

each of R3 and R4independently represents hydrogen or C1-12-alkyl, or R3and R4together may form-C(O)-;

each of R5and R6independently represents hydrogen or C1-12-alkyl, or R5and R6together with the nitrogen to which they are attached, may form a five - or six-membered ring which may include an additional heteroatom selected from O, N and S, or one of R5and R6and one of R3and R4together with the atoms to which they are attached, may form a five - or six-membered ring which may include an additional heteroatom selected from O, N and S, and

R7represents hydrogen or C1-12-alkyl.

In some embodiments of formula I, p is 1 or 2 and in particular embodiments, R is set to 2. In many embodiments, q has a value of 2.

In some embodiments of formula I, Ar is an aryl or 5-12-membered heteroaryl, which may substituted by one or more halogen and preferably one or more F.

In some embodiments of the compounds according to the invention can be a compound of formula II:

where m, Ar, R1and R2are as defined in this specification.

In some embodiments of formula I and formula II R is meant is 1 or 2 and in particular embodiments, R has a value of 1. In many embodiments m is 0 or 1 and R1preferably represents halogen. In some embodiments, Ar represents a possibly substituted aryl, such as phenyl or naphthyl, each of which may substituted (for example, halogen, preferably F). In other embodiments Ar may represent a possibly substituted heteroaryl, such as thienyl, pyridyl or pyrimidyl, each of which may substituted (for example, halogen, preferably F).

In some embodiments of the invention the compounds have the formula I and formula II, where n is 2 and X represents-O-. In such embodiments, both R5and R6can represent hydrogen or, alternatively, one of R5and R6can represent hydrogen while the other represents C1-12-alkyl, preferably methyl. In other embodiments of formula I and formula II, where n has the value 2, and X represents-O-, R3and R4represent hydrogen. In some embodiments of formula I and formula II, where n has the value 2, and X represents-O-, R5and R6together with the nitrogen to which they are attached, may form a four - to - six-membered ring. In other embodiments of formula I and formula II, where n has the value 2, and X represents-O-, R3and R4together may form-C(O)-.

In some embodiments of the invention the compounds have the formula I and formula II, where n is 2 and X represents-NR7-. In such embodiments, both R5and R6can represent hydrogen or, alternatively, one of R5and R6can represent hydrogen while the other represents C1-12-alkyl, preferably methyl. In other embodiments of formula I and formula II, where n has the value 2, and X represents-NR7-, R3and R4represent hydrogen. In some embodiments of formula I and formula II, where n has the value 2, and X represents-NR7-, R5and R6together with the nitrogen to which they are attached, may form a four - to six-membered ring. In other embodiments of formula I and formula II, where n has the value 2, and X represents-NR7-, R3and R4together may form-C(O)-.

In some embodiments of the invention the compounds have the formula I and formula II, where n is equal to 3 and X represents-O-. In such embodiments, both R5and R6can represent hydrogen or, alternatively, one of R5and R6can represent hydrogen while the other represents C1-12-alkyl, preferably methyl. In other embodiments of formula I and formula II, where n is set to 3 and X represents-O-, R and R4represent hydrogen. In some embodiments of formula I and formula II, where n is set to 3 and X represents-O-, R5and R6together with the nitrogen to which they are attached, may form a four - to - six-membered ring. In other embodiments of formula I and formula II, where n is set to 3 and X represents-O-, R3and R4together may form-C(O)-. In yet some additional embodiments of formula I and formula II, where n is set to 3 and X represents-O-, one of R5and R6and one of R3and R4together with the atoms to which they are attached, may form a four - to - six-membered ring, preferably six-membered ring.

In some embodiments of the invention the compounds have the formula I and formula II, where n is equal to 3 and X represents-NR7-. In such embodiments, both R5and R6can represent hydrogen or, alternatively, one of R5and R6can represent hydrogen while the other represents C1-12-alkyl, preferably methyl. In other embodiments of formula I and formula II, where n is set to 3 and X represents-NR7-, R3and R4represent hydrogen. In some embodiments of formula I and formula II, where n is set to 3 and X represents-NR7-, R5and R6the place with the nitrogen to which they are attached, may form a four - to - six-membered ring. In other embodiments of formula I and formula II, where n is set to 3 and X represents-NR7-, R3and R4together may form-C(O)-. In yet some additional embodiments of formula I and formula II, where n is set to 3 and X represents-NR7-one of R5and R6and one of R3and R4together with the atoms to which they are attached, may form a four - to - six-membered ring, preferably six-membered ring.

In some embodiments of formula I and formula II, R2can be a C1-12-aminoalkyl.

In some embodiments of formula I and formula II, R2can be a

;;or

where R5, R6and R7are as defined in this specification.

More specifically, in some embodiments of the compounds according to the invention can be a compound of the formula IIIa or IIIB:

;

where s has a value of from 0 to 4;

each R8independently represents halogeno, C1-12-alkyl,

With1-12-alkoxy, C1-12-halogenoalkane, C1-12-heteroalkyl, cyano, -(O) r-R8-C(=O)NRbRc, -SO2-NRbRwith, -N(Rd)-C(=O)-Reor-C(=O)-R6where r has a value from 0 to 2, each of Ra, Rb, Rcand Rdindependently represents hydrogen or C1-12-alkyl and Rerepresents hydrogen, C1-12-alkyl, C1-12-alkoxy or hydroxy, and

n, R5and R6are as defined in this specification.

In some embodiments of formula IIIa or IIIB s has a value from 0 to 2 and each R8independently represents halogeno, C1-12-alkyl, C1-12-alkoxy or C1-12-halogenoalkane. In many of these embodiments, n has a value of 2. More preferably, when such compounds are compounds of formula IIIa. In such embodiments, R5may represent hydrogen and R6can represent methyl.

When any one of R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, Rc, Rdand Rein this description represents alkyl or contains an alkyl group, such alkyl is preferably a lower alkyl, C1-C6-alkyl, and more preferably1-C4-alkyl.

Typical compounds according to the invention are shown in table 1 together with the melting point or speck the rum mass M+H, and each connection is associated experimental examples (described below). The melting point referred to in table 1, in many cases, refer to the corresponding salts of the merger.

TABLE 1
No.StructureNameTPL or M+N
1N-(2-amino-ethyl)-2-(5-benzosulfimide-1 yloxy)ndimethylacetamide375
22-(5-Benzosulfimide-1 yloxy)ethylamine318
3{2-[5-(2-Permentantly)indan-1-yloxy]ethyl}methylamine350
4(5-Benzosulfimide-1-yl)piperidine-4-ylamine357
5 [2-(6-Benzazolyl-1,2,3,4-tetrahydronaphthalen-1 yloxy)ethyl]methylamine346
6[2-(7-Benzazolyl-1,2,3,4-tetrahydronaphthalen-1 yloxy)ethyl]methylamine346
7(6-Benzazolyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-4-ylamine371
8N-(6-Benzazolyl-1,2,3,4-tetrahydronaphthalen-1-yl)-N'-mutilate-1,2-diamine345
9N'-(6-Benzazolyl-1,2,3,4-tetrahydronaphthalen-1-yl)-N,N-dimethylated-1,2-diamine111,6-to 119.8°C
10N-(6-Benzazolyl-1,2,3,4-tetrahydronaphthalen-1-yl)-N,N'-dimethylated-1,2-diamine359

p> In another aspect of the invention proposed a composition comprising a therapeutically effective amount of at least one of the compounds of formula (I) and a pharmaceutically acceptable carrier.

In another aspect of the invention, a method for treating painful conditions of the Central nervous system (CNS) of a subject, comprising administration to the subject a therapeutically effective amount of the compounds of formula (I). This painful condition may include, for example, psychoses, schizophrenia, manic depressions, neurological disorders, memory disorders, attention deficit disorder, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease or Huntington's disease.

In another aspect of the present invention, a method for treatment of disorders of the gastrointestinal tract in a subject comprising administration to the subject a therapeutically effective amount of the compounds of formula (I).

In another aspect of the present invention, a method for obtaining compounds of formula (I).

Compounds of the present invention can be obtained by using several methods depicted in the illustrative diagrams of the reactions of the synthesis are described below.

Source materials and reagents used in obtaining these compounds generally are either available commercially from such is tashikov, as Aldrich Chemical Co., or obtained by techniques known to experts in the art, the following procedures described in such references as Fieser and Fieser''s Reagents for Organic Synthesis; Wiley & Sons: New York, 1991, Volumes 1-15; Rodd''s Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions, Wiley & Sons: New York, 2004, Volumes 1-56. The following scheme of reactions of synthesis are only an illustration of some of the methods through which may be synthesized compounds of the present invention, and in these schemes reactions of synthesis can be made of various modifications that can be offered to the specialist in the art by reference to the description contained in the application.

Source materials and intermediate compounds shown in schemes of reactions of the synthesis can be selected and, if required, purified using standard techniques, including filtration, distillation, crystallization, chromatography and the like, but not limited to them. Such substances can be characterized by standard means, including physical constants and spectral data.

Unless otherwise stated to the contrary, the reactions described herein, preferably in an atmosphere of inert gas, at atmospheric pressure, at a reaction temperature in the range atriplicifolia -78°C to about 150°C, more preferably in the range of from about 0°C. to about 125°C. and most preferable and convenient to carry out at approximately room temperature (or ambient temperature), for example at about 20°C.

