New benzimidazole derivatives and their use as medicinal agents

FIELD: chemistry.

SUBSTANCE: invention relates to new benzimidazole derivatives with general formula (I), where A represents -CH2-, -C(O), -C(O)-C(Ra)(Rb)-, X represents a -CH- radical; Ra and Rb independently represent a hydrogen atom or (C1-C6)alkyl radical; R1 represents a hydrogen atom or (C1-C8)alkyl radical; R2 represents a (C1-C8)alkyl radical; R3 represents -(CH2)P-Z3, -C(O)-Z'3 or -C(O)-NH-Z"3; Z3 represents (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkyl-N(RN)carbonyl, (C3-C7)cycloalkyl, aryl, arylthio or heteroaryl radical, Z3 is bonded to the -(CH2)P- through a carbon atom, heteroaryl radical, which is a 5-10- member heteroaryl, which contains 1-2 identical or different heteroatoms, chosen from sulphur, nitrogen or oxygen, and optionally substituted with one or more identical or different substitutes, chosen from halogen, nitro group or -(CH2)P'-V30-Y3; aryl radical, chosen from phenyl or naphthyl, optionally substituted with one or more identical or different substitutes, chosen from halogen, nitro group, cyano group, (C2-C6)alkenyl, pyrrolidinyl, phenyl, phenyloxy, phenylalkyloxy, 5-7- member heteroaryl, containing 1-3 nitrogen atoms and -(CH2)p'-V31-Y3; V30 represents -O-, -C(O)-, -C(O)-O- or a covalent bond; V31 represents -O-, -S-, -SO2-, -C(O)-, -C(O)-O-, -N(RN)-, -NH-C(O)- or a covalent bond; Y3 represents a hydrogen atom or (C1-C6)alkyl radical, optionally substituted with one or more identical or different halogen radicals; RN represents a hydrogen atom or (C1-C6)alkyl radical; Z3 represents a radical with a given formula (see below); Z'3 represents a phenyl radical, optionally substituted with one ore more identical or different substitutes, chosen from -(CH2)P"-V'3-Y'3; V'3 represents -O-; Y'3 represents a hydrogen atom or (C1-C6)alkyl radical; Z"3 represents a hydrogen atom or -(CH2)q-A"3 radical; A"3 represents (C1-C6)alkyl, phenyl or thienyl radical; alkyl or phenyl radical can be optionally substituted with one or more identical or different substitutes, chosen from halogen and -V"3-Y"3; V"3 represents -O-, -C(O)-, -C(O)-O- or a covalent bond; Y"3 represents a hydrogen atom or (C1-C6)alkyl radical; p is an integer from 0 to 6; p' and p" independently represent an integer from 0 to 1; q is an integer from 0 to 2; R4 represents a radical with formula -(CH2)S-R'4; R'4 represents a 5-7- member heterocycloalkyl, containing at least one nitrogen atom and optionally substituted with (C1-C6)alkyl; or a radical with formula -NW4W'4; W4 represents a hydrogen atom; W'4 represents a hydrogen atom; s is an integer from 0 to 6; in racemic or enantiomeric form or any combination of the said forms, or its pharmaceutically acceptable salt. The invention also relates to a method of obtaining a compound in paragraph 1, a pharmaceutical composition based on the said compound and its use in making a medicinal agent.

EFFECT: new benzimidazole derivatives have good affinity to certain subtypes of melanocortin receptors.

26 cl, 8 ex

 

The present invention relates to new derivatives of benzimidazole and imidazopyridine. These products have a good affinity for certain sub-types of receptors melanocortin, in particular, MS receptor. They are particularly useful in the treatment of pathological conditions and diseases, which involve one or more receptors melanocortin. The present invention also relates to pharmaceutical compositions containing said products, and to their use in the manufacture of medicines.

Melanocortin are a group of peptides, the predecessor of which is proopiomelanocortin (O.G. ROMs), and have structural similarity: adrenocorticotropic hormone (ACTH), α-melanocytestimulating hormone (α-MSH), β-MSH and γ-MSH (Eipper B.A. and R.E. MainsEndocr. Rev. 1980, 1, 1-27). Melanocortin perform a variety of physiological functions. They stimulate the synthesis of steroids of the cortical substance of the adrenal gland and the synthesis of eumelanin melanocytes. They regulate the mechanisms of nutrients from food, energy metabolism, sexual function, neuronal regeneration, blood pressure and heart rate and pain perception, learning, attention and memory. Melanocortin also have anti-inflammatory and antipyretic properties and controlling the t the secretion of several endocrine or exocrine glands, such as sebaceous, lacrimal and mammary glands, prostate and pancreas (Wikberg, J.E. et al.,Pharmacol. Res. 2000, 42, 393-420; Abdel-Malek Z.A.,Cell Mol. Life. Sci. 2001, 58, 434-441).

Effects of melanocortins involve the participation of a family of membrane receptors specific seven transmembrane domains and are associated with G-protein. To date, cloned and characterized five receptor subtypes, designated MC1-MC5. These receptors differ in their distribution in tissues and affinity to different melanocortin, while MC2 receptors only recognize ACTH. Stimulation of receptors melanocortin activates adenylate cyclase with concomitant production of cyclic AMP. Although the functional roles that are specific to each of the receptors is not fully understood, there is reason to believe that the treatment of pathological disorders or diseases may be associated with affinity to a specific receptor subtypes. Thus, activation MS receptors associated with the treatment of inflammation, while blocking them associated with the treatment of skin cancer. Treatment of disorders of the mechanisms of nutrients from food is associated with receptors MS and MS, obesity treatment with agonists and the treatment of cachexia and anorexia - with their antagonists. Other indications associated with activation of MS and MS Retz is Perov, include disorders of sexual function, neuropathic pain, anxiety, depression and addictive prescription drug. Activation MS receptors associated with the treatment of acne and dermatitis.

The authors of the present invention have found that the new compounds of General formula (I), described later, have a good affinity to the receptor melanocortin. They operate mainly on MC receptors. These compounds, agonists or antagonists of the receptor melanocortin can be used for the treatment of pathological conditions or metabolic diseases, nervous system disorders or skin, the development of which involved one or more receptors melanocortin, such as below as examples: inflammatory conditions, disorders of energy homeostasis, disorders of the mechanisms of nutrients, impaired weight gain (obesity, cachexia, anorexia), disorder of sexual activity (erectile dysfunction), neuropathic pain. May also be marked mental disorders (anxiety, depression, addiction medicine, skin diseases (acne, dermatitis, skin cancer, melanoma). These compounds can also be used to stimulate the regeneration of nerves.

In this regard, an object of the present invention is connected to the e of General formula (I):

in racemic, enantiomeric form or any combinations of these forms, in which:

And denotes-CH2-, -C(O)-, -C(O)-C(Ra)(Rb)-;

X represents-CH-radical or a nitrogen atom;

Raand Rbrepresent, independently, a hydrogen atom or a (C1-C6)alkyl radical;

R1denotes a hydrogen atom or a (C1-C8)alkyl radical;

R2means (C1-C8)alkyl radical;

or R1and R2together with the nitrogen atom to which they are attached, form heterobicyclic or heteroseksualci, optionally substituted by one or more identical or different (C1-C6)alkyl substituents;

R3represents -(CH2)p-Z3, -C(O)-Z'3, -CH(OH)-Z'3or-C(O)-NH-Z3;

Z3means (C1-C6)alkyl, (C2-C6)alkanniny, (C1-C6)alkoxy, (C1-C6)alkylcarboxylic, (C1-C6)alkoxycarbonyl, (C1-C6)alkyl-N(RN)carbonyl, (C3-C7)cycloalkenyl, heterologously, aryl, aaltio or heteroaryl radical, where Z3attached to the radical

-(CH2)pthrough a carbon atom,

(C3-C7)cycloalkenyl and heterologously radicals which may be substituted by one or more identical or different radicals, selected from (C1-C6)alkyl and hydroxy;

heteroaryl radical may be optionally substituted by one or more identical or different substituents selected from halogen, nitro or -(CH2)p-V30-Y3;

the aryl radical may be optionally substituted by one or more identical or different substituents selected from halogen, nitro, ceanography, (C2-C6)alkenyl, geterotsiklicheskie, aryl, aryloxy, aralkylated, heteroaryl and -(CH2)p-V31-Y3;

V30denotes-O-, -C(O)-, -C(O)-O - or a covalent bond;

V31denotes-O-, -S-, -SO2-, -C(O)-, -C(O)-O-, -N(RN)-, -NH-C(O)-, -C(O)-NR'3-, -NH-C(O)-NR'3or a covalent bond;

Y3denotes a hydrogen atom or (C1-C6)alkyl radical, optionally substituted by one or more identical or different halogen radicals;

RNdenotes a hydrogen atom or (C1-C6)alkyl radical;

Z3denotes a radical of the formula

Z'3denotes aryl radical, optionally substituted by one or more identical or different substituents selected from halogen, nitro and -(CH2)p-V'3-Y'3;

V'3denotes-O-, -C(O)-, -C(O)-O-, -NH-C(O), -C(O)-NR'3- or a covalent bond;

Y'3denotes a hydrogen atom or (C1-C6)alkyl radical, optionally substituted by one or more identical or different halogen radicals;

R'3denotes a hydrogen atom, (C1-C6)alkyl or (C1-C6)alkoxy radical;

A”3means (C1-C6)alkyl, aryl or heteroaryl radical;

alkyl and aryl radicals may be optionally substituted by one or more identical or different substituents selected from halogen and

-V3-Y3;

V3denotes-O-, -C(O)-, -C(O)-O-, -C(O)-NH -, or a covalent bond;

Y”3denotes a hydrogen atom or (C1-C6)alkyl radical, optionally substituted by one or more identical or different halogen radicals;

p is an integer from 0 to 6; p' and p” represent, independently, an integer from 0 to 4; q is an integer from 0 to 2;

R4denotes a radical of the formula -(CH2)s-R'4;

R'4denotes heteroseksualci containing at least one nitrogen atom and optionally substituted (C1-C6)alkyl; heteroaryl containing at least one nitrogen atom and optionally substituted (C1-C6)alkyl; or a radical of the formula-NW4 W'4;

W4denotes a hydrogen atom or (C1-C8)alkyl;

W'4denotes a radical of the formula -(CH2)s'-Z4in which Z4denotes a hydrogen atom, (C1-C8)alkyl or (C3-C7)cycloalkenyl radical;

s and s' represent, independently, an integer from 0 to 6;

or its pharmaceutically acceptable salt.

In the above definitions, the expression "halogen" denotes fluorine, chlorine, bromine or iodine, preferably chlorine, fluorine or bromine. The expression "alkyl" (unless specified otherwise) preferably denotes a linear or branched alkyl radical containing from 1 to 6 carbon atoms, such as methyl, ethyl, sawn, ISO-propyl, boutigny, isobutylene, second-boutigny, and tert-boutigny, pentelenyi or amily, isopentenyl, neopentyl, 2,2-dimethylpropylene, sexily, isohexyl or 1,2,2-trimethylpropyl radicals. The term "(1-C8)alkyl" denotes a linear or branched alkyl radicals containing 1-8 carbon atoms, such as radicals containing 1-6 carbon atoms, as stated above, but also heptyl, octyl, 1,1,2,2-TETRAMETHYLBUTYL and 1,1,3,3-TETRAMETHYLBUTYL. The term "alkylaryl" refers to radicals in which the alkyl radical is as defined above and represents, for example, methylcarbamyl ethylcarboxyl. The term "alkyl-N(RN)carbonyl" refers to radicals in which the alkyl radical corresponds to the definition given above, and represents, for example, methylaminomethyl, ethylaminomethyl, N-propyl-N-methylaminomethyl, N,N-diethylaminoethyl.

Alkenyl, unless specifically stated otherwise, denotes a linear or branched radical containing 2-6 carbon atoms and including at least one site of unsaturation (double bond), such as, for example, vinyl, allyl, butenyl or pentenyl.

The term "alkoxy" refers to radicals in which the alkyl radical corresponds to the definition given above, and represents, for example, methoxy, ethoxy, propyloxy or isopropylacetate, and includes linear, secondary or tertiary, butoxy and petrogenetically. The term "alkoxycarbonyl" preferably designates the radicals in which alkoxylation corresponds to the definition given above, and represents, for example, methoxycarbonyl and etoxycarbonyl.

The term "(3-C7)cycloalkyl" denotes a saturated carbon-containing monocyclic system containing 3-7 carbon atoms, and is preferably cyclopropyl, cyclobutyl, cyclopentamine, tsiklogeksilnogo or cycloheptyl rings. The expression "heteroseksualci" denotes condensed the th saturated monocyclic or bicyclic system, containing 2-7 carbon atoms and at least one heteroatom. Specified organic radical can contain several identical or different heteroatoms. Preferably the heteroatoms are selected from oxygen atom, sulfur or nitrogen. As examples of geterotsiklicheskie you can mark ring containing at least one nitrogen atom, such as pyrrolidine, imidazolidine, pyrazolidine, isothiazolin, thiazolidin, isoxazolidine, oxazolidine, piperidine, piperazine, ASEAN (azacycloheptan), azocyclotin, diazepan, morpholine, decahydroquinoline (or decahydroquinoline), and the ring containing no nitrogen atom, such as tetrahydrofuran or tetrahydrothiophene. As examples of geterotsiklicheskie, optionally substituted actigraphy or alkyl, may be noted the lactones and lactams.

The term "heterobinuclear" means unfused saturated hydrocarbon bicyclic system containing 5-8 carbon atoms and at least one heteroatom selected from a nitrogen atom, oxygen and sulfur. As examples of heterobicyclic can be noted azabicycloalkanes and azabicycloalkanes, such as 7-azabicyclo[2,2,1]heptane, 2-azabicyclo[2,2,2]octane or 6-azabicyclo[3,2,1]octane.

