New derivatives benzimidazole and imidazopyridine and their application as medicines

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with the general formula (I) in the racemic, enantiomeric form or in any combination of these forms and in which: A represents -CH2-, -C(O)-, -C(O)-C(Ra)(Rb)-; X represents -CH-; Ra and Rb independently represent the hydrogen atom or a radical (C1-C6)alkyl; Rj represents the atom of hydrogen; a radical (C1-C8)alkyl, not necessarily substituted hydroxyl or by one or more identical or different radicals of halogens; (C2-C6)alkenyl; or a radical of the formula -(CH2)n-X1; R2 represents a radical (C1-C8)alkyl not necessarily substituted hydroxyl or by one or more identical or different radicals of halogens; (C2-C6)alkenyl; or a radical of the formula -(CH2)n-X1; each X1 independently represents (C1-C6)alkoxy, (C3-C7)cycloalkyl or heteroaryl, and radicals (C3-C7)cycloalkyl, aryl and heteroaryl are not necessarily replaced by one or more either identical or various assistants chosen from: -(CH2)n'-V1-Y1, halogen and; V1 represents -O-, -S- or a covalent bond; Y1 represents a radical (C1-C6)alkyl, not necessarily substituted hydroxyl or by one or more identical or different radicals of halogens; n represents an integer from 0 up to 6 and n ' - an integer from 0 up to 2 that if n is equal 0 then X1 does not represent a radical alkoxy); or R1 and R2 form together with the atom of nitrogen to which they are attached, heterobicycloalkyl or heterocycloalkyl, are not necessarily replaced by one or more either identical or various substitutes chosen from: hydroxy, (C1-C6)alkyl, not necessarily substituted by hydroxy, (C1-C6)alkoxycarbonyl, heterocycloalkyl and-C(O)NV1'Y1', in which V1' and Y1' independently represent the atom of hydrogen or (C1-C6)alkyl; or R1 and R2 together form a radical of the formula: R3 represents-Z3, -C(RZ3)(R'Z3)-Z3, -C(RZ3)(R'Z3)-(CH2)p-Z3 or -C(O)Z'3; RZ3 and R'Z3 independently represent atom of hydrogen or a radical (C1-C6)alkyl; Z3 represents Z3b, Z3c, Z3d or Z3e; Z3b represents (C1-C6)alkoxy, (C1-C6)alkythio, (C1-C6)alkylamino, or a radical di((C1-C6)alkyl) amino; Z3c represents aryl or a radical heteroaryl; Z3d represents C1-C6)alkoxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, di((C1-C6)alkyl) aminocarbonyl, (C1-C6)alkyl-C(O)NH-, (C3-C7) cycloalkyl, heterocycloalkyl; and radicals (C3-C7) cycloalkyl and heterocycloalkyl are not necessarily replaced by one or more either identical or various substitutes chosen from: (C1-C6)alkoxy, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl and oxy, radicals aryl and heteroaryl are not necessarily replaced by one or more either identical or various substitutes chosen from: halogen, cyanogen, nitro, azide, oxy, (C1-C6)alkylcarbonyl-(C1-C6)alkenyl, (C1-C6)alkylaminocarbonyl-(C1-C6)alkenyl, -SO2-NR31R32, heterocycloalkyl, heteroaryl or -(CH2)P'-V3-Y3; R31 and R32 form together with atom of nitrogen to which they are attached, heterocycloalkyl, V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -O-C(O)-, -SO2-, -SO2NH-, -NR'3-SO2-, -NR'3-, -NR'3-C(O)-, -C(O)-NR'3-, -NH-C(O)-NR'3- or covalent bonds; Y3 represents the atom of hydrogen; radical (C1-C6)alkyl, not necessarily replaced by one or more either identical or different radicals of halogens; radical aryl or a radical aryl-(C1-C6)alkyl; Z3e represents a radical of the formula