The following Diagram And illustrates one of the methods of synthesis used for producing compounds according to the invention, where X, Ar, m, p, q, R1, R3, R4, R5and R6are as defined in this description. There are many ways of synthesis of indāni and tetraline, which can be used in obtaining the compounds according to the invention, and the method shown in Scheme And is just one of the typical techniques. Specific examples of the use of the technique shown in the Diagram As proposed in the following section the Experiments.

In stage 1, scheme a, the ketoneandrestore to obtain the corresponding alcoholb. The ketone may include, for example, arylsulfonamides, where q is set to 2 and p is 1, arylsulfonate, where q has a value of 2, and p has the value 2, arylsulphatase, where q is set to 2 and p is 3, or similar ketone according to the invention. Accordingly, at this stage can be used arylsulfonate (q=0) and arylsulfonate (q=1). atony andcan be obtained using various methods known in the art, and specific examples of the preparation of such compounds are given below in the section the Experiments of this description. The reduction in stage 1 can be accomplished by treatment of the ketone and sodium borohydride under soft proton solvent.

In stage 2 alcoholbsubjected to chlorination to obtain chlorotrifluoro connectionin. This reaction can be carried out using thionyl chloride under the conditions of a non-polar solvent.

The reaction of alkylation perform on stage 3, exposing the interaction connectiongand a compound of chlorine in obtaining connectiondthat represents a compound of formula 1 according to the invention. In connectiongX can represent-O - or-NR7-where R7is the same as defined above. When one or both of R5and R6represent hydrogen, at this stage you can apply suitable methods of introducing or removing the protective groups.

Valid many variations of the methods described in Scheme A, which is usually quite obvious to experts in the given field of technology. In some embodiments, where X represents Oh, stages 2 and 3 can be replaced by reaction of O-alkylation by treatment with compoundsb suitable halide aminoalkyl or halide heteroalkyl, which can then be modified by introduction of a functional amino group.

Specific details of obtaining compounds of formula I are described below in the Examples section below.

Compounds according to the invention have a selective affinity to 5-HT receptors, including 5-HT6and 5-HT2Athe receptor or both of the receptor, and as such will be useful, as expected, in the treatment of certain CNS disorders such as Parkinson's disease, Huntington's disease, anxiety, depression, manic depression, psychosis, epilepsy, obsessive compulsive disorders, mood disorders, migraine, Alzheimer's disease (enhancement of cognitive memory), sleep disorders, eating disorders such as anorexia, bulimia and obesity, panic disorder, akathisia, attention deficit disorder and hyperactivity disorder (ADHD), attention deficit disorder (add), withdrawal due to abuse drugs, such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal cord injury and/or head injury such as hydrocephalus. It is also expected that such compounds will be useful in the treatment of certain LCD (gastrointestinal) disorders such as functional disorder symptoms such the ICA and irritable bowel syndrome.

Testing

Pharmacology of the compounds of this invention was determined using recognized in the art techniques. In vitro method for determination of the affinity of test compounds for 5-HT6-receptor and 5-HT2Athe receptor is described below.

Introduction and pharmaceutical composition

The present invention includes pharmaceutical compositions containing at least one compound of the present invention or its isomer, racemic or prizemistuyu a mixture of its isomers, or pharmaceutically acceptable salt or MES together with at least one pharmaceutically acceptable carrier, and possibly other therapeutic and/or prophylactic ingredients.

Typically, compounds of the present invention is administered in a therapeutically effective amount by any of the techniques common to agents that are suitable for similar use. Suitable dose ranges are usually 1-500 mg, preferably 1-100 mg per day and most preferably 1-30 mg / day, depending on numerous factors such as the severity of the condition being treated, the age and relative health of the subject, the efficiency of the used connections, ways and forms of administration, indications for the purpose of this introduced the I and the preference and experience of the attending physician. The average specialist in the treatment of such diseases usually able, without undue experimentation, and relying on their personal experience and description of this application, to determine a therapeutically effective amount of the compounds of the present invention for this disease.

Typically, compounds of the present invention is administered in the form of pharmaceutical preparations, including preparations suitable for oral (including transbukkalno and sublingual), rectal, nasal, local, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration, or drugs in a form suitable for administration by inhalation or insufflation. The preferred method of administration is generally oral using the correct mode of administration of daily doses, which can be adjusted according to severity of disease.

The compound or compounds of the present invention together with one or more standard adjuvants, carriers or diluents may be in the form of pharmaceutical compositions and in a standard dosage form. Data pharmaceutical compositions and standard dosage forms may contain standard ingredients in standard proportions, to complement the elegance of the active compounds and agents with or without them, these standard dosage forms may contain any suitable effective amount of the active ingredient in accordance with the designated range of the daily dose that should be used. Data pharmaceutical compositions can be used in the form of solids, such as tablets or filled capsules, in the form of semi-solid substances, powders, drugs with a slow release, or in the form of liquids, such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Drugs, containing approximately one (1) milligram of active ingredient or, in General, from about 0.01 to about one hundred (100) milligrams per tablet, respectively, are suitable typical standard dosage forms.

Compounds of the present invention can be prepared in the form of the drug, presents a large variety of dosage forms for oral administration. Data pharmaceutical compositions and dosage forms as an active ingredient may contain soedineniya or compounds of the present invention or the pharmaceutical is Eski acceptable salt. Pharmaceutically acceptable carrier can be either solid or liquid. Drugs in solid form include powders, tablets, pills, capsules, pills, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, corrigentov, soljubilizatory, lubricants, suspendresume agents, binders, preservatives, tablet disintegrating agents or an encapsulating material. In powders, the carrier is usually a powdered solid substance that is mixed with finely ground active ingredient. In tablets, the active ingredient is usually mixed in suitable proportions with the carrier having the necessary binding capacity, and compacted according to the required shape and size. These powders and tablets preferably contain from about one (1) to approximately seventy (70) percent of the active compounds. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragakant, methylcellulose, sodium carboxymethyl cellulose, low melting wax, cocoa butter and the like, but are not limited to them. The term "drug" is intended to include a drug active compounds from encapsul is the dominant substance, as a carrier, forming a capsule in which the active component with the carrier or without it, is surrounded by carrier, which is in Association with the active component. Similarly includes a wafer and pellet. Tablets, powders, capsules, pills, wafers and cakes can be in the form of solid forms suitable for oral administration.

Other forms suitable for oral administration include liquid forms, including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions or drugs in solid form, which are intended for turning, immediately before use, to liquid form. Emulsions can be prepared in solutions, for example aqueous solutions of propylene glycol, or may contain emulsifying agents such as lecithin, servicemanual, or gum Arabic. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable pigments, corrigentov, stabilizers and thickeners. Aqueous suspensions can be prepared by dispersing finely ground active component in water with viscous substance, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose and other well-known suspendresume agents. The drug is in solid form include solutions suspensions and emulsions can contain, in addition to the active component, colorants, corrigentov, stabilizers, buffering agents, artificial and natural sweeteners, dispersing agents, thickeners, solubilizing agents and the like.

Compounds of the present invention can be prepared in the form of a preparation for parenteral administration (e.g. by injection, for example bolus injection or continue infusion) and may be presented in a standard dosage form in ampoules, pre-filled syringes, containers for small-volume infusion or in the packaging of the medicines for multiple reception with added preservative. These compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous fillers, such as solutions in aqueous polyethylene glycol. Examples of oil or non-aqueous carriers, diluents, solvents or excipients include propylene glycol, polyethylene glycol, vegetable oils (e.g. olive oil) and injectable organic esters (for example, etiloleat) and may contain such agents for drugs, as preservatives, moisturizing, emulsifying or suspendida, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in fo the IU powder, obtained by aseptic selection of sterile solid or by lyophilization from solution to dissolve before use with a suitable filler, such as sterile, pyrogen-free water.

Compounds of the present invention can be prepared in the form of the drug for the local introduction of the epidermis in the form of ointments, creams or lotions, or in the form of a transdermal patch. Ointments and creams, for example, can be prepared in the form of the drug in aqueous or oily base with the addition of suitable thickening agents and/or gelatinous agents. Lotions can be prepared in the form of the drug in water or oil based and usually also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspendida agents, thickeners or coloring agents. Drugs that are appropriate for local injection in the mouth include pellet containing the active agent in a flavored basis, usually sucrose and gum Arabic or tragakant; tablets containing the active ingredient in an inert basis such as gelatin and glycerol or sucrose and gum Arabic; and liquid mouth rinse containing the active ingredient in a suitable liquid carrier.

Compounds of the present invention can be prepared in the form of a preparation for the introduction of the Orme suppositories. First, the melted low-melting wax such as a mixture of glycerides of fatty acids or cocoa butter, and is dispersed to a homogeneous state, for example, by mixing the active ingredient. The molten homogeneous mixture is poured into molds of suitable size, leave to cool and harden.

Compounds of the present invention can be prepared in the form of medication for vaginal administration (pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known, are appropriate in this area).