The expression "aryl" denotes an aromatic radical consisting of a condensed one or more rings, such as phenyl, nattily or fluorenyl radical. The expression "aristeo" refers to a radical in which the aryl radical corresponds to the definition given above, and represents, for example, phenylthio. The expression "aryloxy" refers to radicals in which the aryl radical corresponds to the definition given above, and represents, for example, phenyloxy, naphthyloxy.

The expression "aralkyl" (arylalkyl) preferably designates the radicals in which the aryl and alkyl radicals correspond to the definition given above, and represents, for example, benzyl or phenethyl. The expression "aralkylated" refers to radicals in which kalkilya radicals correspond to the definition given above, and represents, for example, benzyloxy, penetrate.

The expression "heteroaryl" denotes an aromatic radical consisting of one or multiple condensed rings, in which there is at least one ring contains one or more identical or different heteroatoms selected from a sulfur atom, nitrogen or oxygen. As examples of the heteroaryl radical may be mentioned radicals containing at least one nitrogen atom, such as pyrrolyl, imidazolyl, pyrazolyl, isothiazolin, thiazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidyl, hinely, ethanolic, chinoxl the Nile, indolyl, benzoxadiazole, benzothiazolyl, carbazolyl, as well as radicals that do not contain a nitrogen atom, such as thienyl, benzothiazyl, furyl, benzofuran or pyranyl.

In addition, the scope of the present application, the radical (CH2)i(i integer, which may correspond to p, p', p”, s and s', as defined above) denotes a linear or branched hydrocarbon chain with one carbon atom. The radical -(CH2)3- may denote-CH2-CH2-CH2-, and-CH(CH3)-CH2-, -CH2-CH(CH3)- or-C(CH3)2-.

The invention preferably relates to compounds of formula I, defined above and characterized by the fact that X represents-CH - radical; or their pharmaceutically acceptable salts.

Preferably also, the invention relates to compounds of formula I, as defined above, and wherein R1denotes a hydrogen atom or

(C1-C8)alkyl radical, and R2means (C1-C8)alkyl radical; and most preferably R1means (C1-C6)alkyl radical and R2means (C1-C8)alkyl radical; or their pharmaceutically acceptable salts.

Preferably also, the present invention relates to compounds of formula I, defined above and characterized in that oboznachaet is-CH 2-; or their pharmaceutically acceptable salts.

Preferably also, the present invention relates to compounds of formula I, defined above and characterized in that a represents-C(O)-C(Ra)(Rb)and Raand Rbdenote independently a methyl radical; or their pharmaceutically acceptable salts.

Preferably also, the present invention relates to compounds of formula I, defined above and characterized in that a represents-CO-; or their pharmaceutically acceptable salts.

Preferably also, the present invention relates to compounds of formula I, defined above and characterized in that

R4denotes a radical of the formula -(CH2)s-R'4;

R'4denotes heteroseksualci containing at least one nitrogen atom and optionally substituted (C1-C6)alkyl; or a radical of the formula-NW4W'4;

W4denotes a hydrogen atom or (C1-C8)alkyl;

W'4denotes a radical of the formula -(CH2)s'-Z4in which Z4denotes a hydrogen atom or (C1-C8)alkyl radical;

s and s' represent, independently, an integer from 1 to 6;

or their pharmaceutically acceptable salt.

Most preferably the present invention relates to compounds of formula I, defined above and from causesa fact, what R4denotes a radical of the formula -(CH2)s-R'4where R'4denotes a radical of the formula-NW4W'4;

W4means (C1-C8)alkyl radical;

W'4denotes a radical of the formula -(CH2)s'-Z4in which Z4denotes a hydrogen atom or (C1-C8)alkyl radical;

s and s' represent, independently, an integer from 2 to 6; or their pharmaceutically acceptable salts.

Most preferably also, the present invention relates to compounds of formula I, as defined above, and wherein R4denotes a radical of the formula -(CH2)s-R'4;

R'4denotes heteroseksualci containing at least one nitrogen atom and optionally substituted (C1-C6)alkyl and s is an integer from 2 to 6;

and in particular R'4means piperidino or pyrolidine ring; s is an integer from 1 to 4; or their pharmaceutically acceptable salts.

Preferably also, the present invention relates to compounds of formula I, as defined above, and wherein R3represents -(CH2)p-Z3and

Z3means (C1-C6)alkyl, (C2-C6)alkanniny, (C1-C6)alkoxy, (C1-C6)alkylcarboxylic, (C1-C6 )alkoxycarbonyl, (C1-C6)alkyl-N(RN)carbonyl, (C3-C7)cycloalkenyl, heterologously, aryl, aaltio or heteroaryl radical,

(C3-C7)cycloalkenyl and heterologously radicals can be substituted by one or more identical or different radicals selected from (C1-C6)alkyl and hydroxy;

heteroaryl radical may be optionally substituted by one or more identical or different substituents selected from halogen, nitro or -(CH2)p'-V30-Y3;

the aryl radical may be optionally substituted by one or more identical or different substituents selected from halogen, nitro, (C2-C6)alkenyl, geterotsiklicheskie, aryl, aryloxy, aralkylated, heteroaryl and -(CH2)p'-V31-Y3;

V30denotes-O-, -C(O)-, -C(O)-O - or a covalent bond;

V31denotes-O-, -S-, -SO2-, -C(O)-, -C(O)-O-, -N(RN)-, -NH-C(O)-, -C(O)-NR'3or a covalent bond;

Y3denotes a hydrogen atom or (C1-C6)alkyl radical, optionally substituted by one or more identical or different halogen radicals;

RNdenotes a hydrogen atom or (C1-C6)alkyl radical; or

Z3the seat is t a radical of the formula

or their pharmaceutically acceptable salts.

Preferably also, the present invention relates to compounds of formula I, defined above and characterized in that Z3means (C1-C6)alkyl, (C1-C6)alkylcarboxylic, (C1-C6)alkoxycarbonyl, (C1-C6)alkyl-N(RN)carbonyl, (C3-C7)cycloalkenyl, aryl or heteroaryl radical, where the aryl and heteroaryl radicals can be optionally substituted;

and most preferably heteroaryl radical may be optionally substituted by one or more identical or different substituents selected from halogen and (CH2)p'-V30-Y3;

the aryl radical may be optionally substituted by one or more identical or different substituents selected from nitro and (CH2)p'-V31-Y3;

V30denotes-O-, -C(O)-, -C(O)-O - or a covalent bond;

V31denotes-O-, -C(O)-, -C(O)-O - or-SO2-;

Y3means (C1-C6)alkyl radical;

p and p' represent, independently, an integer from 0 to 4; or their pharmaceutically acceptable salts.

Most preferably also, the present invention relates to compounds of formula I, defined above and trichosis fact, that Z3means (C1-C6)alkyl radical; or their pharmaceutically acceptable salts.

Most preferably also, the present invention relates to compounds of formula I, defined above and characterized in that Z3means (C1-C6)alkylcarboxylic, (C1-C6)alkoxycarbonyl or (C1-C6)alkyl-N(RN)carbonyl radicals; or their pharmaceutically acceptable salts.

Most preferably also, the present invention relates to compounds of formula I, defined above and characterized in that Z3denotes heteroaryl, optionally substituted by one or more identical or different substituents selected from halogen and (CH2)p'-V30-Y3;

V30denotes-O-, -C(O)-, -C(O)-O - or a covalent bond;

Y3means (C1-C6)alkyl radical;

p' is an integer from 0 to 4;

and, in particular, Z3denotes thienyl, purely, benzofuranyl, benzothiazolyl, diazolidinyl, personilnya, imidazolidinyl, pyridinoline, indolinyl radical; or their pharmaceutically acceptable salts.

Most preferably also, the present invention relates to compounds of formula I, defined above and characterized in that Z3means (C3-C7 )cycloalkenyl or aryl radical, where the aryl radical may be optionally substituted by one or more identical or different substituents selected from nitro or -(CH2)p'-V31-Y3;

V31denotes-O-, -C(O)-, -C(O)-O-or-SO2-;

Y3means (C1-C6)alkyl radical;

p' is an integer from 0 to 4;

and especially (C3-C7)cycloalkenyl radical selected from cyclopentyl and cyclohexyl; aryl radical denotes a phenyl radical; or their pharmaceutically acceptable salts.

Most preferably also, the present invention relates to compounds of formula I, as defined above, and wherein R3denotes-C(O)-Z'3; or their pharmaceutically acceptable salts.

Most preferably also, the present invention relates to compounds of formula I, defined above and characterized in that Z'3denotes a phenyl radical, optionally substituted by one or more identical or different substituents of the formula -(CH2)p-V'3-Y'3;

V'3represents-O-;

Y'3means (C1-C6)alkyl radical;

p is an integer from 0 to 4; or their pharmaceutically acceptable salts.

Most preferably also present izopet the tion relates to compounds of the formula I, defined above and wherein R3denotes-C(O)-NH-Z3,

Z3represents -(CH2)q-A”3radical;

A”3means (C1-C6)alkyl, phenyl or thienyl radical;

alkyl and aryl radicals may be substituted by one or more identical or different substituents of the formula-V”3-Y3;

V3denotes-O-, -C(O)-, -C(O)-O-or a covalent bond;

Y”3denotes a hydrogen atom or (C1-C6)alkyl radical;

q is an integer from 0 to 1; or their pharmaceutically acceptable salts.

In this application, the symbol ->* denotes the point of connection of the radical. In the case when the website merger is not specified in the radical, this means that the accession is one of the sites that are available on this radical for such a connection.

In accordance with the definitions of the variables of the groups A, X, R1, R2, R3and R4compounds of the present invention can be obtained by liquid-phase synthesis in accordance with the procedures A-D, described below.

A. Receiving in accordance with reaction scheme And

The compounds of formula I of the present invention, in which A represents-C(O)-, can be obtained in accordance with the scheme shown below:

Scheme And

As shown in the diagram And methylated derivative (1) (for X = CH, commercial Union; X = N, the compound obtained by the procedure Baumgartenet al., J. Am. Chem. So., 1952, 74, 3828-3831, from 6-methyl-3-nitropyridine) can be oxidized to carboxylic acid (2) with an aqueous solution of potassium permanganate at a temperature of 100°C for 3-6 hours (according to the procedure Schmelkeset al., J. Am. Chem. Soc., 1944, 1631) or an aqueous solution of sodium dichromate in the presence of sulfuric acid at a temperature of 20-90°C for 1-3 hours (on procedure Howeset al., European J. Med. Chem, 1999, 34, 225-234). Carboxylic acid (2) may be associated with a primary or secondary amine in the presence of a binding agent, such as diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) or carbonyldiimidazole (CDI), in the presence or in the absence of 1-hydroxybenzotriazole (HOBt), in an inert organic solvent such as methylene chloride, tetrahydrofuran or dimethylformamide at ambient temperature for 3-24 hours to obtain the corresponding amide (3). Processing of fluorinated or chlorinated derivative (3) a primary amine in the presence of an inorganic base such as cesium carbonate or potassium, in an inert organic solvent such as dimethylformamide or acetonitrile, at a temperature of 20-100°C t the value of 2-48 hours gives the derivative (4). The nitro-group in the compound (4) is reactivated by treatment with chloride dihydrate tin in an inert solvent, such as ethyl acetate or dimethylformamide, at a temperature of 60-80°C for 3-15 hours or by catalytic hydrogenation in the presence of 10% palladium-on-coal in an inert solvent, such as methanol, ethanol, ethyl acetate or a mixture thereof, at a temperature of 18-25°C for 2-8 hours with obtaining dianiline (5). Derivative (5) can then be treated with an aldehyde in the presence of an oxidant, such as nitrobenzene, DDQ, in an aprotic solvent such as dimethylformamide, at a temperature of 60-180°C for 2-24 hours or in a microwave oven at a temperature of 150-200°C for 5-30 minutes getting benzimidazole (6). Alternatively, the derivative (5) can be subjected to reaction with acid chloride acid or carboxylic acid in the presence of a binding agent, such as diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), carbonyldiimidazole (CDI), hexaflurophosphate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (HBTU), tetrafluoroborate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (TBTU) or hexaphosphate O-(7-azobenzenes-1-yl)-1,1,3,3-tetramethyluronium (HATU), in an inert organic solvent such as methylene chloride, tetrahydrofuran or dimethylformamide at ambient temperature for 3-24 hours to obtain the corresponding amide. Thus obtained amide gives the benzimidazole (6) by treatment with acid, such as acetic acid, hydrochloric acid, polyphosphoric acid, at a temperature of 20-100°C for 2-24 hours or in a microwave oven at a temperature of 80-150°C for 5-30 minutes. Derivative (5) can also be subjected to reaction with a complex imidate ether or chloroacetamide derivative in an organic solvent, such as dimethylformamide, methanol or ethanol, in the presence or in the absence of a tertiary base, sulfur, at a temperature of 20-100°C for 3-24 hours or in a microwave oven at a temperature of 80-150°C for 5-30 minutes with obtaining benzimidazole derivative (6').

Example A1

Hydrochloride of 2-(4-methoxyphenyl)-N,N-bis(3-methylbutyl)-1-(3-piperidine-1-ylpropyl)-1H-benzimidazole-6-carboxamide

Stage 1:3-fluoro-4-nitrobenzoic acid

A mixture of 3-fluoro-4-nitrotoluene (10 g, 1 EQ.) and potassium permanganate (25,5 g, 2.5 EQ.) in water (1 l) was heated at boiling temperature under reflux for 6 hours and then cooled to ambient temperature. The mixture is filtered through celite and the aqueous phase is washed twice with diethyl ether (2 x 300 ml). The aqueous phase is acidified with an aqueous solution of concentrated hydrochloric acid (n) and then concentrated at Pont the leaders introduce pressure at a temperature of 40°C to a volume of approximately 300 ml Formed precipitate was filtered and then washed with petroleum ether and dried to obtain the expected compound in the form of a white solid (6.9 g, yield 58%).