, Z'3 represents a radical aryl, not necessarily replaced by one or more oreither identical or various substitutes chosen from: halogen, nitro and -(CH2)P"-V'3-Y'3; V'3 represents -O-, -C(O)-, -C(O)-O, -C(O)-NR'3-,-NH-C(O)-NR'3- or covalent bonds; Y'3 represents the atom of hydrogen or a radical (C1-C6)alkyl, not necessarily replaced by one or more either identical or different radicals of halogens; R'3 represents the atom of hydrogen (C1-C6)alkyl or a radical (C1-C6)alkoxy; p represents an integer from 1 up to 4; p' and p" independently represent an integer from 0 up to 4; R4 represents a radical of the formula -(CH2)S-R'4; R'4 represents a radical guanidine; heterocycloalkyl containing, at least, one atom of nitrogen and not necessarily substituted (C1-C6)alkyl or aralkyl; heteroaryl containing, at least, one atom of nitrogen and not necessarily substituted (C1-C6)alkyl or a radical of the formula -NW4W'4; W4 represents an atom of hydrogen or (C1-C8) alkyl; W'4 represents a radical of the formula -(CH2)S-Z4; Z4 represents an atom of hydrogen (C1-C8) alkyl, (C3-C7)cycloalkyl, heteroaryl and aryl; s and s' independently represent an integer from 0 up to 6; and i) if R3 represents -C(O)-Z'3 and R4 represents a radical of the formula -(CH2)S-NW4W'4, and W4 and W'4 independently represent an atom of hydrogen or a radical C1-C6)alkyl, then -(CH2)s represents neither radical ethylene nor radical -(CH2)-CH((C1-C4)alkyl) and ii), if R3 represents -Z3c and Z3c represents phenyl or naphthyl, then phenyl and naphthyl are not substituted by cyanogen; also note that if R3 represents -Z3d, then Z3d, represents only one (C3-C7)cycloalkyl or heterocycloalkyl; or to their pharmaceutically acceptable salts. The invention also relates to the method of obtaining the compounds of the formula (I), to a pharmaceutical composition, and to the application of compounds of the formula (I) and (I ').

EFFECT: obtaining new biologically active compounds on their basis, possessing activity with respect to receptors MC4.

41 cl, 535 ex

 

The subject of this application are new derivatives of benzimidazole and imidazopyridine. These products have good affinity to certain subtypes of melanocortin receptors, in particular to the MC4 receptor. They are particularly useful for treating pathological conditions and diseases that involve one or more melanocortin receptors. The invention also relates to pharmaceutical compositions containing said products, and their application to obtain the drug.

Melanocortin are a group of peptides that originate from the same precursor, proopiomelanocortin (POMC, POMC) and which are structurally similar: adrenocorticotropic hormone (ACTH, ACTH), α-melanocyte stimulating hormone (α-MSH), β-MSH and γ-MSH (Eipper B.A. and R.E. Mains, Endocr. Rev. 1980, 1, 1-27). Melanocortin perform numerous physiological functions. They stimulate the synthesis of steroids by the adrenal cortex and eumelanin synthesis by melanocytes. They regulate food intake, 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 regulate the secretion of several endocrine or EC is ocring glands, such as sebaceous, lacrimal and mammary glands, prostate and pancreas (Wikberg J.E. and other Pharmacol. Res. 2000, 42, 393-420; Abdel-Malek Z.A., Cell. Mol. Life. Sci. 2001,58,434-441).

The effect of melanocortins mediated by a family of membrane receptors characteristic seven transmembrane domains and are associated with G-proteins. To date, cloned and characterized five receptor subtypes, named from MC1 to MC5. These receptors differ in their tissue distribution and their affinity to different melanocortin, and MC2 receptors only recognize ACTH. Stimulation of melanocortin receptors activates adenylate cyclase with the production of cyclic AMP. If the specific functional role of each of the receptors is not fully explained, the treatment of pathological disorders or diseases may be associated with affinity to certain subtypes of receptors. Thus, activation of receptors MC1 was associated with the treatment of inflammation, while blocking them was associated with the treatment of skin cancer. Treatment of malnutrition was associated with receptors MC3 and MC4, the treatment of obesity agonists and the treatment of cachexia and anorexia antagonists. Other indications associated with activation of receptors MC3 and MC4 are problems with sexual activity, neuropathic pain, anxiety, depression and drug dependency. Activation is eception MC5 was associated with the treatment of inflammation of the sebaceous glands and dermatoses.