Compounds of the present invention can be prepared in the form of a preparation for nasal administration. These solutions or suspensions injected directly into the nasal cavity using standard tools, such as a dropper, pipette or spray. These drugs can be offered in form, containing single or multiple dose. In the latter case, this introduction can be achieved when the patient enters a suitable specified volume of solution or suspension dropper or pipette. In the case of spray this introduction may be achieved, for example, by using a metering spray gun.

Compounds of the present invention can be prepared in the form of a preparation for aerosol administration, the particularly in the respiratory tract, including intranasal administration. The connection is usually represented by particles of small size, such as about five (5) microns or less. This particle size can be obtained using known in the art methods, for example by micronisation. The active ingredient is present in aerosol cans with a suitable propellant such as a chlorofluorocarbon (CFC), for example DICHLORODIFLUOROMETHANE, Trichlorofluoromethane or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Aerosol can usually also contain a surfactant such as lecithin. The dose can be controlled metering valve. Alternatively, the active ingredients may be present in the form of a dry powder, for example in the form of a powder mix of the compound and a suitable powder base, such as lactose, starch, derivatives of starch, such as hypromellose and polyvinylpyrrolidine (PVP). Powder media usually forms a gel in the nasal cavity. This powder composition may be present in a standard dosage form, for example in the form of capsules or cartridges, for example, gelatin or blister packs from which the powder may be entered using the inhaler.

When required, the preparations can be prepared with enteric-soluble coating, ADAP is new for the introduction of sustained or controlled release of the active ingredient. For example, the compounds of the present invention can be prepared in the form of the drug, intended for devices, transdermal or subcutaneous drug delivery. These delivery systems are preferred when you need slow release connection and when is important that patient a treatment regimen. In transdermal delivery systems connections are often connected to sticking to the skin of the solid substrate. Of interest, the connection can also be combined with a substance that promotes the penetration of, for example, Azone (1-dodecylsulfate-2-one). Delivery system with a slow release injected subcutaneously in the subdermal layer surgically or by injection. In these subdermal implants connection encapsulated in a soluble in the lipid membrane, such as silicone rubber, or biodegradation polymer, such as polylactic acid.

The pharmaceutical preparations are preferably in a standard dosage forms. In such form the preparation is divided into standard doses containing appropriate quantities of the active component. Standard dosage form can be a drug in the package, where the package contains discrete quantities of preparation, such as packaged tablets, capsules fruit is s and powders in vials or ampoules. Standard dosage form can be a single capsule, tablet, wafer or wafer, or it can represent a suitable number of any of these in packaged form.

Other suitable pharmaceutical carriers and their preparations are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. Typical pharmaceutical preparations containing the compound of the present invention is described below in the examples.

EXAMPLES

To enable specialists in this field more clearly understand and to practice the present invention, the following preparation examples and examples. They should be considered only as illustrative and typical, but not limiting the scope of invention.

Preparatory example 1

6-Benzazolyl-3,4-dihydro-2H-naphthalene-1-he

The method of synthesis described in this preparation example, carried out in accordance with the process shown in Scheme B.

Stage 1

Methyl ester of 4-(3-forfinal)-4-oxomalonate acid

A solution of 3-forventelige (35,38 g, 285,07 ml) in 35 ml of dimethylformamide (DMF) was added to a heated (48°C) solution of methyl acrylate (26,28 ml, 25,03 g, 290,7 mmol) and powdered KCN in argon atmosphere. This reactionuses was stirred at 40°C for 2 hours and then was poured into 500 ml of water. The aqueous phase was extracted twice with 500 ml Et2O (diethyl ether) and once with 250 ml EtOAc (ethyl acetate). The combined organic layers were washed with water and saturated brine and then dried over MgSO4. The solvent is evaporated under reduced pressure to get 50,89 g (242,2 mmol, 84,93%) of methyl ester of 4-(3-forfinal)-4-oxomalonate acid in the form of oil. MS(mass spectrometry): 211 (M+N)+.

Stage 2

4-(3-Forfinal)butyric acid

A solution of methyl ester 4-(3-forfinal)-4-oxomalonate acid (of 28.27 g, 134,49 mmol), hydrazine monohydrate (26,1 ml, 26,93 g, 537,96 mmol) and KOH (22,64 g, 403,47 mmol) in ethylene glycol (150 ml) was heated to the temperature of reflux distilled in an atmosphere of argon and subjected to reflux distilled for 2 hours. This reaction mixture was cooled and diluted with 1.5 liters of water, was added 500 ml of Et2O and the mixture was acidified by adding 6 M HCl under stirring, then add another 500 ml Et2O. the Organic layer was removed and the aqueous layer was extracted twice, using each time with 250 ml of a mixture of Et2O/EtOAc (3:1) from a volume of 500 ml the combined organic layers were washed with water, saturated brine and then dried over MgSO4. The solvent is evaporated under reduced pressure to obtain brownish oil, which was suirable through silica gel, using a mixture of Gex the us/EtOAc (9:1). After removal of the solvent under reduced pressure received 18,44 g (101,21 mmol, 75,26 %) of 4-(3-forfinal)butyric acid in the form of oil. MS: 183 (M+N)+.

Stage 3

6-Fluoro-3,4-dihydro-2H-naphthalene-1-he

The solution methanesulfonic acid (75 ml) and P2O5was stirred at 85°C for 15 minutes; this time a large part of the P2O5it was already dissolved. Was added dropwise 15 ml methanesulfonic acid and the mixture was stirred at 85°C for 2 hours. This reaction mixture was poured into 500 ml of water and was extracted twice with 400 ml of EtOAc. The combined organic layers were washed with saturated NaHCO3, water and saturated brine and then dried over MgSO4. The solvent was removed under reduced pressure to obtain oil, which was suirable through silica gel using a mixture of hexane/EtOAc (9:1). After removal of the solvent under reduced pressure was awarded the 6.06 g (36,91 mmol, 53,97%) of 6-fluoro-3,4-dihydro-2H-naphthalene-1-it is in the form of a yellow oil. MS: 165 (M+N)+.

Stage 4

6-Phenylsulfanyl-3,4-dihydro-2H-naphthalene-1-he

A solution of 6-fluoro-3,4-dihydro-2H-naphthalene-1-it (5,51 g, 33,56 mmol), bentolila (4,07 g, 3,79 ml, 36,92 mmol) and K2CO3(9.28 are g, 67,12 mmol) in 50 ml of N-methylpyrrolidinone (NMP) were heated to 80°C in an argon atmosphere and stirred at 80°is within 2 hours. This reaction mixture was poured into 500 ml of water and diluted with 300 ml EtOAc. The layers were separated and the aqueous layer was twice extracted with 250 ml of EtOAc. The combined organic layers were washed with water, saturated brine and then dried over MgSO4. The solvent was removed under reduced pressure to obtain oil, which was suirable through silica gel using a mixture of hexane/EtOAc (9:1). After removal of the solvent under reduced pressure was obtained with 8.05 g (31,65 mmol, 94,31%) 6-phenylsulfanyl-3,4-dihydro-2H-naphthalene-1-it is in the form of a pale yellow oil. MS: 255 (M+N)+.

Stage 5

6-Benzazolyl-3,4-dihydro-2H-naphthalene-1-he

A solution of 6-phenylsulfanyl-3,4-dihydro-2H-naphthalene-1-it (8,05 g, 31,65 mmol) in a mixture of Meon (methanol)/MeCN (acetonitrile) (50 ml each) was stirred at room temperature. OXONE™(monopersulfate potassium, 77,83 g, 126,60 mmol) was dissolved in 50 ml of water was added to the stirred reaction. This reaction mixture was stirred for 15 hours and then was evaporated under reduced pressure. The resulting aqueous residue was diluted with 500 ml of water and was extracted three times with 300 ml of EtOAc. The combined extracts were washed with water, saturated brine and dried over MgSO4. The solvent was removed under reduced pressure to obtain oil, which was suirable through silica gel with hexane, then with chloroform. After UDA is possible solvent under reduced pressure received 6,55 g (22,87 mmol, 72,27%) 6-benzazolyl-3,4-dihydro-2H-naphthalene-1-it is in the form of a white solid, which was recrystallize from a mixture of EtO2/hexane. MS: 287 (M+N)+.

Similarly, using the above technique with 3-chlorobenzamido in stage 4, was obtained 6-(3-chlorobenzenesulfonyl)-3,4-dihydro-2H-naphthalene-1-it. MS: 287 (M+N)+.

Preparatory example 2

7-Benzazolyl-3,4-dihydro-2H-naphthalene-1-he

The method of synthesis described in this preparation example, carried out in accordance with the process shown in Scheme C.

Stage 1

4-(4-Forfinal)-4-oxomalonate acid

Torbenson (50 ml, 530 mmol) and aluminum trichloride (156 g of 1.17 mol) was added to 500 ml of methylene chloride and the reaction mixture was stirred. To stir the reaction mixture was added succinic anhydride (50 g, 500 mmol), all at once, and this reaction mixture was stirred at room temperature for 2 hours. The reaction was stopped by gently adding 10% HCl, and the reaction mixture was added to 500 ml of water. This aqueous mixture was extracted twice with 250 ml of methylene chloride, the combined organic layers were dried (MgSO4) and evaporated under reduced pressure to obtain 62 g (316 mmol, 59,6%) of 4-(4-forfinal)-4-oxomalonate acid in the form of the crude solid in the society. MS: 197 (M+N)+.