1H NMR (400 MHz, DMSO-d6): δ to 7.93 (m, 2H), 8,25 (m, 1H), 13,95 (m, 1H).

Stage 2:3-fluoro-N,N-bis(3-methylbutyl)-4-nitrobenzamide

Hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (4.4 g, 1.1 EQ.) in a solution of chloroform (25 ml) and 1-hydroxybenzotriazole (HOBt) (3,05 g, 1.1 EQ.) in THF solution (40 ml) was successively added 3-fluoro-4-nitrobenzoic acid (3.8 g, 1 EQ.) in a solution of aqueous THF (30 ml). The mixture is stirred for 1 hour at a temperature of about 20°C and then add vitaminen (3.6 g, 1.1 EQ.) in solution in THF (30 ml). After stirring for 16 hours at a temperature of about 20°C. the reaction mixture was concentrated under reduced pressure at 40°C. the Residue is taken dichloromethane (200 ml) and water (70 ml). After decantation and extraction, the combined organic phases are washed with salt water, dried over Na2SO4and then concentrate under reduced pressure at 40°C. Purification of compounds flash chromatography on silica gel (eluent: heptane/ethyl acetate, 9:1) produces the expected compound in the form of a yellow oil (4.3 g, yield 65%).

MC/LC: Calculation MM = 324,4; m/z = 325,2 (MH+)

1H NMR 400 MHz, DMSO-d6): δ 0.69 (m, 6H), of 0.93 (m, 6H), 1,35-to 1.60 (m, 6H), to 3.09 (m, 2H), 3,41 (m, 2H), 7,38 (d, 1H) 7,63 (d, 1H), 8,21 (t, 1H).

Stage 3:N,N-bis(3-methylbutyl)-4-nitro-3-[(3-piperidine-1-ylpropyl)amino]benzamide

A mixture of 3-fluoro-N,N-bis(3-methylbutyl)-4-nitrobenzamide (430 mg, 1 EQ.), 3-piperidinophenyl (212 mg, 1.1 EQ.) and potassium carbonate (365 mg, 2 EQ.) in acetonitrile (10 ml) is heated at the boiling point under reflux for 3 hours and then concentrated under reduced pressure at 40°C. the Residue is taken dichloromethane (50 ml) and water (20 ml). After decantation and extraction, the combined organic phases are washed with salt water, dried over

Na2SO4and then concentrate under reduced pressure at 40°C. Purification of the residue with flash chromatography on silica gel (eluent: heptane/ethyl acetate, 1:1 - 100% ethyl acetate) to give the expected compound as a yellow oil (460 mg, yield 78%).

MC/LC: Calculation MM = 466,6; m/z = 447,3 (MH+)

1H NMR (400 MHz, DMSO-d6): δ of 0.68 (d, 6H), to 0.92 (d, 6H), 1,31 was 1.69 (m, 12H), of 1.74 (m, 2H), 2,32 (m, 6H), 3,10 (m, 2H), 3,38 (m, 4H), 6,53 (d, 1H), 6,91 (m, 1H), of 8.09 (d, 1H), 8,44 (t, 1H).

Stage 4:4-amino-N,N-bis(3-methylbutyl)-3-[(3-piperidine-1-ylpropyl)amino]benzamide

N,N-bis(3-methylbutyl)-4-nitro-3-[(3-piperidine-1-ylpropyl)amino]benzamide (1 g) in a solution mixture of ethyl acetate/ethanol 2:1 (100 ml) and 10% palladium-on-coal (100 mg) was injected in the autoclave. After stirring for 3 hours in an atmosphere of hydrogen (3 bar) at a temperature of about 20°C. the catalyst is removed filter is the Finance through celite and the filtrate concentrated under reduced pressure at 40°C. to obtain the expected compound in the form of oil (910 mg, yield 97%).

MC/LC: Calculation MM = 416,6; m/z = 417,3 (MH+)

1H NMR (400 MHz, DMSO-d6): δ 0,81 (d, 12H), 1,39 was 1.69 (m, 12H), at 1.73 (m, 2H), 2,32 (m, 6H), 3,03 (m, 2H), 3,38 (m, 4H), 4,62 (c, 1H), 4,76 (c, 2H), 6,36 (c, 1H), 6.42 per (AB, 1H), 6,50 (AB, 1H).

Stage 5:Hydrochloride of 2-(4-methoxyphenyl)-N,N-bis(3-methylbutyl)-1-(3-piperidine-1-ylpropyl)-1H-benzimidazole-6-carboxamide

p-Anisaldehyde (27 mg, 1.3 EQ.) added to a solution of 4-amino-N,N-bis(3-methylbutyl)-3-[(3-piperidine-1-ylpropyl)amino]benzamide (62 mg) in nitrobenzene (2 ml). The mixture is heated at a temperature of 130°C for 6 hours. Purification of the mixture flash chromatography on silica gel (eluent: 100% dichloromethane - a mixture of dichloromethane/methanol, 9:1) produces the expected compound in free base form. Adding 1N hydrochloric acid in diethyl ether is formed corresponding cleaners containing hydrochloride salt. The formed precipitate is filtered and dried to obtain the expected monohydrochloride compound (58 mg, yield 68%).

MS/LC: Calculation MM = 532,8; m/z = 533,5 (MH+)

1H NMR (400 MHz, DMSO-d6): δ of 0.68 (d, 6H), of 0.95 (d, 6H), 1,26 was 1.69 (m, 12H), and 2.27 (m, 2H), 2,72 (m, 2H), 3,03 (m, 2H), 3,25 (m, 4H), of 3.45 (m, 2H), 3,91 (c, 3H), 4,56 (t, 2H), 7,27 (AB, 2H), 7,50 (AB, 1H), 7,87 (AB, 1H), 7,92 (AB, 1H), 8,15 (c, 1H), 10,89 (c, 1H).

Example A2

Hydrochloride of 2-(4-methoxybenzyl)-N,N-bis(3-methylbutyl)-1-(3-piperidine-1-ylpropyl)-1H-benzimidazole-6-carboxamide

4-Methoxyphenylacetylene 32 mg, 1.1 EQ.) added to a solution of 4-amino-N,N-bis(3-methylbutyl)-3-[(3-piperidine-1-ylpropyl)amino]benzamide (66 mg) in acetic acid (2 ml). The mixture is heated at 100°C for 18 hours, then cooled and concentrated under reduced pressure. Add saturated aqueous sodium hydrogen carbonate solution to the resulting residue dissolved in dichloromethane. After decantation and extraction combined organic phases are washed with salt water, dried over Na2SO4and concentrate under reduced pressure. Purification of the obtained residue flash chromatography on silica gel (eluent: 100% dichloromethane - a mixture of dichloromethane/methanol, 9:1) produces the expected compound in free base form. Adding 1N hydrochloric acid in diethyl ether is formed corresponding cleaners containing hydrochloride salt. The formed precipitate is filtered and dried to obtain the expected monohydrochloride compound (51 mg, yield 59%).

MS/LC: Calculation MM = 546,8; m/z = 547,5 (MH+)

1H NMR (400 MHz, DMSO-d6): δ 0,63 (d, 6H), were 0.94 (d, 6H), 1,24-of 1.92 (m, 12H), 2,11 (m, 2H), by 2.73 (m, 2H), 3,03 be 3.29 (m, 6H), 3,40 (m, 2H), 3,74 (c, 3H), 4,56 (t, 2H), 4,62 (c, 2H), of 6.96 (AB, 2H), 7,43 (m, 3H), 7,79 (AB, 1H), 8,03 (c, 1H), 11,02 (c, 1H).

Example A3

Hydrochloride of 2-[3-(methylamino)-3-oxopropyl]-N,N-bis(3-methylbutyl)-1-(3-piperidine-1-ylpropyl)-1H-benzimidazole-6-carboxamide

TBTU (67 mg, 1 EQ.) and dies populationin (70 μl, 2 EQ.) successively added to a solution of N-methylethanol acid (26 mg, 1 EQ.) in DMF (1 ml). After stirring for 30 minutes at ambient temperature to the mixture add a solution of 4-amino-N,N-bis(3-methylbutyl)-3-[(3-piperidine-1-ylpropyl)amino]benzamide (66 mg) in DMF (1 ml). The mixture is stirred for 15 hours at a temperature of about 20°C, then diluted with ethyl acetate (10 ml) and add saturated aqueous solution of sodium bicarbonate (4 ml). After decantation and extraction combined organic phases are washed with salt water, dried over Na2SO4and concentrate under reduced pressure at 40°C. the thus Obtained oil solubilizer in acetic acid (2 ml). The mixture is heated at a temperature of 100°C for 18 hours and then cooled to ambient temperature and concentrate under reduced pressure at 40°C. Add saturated aqueous solution of sodium bicarbonate to the resulting residue dissolved in dichloromethane. After decantation and extraction combined organic phases are washed with salt water, dried over Na2SO4and concentrate under reduced pressure. Purification of the obtained residue flash chromatography on silica gel (eluent: 100% dichloromethane - a mixture of dichloromethane/methanol, 85:15) to give the expected compound in free base form. When adding a 1N solution of CHL is estevadeordal acid in diethyl ether is formed corresponding cleaners containing hydrochloride salt. The formed precipitate is filtered and dried to obtain the expected monohydrochloride compound (64 mg, yield 54%).

MS/LC: Calculation MM = 511,8; m/z = 512,4 (MH+)

1H NMR (400 MHz, DMSO-d6): δ 0,65 (d, 6H), were 0.94 (d, 6H), 1,24-1,90 (m, 12H), to 2.29 (m, 2H), 2,56 (d, 3H), 2,82 (m, 2H), with 2.93 (t, 2H), and 3.16 (m, 4H), 3.33 and-to 3.52 (m, 6H), 4,63 (t, 2H), 7,46 (AB, 1H), 7,43 (m, 3H), 7,82 (AB, 1H), 8,10 (c, 1H), to 8.20 (m, 1H), 10,86 (c, 1H).

Example A4

Hydrochloride of 2-(1-benzofuran-2-yl)-N,N-dibutil-1-(3-piperidine-1-ylpropyl)-1H-benzimidazole-6-carboxamide

1-Benzofuran-2-carbaldehyde (450 mg) are added to a solution of 4-amino-N,N-dibutil-3-[(3-piperidine-1-ylpropyl)amino]benzamide (1 g) in nitrobenzene (5 ml)is introduced into the reaction tube "Personal Chemistry®". The test tube is closed with a lid, placed in a microwave "Personal Chemistry®and heated under stirring with a magnetic stirrer at 200°C for 20 minutes. Purification of the resulting mixture flash chromatography on silica gel (eluent: 100% dichloromethane - a mixture of dichloromethane/methanol, 95:5) leads to obtain the desired compounds in the free base form. Adding 1N hydrochloric acid in diethyl ether is formed corresponding cleaners containing hydrochloride salt. The formed precipitate is filtered and dried to obtain the expected monohydrochloride compound (780 mg, yield 54%).

MS/LC: Calculation MM = 514,7; m/z = 515,5 (MH+)

1H NMR (400 MHz, LCA is-d 6): δ 0.70 and (users, 3H), 0,95 (users, 3H), 1,28-of 1.88 (m, 12H), a 2.36 (m, 2H), and 2.83 (m, 2H), with 2.93 (t, 2H), up 3.22 (m, 4H), to 3.36 (d, 2H), 3,42 (m, 2H), 4,78 (t, 2H), 7,33 (AB, 1H), 7,42 (t, 1H), 7,52 (t, 1H), 7,79 (AB, 1H), 7,87 (AB, 1H), to $ 7.91 (c, 1H), of 7.96 (c, 1H).

Example A5

Hydrochloride ethyl 4-({[6-{[bis(3-methylbutyl)amino]carbonyl}-1-(3-piperidine-1-ylpropyl)-1H-benzimidazole-2-yl]carbonyl}amino)benzoate

The triethylamine (100 μl), ethyl 4-[(chloroacetyl)amino]benzoate (173 mg) and sulfur (12 mg) were successively added to a solution of 4-amino-N,N-bis(3-methylbutyl)-3-[(3-piperidine-1-ylpropyl)amino]benzamide (100 mg) in ethanol (3 ml), placed in the reaction tube "Personal Chemistry®". The test tube is closed with a lid, placed in a microwave "Personal Chemistry®and heated under stirring with a magnetic stir bar at 130°C for 20 minutes. The ethanol is then evaporated and to the residue is added water and dichloromethane. After decantation and extraction combined organic phases are washed with salt water, dried over Na2SO4and concentrate under reduced pressure at 40°C. Purification of the compounds obtained flash chromatography on silica gel (eluent: 100% dichloromethane - a mixture of dichloromethane/methanol, 85:15) leads to obtain the desired compounds in the free base form. Adding 1N hydrochloric acid in diethyl ether is formed corresponding cleaners containing hydrochloride salt. Formed the tank is filtered and dried to obtain the expected monohydrochloride compound (80 mg, yield 51%).

MS/LC: Calculation MM = 617,8; m/z = exports, as against 618.5 (MH+)

1H NMR (400 MHz, DMSO-d6): δ 0,62 (users, 6H), 0,95 (users, 6H), of 1.32 (t, 3H), 1,37 is 1.75 (m, 12H), is 2.30 (m, 2H), and 2.83 (m, 2H), with 2.93 (t, 2H), 3,17 (m, 4H), 3,37-of 3.48 (m, 4H), 4,30 (kV, 2H), 4,77 (t, 2H), 7,30 (AB, 1H), 7,87 (AB, 1H), 7,88 (c, 1H), 7,97 (AB, 1H), 8,06 (AB, 1H), 10,14 (c, 1H), 11,25 (c, 1H).