Applicants have found that the new compounds of General formula (I), described below, have a good affinity to melanocortin receptors. They preferably operate on the MC4 receptor. These compounds, agonists or antagonists of melanocortin receptors can be used for the treatment of pathological conditions or diseases of metabolism, nervous system or dermatological diseases involving one or more melanocortin receptors, such as the following examples: inflammatory conditions, disorders of energy homeostasis, impaired food intake, impaired weight gain (obesity, cachexia, anorexia), disorders of sexual activity (erectile dysfunction), pain and, in particular neuropathic pain. You can also mental health problems (anxiety, depression), drug dependency, skin diseases (inflammation of the sebaceous glands, dermatitis, skin cancer, melanoma). These compounds can also be used to stimulate nerve regeneration.

Therefore, an object of the present invention is a compound of General formula (I)

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

A represents A-CH2-, -C(O)-, -C(O)-C(Rand)(Rb)-;

X represents-CH - or-N-;

p> Randand Rbindependently represent a hydrogen atom or the radical (C1-C6)alkyl;

R1represents a hydrogen atom; a radical (C1-C8)alkyl, optionally substituted by hydroxy or one or more identical or different halogen radicals; (C2-C6)alkenyl; or a radical of the formula -(CH2)n-X1;

R2represents the radical (C1-C8)alkyl, optionally substituted by hydroxy or one or more identical or different halogen radicals; (C2-C6)alkenyl; or a radical of the formula -(CH2)n-X1;

each X1independently represents a C1-C6)alkoxy, (C3-C7)cycloalkyl, substituted, heteroseksualci, aryl or heteroaryl,

moreover, the radicals (C3-C7)cycloalkyl, heteroseksualci, aryl and heteroaryl optionally substituted by one or more identical or different substituents selected from: -(CH2)n'-V1-Y1, halogen, nitro, cyano and aryl;

V1represents-O-, -S - or a covalent bond;

Y1represents the radical (C1-C6)alkyl, optionally substituted by one or more identical or different halogen radicals;

n represents an integer from 0 to 6 and n' an integer from 0 to 2 (and it should be understood that, if n is equal to 0, then the and X 1does not represent a radical alkoxy);

or R1andR2form together with the nitrogen atom to which they are attached, heterobicyclic or heteroseksualci, optionally substituted by one or more identical or different substituents selected from: hydroxy, (C1-C6)alkyl, optionally substituted hydroxy,(C1-C6)alkoxycarbonyl, heterocyclization and-C(O)NV1'Y1'where V1' and Y1' independently represent a hydrogen atom or a (C1-C6)alkyl; or R1and R2together form a radical of the formula:

R3represents-Z3, -C(RZ3)(R'Z3)-Z3, -C(RZ3)(R'Z3)-(CH2)p-Z3or-C(O)-Z'3;

RZ3and R'Z3independently represent a hydrogen atom or the radical (C1-C6)alkyl;

Z3isZ3a,Z3b,Z3c,Z3dorZ3e;

Z3arepresents the radical (C1-C6)alkyl;

Z3brepresents the radical (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkylamino or di((C1-C6)alkyl)amino;

Z3crepresents aryl or heteroaryl;

Z3dis (C1-C6)alkoxycarbonyl, Amin is carbonyl, (C1-C6)alkylaminocarbonyl, di((C1-C6)alkyl)aminocarbonyl, (C1-C6)alkyl-C(O)-NH-, (C3-C7)cycloalkyl, heteroseksualci;

moreover, the radicals (C3-C7)cycloalkyl and heteroseksualci optionally substituted by one or more identical or different substituents selected from: halogen, nitro, (C1-C6)alkoxy, optionally substituted by one or more identical or different radicals halogen, (C1-C6)alkyl, optionally substituted by one or more identical or different radicals halogen, (C1-C6)alkylsulphonyl, (C1-C6)alkoxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, di((C1-C6)alkyl)aminocarbonyl and hydroxy,

the aryl radicals and heteroaryl optionally substituted by one or more identical or different substituents selected from: halogen, cyano, nitro, azido, hydroxy, (C1-C6)alkoxycarbonyl-(C1-C6)alkenyl, (C1-C6)alkylaminocarbonyl-(C1-C6)alkenyl, -SO2-NR31R32, geterotsiklicheskie, heteroaryl or -(CH2)p'-V3-Y3;