Stage 2

4-Oxo-4-(4-phenylsulfanyl)butyric acid

4-(4-Forfinal)-4-oxomethane acid (10.0 g, 51 mmol), thiophenol (5,2 g, 51 mmol) and powdered potassium carbonate (13.8 g, 100 mmol) was added to 25 ml of dimethyl sulfoxide (DMSO). This reaction mixture was heated to 110°C for 2 hours, then cooled and diluted by adding 250 ml of water. This aqueous mixture was extracted three times with 100 ml EtOAc, the combined organic layers were dried (MgSO4) and evaporated under reduced pressure to obtain 11 g (a 38.5 mmol, 75,5%) 4-oxo-4-(4-phenylsulfanyl)butyric acid in the form of a crude solid. MS: 287 (M+N)+.

Stage 3

4-(4-Phenylsulfanyl)butyric acid

Powdered zinc (66 g) was washed with 2% HCL, was added to a solution of HgCl2(6 g) in 50 ml of 6 M HCl. This mixture was intensively shaken for 5 minutes and the excess liquid decantation. Then the mixture was added to a mechanically stirred suspension of 4-oxo-4-(4-phenylsulfanyl)butyric acid (6.5 g, 22.7 mmol) in 450 ml of 6 M HCl and this reaction mixture was stirred at room temperature for 5 days. The mixture is then decantation, removing excess HCl, and was suppressed by adding 250 ml of water. This aqueous mixture was extracted three times with 100 ml of EtOAc and the joint is haunted organic layers was dried under reduced pressure to obtain 5.0 g (18.4 mmol, 81%) of 4-(4-phenylsulfanyl)butyric acid in the form of a crude solid. MS: 273 (M+N)+.

Stage 4

7-Phenylsulfanyl-3,4-dihydro-2H-naphthalene-1-he

4-(4-Phenylsulfanyl-phenyl)-butyric acid (5.0 g, 18.4 mmol) was dissolved in 50 ml of tetrahydrofuran (THF). Added oxalicacid (1.8 ml, 20 mmol) and one drop of DMF, and this reaction mixture was stirred for 1 hour and then evaporated to dryness under reduced pressure. The obtained residue was dissolved in 40 ml of 1,2-dichloroethane was added aluminum trichloride (0,85 g, 25 mmol), all at once. This reaction mixture was stirred for 1 hour and was suppressed by addition of 2% HCl. This aqueous mixture was extracted twice with 100 ml EtOAc, the combined organic layers were dried (MgSO4) and was evaporated obtaining of 2.54 g (10 mmol, 55,5%) 7-phenylsulfanyl-3,4-dihydro-2H-naphthalene-1-it is in the form of a resinous residue. MS: 255 (M+N)+.

Stage 5

7-Benzazolyl-3,4-dihydro-2H-naphthalene-1-he

7-Phenylsulfanyl-3,4-dihydro-2H-naphthalene-1-it was dissolved in 50 ml Meon and stirred at room temperature. OXONE™ (13.5 g, 22 mmol) was dissolved in 10 ml of water was added to the stirred reaction. This reaction mixture was stirred for 8 hours and then was evaporated under reduced pressure. The resulting aqueous residue rasba the Lyali 200 ml water and three times was extracted with 100 ml EtOAc. The combined extracts were dried over MgSO4and the solvent was removed under reduced pressure to obtain oil, which was suirable through silica gel with a mixture of 1:1 EtOAc/hexane. After removal of the solvent under reduced pressure was obtained 1.7 g (5.9 mmol, 59%) 7-benzazolyl-3,4-dihydro-2H-naphthalene-1-it is in the form of oil. MS: 287 (M+N)+.

Similarly, using the above technique with 4-fermentation in stage 2, was obtained 7-(4-permentantly)-3,4-dihydro-2H-naphthalene-1-it. MS: 287 (M+N)+.

Preparatory example 3

5-Phenylsulfonyl-1-he

The method of synthesis described in this preparation example, carried out in accordance with the process shown in the Diagram,

Stage 1

5-Fenilalanina-1-he

5-fluoro-1-indanone from Sigma Aldrich Chemical Co. (Cat No. 18566-3) were treated with bentolila in the presence of potassium carbonate using the method of stage 4 of example 1 to obtain 5-fenilalanina-1-it. MS: 241 (M+N)+.

Stage 2

5-phenylsulfonyl-1-he

5-Fenilalanina-1-he was treated with OXONE™ using techniques of stage 5 of example 1 to obtain 5-phenylsulfonyl-1-it. MS: 273 (M+N)+.

Example 1

[2-(6-Benzazolyl-1,2,3,4-tetrahydronaphthalen-1 yloxy)ethyl]METI the Amin

The method of synthesis described in this example was performed in accordance with the process shown in Scheme D.

Stage 1

6-Benzazolyl-1,2,3,4-tetrahydronaphthalen-1-ol

6-Benzazolyl-3,4-dihydro-2H-naphthalene-1-he (1.31 g, 4.6 mmol) and borohydride sodium (0.35 g, 9.3 mmol) was added to 50 ml of methanol and this reaction mixture was stirred at room temperature for one hour. Then the reaction mixture was added water (200 ml) and received a precipitate in the form of white crystals, which were collected by filtration and dried in an atmosphere of N2to obtain 1.2 g (4,16 mmol, 90%) 6-benzazolyl-1,2,3,4-tetrahydronaphthalen-1-ol, MS: 289 (M+N)+.

Stage 2

Ethyl ester (6-benzoylphenyl-1,2,3,4-tetrahydronaphthalen-1 yloxy)acetic acid

6-Benzazolyl-1,2,3,4-tetrahydronaphthalen-1-ol (1.2 g, 4,16 mmol) was dissolved in 60 ml of dry DMF, and this reaction mixture was cooled in an ice bath. Was added sodium hydride (0.2 g of a 60% solids in oil, washed hexane), and the reaction mixture was stirred in nitrogen atmosphere for 20 minutes. Was added dropwise ethylbromoacetate (0,55 ml) and stirring continued for three hours, during which the reaction mixture gave the opportunity to warm up to room temperature the s. In the reaction mixture was added water (250 ml) and this aqueous mixture was extracted twice with 150 ml of EtOAc. The combined organic layers were washed with water, brine, dried over MgSO4and the solvent was removed under reduced pressure to obtain oil, which was suirable through silica gel with moderate pressure with a mixture of 4:1 EtOAc/hexane. After removal of the solvent under reduced pressure was obtained 0.75 g (2.0 mmol, 48%) ethyl ester (6-benzazolyl-1,2,3,4-tetrahydronaphthalen-1 yloxy)acetic acid in the form of oil. MS: 375 (M+N)+.

Stage 3

2-(Benzazolyl-1,2,3,4-tetrahydro-1-yloxy)-N-methylacetamide

Ethyl ester (6-benzazolyl-1,2,3,4-tetrahydronaphthalen-1 yloxy)acetic acid (0.75 g, 2.0 mmol) was dissolved in 25 ml of methanol was added aqueous NaOH (15 ml of 25% solution). This reaction mixture was heated to 50°C for ten minutes, then cooled, diluted with 20 ml water and acidified by adding 1 N. HCl. The resulting aqueous mixture three times was extracted with 100 ml EtOAc. The combined organic layers were washed with water, brine, dried over MgSO4and the solvent was removed under reduced pressure. The obtained residue was dissolved in 30 ml of dry tetrahydrofuran (THF), was added oxalicacid (0.8 ml) and dimethylformamide (one drop). This reaction mixture was stirred for chetyrehsot in nitrogen atmosphere at room temperature, then the solvent was removed under reduced pressure. The residue was dissolved in 25 ml of dioxane and the resulting solution was added dropwise to a solution of 2.0 g of methylaminopropane in 25 ml of 1 N. NaOH at 0°C. the precipitate was collected, dried in air and was suirable through silica gel with moderate pressure with a mixture of 4:1 EtOAc/hexane. After removal of the solvent under reduced pressure was obtained 0.6 g (1,67 mmol, 83,5%) (2-(6-benzazolyl-1,2,3,4-tetrahydronaphthalen-1 yloxy)-N-methylacetamide in the form of oil. MS: 360 (M+N)+.

Stage 4

[2-(6-Benzazolyl-1,2,3,4-tetrahydronaphthalen-1 yloxy)ethyl]methylamine

(2-(6-Benzazolyl-1,2,3,4-tetrahydronaphthalen-1 yloxy)-N-methylacetamide (0.7 g, 1.9 mmol) was dissolved in 25 ml dry THF. Added borohydride (10 ml of 1 n solution in THF) and this reaction mixture was subjected to reflux distilled for three hours in nitrogen atmosphere. The reaction mixture was cooled and was added 25 ml of 25% aqueous solution of HCl. This reaction mixture was subjected to reflux distilled for 10 minutes, cooled and the solvent was removed under reduced pressure. The aqueous residue was podslushivaet by adding dropwise 1 N. aqueous NaOH and the aqueous mixture three times was extracted with 50 ml EtOAc. The combined organic layers were washed with water, brine and dried over MgSO4. The residue was recrystallize from a mixture of Et2O/MeOH/HCl with what rucenim 380 mg (1.1 mmol, 58%)

[2-(6-benzazolyl-1,2,3,4-tetrahydronaphthalen-1 yloxy)-ethyl]methylaminopropane. MS: 346 (M+N)+.