In accordance with reaction scheme a and according to the method similar to the procedures applied to the synthesis of the hydrochloride of 2-(4-methoxyphenyl)-N,N-bis(3-methylbutyl)-1-(3-piperidine-1-ylpropyl)-1H-benzimidazole-6-carboxamide, 2-(4-methoxybenzyl)-N,N-bis(3-methylbutyl)-1-(3-piperidine-1-ylpropyl)-1H-benzimidazole-6-carboxamide, 2-[3(methylamino)-3-oxopropyl]-N,N-bis(3-methylbutyl)-1-(3-piperidine-1-ylpropyl)-1H-benzimidazole-6-carboxamide, 2-(1-benzofuran-2-yl)-N,N-dibutil-1-(3-piperidine-1-ylpropyl)-1H-benzimidazole-6-carboxamide or ethyl-4-({[6-{[bis(3-methylbutyl)amino]carbonyl}-1-(3-piperidine-1-ylpropyl)-1H-benzimidazole-2-yl]carbonyl}amino)benzoate, get the following connection:

where R1R2N denotes one of the radicals below:

R3denotes one of the radicals below:

one or more substituents selected from
U = H, F, Cl, Br, I, NO2, OMe, OEt, OPh, SMe, SEt, SCF3, Me, Et, iPr, tBu, CN, CF3, OCF3C(O)OMe, C(O)OEt, C(O)Me, C(O)Et, C(O)NHMe, C(O)NH2, NMe2NEt2, NHCOMe, Phe, OCH2Ph, SO2Me
V = H, F, Cl, Br, I, NO2, OMe, Me, Et, iPr, CF3, OCF3C(O)OMe, C(O)Me, C(O)NHMe, SO2Me

and R4indicates one of the following radicals:

B. Receiving in accordance with reaction scheme B

The compounds of formula I of the present invention, in which a represents-(CO) -, and R3denotes-C(O)-Z'3(Z'3denotes aryl radical, shown by the symbol Ar), can be obtained in accordance with reaction scheme B:

As shown in scheme B, the derivative (7) can be oxidized with manganese dioxide in an aprotic solvent such as tetrahydrofuran, dioxane or chromium trioxide, in acid, such as acetic acid, at a temperature of 20-80°C for 10-96 hours with derivatization (8).

Example B1

Hydrochloride of 2-(4-methoxybenzoyl)-N,N-bis(3-methylbutyl)-1-(3-piperidine-1-ylpropyl)-1H-benzimidazole-6-carboxamide

Manganese dioxide (500 mg) are added to a solution of 2-(4-methoxybenzyl)-N,N-bis(3-methylbutyl)-1-(3-piperidine-1-ylpropyl)-1H-benzimidazole-6-carboxamide (171 mg) obtained by the procedure of example A2) in 1,4-dioxane (5 ml). The mixture is heated at 70°C for 24 hours and then add a new portion of manganese dioxide (500 mg). After stirring at a temperature of 70°C for 24 hours again add a portion of manganese dioxide (500 mg) and stirred at 70°C for 24 hours, after which the mixture is cooled to ambient temperature, concentrated under reduced pressure and filtered to celite. The filtrate is concentrated under reduced pressure at a temperature of 40°C to obtain the expected compound in free base form. Adding 1N hydrochloric acid in diethyl ether is formed corresponding cleaners containing hydrochloride salt. The formed precipitate is filtered, washed with diethyl ether, then recrystallized from a mixture of dichloromethane/diethyl ether and dried to obtain the expected cleaners containing hydrochloride of the compound (50 mg, yield 26%).

MS/LC: Calculation MM = 560,8; m/z = 561,4 (MH+)

1H NMR (400 MHz, DMSO-d6): δ 0,65 (d, 6H), of 0.95 (d, 6H), 1,25-to 1.79 (m, 12H), 2,28 (m, 2H), 2,82 (m, 2H), and 3.16 (m, 4H), 3,32-of 3.48 (m, 4H), 3,89 (c, 3H), br4.61 (t, 2H), 7,13 (AB, 2H), 7,30 (AB, 1H), 7,89 (AB, 1H), 8,33 (AB, 2H), 10,48 (c, 1H).

In accordance with scheme R the B shares and the way similar to the procedure described with reference to the synthesis of the hydrochloride of 2-(4-methoxybenzoyl)-N,N-bis(3-methylbutyl)-1-(3-piperidine-1-ylpropyl)-1H-benzimidazole-6-carboxamide, get the following connection:

where R1R2N denotes one of the following radicals:

R3indicates one of the following radicals:

and R4indicates one of the following radicals:

C. Receiving in accordance with reaction scheme

The compounds of formula I of the present invention, in which a represents-CH2-can be obtained in accordance with reaction scheme C below:

As shown in the diagram, the derivative (4)obtained in accordance with the procedure illustrated in reaction scheme A, can be restored to the compound (9) using borane or lithium aluminum hydride in an aprotic solvent such as tetrahydrofuran or diethyl ether, at a temperature of 0-70°C for 3-24 hours. Dianiline (9) can then be treated with an aldehyde in the presence of an oxidant, such as nitrobenzene, at a temperature in the range of 60-140°C for 2-24 hours in an aprotic solvent such as dimethylformamide, to obtain the b is intimidate (10). Alternatively, the derivative (9) can be subjected to reaction with acid chloride acid or carboxylic acid in the presence of a binding agent, such as diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), carbonyldiimidazole (CDI), hexaflurophosphate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (HBTU), tetrafluoroborate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (TBTU) or hexaphosphate O-(7-azobenzenes-1-yl)-1,1,3,3-tetramethyluronium (HATU), in an inert organic solvent such as methylene chloride, tetrahydrofuran or dimethylformamide at ambient temperature for 3-24 hours with formation of the corresponding amide. Thus obtained amide gives the benzimidazole (10) by treatment with acid, such as acetic acid, hydrochloric acid, polyphosphoric acid, at a temperature of 20-100°C. for 2-24 hours. Derivative (9) can also be subjected to reaction with a complex imidate ether or chloroacetamide derivative in an inert organic solvent such as dimethylformamide, at a temperature of 20-100°C for 3-24 hours with the formation of the benzimidazole derivative (10).

Receive in accordance with the procedure of reaction scheme C'

Compound (10) can also be obtained in accordance with scheme C':

p>

As shown in the diagram C', amide (6), obtained in accordance with reaction scheme A, can be restored to the appropriate amine (10) using borane or lithium aluminum hydride in an aprotic solvent such as tetrahydrofuran or diethyl ether, at a temperature of 0-70°C for 1-6 hours.

Example C1

The dihydrochloride methyl 4-[6-{[bis(3-methylbutyl)amino]methyl}-1-(3-piperidine-1-ylpropyl)-1H-benzimidazole-2-yl]benzoate

Stage 1:4-{[bis(3-methylbutyl)amino]methyl}-N2-(3-piperidine-1-ylpropyl)benzene-1,2-diamine

A solution of lithium aluminum hydride (36 ml, 1N in THF) is added dropwise to a solution of N,N-bis(3-methylbutyl)-4-nitro-3-[(3-piperidine-1-ylpropyl)amino]benzamide (1.6 g), cooled to 0°C. the Mixture is taken away and bring in conditions with a temperature of 20°C and then heated to boiling under reflux for 6 hours and hydrolyzing with water, cooled to 0°C, then treated with 1N solution of soda. After addition of dichloromethane, the mixture is filtered through celite. After decantation of the filtrate and extraction combined organic phases are washed with 1N soda and then with salt water, dried over Na2SO4and then concentrate under reduced pressure at a temperature of 40°C to obtain the expected compound in the form of an oil (1.23 g, o is d 85%).

MS/LC: Calculation MM = 402,7; m/z = 403,3 (MH+)

1H NMR (400 MHz, DMSO-d6): δ 0,81 (d, 12H), 1.28 (in m, 4H), to 1.38 (m, 2H), 1,48 (m, 6H), 1,71 (m, 2H), 2,31 (m, 10H), a 3.01 (m, 2H), 3,29 (m, 2H), 4,28 (m, 2H), 4,6 (m, 1H), 6.30-in (AB, 1H), 6,38 (c, 1H), gold 6.43 (AB, 1H).

Stage 2:The dihydrochloride methyl 4-[6-{[bis(3-methylbutyl)amino]methyl}-1-(3-piperidine-1-ylpropyl)-1H-benzimidazole-2-yl]benzoate

Methyl-4-formylbenzoate (33 mg, 1 EQ.) added to a solution of 4-{[bis(3-methylbutyl)amino]methyl}-N2-(3-piperidine-1-ylpropyl)benzene-1,2-diamine (80 mg) in nitrobenzene (2 ml). The mixture is heated at a temperature of 130°C for 18 hours. Purification of the mixture flash chromatography on silica gel (eluent: 100% dichloromethane - a mixture of dichloromethane/methanol, 7:3) leads to obtain the desired compounds in the free base form. Adding 1N hydrochloric acid in diethyl ether is formed corresponding cleaners containing hydrochloride salt. The formed precipitate is filtered and dried to obtain the expected monohydrochloride compound (47 mg, yield 41%).

MS/LC: Calculation MM = 546,8; m/z = 547,3 (MH+)

1H NMR (400 MHz, DMSO-d6): δ 0,86 (m, 12H), 1,21-of 1.75 (m, 12H), a 2.36 (m, 2H), 2,81 (m, 2H), 3,05 (m, 6H), 3,91(c, 3H), 4,33 (m, 2H), 4,47 (d, 2H), 7,46 (AB, 1H), 7,79 (AB, 1H), 7,98 (AB, 1H), 8,16 (AB, 1H), at 8.36 (c, 1H), 10,18 (c, 1H), of 10.73 (c, 1H).

In accordance with the procedure shown in reaction scheme C, and manner analogous to the procedure described for the synthesis of hydrochloride of methyl 4-[6-{[bis(3-methylbutyl)the Mino]methyl}-1-(3-piperidine-1-ylpropyl)-1H-benzimidazole-2-yl]benzoate, receive the following connections:

where R1R2N denotes one of the following radicals:

R3indicates one of the following radicals:

one or more substituents selected from
U = H, F, Cl, Br, I, NO2, OMe, SMe, Me, Et, iPr, tBu, CF3, OCF3C(O)OMe, C(O)OEt, C(O)Me, C(O)Et, C(O)NHMe, C(O)NH2
V = H, F, Cl, Br, I, NO2, OMe, Me, Et, iPr, CF3, OCF3

and R4represents the following radical:

D. Obtaining, in accordance with reaction scheme D

The compounds of formula (I), in which a represents-C(O)-C(Ra)(Rb)-, can be obtained in accordance with the following scheme D:

As shown in scheme D, the derivative (11) can be subjected to alkylation in the presence of a strong base such as tert-butyl potassium, α-chlorovinyl derivative in a polar aprotic solvent such as dimethylformamide, at a temperature of 0-20°C. for 0.5-2 hours established the eating of the compound (12). Derivative (13) can be further optionally subjected to alkylation in the presence of a strong base such as sodium hydride, and an alkylating agent, such as alkylated, in an aprotic solvent such as dimethylformamide, at a temperature of 0-20°C for 1-4 hours with the formation of compound (13). Ester (13) may be further subjected to saponification in the presence of inorganic bases such as lithium hydroxide or potassium hydroxide, in a mixture of polar solvents, such as water and methanol, at a temperature of 20-80°C for 1-6 hours. The obtained carboxylic acid (14) may be further associated with a primary or secondary amine in the presence of a binding agent, such as diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) or carbonyldiimidazole (CDI), in the presence or in the absence of 1-hydroxybenzotriazole (HOBt), in an inert organic solvent such as methylene chloride, tetrahydrofuran or dimethylformamide, at a temperature of about 20°C for 3-24 hours. Alternatively, the acid (14) can be treated tional or oxalylamino in an aprotic solvent such as dichloromethane or toluene, at a temperature of 40-60°C for 2-16 hours, and then thus obtained acid chloride of the acid may be subjected to reaction with primary or in orignum an amine in the presence of a tertiary base, such as triethylamine, diisopropylethylamine, in an aprotic solvent such as dichloromethane or tetrahydrofuran, at a temperature of 0-20°C. for 0.5-4 hours with the formation of the amide (15). Processing of fluorinated or chlorinated derivative (15) primary amine in the presence of an inorganic base such as cesium carbonate or potassium, in an inert organic solvent such as dimethylformamide or acetonitrile, at a temperature of 20-100°C. for 2-48 hours leads to the formation of a derivative (16). The nitro-group in the compound (16) restore digidrirovanny with tin chloride in an inert solvent, such as ethyl acetate or dimethylformamide, at a temperature of 60-80°C for 3-15 hours, or by catalytic hydrogenation in the presence of 10% palladium-on-coal in an inert solvent, such as methanol, ethanol, ethyl acetate or a mixture of these solvents, at a temperature of 18-25°C for 2-8 hours with the formation of dianiline (17). Dianiline (17) can then be subjected to treatment with aldehyde in the presence of an oxidant, such as nitrobenzene or DDQ, in an aprotic solvent such as dimethylformamide, at a temperature of 60-140°C for 2-24 hours with the formation of benzimidazole (18). Alternatively, the derivative (17) can be subjected to reaction with acid chloride acid or carboxylic acid in the presence with azmoudeh agent, such as diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), carbonyldiimidazole (CDI), hexaflurophosphate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (HBTU), tetrafluoroborate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (TBTU) or hexaphosphate O-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium (HATU), in an inert organic solvent such as methylene chloride, tetrahydrofuran or dimethylformamide, at ambient temperature for 3-24 hours with formation of the corresponding amide. Thus obtained amide leads to the formation of benzimidazole (18) by treatment with acid, such as acetic acid, hydrochloric acid, polyphosphoric acid, at a temperature of 20-100°C. for 2-24 hours. Derivative (17) can also be subjected to reaction with a complex imidate ether or chloroacetamide derivative in an inert organic solvent such as dimethylformamide, at a temperature of 20-100°C for 3-24 hours with the formation of the benzimidazole derivative (18).