R31and R32together with the nitrogen atom to which they are attached, form heteroseksualci;

V3represents-O-, -S-, -C(O)-, -C(O)-O-, -O-C(O)-, -SO2 -, -SO2NH-, -NR'3-SO2-, -NR'3-, -NR'3-C(O)-, -C(O)-NR'3-, -NH-C(O)-NR'3- or a covalent bond;

Y3represents a hydrogen atom; a radical (C1-C6)alkyl, optionally substituted by one or more identical or different halogen radicals; aryl radical, optionally substituted by one or more identical or different substituents selected from: halogen, nitro, (C1-C6)alkyl and (C1-C6)alkoxy; or a radical aryl-(C1-C6)alkyl, optionally substituted by one or more identical or different substituents selected from: halogen, nitro,(C1-C6)alkyl and (C1-C6)alkoxy;

Z3erepresents a radical of the formula

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

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

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

R'3represents a hydrogen atom, (C1-C6)alkyl or (C1-C6)Ala is XI;

p represents an integer from 1 to 4; p' and p independently represent an integer from 0 to 4;

R4represents a radical of the formula -(CH2)s-R'4;

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

W4represents a hydrogen atom or a (C1-C8)alkyl;

W'4represents a radical of the formula -(CH2)s'-Z4;

Z4represents a hydrogen atom, (C1-C8)alkyl, optionally substituted by one or more identical or different substituents selected from (C1-C6)alkoxy, (C1-C6)alkylthio and hydroxy; (C2-C6)alkenyl; (C3-C7)cycloalkyl, optionally substituted by one or more identical or different (C1-C6)alkilani; cyclohexene; heteroaryl and aryl;

and aryl radicals and heteroaryl optionally substituted by one or more identical or different radicals selected from: the formula -(CH2)s-V4-Y4, hydroxy, halogen, nitro and cyano;

V4represents-O-, -S-, -NH-C(O)-, -NV4'- ricouletoac communication;

Y4represents a hydrogen atom or the radical (C1-C6)alkyl, optionally substituted by one or more identical or different halogen radicals;

V4' represents a hydrogen atom or a (C1-C6)alkyl;

s" represents an integer from 0 to 4;

or Z4represents a radical of the formula

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

and (i) if R3represents-C(O)-Z'3and R4represents a radical of the formula -(CH2)sNW4W'4andW4and W'4independently represent a hydrogen atom or the radical (C1-C6)alkyl, then -(CH2)srepresents neither the ethylene radical or the radical -(CH2)-CH((C1-C4)alkyl) and (ii)if R3represents-Z3cand Z3crepresents phenyl or naphthyl, then the phenyl and naphthyl are not substituted by cyano; and it should be understood that, if R3represents-Z3dthen Z3dis only one (C3-C7)cycloalkyl or heteroseksualci; or its pharmaceutically acceptable salt.

In the definitions above, the expression represents a halogen radical of fluorine, chlorine, bromine or iodine, preferably chlorine, fluorine or bromine. The expression alkyl (unless otherwise specified), preferably represents a linear or Razvitie the hydrated alkyl radical, containing from 1 to 6 carbon atoms, such as radicals methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl andtert-butyl,pentyl or amyl, isopentyl, neopentyl, 2,2-dimethylpropyl, hexyl, isohexyl or 1,2,2-trimethylpropyl. The term (C1-C8)defines a linear alkyl or branched alkyl radical containing from 1 to 8 carbon atoms, such as radicals containing from 1 to 6 carbon atoms as defined above, but also heptyl, octyl, 1,1,2,2-TETRAMETHYLBUTYL, 1,1,3,3-TETRAMETHYLBUTYL. The term hydroxyalkyl determines the radicals in which the alkyl radical is a radical according to the definition given above, such as, for example, hydroxymethyl, hydroxyethyl. The phrase, alkyl, substituted hydroxy, shall mean any linear or branched alkyl chain containing a hydroxy radical, located along the chain; thus, for a chain containing 3 carbon atoms and one hydroxy radical, as examples of HO-(CH2)3-, CH3-CH(OH)-CH2andCH3-CH2-CH(OH)-.