Similarly, received

{2-[5-(2-permentantly)indan-1-yloxy]ethyl}methylamine, MS: 350 (M+N)+and

[2-(7-benzazolyl-1,2,3,4-tetrahydronaphthalen-1 yloxy)ethyl]methylamine, MS: 346 (M+N)+,

starting at stage 1 with 5-(2-perpenicular)indan-1-it 7-benzazolyl-3,4-dihydro-2H-naphthalene-1-it, respectively.

Example 2

N-(6-Benzazolyl-1,2,3,4-tetrahydronaphthalen-1-yl)-N'-mutilate-1,2-diamine

The method of synthesis described in this example was performed in accordance with the process shown in Scheme E.

Stage 1

2-(5-Benzosulfimide-1 yloxy)ndimethylacetamide

2-(5-Benzosulfimide-1 yloxy)ndimethylacetamide was obtained from ethyl ester (6-benzazolyl-1,2,3,4-tetrahydronaphthalen-1 yloxy)acetic acid using the technique of stage 3 of example 1, where methylaminopropane was replaced with ammonia. MS: 332 (M+N)+.

Stage 2

(5-Benzosulfimide-1 yloxy)acetonitrile

2-(5-Benzosulfimide-1 yloxy)ndimethylacetamide (1.1 g, 3.3 mmol) was dissolved in 10 ml of pyridine, given the reaction mixture was stirred and cooled in an ice bath. Was added dropwise triftormetilfullerenov anhydride (2 m is) and the reaction mixture gave the opportunity to warm to room temperature. The reaction was stopped by adding 100 ml of 10% aqueous HCl and the aqueous phase was twice extracted with 150 ml EtOAc. The combined organic layers were washed with water, brine and dried over MgSO4the residue was purified by chromatography under moderate pressure by elution through silica gel using a mixture of EtOAc/hexane (1:5) and result was obtained 0.5 g (1.6 mmol, 48.5 percent) (5-benzosulfimide-1 yloxy)acetonitrile. MS: 314 (M+N)+.

Stage 3

N-(6-Benzazolyl-1,2,3,4-tetrahydronaphthalen-1-yl)-N'-mutilate-1,2-diamine

(5-Benzosulfimide-1 yloxy)acetonitrile was restored to N-(6-benzazolyl-1,2,3,4-tetrahydronaphthalen-1-yl)-N'-mutilate-1,2-diamine using borohydride in THF as a result of executing the method of stage 4 of Example 1. MS: 318 (M+N)+.

Example 3

N-(6-Benzazolyl-1,2,3,4-tetrahydronaphthalen-1-yl)-N'-mutilate-1,2-diamine

The method of synthesis described in this example was performed in accordance with the process shown in Scheme J.

Stage 1

6-Benzazolyl-1-chloro-1,2,3,4-tetrahydronaphthalen

6-Benzazolyl-1,2,3,4-tetrahydronaphthalen-1-ol (0.65 g, of 2.26 mmol) was dissolved in 50 ml of toluene was added 1 ml of thionyl chloride. This reaction was subjected to reflux distilled for one hour and C is the cooled. The solvent was removed under reduced pressure to obtain 6-benzazolyl-1-chloro-1,2,3,4-tetrahydronaphthalene (0.6 g, 86,3%) in the form of crude oil. MS: 308 (M+N)+.

Stage 2

tert-Butyl ether [2-(6-benzazolyl-1,2,3,4-tetrahydronaphthalen-1 ylamino)ethyl]methyl-

carbamino acid

6-Benzazolyl-1-chloro-1,2,3,4-tetrahydronaphthalen (0.6 g, of 1.95 mmol), tert-butyl methyl ether (2-amino-ethyl)methylcarbamate acid (0,512 g 2,925 mmol), sodium iodide (0.1 g) and potassium carbonate (0.5 g) was added to 50 ml of acetonitrile and this reaction mixture was subjected to reflux distilled within 120 hours. The reaction mixture was cooled and diluted with 200 ml of water. This aqueous mixture was extracted twice with 200 ml EtOAc, the combined organic layers were washed with water, brine and dried over MgSO4. The solvent was removed under reduced pressure and the resulting oil was suirable through silica gel (using chromatography moderate pressure) using for elution of a mixture of EtOAc/hexane 20%/80%. After removal of the solvent under reduced pressure was obtained 0.4 g (0.9 mmol, 46%) of tert-butyl methyl ether [2-(6-benzazolyl-1,2,3,4-tetrahydronaphthalen-1 ylamino)ethyl]methylcarbamate acid in the form of oil. MS: 446 (M+N)+.

Stage 3

N-(6-Benzazolyl-1,2,3,4-tetrahydronaphthalen-1-yl)-N'-mutilate-1,2-diamine

tert-Butyl ether [2-(6-benzazolyl-1,2,3,4-tetrahydronaphthalen-1 ylamino)ethyl]methylcarbamate acid (0.4 g, 0.9 mmol) was dissolved in 20 ml of tetrahydrofuran was added 20 ml of 10% HCl in Et2O. This reaction mixture was subjected to reflux distilled for one hour and then cooled. The solvent is evaporated under reduced pressure and the obtained solid substance perekristalizovanny from a mixture of EtOH-Et2O to obtain 0.3 g (0.87 mmol, 97%) of N-(6-benzazolyl-1,2,3,4-tetrahydronaphthalen-1-yl)-N'-mutilate-1,2-diamine in the form of cleaners containing hydrochloride salt. MS: 345 (M+N)+.

Additional compounds obtained using the method of example 3, are shown in Table 1.

Example 4

Drugs

Pharmaceutical preparations for delivery in different ways is prepared in the form of the drug thus, as shown in the following tables. "Active ingredient" or "active compound" in the context of these tables means one or more compounds of formula I.

Composition for oral administration

Ingredient% mass/mass
The active ingredient20,0%
Lactose79,5%
Magnesium stearate 0,5%

The ingredients are mixed and distributed in capsules, each containing approximately 100 mg; one capsule approximately corresponds to the full daily dose.

Composition for oral administration

Ingredient% mass/mass
The active ingredient20,0%
Magnesium stearate0,5%
Nitrocresols2,0%
Lactose76,5%
PVP (polyvinylpyrrolidine)1,0%

The ingredients are combined and granularit solvent, such as methanol. Then the product is dried and formed into tablets (containing approximately 20 mg of active compound) using a suitable tablet machine.

Composition for oral administration

IngredientNumber
Active connection1.0 g
Fumaric acid 0.5 g
Sodium chloride2.0 g
Methylparaben0.15 g
Propylparaben0.05 g
Crystal sugar25,5 g
Sorbitol (70% solution)is 12.85 g
Veegum K (Vanderbilt Co.)1.0 g
Corrigenta 0.035 ml
Dyes0.5 mg
Distilled waterhow much you want to 100 ml

The ingredients are mixed to obtain a suspension for oral administration.

Parenteral drug

Ingredient% mass/mass
The active ingredient0.25 g
Sodium chloridehow many is required to obtain isotonic
Water for injections100 ml

The active ingredient p is straut in a portion of water for injection. Then added with stirring sodium chloride in a quantity sufficient to obtain isotonic. The solution is injected balance water for injection, filtered through the 0.2 micron membrane filter and packaged under sterile conditions.

The preparation of suppositories

Ingredient% mass/mass
The active ingredient1,0%
Polyethylene glycol 100074,5%
Polyethylene glycol 400024,5%

The ingredients are melted, mix in the steam bath and poured into forms containing a total mass of 2.5,

Product for local introduction

0,15
Ingredientgrams
Active connection0,2-2
Span 602
Tween 602
Vaseline oil5
Vaseline10
Methylparaben
Propylparaben0,05
BHA (bottled hydroxyanisol)0,01
Waterhow much you want to 100 g

All ingredients, except water, are combined and heated with stirring to about 60°C. Then, under vigorous stirring to obtain an emulsion of the ingredients, add enough water, heated to approximately 60°C, and then add as much water as required to obtain a total mass of about 100 g

Nasal preparations in the form of spray.

Some aqueous slurry containing from about 0.025 to 0.5 percent of the active compounds are prepared in the form of nasal preparations in the form of a spray. These drugs may contain inactive ingredients, such as microcrystalline cellulose, sodium carboxymethyl cellulose, dextrose, and the like. To summarize the pH can be added hydrochloric acid. Nasal preparations in the form of spray can be delivered through a metering dispenser for nasal spray, usually delivering approximately 50-100 microliters drug injection. Normal doses of represents 2-4 each injection is 4-12 hours.

Example 5

Research associate radio

This example illustrates a study of the compounds of formula I by in vitro binding of the radio.