Example D1

N,N-Diisobutyl-2-[2-(4-methoxyphenyl)-1-(3-piperidine-1-ylpropyl)-1H-benzimidazole-6-yl]-2-methylpropanamide

Stage 1:ethyl 2-(3-chloro-4-nitrophenyl)propanoate

To a solution of DMF (80 ml), cooled to 0°C, add tre the-butyl potassium (11,22 g, 2 EQ.). Add dropwise a solution of 1-chloro-2-nitrobenzene (7,87 g, 1 EQ.) and ethyl 2-chloropropionate (7 ml, 1.1 EQ.) within 45 minutes to a mixture, supported at temperatures below 5°C. After the addition stirring is continued for 2 hours at 0°C and the mixture is then subjected to hydrolysis at a given temperature 1N solution of hydrochloric acid and add ethyl acetate. After decantation and extraction combined organic phases are washed with salt water, dried over Na2SO4and concentrate under reduced pressure. Purification with flash chromatography on silica gel (eluent: heptane/dichloromethane, 8:2 to 6:4) leads to the formation of the expected compound in the form of a yellow oil (8,28 mg, yield 64%).

1H NMR (400 MHz, DMSO-d6): δ 1.14 in (t, 3H), of 1.42 (d, 3H), 3,99 (kV, 1H), 4,08 (m, 2H), 7,52 (AB, 1H), 7,71 (c, 1H), 8,05 (AB, 1H).

Stage 2:ethyl 2-(3-chloro-4-nitrophenyl)-2-methylpropanoate

A solution of ethyl 2-(3-chloro-4-nitrophenyl)propanoate (14.1 g) is added dropwise to a suspension of sodium hydride (60% in oil, 2.4 g, 1.1 EQ.) in DMF (15 ml), cooled to 0°C. After stirring for 1 hour at this temperature to the mixture is added dropwise a solution under the conditions (and 3.72 ml, 1.1 EQ.) in DMF (40 ml). Stirring is continued for 3 hours at ambient temperature. The reaction medium is cooled to a temperature below 0°C and then added dropwise atilas the tat, water, saturated sodium bicarbonate, and then water again. After decantation and extraction combined organic phases are washed with salt water, dried over Na2SO4and concentrate under reduced pressure with the formation of the expected compound in the form of an oil which crystallizes. The crystals are washed with heptane and dried (13.8 g, yield 94%).

1H NMR (400 MHz, DMSO-d6): δ of 1.12 (t, 3H), and 1.54 (c, 6H), 4.09 to (q, 1H), 7,50 (AB, 1H), 7,66 (c, 1H), 8,04 (AB, 1H).

Stage 3:2-(3-chloro-4-nitrophenyl)-2-methylpropanoate acid

2n solution of potassium hydroxide (18 ml) was added to a solution of ethyl 2-(3-chloro-4-nitrophenyl)-2-methylpropanoate (1 g) in methanol (20 ml) at a temperature of approximately 20°C. Then the mixture is heated at 80°C for 1.5 hours, then cooled to ambient temperature. The methanol is evaporated by concentrating the mixture under reduced pressure. The remaining aqueous phase is washed with dichloromethane, cooled to 0°C and acidified with acetic acid. After adding dichloromethane, decanting and extraction combined organic phases are washed with salt water, dried over Na2SO4and concentrate under reduced pressure with the formation of the expected compound in the form of an oil which crystallizes (852 mg, 95%).

1H NMR (400 MHz, DMSO-d6): δ 1,52 (c, 6H), 7,53 (AB, 1H), 7,66 (c, 1H), 8,04 (AB, 1H), 12,72 (c, 1H).

Stage 4:2(3-chloro-4-nitrophenyl)-N,N-Diisobutyl-2-methylpropanamide

Thionyl chloride (0.54 ml, 4 EQ.) added to a solution of 2-(3-chloro-4-nitrophenyl)-2-methylpropanoic acid (500 mg) in dichloromethane (1 ml). The mixture is heated at the boiling point under reflux for 16 hours and then cooled to ambient temperature. The solvent is evaporated under reduced pressure at 40°C (in case of joint evaporation with toluene). To the solution thus obtained carboxylic acid in dichloromethane (1 ml), cooled to 0°C, sequentially add diisopropylethylamine (0,42 ml, 1.2 EQ.) and diisobutylamine (0,36 ml, 1 EQ.). After the addition stirring is continued for 3 hours at ambient temperature, after which the mixture is concentrated under reduced pressure at 40°C. the Residue is dissolved in ethyl ether and the organic phase is successively washed with 1N soda, saturated solution of sodium bicarbonate, salt water, then dried over Na2SO4and concentrate under reduced pressure at 40°C. Purification with flash chromatography on silica gel (eluent: heptane/ethyl acetate 8:2 to 7:3) leads to the formation of the expected compound in the form of an oil which crystallizes (0,585 g, yield 82%).

MS/LC: Calculation MM = 354,9; m/z = 355,2 (MH+)

1H NMR (400 MHz, CDCl3): δ 0,58 (d, 6H), of 0.90 (d, 6H), was 1.58 (m, 6H), of 1.74 (m, 1H), 1,95 (m, 1H), 2,65 (d, 2H), 3.27 to (d, 2H), 7,30 (AB, 1H), 7,44 (c, 1H), to $ 7.91 (AB, 1H).

Stage 5:N,N-Diisobutyl-2-methyl-2-{4-nitro-3-[(3-piperidine-1-ylpropyl)amino]phenyl}propanamide

A mixture of 2-(3-chloro-4-nitrophenyl)-N,N-Diisobutyl-2-methylpropanamide (2,39 g), 3-piperidylamine (1.9 g, 2 EQ.) and potassium carbonate (1.8 g, 2 EQ.) in DMF (40 ml) is heated at a temperature of 100°C for 24 hours and then cooled to ambient temperature. To the medium was added water and ethyl acetate. After decantation and extraction of the obtained organic phases are washed with salt water, dried over Na2SO4and concentrate under reduced pressure. Purification of the obtained residue flash chromatography on silica gel (eluent: dichloromethane 100% a mixture of dichloromethane/ethanol 6:4) leads to the formation of the expected compound in the form of a yellow oil (1.6 g, yield 51%).

MS/LC: Calculation MM = 460.7 M.; m/z = 461,4 (MH+)

1H NMR (400 MHz, CDCl3): δ 0,57 (d, 6H), to 0.89 (d, 6H), 1,50 (m, 2H), and 1.56 (m, 6H), and 1.63 (m, 4H), 1.77 in (m, 1H), 1,89 (m, 3H), 2,43 (m, 6H), to 2.75 (d, 2H), 3,29 (d, 2H), 3,32 (m, 2H), 6,58 (AB, 1H), 6,67 (c, 1H), 8,15 (AB, 1H), 8,29 (t, 1H).

Stage 6:2-{4-amino-3-[(3-piperidine-1-ylpropyl)amino]phenyl}-N,N-Diisobutyl-2-methylpropanamide

N,N-Diisobutyl-2-methyl-2-{4-nitro-3-[(3-piperidine-1-ylpropyl)amino]phenyl}propanamide (1.6 g) in a solution mixture of ethyl acetate/ethanol 2:1 (100 ml) and 10% palladium-on-coal (160 mg) was injected in the autoclave. After stirring for 4 hours in an atmosphere of hydrogen (3 bar) at a temperature of about 20°With the catalyst UD is given by filtration through celite and the filtrate concentrated under reduced pressure at a temperature of 40°C with the formation of the expected compound in the form of an oil (1.4 g, yield 94%).

MS/LC: Calculation MM = 430,7; m/z = 431,4 (MH+)

1H NMR (400 MHz, CDCl3): δ 0,45 (d, 6H), of 0.79 (d, 6H), of 1.35 (m, 8H), for 1.49 (m, 4H), to 1.70 (m, 3H), of 1.85 (m, 1H), 1,89 (m, 3H), 2,33 (m, 6H), and 2.79 (d, 2H), 2,97 (t, 2H), 3,11 (m, 2H), 4,45 (m, 2H), 6,18 (c, 1H), 6.30-in (AB, 1H), 6,48 (AB, 1H).

Stage 7:the hydrochloride of N,N-Diisobutyl-2-[2-(4-methoxyphenyl)-1-(3-piperidine-1-ylpropyl)-1H-benzimidazole-6-yl]-2-methylpropanamide

A mixture of 2-{4-amino-3-[(3-piperidine-1-ylpropyl)amino]phenyl}-N,N-Diisobutyl-2-methylpropanamide (34 mg) and p-anisaldehyde (13 mg) in nitrobenzene (1 ml) is heated at a temperature of 120°C for 24 hours and then cooled to ambient temperature. Purification of the mixture flash chromatography on silica gel (eluent: dichloromethane 100% a mixture of dichloromethane/methanol, 85:15) leads to the formation of the expected compound in free base form. Adding 1N hydrochloric acid in diethyl ether is formed corresponding cleaners containing hydrochloride salt. The formed precipitate is filtered and dried to obtain the expected monohydrochloride compound (12 mg, yield 60%).

MS/LC: Calculation MM = 546,8; m/z = 547,4 (MH+)

1H NMR (400 MHz, CDCl3): δ 0,44 (d, 6H), or 0.83 (d, 6H), of 1.30 (m, 2H), 1,58 (c, 6H), 1,71 (m, 6H), to 2.18 (m, 2H), 2,72 (m, 4H), 3,01 (m, 2H), 3,21 (m, 4H), 3,89 (c, 3H), of 4.54 (t, 2H), 7.23 percent (AB, 2H), 7,28 (m, 1H), 7,76 (AB,1H), 7,86 (m, 3H), 10,41 (c, 1H).

In accordance with reaction scheme D and manner analogous to the procedure described with reference to the synthesis hydroch oride N,N-Diisobutyl-2-[2-(4-methoxyphenyl)-1-(3-piperidine-1-ylpropyl)-1H-benzimidazole-6-yl]-2-methylpropanamide, receive the following connections:

where R1R2N denotes one of the following radicals:

R3indicates one of the following radicals:

one or more substituents selected from
U = H, F, Cl, Br, I, NO2, OMe, Me, iPr, tBu, CF3, OCF3C(O)OMe,
V = H, NO2, OMe

and R4indicates one of the following radicals:

The object of the present invention is also a method of obtaining the compounds of formula (I)defined above, in accordance with which the compound of General formula

where A, X, R1, R2, R4have the above values, handle

i) or aldehyde of General formula R3CHO, in which R3has the meaning indicated above, in the presence of an oxidant;

ii) or the acid chloride of the acid of General formula R3COCl, in which R3has the meaning indicated above, when outstay acid;

iii) or a carboxylic acid of General formula R3C(O)IT, in which R3has the meaning indicated above, in the presence of a binding agent, followed by treatment of the thus obtained acid amide;

iv) or chloroacetamide derivative of General formula Z3-NH-C(O)CH2Cl, where Z3has the meaning indicated above, in the presence of tertiary bases and sulphur.

In the process the aldehyde R3CHO used the oxidant may represent, for example, nitrobenzene. In the case of treatment of the acid chloride acid

R3COCl used this acid can imagine acetic acid. Similarly, in the case of treatment of carboxylic acid R3C(O)HE subsequent acid treatment of the obtained amide may be carried out using acetic acid.

The object of the present invention is also the compound of General formula (I):

in racemic, enantiomeric form or any combinations of these forms, where

And denotes-CH2-, -C(O)-, -C(O)-C(Ra)(Rb)-,

X represents-CH - or a nitrogen atom;

Raand Rbrepresent, independently, a hydrogen atom or a (C1-C6)alkyl radical;

R1denotes a hydrogen atom or a (C1-C8)alkyl radical;

R2means (C1-C8 )alkyl radical;

or R1and R2together with the nitrogen atom to which they are attached, form heterobicyclic or heteroseksualci, optionally substituted by one or more identical or different (C1-C6)alkyl substituents;

R3represents -(CH2)p-Z3, -C(O)-Z'3, -CH(OH)-Z'3or-C(O)-NH-Z3;

Z3means (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylcarboxylic, (C1-C6)alkoxycarbonyl, (C1-C6)alkylaminocarbonyl, (C3-C7)cycloalkenyl, heterologously, aryl or heteroaryl radical,

(C3-C7)cycloalkenyl and heterologously radicals can be substituted by one or more identical or different radicals selected from (C1-C6)alkyl and hydroxy;

the aryl radical may be optionally substituted by one or more identical or different substituents selected from halogen, nitro or -(CH2)p'-V3-Y3;

V3denotes-O-, -S-, -C(O)-, -C(O)-O-, -NH-C(O)-, -C(O)-NR'3-, -NH-C(O)-NR'3or a covalent bond;

Y3denotes a hydrogen atom or (C1-C6)alkyl radical, optionally substituted by one or more identical or different is halogen radicals;

or Z3denotes a radical of the formula

Z'3denotes aryl radical, optionally substituted by one or more identical or different substituents selected from halogen, nitro and -(CH2)p-V'3-Y'3;

V'3denotes-O-, -C(O)-, -C(O)-O-, -NH-C(O)-, -C(O)-NR'3- or a covalent bond;

Y'3denotes a hydrogen atom or (C1-C6)alkyl radical, optionally substituted by one or more identical or different halogen radicals;

R'3denotes a hydrogen atom, (C1-C6)alkyl or (C1-C6)alkoxyalkyl;

Z3denotes a hydrogen atom or A3-C(O)-O-(C1-C6)alkyl,

-A3-C(O)-NH-(C1-C6)alkyl or-A3-O-(C1-C6)alkyl radical;

And3denotes a linear or branched hydrocarbon chain containing 1-6 carbon atoms, or Allenby radical;

p, p' and p” is an integer from 0 to 4;

R4denotes a radical of the formula -(CH2)s-R'4;

R'4denotes heteroseksualci containing at least one nitrogen atom and optionally substituted (C1-C6)alkyl; heteroaryl containing at least one nitrogen atom and optionally substituted (C1 -C6)alkyl; or a radical of the formula-NW4W'4;

W4denotes a hydrogen atom or (C1-C8)alkyl;

W'4denotes a radical of the formula -(CH2)s'-Z4in which Z4denotes a hydrogen atom, (C1-C8)alkyl or (C3-C7)cycloalkenyl radical;

s and s' represent, independently, an integer from 0 to 6; or their pharmaceutically acceptable salt.