Under alkenyl, unless otherwise specified, is meant a linear or branched alkyl radical, of soderjali from 1 to 6 carbon atoms and containing at least one unsaturated bond (double bond), such as, for example, vinyl, allyl, propenyl, butenyl or pen is Anil.

The term alkoxy determines the radicals in which the alkyl radical is a radical according to the definition given above, such as, for example, the radicals methoxy, ethoxy, propyloxy or isopropoxy, but also linear, secondary or tertiary, butoxy, pentyloxy. The term alkoxycarbonyl preferably determines the radicals in which the alkoxy radical is a radical according to the definition given above, such as, for example, methoxycarbonyl, etoxycarbonyl. The term alkylthio determines the radicals in which the alkyl radical is a radical according to the definition given above, such as, for example methylthio, ethylthio. The term guanidine represents the radical-NHC(=NH)NH2.

The term (C3-C7)cycloalkyl determines the saturated carbon monocyclic system which contains from 3 to 7 carbon atoms, and preferably ring cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Expression heteroseksualci determines condensed monocyclic or bicyclic saturated system containing from 2 to 9 carbon atoms and at least one heteroatom. This radical can contain several identical or different heteroatoms. Preferably the heteroatoms are selected from oxygen, sulfur or nitrogen. As an example, heterotic is valkila can be called rings, 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), but also rings not containing a nitrogen atom such as tetrahydrofuran or tetrahydrothiophene. As an example of cycloalkyl or geterotsiklicheskie, substituted hydroxy, it can be noted, for example, pyrrolidine, imidazolidine.

The term heterobinuclear determines unfused saturated hydrocarbon bicyclic system containing from 5 to 8 carbon atoms and at least one heteroatom selected from nitrogen, oxygen and sulfur. As an example of heterobinuclear 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 represents an aromatic radical, formed by the ring or condensed rings, such as phenyl, naphthyl, fluorenyl or ontril. Expression heteroaryl determines aromatic radical, formed by the ring or condensed rings, at least one ring containing one or more identical or different heteroatoms selected from sulfur, nitrogen or oxygen as an example of radical heteroaryl can be noted radicals, containing at least one nitrogen atom, such as pyrrolyl, imidazolyl, pyrazolyl, isothiazolin, thiazolyl, isoxazolyl, oxazolyl, triazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidyl, hinely, ethanolic, honokalani, indolyl, dihydroindole, benzoxadiazole, carbazolyl, phenoxazines, but also radicals,not containing a nitrogen atom, such as thienyl, benzothiazyl, furyl, benzofuran, dibenzofuran, dihydrobenzofuran, dibenzothiazyl, thioxanthenes or pyranyl. The term aralkyl(arylalkyl) preferably defines radicals, which radicals the aryl and alkyl are radicals in accordance with the definition given above, such as, for example, benzyl or phenethyl. As examples of the aryl or heteroaryl, substituted hydroxy, it can be noted, for example, fluorine, acridan, xanthene, benzothiazolium, anthraquinone, thioxanthen, benzocoumarin.

Also in this application, the radical (CH2)i(and an integer i can imagine n, n', p, p', p", s, s' and s', as defined above), represents a linear or branched hydrocarbon chain containing i carbon atoms. Thus, the radical -(CH2)3- may represent-CH2-CH2-CH2but also-CH(CH3)-CH2-, -CH2-CH(CH3)- or-C(CH3)2-.

Also in accordance with the present application, if the radical is determined by the four who uloi-B-D-E, in which D represents, for example, -C(O)-NH-, this means that the carbon atom of a group-C(O)-NH - is associated with B, and the nitrogen atom - E.

Preferably the invention relates to compounds of formula I, as defined above, and wherein X is-CH-; or their pharmaceutically acceptable salts.