In vitro binding activity of compounds of this invention was determined as follows. Double the measurement of the affinity of 5-HT6the ligand was performed by competitive binding of [3H]LSD on cell membranes obtained from cells NECK, stably expressing recombinant 5-HT6-the receptor is human. Double the measurement of the affinity of 5-HT2Athe ligand was performed by competitive binding of [3H]ketanserina (3-(2-(4-(4-perbenzoic)piperidino)ethyl)-2,4(1H,3H)-chineselanguage) on cell membranes obtained from cells Cho-K1, stably expressing recombinant 5-HT2A-the receptor is human. Membranes from cell lines NEC were prepared using methods described by Monsma et al., Molecular Pharmacology, Vol.43 pp.320-327 (1993), and from cell lines Cho-K1 thus, as described Bonhaus et al., Br J Pharmacol. Jun; 115(4): 622-8 (1995). When determining the affinity for 5-HT6-receptor all measurements were performed in buffer for analysis containing 50 mm Tris-HCl, 10 mm MgSO4, 0.5 mm EDTA, 1 mm ascorbic acid, pH 7.4, at 37°C in a reaction volume of 250 microliters. When determining the affinity for 5-HT2A-receptor all measurements were performed in buffer for analysis, terasem 50 mm Tris-HCI, 5 mm ascorbic acid, 4 mm CaCl2, pH 7.4 at 32°C in a reaction volume of 250 microliters. Analytical tubes containing [3H]LSD and [3H]ketanserin (5 nm), the competing ligand and the membrane incubated in water thermostatic shaker for 75 minutes at 37°C (5-HT6or for 60 minutes at 32°C (5-HT2A), filtered Packard GF-B plates (pre-soaked with 0.3% PEI (polyethylenimine)) using 96-well harvester cells Packard and washed 3 times with cooled to 0°C. 50 mm Tris-HCl. Binding of [3H]LSD and [3H]ketanserina determined by the number of radioactive disintegrations per minute using a Packard TopCount.

The displacement of [3H]LSD and [3H]ketanserina of binding sites were quantitatively determined by approximation of the data according to the concentration of binding to a 4-parameter logistic equation

where Hill is the hill coefficient, [ligand] is the concentration of competing radioligand and IC50represents the concentration of radioligand, providing half of the maximum specific binding of radioligand. Window specific binding is the difference between the parameters Bmax and "basal".

Using the methods of this example tested the connection is of formula I, and it was found that they are selective 5-HT6-antagonists, selective 5-HT2Aantagonists or selective antagonists of both receptors. For example, the compound 2-(6-benzazolyl-1,2,3,4-tetrahydronaphthalen-1 yloxy)ethyl]methylamine showed pKi for a total of 8.74 5-HT6-receptor and pKi 7,21 5-HT2A-receptor.

Example 6

Enhancing cognitive abilities

The properties of the compounds according to the invention to enhance cognitive abilities can be studied on a model of learning in animals: on the model of the problem of object recognition". Used male Wistar rats (Charles River, The Netherlands) at the age of 4 months. Compounds were prepared daily, dissolved in saline solution and tested in three doses. Introduction always gave in b/W (intraperitoneally) (volume injection of 1 ml/kg) 60 minutes prior to T1. Of scopolamine hydrobromide were injected with 30 minutes after injection of the compounds. Two experiments investigated two equal test groups that were formed out of 24 rats. The order of test doses were determined randomly. These experiments were performed using Protocol a double-blind study. All rats were treated once each of the doses. The test object recognition performed thus, as described Ennaceur, A., Delacour, J., 1988, A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data. Behav. Bran Res. 31, 47-59.

1. The compound of formula I:
;
or its pharmaceutically acceptable salt,
where m has a value of 0;
p has a value from 1 to 2;
q has a value of 2;
Ar represents phenyl, possibly substituted with halogen;
;
R2represents a
X represents-O - or-NR7-;
n has a value of 2 or 3;
each of R3and R4independently represents hydrogen, or R3and R4
together may form-C(O)-;
each of R5and R6independently represents hydrogen or C1-12-alkyl,
or one of R5and R6and one of R3and R4together with the atoms to which they are
attached, may form a six-membered ring; and
R7represents hydrogen or C1-12alkyl.

2. The compound according to claim 1, where n has a value of 2.

3. The compound according to claim 2, where X represents-0-.

4. The compound according to claim 3, where R3and R4represent hydrogen.

5. The compound according to claim 4, where R5and R6represent hydrogen.

6. The compound according to claim 4, where one of R5and R6represents hydrogen and the other represents C1-12alkyl.

7. The compound according to claim 2, where X represents a-NR7-.

8. The connection according to claim 7, where R3and R4represent water is od.

9. The connection of claim 8, where one of R5and R6represents hydrogen and the other represents C1-12alkyl.

10. The compound according to claim 1, where n has a value of 3.

11. The connection of claim 10, where X represents-O-.

12. The connection of claim 10, where X represents a-NR7-.

13. The connection section 12, where one of R5and R6and one of R3and R4together with the atoms to which they are attached, form a six-membered ring.

14. The compound according to claim 1, where R2is:
;; or,
where R5, R6and R7are as set forth in claim 1.

15. The compound according to claim 1, where the specified compound is a compound of formula II:
;
and where Ar denotes phenyl, a m, R1and R2are as set forth in claim 1.

16. The compound according to claim 1, where the specified compound is a compound of formula IIIa or IIIb:
;;
where
s has a value from 0 to 1;
each R8independently represents halogen; and
n, R5and R6are as set forth in claim 1.

17. Connection P16, where n has a value of 2.

18. The connection 17, where the join is a join of four who uly IIIa.

19. Connection p, where R5represents hydrogen and R6represents methyl.

20. The compound according to claim 1, where the specified connection is selected:
N-(2-amino-ethyl)-2-(5-benzazolyl-indan-1-yloxy)-ndimethylacetamide;
2-(5-benzazolyl-indan-1-yloxy)-ethylamine;
{2-[5-(2-fluoro-benzazolyl)-indan-1-yloxy]-ethyl}-methyl-amine;
(5-benzol sulfonyl-indan-1-yl)-piperidine-4-yl-amine;
[2-(6-benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-yloxy)-ethyl]-methyl-amine;
[2-(7-benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-yloxy)-ethyl]-methyl-amine;
(6-benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-yl)-piperidine-4-yl-amine;
N-(6-benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-yl)-N'-methyl-ethane-1,2-diamine;
N'-(6-benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-yl)-N,N-dimethyl-ethane-1,2-diamine; and
N-(6-benzazolyl-1,2,3,4-tetrahydro-naphthalene-1-yl)-N,N'-dimethyl-ethane-1,2-diamine.

21. Pharmaceutical composition with selective affinity to 5-HT receptors containing the compound of the formula I according to any one of claims 1 to 20 in a mixture with a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide salts of formula I , containing an anion selected from a group consisting of phosphate, sulphate, succinate, malate, citrate, fumarate, maleate and edisilate. The invention also relates to a method for synthesis of salts in paragraph 1, to a pharmaceutical composition, a method of inhibiting monoamine receptor activity, as well as to use of at least one salt in paragraph 1.

EFFECT: obtaining novel biologically active compounds which are active as inhibitors or inverse agonists of the monoamine receptor.

50 cl, 9 ex, 9 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and their acid-additive and basic salts as FAAH enzyme inhibitors, method of producing said compounds, a pharmaceutical composition based on said compounds and their use, as well as to intermediate compounds of formula (IIa). In general formula (I) , m is an integer ranging from 1 to 4; n is equal to 1 or 2; o is equal to 1 or 2; A is selected from one or several groups X, Y; X denotes a methylene group optionally substituted with one group which is C1-6-alkyl; Y denotes a C2-alkynylene group; B denotes a covalent bond or C1-6-alkylene group; G denotes a covalent bond, an oxygen atom; R1 denotes an R4 group optionally substituted with one or more R5 and/or R6 groups; R4 denotes a group selected from oxazolyl, isoxazolyl, thiazolyl, phenyl, pyridinyl, naphthyl, quinolinyl, isoquinolinyl; R5 denotes a halogen atom, a cyano group, C1-6-alkyl, C1-6-alkoxy, C1-6-fluoroalkyl, C1-6-fluroalkoxy, NR7R8; R6 denotes a phenyl group, phenyloxy or pyrimidinyloxy; where R6 group(s) can be substituted with one or two R5 groups which are identical or different from each other; R7 and R8 independently denote a C1-6-alkyl group; R2 denotes a hydrogen atom; R3 denotes a hydrogen atom or C1-C6-alkyl group. In general formula (IIa) , m is an integer ranging from 1 to 2; n equals 2, o equals 2; A denotes X, X denotes a methylene group; B denotes a C1-6-alkylene group; G denotes a covalent bond; R1 denotes an R4 group optionally substituted with one or more R5 and/or R6 groups; R4 denotes phenyl; R5 denotes a halogen atom, C1-6alkoxy; R6 denotes a phenyl group; R2 denotes a hydrogen atom.

EFFECT: compounds can be used for treating and preventing diseases mediated by FAAH enzyme activity, such as acute and chronic pain, dizziness, vomiting, nausea, disrupted eating behaviour, neurologic and psychiatric pathologies, acute and chronic neurodegenerative diseases etc.