Preferably the present invention relates to compounds of formula I, defined above, and wherein R1denotes a hydrogen atom or (C1-C8)alkyl radical and R2means (C1-C8)alkyl radical, or their pharmaceutically acceptable salts.

The present invention also preferably relates to compounds of formula I, defined above, and characterized in that X represents-CH-, or their pharmaceutically acceptable salts.

Preferably, the present invention also relates to compounds of formula I, defined above, and characterized in that a represents-CH2-or their pharmaceutically acceptable salts.

Preferably, the present invention also relates to compounds of formula I, defined above, and characterized in that a represents-C(O)-C(Ra)(Rb)and Raand Rbrepresent, independently, a methyl for the al; or their pharmaceutically acceptable salts.

Preferably, the present invention also relates to compounds of formula I, defined above, and characterized in that a represents-C(O)-; or their pharmaceutically acceptable salts.

Most preferably, the present invention relates to compounds of formula I, defined above, and characterized in that

R4denotes a radical of the formula -(CH2)s-R'4;

R'4denotes heteroseksualci containing at least one nitrogen atom selected from piperidine and pyrrolidine, heterocycle, optionally substituted

(C1-C6)alkyl; or a radical of the formula-NW4W'4;

W4denotes a hydrogen atom or (C1-C8)alkyl;

W'4denotes a radical of the formula -(CH2)s'-Z4in which Z4denotes a hydrogen atom or (C1-C8)alkyl radical;

s and s' represent, independently, an integer from 0 to 6; or their pharmaceutically acceptable salts.

Most preferably also, the present invention relates to compounds of formula I, defined above, and wherein R3represents -(CH2)p-Z3or-C(O)-Z'3;

Z3means (C1-C6)alkoxy, (C1-C6)alkylcarboxylic, (C1-C6)aldoxycarb the ilen, (C1-C6)alkylaminocarbonyl, aryl or heteroaryl radical,

the aryl radical may be optionally substituted by one or more identical or different substituents of the formula -(CH2)p'-V3-Y3;

V3denotes-O-, -C(O)-, -C(O)-O - or-C(O)-NH-;

Y3means (C1-C6)alkyl radical;

Z'3denotes aryl radical, optionally substituted by one or more identical or different substituents of the formula -(CH2)p-V'3-Y'3;

V'3represents-O-;

Y'3means (C1-C6)alkyl radical;

p, p' and p” represent an integer from 0 to 4; or their pharmaceutically acceptable salts;

and in particular the aryl radical is a phenyl radical and a heteroaryl radical selected from tienie and purile.

The compounds I of the present invention possess useful pharmacological properties. As shown, the compounds I of the present invention have a good affinity for certain sub-types of receptors melanocortin, in particular, MC receptors.

Compounds of the present invention can be thus used in various therapeutic applications. They can be used with success for the treatment of pathological conditions or metabol the mental disorders in the nerve or skin system in the development of which involved one or more receptors melanocortin, such as inflammatory conditions, disorders of energy homeostasis, disorders of the mechanisms of nutrients from the food violations mechanisms maintain weight (obesity, cachexia, anorexia), disorders of sexual activity (erectile dysfunction), neuropathic pain, and mental disorders (anxiety, depression, addiction medicine, skin diseases (acne, dermatitis, skin cancer, melanoma). They can also be used to stimulate nerve regeneration. Later in the experimental part of this application provides an illustration of the pharmacological properties of the compounds of the present invention.

The object of the present invention are also pharmaceutical compositions containing as active ingredient at least one product of formula I, defined above, and pharmaceutically acceptable salts of said product of formula I in combination with a pharmaceutically acceptable carrier.

Pharmaceutically acceptable salt includes, in particular, additive salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, diphosphate, or nitrate, or organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, is ACHAT, methanesulfonate, p-toluensulfonate, pamoate and stearate. Additive salts of bases, such as sodium hydroxide or potassium, are also included in the scope of the present invention, in the case when they can be used. Other examples of pharmaceutically acceptable salts are described in the corresponding manual ("Salt selection for basic drugs",Int. J. Pharm. (1986), 33, 201-217).

The object of this application is also the use of compounds of the present invention in obtaining medications for treating disorders weight, such as obesity, cachexia and anorexia, mental disorders such as anxiety and depression, neuropathic pain, disorders of sexual function such as erectile dysfunction.

The pharmaceutical compositions can be in the form of solids, for example, can be powders, granules, tablets, gelatin capsules or suppositories. Appropriate solid carriers can include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone and wax.

Pharmaceutical compositions containing the compounds of the present invention can also be obtained in liquid form, e.g. as solutions, emulsions, suspensions or syrups. Appropriate liquid the media can be a, for example, water, organic solvents such as glycerol or glycols, and mixtures thereof in varying proportions in water, added to the pharmaceutically acceptable oils or fats. Sterile liquid composition can be used for intramuscular, intraperitoneal or subcutaneous injection, and sterile compositions can also be administered intravenously.

All technical and scientific terms used in the present description, are conventional and well-known experts in the given field values. In addition, all patents (or patent applications), and other references included in the present description as a reference.

Experimental part

Compounds of the present invention, obtained in accordance with the previously described procedures of examples A, B, C, C' and D, are presented in the table below.

Compounds were characterized by their retention time (rt) and the molecular peak as determined by mass spectrometry (MH+).

For mass spectroscopy using a quadrupole mass spectrometer with a single focus (Micromass, Platform model), equipped with a source for electrocapillary with a resolution of 0.8 Yes 50% of the field. The calibration is carried out monthly using substances with masses in the range of 80 and 1000 Da, and a calibration mixture of sodium iodide and rubidium iodide in which aStore mixture of isopropanol/water (1/1 vol.).

For conducting liquid chromatography using the system of Waters, including built-in degasser, four-stroke pump Waters 600, injector for introducing samples Gilson 233 and UV detector Waters PAD 996 UV.

Below shows the elution conditions:

Eluent: A - water + 0,04% triperoxonane acid; B-acetonitrile

T (min)And%B%
1955
8,5595
10,5595
10,6955
14,9955
15,0955

The flow rate: 1 ml/min; injectively volume: 10 μl; column: Uptisphere ODS 3 µm 75·4.6 mm, e

The following examples are given to illustrate the above procedures and in any case can not be considered as limiting the scope of the present invention.

The following table rt (min) mean retention time in min the tah

Pharmacological study

The affinity of compounds of the present invention with respect to different subtypes of receptors melanocortin measured in accordance with procedures similar to those described for MC receptors.

Study of the affinity of compounds against MS receptor melanocortin

The affinity of compounds of the present invention to MC receptors determine when measuring inhibition of binding of [125I]-[Nle4, D-Phe7]-α-MSH c by membrane preparations from transfected Cho-K1 cells.

Cells Cho-K1, stably expressing human MSH receptors were cultured in medium RPMI 1640 containing 10% fetal calf serum, 2 mm glutamine, 100 U/ml penicillin, 0.1 mg/ml streptomycin and 0.5 mg/ml G418. Cells are harvested using 0.5 mm EDTA and centrifuged at 500 g for 5 minutes at 4°C. the Precipitate resuspended in phosphate buffer solution (PBS) and centrifuged at 500 g for 5 minutes at 4°C. the Precipitate resuspended in the environment, tereasa 50 mm Tris-buffer, a pH of 7.4, and then centrifuged at 500 g for 5 minutes at 4°C. Cells are lysed by ultrasonic treatment and centrifuged at 39000 g for 10 minutes at 4°C. the Precipitate resuspended in a medium containing 50 mm Tris-buffer, pH 7.4 and centrifuged at 50000 g for 10 minutes at 4°C. Membranes obtained in the last draft, stored at a temperature of -80°C.

Measurement of competitive inhibition of binding of [125I]-[Nle4, D-Phe7]-α-MSH (Amersham Biosciences) with MC receptors is carried out in a double repeat using polypropylene 96-cell plates. Cell membranes (50 μg protein/cell) and incubated with [125I]-[Nle4, D-Phe7]-α-MSH (0.5 nm) for 90 minutes at 37°C in 50 mm Tris-HCl buffer, pH of 7.4, containing 0.2% of bovine serum albumin (BSA), 5 mm MgCl2and 0.1 mg/ml bacitracin.

Associated [125I]-[Nle4, D-Phe7]-α-MSH is separated from free [125I]-[Nle4, D-Phe7]-α-MSH by filtration through glass fiber filters GF/C Unifilter, PerkinElmer), pre-soaked in 0.1% polyethylenimine (PAYS)using a Filtermate 196 (PerkinElmer). The filters are washed with 50 mm Tris-HCl buffer, pH of 7.4 at a temperature of 0-4°C and the radioactivity determined using a counter (Top Count, PerkinElmer).

Specific binding is determined at the subtraction of the non is practical binding (determined in the presence of 0.1 μm Nle 4, D-Phe7-α-MSH) from the overall binding. Data analyzed using the computer program by the method of nonlinear regression (DL) and determine the values of the constants of inhibition (Ki).

Agonistic or antagonistic activity of the compounds of the present invention to MS receptor is determined by measuring the production of cyclic AMP cells Cho-K1, transfitsirovannykh receptor MS.

Measurement of the production of intracellular cyclic AMP

using MS receptors

Cho-K1 cells expressing MC receptors melanocortins, cultured in 384-cell tablets in medium RPMI 1640 containing 10% fetal calf serum, 0.5 mg/ml G418. Cells are washed twice with 50 μl of medium RPMI 1640, containing 0.2% BSA and 0.5 mm 3-isobutyl-1-methylxanthines (IBMX).

For measuring agonistic effect connection of the cells incubated for 5 minutes at 37°C in the presence of 0.5 mm IBMX and then stimulate the production of cyclic AMP by adding this compound at concentrations from 1 nm to 10 μm, when measuring in a double repeat for 20 minutes at 37°C. the Antagonistic effect of the compounds is determined by inhibition of stimulating the production of cyclic AMP induced Nle4, D-Phe7-α-MSH concentrations from 1 nm to 10 μm, p is outstay the compounds, at concentrations from 1 nm to 10 μm, when measuring in a double repeat for 20 minutes at 37°C.

Reaction medium was removed and add 80 ál lyse buffer. The level of intracellular cyclic AMP measured in a competitive test with fluorescent cyclic AMP (CatchPoint, Molecular Devices).

Tests conducted by the above procedures, allowed to show that the products according to the present invention have a good affinity to MC receptors, so the inhibition constant Kion these receptors is less than micromolar values for most compounds used in the examples.

1. The compound of General formula (I)

in racemic, enantiomeric form or any combinations of these forms, where
A denotes-CH2-, -C(O)-, -C(O)-C(Ra)(Rb)-,
X represents-CH-radical;
Raand Rbrepresent, independently, a hydrogen atom or a (C1-C6)alkyl radical;
R1denotes a hydrogen atom or a (C1-C8)alkyl radical;
R2means (C1-C8)alkyl radical;
R3represents -(CH2)p-Z3-C(O)-Z'3or-C(O)-NH-Z3;
Z3means (C1-C6)alkyl, (C2-C6)alkanniny, (C1-C6)alkoxy, (C1-C61-C6)alkoxycarbonyl, (C1-C6)alkyl-N(RN)carbonyl, (C3-C7)cycloalkenyl, aryl, aaltio or heteroaryl radical, Z3attached to the radical -(CH2)pthrough a carbon atom,
heteroaryl radical, which represents a 5-10 membered heteroaryl, including 1-2 identical or different heteroatoms selected from sulfur, nitrogen or oxygen, and optionally substituted by one or more identical or different substituents selected from halogen, nitro or -(CH2)p'-V30-Y3;
aryl radical selected from phenyl or naphthyl, optionally substituted by one or more identical or different substituents selected from halogen, nitro, ceanography, (C2-C6)alkenyl, pyrrolidinyl, phenyl, phenyloxy, phenylalkylamine, 5-7-membered heteroaryl containing 1-3 nitrogen atom, and -(CH2)p'-V31-Y3;
V30denotes-O-, -C(O)-, -C(O)-O - or a covalent bond;
V31denotes-O-, -S-, -SO2-, -C(O)-, -C(O)-O-, -N(RN)-, -NH-C(O)- or a covalent bond;
Y3denotes a hydrogen atom or a (C1-C6)alkyl radical, optionally substituted by one or more identical or different halogen radicals;
RNdenotes a hydrogen atom or a (C1-C6)and kileny radical;
Z3denotes a radical of the formula

Z'3denotes a phenyl radical, optionally substituted by one
or more identical or different substituents selected from
-(CH2)p-V'3-Y'3;
V'3represents-O-;
Y'3denotes a hydrogen atom or (C1-C6)alkyl radical;
Z3denotes a hydrogen atom or -(CH2)q-A"3radical;
A"3means (C1-C6)alkyl, phenyl or thienyl radical; the alkyl and phenyl radicals can be optionally substituted by one or more identical or different substituents selected from halogen and-V3-Y3;
V3denotes-O-, -C(O)-, -C(O)-O - or a covalent bond;
Y"3denotes a hydrogen atom or a (C1-C6)alkyl radical;
p is an integer from 0 to 6; p' and p" represent, independently, an integer from 0 to 1; q is an integer from 0 to 2;
R4denotes a radical of the formula -(CH2)s-R'4;
R'4represents a 5-7 membered heteroseksualci containing at least one nitrogen atom and optionally substituted (C1-C6)alkyl; or a radical of the formula-NW4W'4;
W4denotes a hydrogen atom;
W'4denotes a hydrogen atom;
s oboznachaet is an integer from 0 to 6;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, wherein R1means (C1-C6)alkyl radical; R2means (C1-C6)alkyl radical; or its pharmaceutically acceptable salt.