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound N-(1-{(3R)-3-(3,5-difluorophenyl)-3-[1-(methylsulfonyl) piperidin-4-yl]propyl}piperidin-4-yl)-N-ethyl-2-[4- (methylsufonyl)phenyl]acetamide or its pharmaceutically acceptable salts. The invention also relates to a method for synthesis of the compound in paragraph 1, as well as to a pharmaceutical composition.

EFFECT: obtaining a novel biologically active compound with activity towards CCR5 (chemokine receptor 5).

6 cl, 6 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention is related to new compounds of formula (I): , in which: Ra and Ra', identical or different, mean atom of hydrogen or alkyl, R1 means atom of hydrogen or alkyl, cycloalkyl, heterocycloalkyl or aryl, R2 means group of formula -(CH2)x-(CO)y-Y or -(CO)y-(CH2)x-Y, in which, x = 0, 1, 2, 3 or 4, y = 0 or 1, Y means atom of hydrogen or the following group: hydroxyl, alkyl, cycloalkyl, alkyloxyl, aryl, heteroaryl or -NR11R12, besides, Y is not an atom of hydrogen, when x=y=0, R11 and R12, identical or different, mean atom of hydrogen or the following group: alkyl, cycloalkyl, alkyloxyl or -NR13R14, or R11 and R12 together with atom of nitrogen, to which they are connected, create mono- or bicyclic structure, which contains 4-10 links and unnecessarily contain additionally 1-3 heteroatoms and/or 1-3 ethylene unsaturated links, besides this cycle is not necessarily substituted in any of positions with 1-3 groups, selected from atoms of halogen and hydroxyl, alkyl, cycloalkyl and alkyloxygroups; R13 and R14, identical or different, mean atom of hydrogen or alkyl, R3 means 1-3 groups, identical or different, available in any position of cyclic structure, to which they are connected, and selected from atoms of halogen; R5 means atom of hydrogen, R4 is selected from groups of formulae (a), (b), (c), which are not necessarily substituted with aryl group, described below: (a), (b), (c), in which p=0,1,2 or 3; m=0,1 or 2, and either a) X means link -N(R10)-, in which R10 is selected from: -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, - or R10 with atom of nitrogen, with which it is connected, and with atom of carbon, available in any position of cyclic structure of formula (a), but not with neighboring to mentioned atom of nitrogen, creates bridge, containing 3-5 links, or, b) X means link -C(R6)(R7)-, where R6 is selected from the following: atom of hydrogen, atom of halogen, group -(CH2)x-OR8, -(CH2)x-NR8R9, -(CH2)x-CO-NR8R9 or -(CH2)x-NR8-COR9, in which x=0,1,2,3 or 4, alkyl, cycloalkyl, heterocycloalkyl, aryl, heterocycloalkyl, condensed with aryl, besides, alkyl, cycloalkyl or aryl groups are not necessarily substituted with 1 or several groups, selected from groups: R, R', -OR, -NRR', -COR; R7 is selected from atoms of hydrogen and halogen and the following groups: alkyls, -OR, -NRR', -NR-CO-R', -NR-COOR', -R8 and R9 are selected, independently from each other, from atom of hydrogen and the following groups: alkyls, cycloalkyls, aryls, -CO-alkyls, besides, alkyls and aryls are unnecessarily substituted with one or several groups, selected from groups: R, R', -OR, or R8 and R9 together create heterocycloalkyl,- R and R' mean, independently from each other, atom of hydrogen or alkyl, cycloalkyl, besides, mentioned hetero aryl groups represent aromatic groups, including from 5 to 10 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen and/or sulfur; besides mentioned heterocycloalkyl groups represent cycloalkyl groups, including from 5 to 6 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen or sulfur; in the form of base or acid-additive salt, and also in the form of hydrate or solvate. Invention is also related to medicinal agent, to pharmaceutical composition, to application, to method of production, and also to compounds of formulas (VI), (XVIII), (XIX).

EFFECT: new biologically active compounds have activity of agonists of melanocortin receptors.

27 cl, 16 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention refers to the new compounds of formula (I): whereat R1 is -SO2NR102R103, -NR101SO2R104 or -COOR105 whereat R101 is hydrogen atom, R102 and R103 each independently represents hydrogen atom or C1-4 alkyl, R104 is C1-4 alkyl and R105 is hydrogen atom or C1-4 alkyl ; X is bond, -CH2- or -O-; Y is -CH2-; ring A and ring B, which are same or different, each independently is benzene, pyridine, pyrazol or piperidine which can have the following substituents: C1-4 alkyl or halogen; ring D is piperidine; R2 is whereat the arrow shows the position of the bond with the ring D; R51 is (1) hydrogen atom a, (2) C1-6alkyl, which can have the following substituents: (a) hydroxy, (b) methoxy, (c) cyano, (d) carboxy, (e) halogen, (f) methyl sulphonylamino, (g) C3-8cycloalkyl or phenyl, which can have the following substituents: methyl, halogen, hydroxy or methoxy, (h) thienyl, pyrazolyl, tetrahydropyranyl, thiazolyl, isooxalyl, imidazolyl, tetraazolyl, pyridyl, pyrimidinyl which can have the following substituents: methyl, trifluoromethyl or hydroxy, (3) C2-10alkenyl, (4) C2-10alkynyl, (5) phenyl which can have the following substituents: C1-4alkyl or halogen, or (6) pyridine or tetrahydropyran; R52 is (1) hydrogen atom a, (2) C1-6alkyl which can have the following substituents: (a) hydroxy, (b) methoxy, (c) carboxy, (d) C3-8cycloalkyl, (e) phenyl or (f) oxo, (3) C3-8cycloalkyl or phenyl which can have the following substituents: C1-4alkyl, hydroxy, cyano, oxo, carbamoyl, N-methyl aminocarbonyl, carboxy, halogen, methoxy, trifluoromethoxy, methythio, methylsulphonyl, acetylamino, dimethylamino, acetyl, tetraazolyl, trifluoromethyl or methylsulphonylamino (4) C3-10cycloalkenyl, (5) adamantyl, (6) thienyl, pyrazolyl, tetrahydropyranyl, isoxaazolyl, isothiazolyl, thiadiazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, quinolyl, indolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, dioxaindanyl, benzodioxaindanyl which can have the following substituents: C1-4alkyl, hydroxy, oxo, halogen, azido or trifluoromethyl or (7) benzyloxy groups; and R53 is hydrogen atom or C1-6alkyl; to its salts or its solvates. The invention refers also to the regulator CCR5, to the agent of prevention and/or treatment of HIV infection, immunological or inflammatory diseases, to the pharmaceutical composition, to the medicinal preparation, to the method of disease treatment or prevention as well as to the application of compound as in claim 1.

EFFECT: obtaining of new bioactive compounds possessing anti CCR5 receptor activity.

23 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the general formula: , where R1 is an inferior alkyl, -(CH2)n-aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluormethyl, or pyridine; R2 is an inferior alkyl, -(CH2)n- aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluoromethyl, nitro-, cyano-, -NR'R", hydroxy-, or heteroaryl group that is a monovalent heterocyclic 5- or 6-membered aromatic radical with N atoms, either R2 is a heteroaryl that is monovalent heterocyclic 5- or 6-membered aromatic radical where heteroatoms are chosen from N, O or S group, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl or halogen; R3 is pyridine or aryl, unsubstituted or substituted by a halogen or inferior alkyl; R4 is hydrogen or hydroxy-. A is -S(O)2- or -C(O)-; X, Y are -CH2- or -O- independently from each other, though both X and Y should not be -O- at the same time; R'R" are hydrogen or inferior alkyl independently from each other; n is 0, 1 or 2. Also the invention concerns pharmaceutically acceptable additive salts and acids of the compounds, and a medicine based on it.

EFFECT: new biologically active compounds show inhibition effect in glycine absorption.

21 cl, 214 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula I: , where: a is 0 or whole number of 1 to 3; each R1 is selected independently out of the halogens; b is 0 or whole number of 1 to 3; each R2 is selected independently out of the halogens; W is linked in 3 or 4 position against the nitrogen atom in piperidine ring and is O; c is 0 or whole number of 1 to 4; each R3 is selected independently out of (1-4C)alkyls; or two groups of R3 are linked together forming (1-3C)alkylene or oxyrane-2,3-diyl; R4 is a bivalent group of the formula: -(R4a)d-(A1)e-(R4b)t-Q-(R4c)g-(A2)h-(R4d)i-, where each of d, e, f, g, h and i is selected independently out of 0 or 1; each of R4a, R4b, R4c and R4d is selected independently out of (1-10C)alkylene, where each alkylene group is unsubstituted or substituted by 1-5 substitutes selected independently out of (1-4C)alkyl, fluorine and hydroxy-; each of A1 and A2 is selected independently out of (3-7C)cycloalkylene, (6-10C)arylene, -O-(6-10C)arylene, (6-10C)arylene-O-, (2-9C)heteroarylene and (3-6C)heterocyclene where each cycloalkylene is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogens, (1-4C)alkyl, (1-4C)alkoxy-, -S(O)2-(1-4C)alkyl, hydroxy-, nitro- and trifluormethoxy; Q is selected out of -O-, -S(O)2-, -N(Qa)C(O)-, -C(O)N(Qb)-; -N(QC)S(O)2-, -S(O)2N(Qd)-, -N(Qe)C(O)N(Qf)- and -N(Qk) links; each of Qa, Qb, Qc, Qd, Qe, Qf and Qk is selected independently out of hydrogen, (1-6C)alkyl and A3, where alkyl group is unsubstituted or substituted by 1-3 substitutes selected independently out of fluorine, hydroxy- and (1-4C)alkoxy-; or together with nitrogen atom and R4b or R4c group to which they are linked they form 4-6-membered azacycloalkylene group; A3 is selected independently out of (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroalkyl and (3-6C)heterocyclyl, where each cycloalkyl is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogen, (1-4C)alkyl and (1-4C)alkoxy-, if the number of adjacent atoms in the shortest chain between two nitrogen atoms, to which R4 is linked, lies within 4 to 16; R5 is hydrogen or (1-4C)alkyl; R6 is -NR6aCR6b(O), and R7 is hydrogen; either R6 and R7 together form -NR7aC(O)-CR7b=CR7c-; each of R6a and R6b is hydrogen or (1-4C)alkyl independently; and each of R7a, R7b and R7c is hydrogen or (1-4C)alkyl independently; or the pharmaceutically acceptable salts, solvates or stereoisomers of the claimed compounds. The invention also concerns compounds of the formula I, 1-[2-(2-chlor-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-5-methoxuphenylcarbamoyl)ethyl] piperidine-4-yl ether of biphenyl-2-ylcarbamine acid or its pharmaceutically acceptable salt or solvate, pharmaceutical composition, method of pulmonary disease treatment, method of bronchial lumen dilation for a patient, method of treatment of chronic obstructive pulmonary disease or asthma, method of obtaining the compound of the formula I, medicine based on it, and application of compounds described in any of the paragraphs 1, 13, 14, 24, 25, 26, 27 or 28.

EFFECT: obtaining of new biologically active compounds with high activity rate of both antagonist of muscarine receptors and β2 agonist of adrenergic receptors.

42 cl, 186 ex

FIELD: chemistry.

SUBSTANCE: description is given of amides of piperazinyl- or piperidinylaminesulphoamic acid with genera formula (I) , in which R1 and R2 together with a nitrogen atom, to which they are bonded, represent a 6-member aliphatic heterocyclyl, containing two atoms of nitrogen as heteroatoms. The indicated extra atom of nitrogen is substituted with radical R, where R represents COOR', and R' represents (C1-C6)alkyl or benzyl, or phenyl, substituted with trifluoromethyl and aminocarbonyl, or R1 represents hydrogen, and R2 represents a group with formula , in which R9 represents (C1-C8)alkoxycarbonyl or phenyl, substituted with haloid(C1-C6)alkyl or aminocarbonyl; R3 represents phenyl or phenyl(C1-C4)alkyl, containing two substitutes, chosen from halogen and haloid(C1-C6)alkyl. Description is given of the use of formula (I) compounds as inhibitors of steroid sulphatase.

EFFECT: compound has inhibition effect to steroid sulphatase.

7 cl, 2 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds, namely, to N-substituted derivatives of piperidine of the formula (I): or their pharmaceutically acceptable salts, amides, esters wherein values R1, R, R3, m, X, n, W, Ar1 and Ar2 are disclosed in the invention claim. Also, invention relates to methods for inhibition of activity and methods for inhibition of activation of monoamine receptors. Methods involve contacting monoamine receptors or system comprising monoamine receptors with the effective amount of one or some compounds of the formula (I). Except for, invention relates to using compounds of the formula (I) in treatment of psychotic diseases.

EFFECT: valuable medicinal properties of compounds.

35 cl, 1 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes derivatives of aminotetraline of the formula (I) wherein R1 means (C1-C6)-alkyl; R2 means halogen atom or -OR'; R3 means hydrogen atom (H) or -OR' wherein R' means (C1-C6)-alkyl or -SO2R'' wherein R'' means phenyl, thienyl, isoxazolyl; R4 means (C1-C6)-alkyl, phenyl, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, diazepinyl, furanyl, isoxazolyl, imidazolyl and pyrazolyl that can be substituted optionally, and pharmaceutical compositions containing derivatives of aminotetraline. Proposed compounds are selective antagonists of M2/M3 muscarinic receptors and designated for treatment and prophylaxis of diseases associated with smooth muscle disorder.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 1 tbl, 16 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel α-(N-sulfonamido)acetamides of the formula (I) or their optical isomers wherein values R1, R, R2 and R3 are given in the invention claim. Proposed compounds are inhibitors of production of β-amyloid peptide and can be used for inhibition of production of β-amyloid peptide. Also, invention relates to pharmaceutical composition based on these compounds and to a method for inhibition of production of β-amyloid peptide.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 23 sch, 4 tbl, 501 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to 4,4'-sulfonyl-bis-(N,N'-dimethylammoniomethyleneaniline)-chloride, 6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-sulfonate of the formula (I) eliciting antibacterial, antimycobacterial and immunotropic activities. Also, invention describes a pharmaceutical composition based on compound of the formula (I).

EFFECT: valuable medicinal properties of compounds and composition.

3 cl, 7 tbl, 2 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing acid-additive salts of compounds of the formula (I):

wherein R1, R2 and R3 represent alkyl comprising from 1 to 12 carbon atoms. Substances of the formula (I) are inhibitors of cellular Na+/H+ antiporter and therefore can be used in treatment of arrhythmia arising from oxygen insufficiency. Method involves the following stages: alkyl-derivatives of 4-chloro-5-methanesulfonylbenzoic acid are converted to ester that is subjected for reaction with alkyl sulfinate, and prepared substance is treated with guanidine followed by preparing acid-additive salts of compound of the formula (I). Method provides the best yield of the end product and simplified the technology.

EFFECT: improved preparing method.

10 cl, 3 ex

The invention relates to thiosulfonate compounds of General formula Ia, which can be used as inhibitors of the matrix metalloprotease-13 (MMP-13)

The invention relates to a method of asymmetric obtain florfenicol formula I, which consists of the following stages: 1) stage rehospitalised opening of chiral epoxide of formula II by sequential processing of a strong base, Lewis acid and dichloroacetonitrile getting oxazoline formula (III); (II) stage selective inversion/isomerization received oxazoline formula (III) by sequential processing of the tertiary amine and the lower alkylsulfonamides, water, acid and alkali metal hydroxide getting oxazoline formula (IV); (III) stage of processing oxazoline formula IV agent fluorination and subsequent acid hydrolysis

Multicore bisazide // 2067572
The invention relates to new compounds of General formula I

< / BR>
Z=-SO2-, -X--Y--X-

X=O,S

Y=0, S, SO2; CO.,

which can be used as light-sensitive components of photoresists

The invention relates to new derivatives of benzonitrile formula I

where n = 1-2

Y is a group -(CH2)m- where: m = 0-1, or SNAN,

Z is hydrogen or a saturated unbranched alkyl with 1-3 carbon atoms;

And group

-- (CH2)q-Rcor -(CH2)q-Rc< / BR>
where Ra, Ra' and Ra" are each independently from each other the unbranched oxyalkyl or alkyl with 1-5 carbon atoms

Rc - saturated unbranched alkyl with 1-4 carbon atoms which may be substituted by fluorine atoms;

P = 1-2

q = 2-5 of the racemate, or pharmaceutically acceptable salts, which possess antiarrhythmic activity, and compositions comprising the compounds I for the treatment of cardiac arrhythmia

FIELD: chemistry.

SUBSTANCE: invention relates to improved method of preparing solid particles used as phenolic antioxidants and including in, in fact, crystal form compound of formula: in which one of R1 and R2 independently on each other represent hydrogen atom or C1-C4alkyl, and the other one represents C3-C4alkyl; x represents zero (direct bond) or number from one to three; and Y represents C8-C22alkoxy or groups of incomplete formulas

or in which one of R1' and R2' independently on each other represent hydrogen atom or C1-C4alkyl, and the other one represents C3-C4alkyl; x represents zero (direct bond) or number from one to three; y represents number from two to ten; and z represents number from two to six, in which homogeneous water dispersion is prepared, which includes compound (I) or mixture of such compounds, where R1, R2, R1' R2', Y, x, y and z have values given above, by addition of incomplete ether of fatty acid polyoxyethylene sorbitan and inoculating crystals, and obtained crystals are separated from dispersion and process is carried out until solid particles are obtained. Invention also relates to novel crystal forms pentaerythrite tetrakis-[3-(3,5-ditret-butyl-4-hydroxyphenyl)propionate], (µ-form) of pentaerythrite tetrakis 3-(3,5-ditret-butyl-4-hydroxyphenyl)propionate], crystal form of N,N'-hexane-1,6-diyl-bis-[3-(3,5-ditret-butyl-4-hydroxyphenyl propionamide)], crystal form of N,N'-hexane-1,6-diyl-bis-[3-(3,5-ditret-butyl-4-hydroxyphenyl propionamide)] and crystal modification (β-form) of N,N'-hexane-4,6-diylbis-[3-(3,5-ditret-butyl-4- hydroxyphenyl propionamide)].

EFFECT: elaboration of improved method of preparing solid particles used as phenolic antioxidants.

10 cl, 2 ex

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