3. The compound according to claim 1, characterized in that a represents-CH2-; or its pharmaceutically acceptable salt.

4. The compound according to claim 1, characterized in that a represents-C(O)-C(Ra)(Rb)-, and Raand Rbrepresent, independently, a metal radical; or its pharmaceutically acceptable salt.

5. The compound according to claim 1, characterized in that a represents-C(O)-; or its pharmaceutically acceptable salt.

6. The compound according to any one of claims 1 to 5, characterized in that R4denotes a radical of the formula -(CH2)s-R'4;
R'4denotes heteroseksualci containing at least one nitrogen atom and optionally substituted (C1-C6)alkyl; and s is an integer from 2 to 6; or its pharmaceutically acceptable salt.

7. The connection according to claim 6, characterized in that R'4means piperidino or pyrolidine ring; s is an integer from 2 to 4; or its pharmaceutically acceptable salt.

8. The compound according to any one of claims 1 to 5, characterized in that
R3represents -(CH2)p-Z3; or its pharmaceutically acceptable salt.

9. The connection of claim 8, characterized in that
Z3means (C1-C6)alkyl, (C1-C6)alkylcarboxylic, (C1-C6)alkoxycarbonyl, (C1-C6)alkyl-N(RN)carbonyl, (C3-C7)cycloalkenyl, aryl or heteroaryl radical, where the aryl and heteroaryl radicals can be optionally substituted; or its pharmaceutically acceptable salt.

10. The connection according to claim 9, characterized in that
heteroaryl radical may be optionally substituted by one or more identical or different substituents selected from halogen and -(CH2)p'-V30-Y3;
the aryl radical may be optionally substituted by one or more identical or different substituents selected from nitro and -(CH2)p'-V31-Y3;
V30denotes-O-, -C(O)-, -C(O)-O - or a covalent bond;
V31denotes-O-, -C(O)-, -C(O)-O - or-SO2-;
Y3means (C1-C6)alkyl radical;
p denotes an integer from 0 to 4, and p' represents an integer from 0 to 1; or its pharmaceutically acceptable salt.

11. The connection according to claim 9, characterized in that Z3means (C1-C6)alkyl radical; or its pharmaceutically acceptable salt.

12. The connection according to claim 9, characterized in that Z3putting the AET (C 1-C6)alkylcarboxylic, (C1-C6)alkoxycarbonyl or (C1-C6)alkyl-N(RN)carbonyl radical; or its pharmaceutically acceptable salt.

13. The connection according to claim 9, characterized in that Z3denotes heteroaryl radical, which may be optionally substituted by one or more identical or different substituents selected from halogen and -(CH2)p'-V30-Y3;
V30denotes-O-, -C(O)-, -C(O)-O - or a covalent bond;
Y3means (C1-C6)alkyl radical;
p' represents an integer 0 or 1; or its pharmaceutically acceptable salt.

14. The connection 13, characterized in that Z3denotes thienyl, purely, benzofuranyl, benzothiazolyl, diazolidinyl, personilnya, imidazolidinyl, pyridinoline, indolinyl radical; or its pharmaceutically acceptable salt.

15. The connection according to claim 9, characterized in that Z3means (C3-C7)cycloalkenyl or aryl radical, where the aryl radical may be optionally substituted by one or more identical or different substituents selected from nitro or (CH2)p'-V31-Y3;
V31denotes-O-, -C(O)-, -C(O)-O - or-SO2-;
Y3means (C1-C6)alkyl radical;
p' denotes a whole the e number 0 or 1; or its pharmaceutically acceptable salt.

16. The connection of clause 15, wherein (C3-C7)cycloalkenyl radical selected from cyclopentyl and cyclohexyl; specified aryl radical is a phenyl radical; or its pharmaceutically acceptable salt.

17. The compound according to any one of claims 1 to 5, characterized in that R3denotes-C(O)-Z'3; or its pharmaceutically acceptable salt.

18. The connection 17, characterized in that Z'3denotes a phenyl radical, optionally substituted by one or more identical or different substituents of the formula -(CH2)p-V'3-Y'3;
V'3is-O-;
Y'3means (C1-C6)alkyl radical;
R" is an integer from 0 to 1; or its pharmaceutically acceptable salt.

19. The connection according to one of claims 1 to 5, characterized in that R3denotes-C(O)-NH-Z3;
Z3represents -(CH2)q-A"3radical;
A"3means (C1-C6)alkyl, phenyl or thienyl radical;
alkyl and phenyl radicals can be optionally substituted by one or more identical or different substituents of the formula-V"3-Y3;
V3denotes-O-, -C(O)-, -C(O)-O-;
Y"3denotes a hydrogen atom or a (C1-C6)alkyl radical; q is an integer from 0 to 1; or its pharmaceutically acceptable salt.

20. The method of obtaining the compounds of formula (I) according to claim 1, characterized in that the compound of General formula

in which A, X, R1, R2, R4have the meanings indicated in claim 1, handle
i) or aldehyde of General formula R3CHO, in which R3has the meaning specified in claim 1, in the presence of an oxidant;
ii) or the acid chloride of the acid of General formula R3COCl, in which R3has the meaning specified in claim 1, in the presence of an acid;
iii) or a carboxylic acid of General formula R3C(O)IT, in which R3has the meaning specified in claim 1, in the presence of a binding agent, followed by treatment of the thus obtained amide acid;
iv) or chloroacetamide derivative of General formula Z3-NH-C(O)CH2Cl, where Z3has the meaning specified in claim 1, in the presence of tertiary bases and sulphur.

21. Pharmaceutical composition having affinity towards the receptor MS containing as active ingredient at least one compound according to any one of claims 1 to 19 in combination with a pharmaceutically acceptable carrier.

22. The use of compounds according to one of claims 1 to 19 in getting medicines for treating disorders of the mechanisms of weight maintenance, mental destroy the TV, neuropathic pain, disorders of sexual activity.

23. The use of compounds according to article 22 of obtaining drugs for treatment of disorders of the mechanisms maintaining weight, such as obesity, cachexia and anorexia.

24. The use of compounds according to item 22 in obtaining medications for treatment of mental disorders such as anxiety and depression.

25. The use of compounds according to article 22 of obtaining drugs for the treatment of neuropathic pain.

26. The use of compounds according to article 22 of obtaining drugs for treatment of disorders of sexual activity, such as erectile dysfunction.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to new pyrimidine derivatives with general formula (I), their tautomeric or stereoisomeric form, in free form, in form of pharmaceutically acceptable salt or C1-6alkyl ester which are effective antagonists of CRTH2 (G-protein-associated chemoattractant receptor, ex prone on Th2 cells) and can be used for preventing and treating diseases related to CRTH2 activity, particularly in treatment of allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, diseases related to eosinophil. In formula (I) R1 is hydrogen, or in which n is an integer from 0 to 6; -Q1- is -NH-, -N(C1-6alkyl)- or -O; Y is hydrogen, C1-6alkyl, C3-6cycloalkyl, optionally substituted with C1-6alkyl, C3-6cycloalkyl, condensed with a benzene ring, phenyl, naphthyl or 5-6-member heteroaryl, possibly condensed with a benzene ring, and containing at least one heteroatom, chosen from a group consisting of oxygen and nitrogen, where the said phenyl, naphthyl or heteroaryl are optionally substituted on the displaceable position with one or several substitutes, chosen from a group consisting of cyano, halogen, nitro, guanidine, pyrroyl, sulfamoyl, phenyloxy, phenyl, di(C1-6)alkylamino, C1-6alkanoylamino, C1-6alkyl, optionally mono-, di- or tri-substituted with halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen and C1-6alkylthio, optionally mono-, di- or tri-substituted with halogen; or phenyl, condensed with 1,3-dioxolane; R2 is hydrogen or C1-6alkyl; R3 is a halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen, or , R3a and R3b are independently C3-8cycloalkyl or C1-6alkyl, this C1-6alkyl is optionally substituted with hydroxyl, carboxy, C3-6cycloalkylcarbamoyl, C5-6heterocyclocarbonyl containing a heteroatom in form of nitrogen, or C1-6alkoxy, q is an integer from 1 to 3; R3c is hydrogen, hydroxyl or carboxy; Xa is -O-; R4 is hydrogen, halogen, di(C1-6alkyl) amino or C1-6alkyl, optionally substituted C1-6alkoxy or mono- , di- or tri-substituted with halogen; R5 is hydrogen or C1-6alkyl; and R6 is carboxy, carboxamide, nitrile or tetrazolyl.

EFFECT: wider field of use of compounds.

32 cl, 9 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: in new compounds with general formula (I): , R1 stands for a naphthyl group, which can be substituted with a halogen atom, W represents a bond, a equals 0, 1 or 2, X1 represents C1-4alkylene, which can be substituted with a hydroxy group, Y1 represents -C(O)-,A represents a piperazine ring or piperidine ring, X2 represents a bond, Y2 represents -C(O)-, -S(O)2- or -C(=NR7)- (where R7 represents a hydrogen atom), X3 represents C1-4alkylene, which can be substituted with a hydroxyl group, oxo group or C1-6alkyl group; or C2-4alkylene, which can be substituted with a C1-6alkyl group, where two alkyl groups can be bonded to each other forming, together with carbon atoms to which they are bonded, an aryl ring when X3 represents C2-4alkylene, substituted with two alkyl groups, Z3 represents -N(R4)- or a bond (where R4 represents a hydrogen atom, C1-6alkyl group, which can be substituted with a hydroxy group or methoxy group, or acyl group), represents a single or double bond, where if represents a single bond, then Z1 represents -C(R2)(R2')-, -N(R2)- or -O- and Z2 represents C(R3)(R3')-, -N(R3)-, -O- or a bond (under the condition that, when Z2 represents -O-, then Z is different from -O-), and when represents a double bond, then Z1 represents -C(R3)= or a nitrogen atom and Z2 represents =C(R3)- or a nitrogen atom, each of R2, R2', R3 and R3' represents a hydrogen atom or C1-6alkylene. The invention also relates to salts of the given new compounds. The invention also relates to compounds, chosen from the group, to pharmaceutical compositions, to use of compounds in sub-paragraph 1 or 2, to prevention or treatment methods, as well as to the method of obtaining compounds in paragraph 1.

EFFECT: obtaining new biologically active compounds, which inhibit activated factor X of blood clotting and have anticoagulation activity and antithrombotic activity.

33 cl, 46 ex, 1 tbl

FIELD: chemistry; medicine.

SUBSTANCE: in novel triazole derivatives of general formula I or their pharmaceutically acceptable salts R4 is hydrogen; X is selected from group, consisting of single bond, NH- and groups: , values of R1-R3 radicals are given in description, pharmaceutical composition containing them, and application of novel compounds for obtaining medication for treating hyperglycemia, insulin-resistance, type 2 diabetes, fat exchange derangements, obesity, atheroslerosis and metabolic syndrome.

EFFECT: medications possess higher efficiency.

26 cl, 8 ex, 2 tbl

FIELD: chemistry; medicine.

SUBSTANCE: compounds of claimed invention possess properties of positive allosteric modulator mGluR5. In general formula I , W represents 6-member heterocycloalkyl ring with 1-2 heteroatoms, selected from N, O; R1 and R2 independently represent hydrogen, C1-C6-alkyl; P and Q each independently is selected from: , R3, R4, R5, R6 and R7 independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-member heteroaryl with 1-2 atoms N as heteroatoms; 6-member heterocycle with 2 heteroatoms representing N, O; phenyl, optionally substituted with halogen; naphtyl; -OR8; where optionally two substituents together with located between them atoms form 9-10-member bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S; R8 represents hydrogen, C1-C6-alkyl; D, E, F, G and H independently represent -C(R3)=, -O-, -N=, -N(R3)- or -S-; A represents ethinyl, -C(=O)NR8- or group of formula . B represents -C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6-alkenyl-. Invention also relates to pharmaceutical composition based on invention compounds.

EFFECT: novel compounds possess useful biological proprties.

20 cl, 3 dwg, 75 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: described are novel chemical biologically active substances. As substances, educing negative impact of herbicide 2,4-dichlorophenoxyacetic acid on sunflower plant, proposed are 4,6-dimethyl-2-chlor-3-(5-X-1,2,4-oxadiazolyl-3)pyridines of formula 1-3

EFFECT: extension of line of biologically active substances, obtained by synthetic way, for their application in agriculture as antidotes for 2,4-D.

1 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (I) or to its pharmaceutically acceptable salts or to it solvates, where m is equal 0 to 3, X stands for N, Y stands for -SO2-, each R1 independently stands for halogen, C1-C12alkyl, halogen(C1-C12)alkyl, hydroxy(C1-C6)alkyl, R2 stands for aryl or heteroaryl which represents monocyclic radical containing 5 to 12 atoms in a cycle, including one, two or three nitrogen heteroatoms in a cycle optionally substituted with halogen or cyano, each R3 and R4 independently stands for C1-C12alkyl, or R3 and R4 together with carbon atom whereto they are attached, form the cyclic group containing 3-6 atoms in a cycle, and each R5, R6, R7, R8 and R9 stands for hydrogen. Besides, the invention concerns the pharmaceutical composition.

EFFECT: preparation of the new biologically active compounds with antagonistic action to 5-NT6 receptor.

15 cl, 6 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compounds of formula (I), their obtaining and application as elastase inhibitors, and can be applied in medicine, where Y = CH; R№ represents H or alkyl; RІ represents phenyl or 5-6-memner heteroaryl, G1 represents phenyl; R5 represents H, halogen, alkyl, CN or fluorinated alkyl; n=1-3; R4 = H; L represents bond, O, NR29 or alkyl; or R4 and L are bound together in such way that group -NR4L- represents 5-7-member asacyclic ring; G2 represents phenyl, 5-6-member heteroaryl, cycloalkyl, C4-7-heterocycle, bicycle from two condensed, bound with direct bond or separated with O atom rings, selected from phenyl, 5-6-member heteroaryl, cycloalkyl or C4-7-heterocycle; or when L does not represent bond, G2 represents H; s = 0-2; R25 represents H, alkyl or cycloalkyl; R29 represents H or alkyl.

EFFECT: obtaining novel biologically active compounds.

10 cl, 95 ex, 1 tbl

FIELD: chemistry; pharmacology.

SUBSTANCE: invention refers to new benzofuran and benzothiophen derivatives of general formula I, , wherein X is chosen from O and S; R1 is chosen from H, (C1-C6)alkyl, C(O)(C1-C6) alkyl and benzoyl; R2 is chosen from phenyl optionally substituted with 1 or 2 substitutes, each independently chosen from CN, NO2, (C1-C6)alkyl, (C1-C6)alkoxy, halogen, halogen(C1-C6)alkyl, pyridyl or benzo[1,3]dioxolyl optionally substituted with (C1-C6)alkyl. There are disclosed pharmaceutical composition based on compounds I and method of treatment.

EFFECT: compounds can be used to treat or prevent diseases associated with malignant cell proliferation.

26 cl, 7 tbl, 365 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a compound with general formula where R' stands for phenyl, unsubstituted or substituted with one or more substitutes, chosen from a group comprising alkyl, alkoxy group, halogen, -(CH2)oOH, -C(O)H, CF3, CN, S-alkyl, -S(O)1,2-alkyl, -C(O)NR'R", -NR'R"; R2 and R3 independently stand for hydrogen, halogen, alkyl, alkoxy group, OCHF2, OCH2F, OCF3 or CF3 and R4 and R5 independently stand for hydrogen, -(CH2)2SCH3, -(CH2)2S(O)2CH3, -(CH2)2S(O)2NHCH3, -(CH2)2NH2, -(CH2)2NHS(O)2CH3 or -(CH2)2NHC(O)CH3, R' stands for hydrogen, alkyl, -(CH2)oOH, -S(O)2- alkyl, -S(O)-alkyl, -S-alkyl; R" stands for hydrogen or alkyl; o stands for 0, 1, 2 or 3. The invention also relates to use of formula I compounds in making medicinal preparations for treating schizophrenia, for treating positive and negative symptoms of schizophrenia and medicine for treating schizophrenia.

EFFECT: obtaining new compounds with useful biological properties.

55 cl, 421 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new a compound of formula I or formula II, or to its pharmaceutically acceptable salts, I II, where X is S; R1 is H or C1-C6alkyl; R2 is NR5R6; R3 is aryl, substituted with a halogen; R4 is H; R5 is H; R6 is H; R7 is CH2NR8R9 where R8 is H, C1-C10alkyl, C3-C8cycloalkyl, aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), heterocycle(C1-C6alkyl), heterocycle(C2-C6alkenyl), hydroxyl(C1-C6alkyl), hydroxyl(C2-C6alkyl), C1-C6alkoxycarbonyl, aryl(C1-C6alkoxy)carbonyl, carbamoyl(C1-C6alkyl); where the above mentioned aryl is an aromatic ring and is not substituted or substituted with one to three substituting groups, each of which, independently from the others, is chosen from: methylenedioxy, hydroxy, C1-C6-alkoxy, halogen, C1-C6alkyl, trifluoromethyl, trifluoromethoxy, NO2, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH-acyl, N(C1-C6alkyl)-acyl, hydroxy(C1-C6alkyl), dihydroxy(C1-C6alkyl), CN, C(=O)O(C1-C6alkyl), phenyl, phenyl(C1-C6alkyl), phenyl(C1-C6alkenyl), phenoxy and phenyl(C1-C6alkoxy), R9 is H, C1-C10alkyl, heterocycle(C1-C6alkyl) or heterocycle(C2-C6alkenyl); where the above mentioned heterocycle represents a 5-member saturated monocyclic ring system, consisting of carbon atoms, as well as heteroatoms, chosen from a group comprising N, O, and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes NO2, aryl(C1-C6alkyl), arylsulphonyl; or R8 and R9 together with nitrogen, to which they are bonded, form a heterocycle, which represents a 5 - 7-member saturated monocyclic ring system, consisting of carbon atoms, as well as one to three heteroatoms, chosen from a group comprising N, O and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes C1-C6alkoxy, hydroxy, C1-C6alkyl, C2-C6-alkenyl, C(=O)O(C1-C6alkyl), C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6-alkyl)2, hydroxy(C1-C6alkyl), dihydroxy(C2-C6alkyl), aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), aryl(C1-C6alkoxy) and pyrimidin-2-yl; and m equals 0. The invention also relates to a pharmaceutical composition, as well as to use of formula I or formula II compounds.

EFFECT: obtaining new biologically active compounds, with inhibitory properties towards casein kinase 1ε.

32 cl, 3 tbl

FIELD: chemistry.

SUBSTANCE: present invention refers to compounds of general formula (I) in the state of base salt or acid-addition salt, to method of their preparation and to the pharmaceutical composition thereof In the said formula R1 is (C1-C6)alkyl; (C3-C7)cycloalkyl unsubstituted or substituted once or more than once; (C3-C7)cycloalkylmethyl unsubstituted or substituted once or more than once; phenyl unsubstituted or substituted ; benzyl unsubstituted or substituted once or twice ; thienyl unsubstituted or substituted ; R2 is atom hydrogen or (C1-C3)alkyl; R3 is (C1-C5)alkyl; R4, R5, R6, R7, each R8 and R9 independently represents the atom of hydrogen, atom of halogen, (C1-C7)alkyl, (C1-C5)alkoxy or trifluoromethyl radical; n is 0, 1 or 2; Alk is (C1-C4)alkyl.

EFFECT: new compounds possess useful biological activity.

5 cl, 5 tbl, 4 ex

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 relates to novel imidazole derivatives of formula (I): and to its salts with acid, where: R1 and R2 represent hydrogen; Q represents (CH2)m-X-(CH2)n-A; A represents direct bond, O, SO2, NR5; X represents direct bond, O, SO2, C(O) or NR5; Z represents group selected from : m and n represent, each independently, 0, 1, 2, 3 or 4; p represents 1, 2, 3 or 4; q represents 0, 1 or 2; dotted line means that R8 and/or R9 can be situated in any position of benzothiophene ring; R3 and R8 represent, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11, OSO2NR10R11 or NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10; when Q-Z represents n 0, 1 or 2 and p represents 1, one of R3 and R8 represents hydroxy, nitro, NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CONR10R11, and the other represents hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11 OSO2NR10R11, NR12SO2NR10R11, CO2R10; R4 and R9 represent, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CHO; when p represents 2, 3 or 4, R9 can be similar or different; R6 and R7 represent hydrogen; each R5, R10, R11 and R12 represents hydrogen; when Z represents and p represents 1, then R8 and R9 can also together with phenyl ring form benzoxathiazine dioxide. Invention also relates to pharmaceutical composition and to application of derivatives by any of ii.1-25.

EFFECT: obtaining novel biologically active compounds which possess inhibiting activity with respect to aromatase and/or steroid-sulfatase and/or carboanhydrase.

36 cl, 67 ex, 5 tbl

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: invention refers to Sertaconasole mononitrate process by reaction of 1-(2,4-dichlorphenyl)-2-(1H-imidazole-1-yl)ethanol and 3-bromomethyl-7-chlorbenzo[b]thiophene with tetrabutylammonium hydrosulphate and sodium hydroxide in toluene at 30-45°C. Produced free base of Sertaconasole is transferred into Sertaconasole mononitrate monohydrate with the latter being transferred into Sertaconasole mononitrate. There is disclosed and characterised intermediate Sertaconasole mononitrate monohydrate.

EFFECT: method allows simplifying process technology considerably.

6 cl, 5 dwg, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (I) where R1 stands for hydrogen or linear, branched, saturated or unsaturated hydrocarbon radical; D stands for nitrogen atom or C-R2; E stands for nitrogen atom or C-R3; F stands for nitrogen atom or C-R4; G stands for nitrogen atom or C-R5; R2, R3, R4 and R5 are identical or different and individually represent hydrogen, halogen, alkoxy, linear or branched, saturated or unsaturated hydrocarbon radical; W stands for oxygen atom; X stands for radical of formula radical -(CH2)k-C(O)-(CH2)m-, -(CH2)n- or -(CH2)r-O-(CH2)s-, where k, m, r and s are equal to integers 0 to 6, and n is equal to an integer 1 to 6. Said radicals are optionally substituted with one or more substitutes independently chosen from the group consisting of R7; Y stands for radical of formula radical -(CH2)i-NH-C(O)-(CH2)j-, -(CH2)n-, -(CH2)r-O-(CH2)s-, -(CH2)t-NH-(CH2)u-, where i, j, n, r, s, t and u are equal to integers 0 to 6. Said radicals are optionally substituted C1-3alkyl, or C1-3alkyl-C1-3alkylsulphonylamino; radicals R7, B, R8, A, R9 are as it is presented in the patent claim. The invention also describes the pharmaceutical composition possessing inhibitory activity of receptor tyrosine kinase to KDR receptor including described compounds.

EFFECT: compounds possess inhibitory activity of receptor tyrosine kinase to KDR receptor and can be effective in therapy of the diseases associated uncontrolled angiogenesis.

29 cl, 746 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with general formula I, where R1 represents -(CHR')q-aryl or -(CHR')q-thiophen, which are unsubstituted or mono-, di- or tri-substituted with (inferior)alkyl, (inferior)alkoxy, CF3 or haloid, or represents (inferior)alkyl, (inferior)alkenyl, -(CH2)n-Si(CH3)3, -(CH2)n-O-(inferior)alkyl, -(CH2)n-S- (inferior)alkyl, -(CH2)q-cycloalkyl, -(CH2)n-[CH(OH)]m-(CF2)p-CHqF(3-q), or represents -(CH2)n-CR2-CF3, where two radicals R together with a carbon atom form a cycloalkyl ring; R' represents hydrogen or (inferior)alkyl; n is 1, 2 or 3; m is 0 or 1; p is 0, 1,2, 3, 4, 5 or 6; q is 0, 1, 2 or 3; R2 represents hydrogen or (inferior)alkyl; R3 represents hydrogen, (inferior)alkyl, CH2F, aryl, optionally mono-, di- or tri-substituted with a haloid, or represents -(CH2)nNR5R6, where R5 and R6 independently represent hydrogen or (inferior)alkyl; R4 represents one of the following groups a) or b), where R7 represents inferior)alkyl or -(CH2)ncycloalkyl; R8 and R9 independently represent hydrogen, (inferior)alkyl, -(CH2)n-cycloalkyl or -C(O)-phenyl. The invention also relates to pharmaceutically used acid addition salts of these compounds, optically pure enantiomers, racemates or diastereomeric mixtures, as well as compounds with general formula I-1, and medicinal agent.

EFFECT: obtaining new biologically active compounds, designed for inhibiting γ-secretase.

16 cl, 83 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel compound represented by formula I, where R1 and R2 are similar or different and each represents: (I) C1-10alkyl group optionally substituted with 1-3 substituents selected from C3-10cycloalkyl group, C1-6alkoxycarbonyl group b C1-6alkoxygroup; (2) C6-14aryl group optionally substituted with 1-3 substituents selected from halogen atom, carboxyl group, C1-6alkoxycabonyl group b carbamoyl group; or (3) C7-13aralkyl group; R3 represents C6-14aryl group optionally substituted with 1-3 substituents selected from C1-6alkyl group, optionally substituted with 1-3 halogen atoms, halogen atom, C1-6alkoxycarbonyl group, carboxyl group, hydroxy group, C1-6alkoxygroup, optionally substituted with 1-3 halogen atoms; R4 represents amino group; L represents C1-10alkylene group; Q represents bond, C1-10alkylene group or C2-10alkenylene group; and X represents: (1) hydrogen atom; (2) cyanogroup; (3) (3a) carboxyl group; (3b) carbamoyl group; and further as presented in invention formula. Invention also describes medication for treating diabetes, peptidase inhibitor, application of formula I compound, method of prevention or treatment of diabetes, method of peptidase inhibiting and method of obtaining formula I compounds.

EFFECT: obtaining novel compounds which have peptidase-inhibiting activity and are useful as medication for prevention and treatment of diabetes.

16 cl, 433 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I) compounds and to their use in treating diseases related to lipid storage disorders, such as atherosclerosis and diabetes. In R1 represents hydrogen, alkyl, halogen, formyl, hydroxyalkyl or trifluoromethyl, R2 represents hydrogen, alkyl or halogen, R3 represents hydrogen or alkyl, R4 represents hydrogen, alkyl, hydroxy or alkoxy, R5 and R6 are chosen from hydrogen, alkyl, phenylalkyl, hydroxyalkyl, alkoxycarbonyl and phenyl, A represents aryl or heterocyclyl, m equals 0-3, n equals 0-1, p equals 0-3, sum of m, n and p equals 1-4, the bond between carbon atoms Ca and Cb is a single or double carbon-carbon bond.

EFFECT: obtaining new biologically active compounds.

27 cl, 147 ex

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