Preferably the invention relates to compounds of formula I, as defined above, characterized in that X represents-CH-, and A represents A-CH2and , more specifically

R1andR2independently represent a radical (C1-C8)alkyl;

R3represents-Z3c, -C(RZ3)(R'Z3)-Z3c, -C(RZ3)(R'Z3)-Z3d, -C(RZ3)(R'Z3)-(CH2)p-Z3d;

R4represents a radical of the formula -(CH2)s-R'4;

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

W4represents a hydrogen atom or a (C1-C8)alkyl;

W'4represents a radical of the formula -(CH2)s'-Z4;

Z4represents a hydrogen atom;

s represents an integer from 2 to 4; s' represents an integer from 0 to 4; and preferably

heteroseksualci represented by R'4represents piperidino to what ICO;

RZ3and R'Z3represent a hydrogen atom;

Z3cis thienyl, furyl or phenyl,

moreover, the phenyl radical substituted by one or more identical or different substituents selected from halogen and -(CH2)p'-V3-Y3;

V3represents-O-, -C(O)-, -C(O)-O-, -C(O)-NR'3- or a covalent bond;

R'3represents a hydrogen atom or the radical (C1-C6)alkyl;

Y3represents a hydrogen atom; a radical (C1-C6)alkyl, optionally substituted by one or more identical or different halogen radicals;

Z3dis (C1-C6)alkoxycarbonyl or heteroseksualci, and preferably heteroseksualci is imidazolidin; or their pharmaceutically acceptable salts.

Preferably the invention also relates to compounds of formula I, as defined above, characterized in that X represents-CH-, and A represents-C(O)-C(Rand)(Rb)-, in which Randand Rbrepresent the methyl radical; and more specifically

R1and R2independently represent a radical (C1-C8)alkyl;

R3represents-Z3c, -C(RZ3)(R'Z3)-Z3c, -C(RZ3)(R'Z3)-Z3dor-C(RZ3)(R'Z3)-(CH2)p-Z3d;

R4represents a radical of the formula -(CH )s-R'4;

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

W4represents a hydrogen atom or a (C1-C8)alkyl;

W'4represents a radical of the formula -(CH2)s'-Z4;

Z4represents a hydrogen atom, a phenyl radical or heteroaryl;

s represents an integer from 2 to 4; s' represents an integer from 0 to 4; and preferably

RZ3andR'Z3independently represent a hydrogen atom;

Z3crepresents the radical thienyl, optionally substituted (C1-C6)alkoxycarbonyl; or phenyl substituted by one or more identical or different substituents selected from: halogen, nitro or -(CH2)p'-V3-Y3;

V3represents-O-, -C(O)-, -C(O)-O-, -C(O)-NR'3- or a covalent bond;

Y3represents a hydrogen atom; a radical (C1-C6)alkyl, optionally substituted by one or more identical or different halogen radicals;

R'3represents a hydrogen atom;

Z3drepresents the radical (C1-C6)alkoxycarbonyl;

heteroseksualci represented by R'4represents piperidine;

heteroaryl, presents Z represents a pyridine; or their pharmaceutically acceptable salts.

Preferably the invention also relates to compounds of formula I, as defined above, characterized in that X represents-CH-, and A represents-C(O)-,

and more specifically, R3represents-C(O)-Z'3;

R1and R2independently represent a radical (C1-C8)alkyl;

Z'3represents a phenyl radical, optionally substituted by one or more identical or different substituents selected from halogen, nitro and -(CH2)R-V'3-Y'3;

V'3represents-O-, -C(O)-O - or a covalent bond;

Y'3represents a hydrogen atom or the radical (C1-C6)alkyl;

p represents the integer 0;

R4represents a radical of the formula -(CH2)s-R'4and R'4represents a radical of the formula-NW4W'4;

W4represents a hydrogen atom or a (C1-C8)alkyl;

W'4represents a radical of the formula -(CH2)s'-Z4and Z4represents a hydrogen atom;

s represents an integer from 2 to 4; s' represents an integer from 0 to 4;

or their pharmaceutically acceptable salts.

Preferably the invention also relates to compounds of formula I, as defined above, characterized in that X represents-CH-, and A, not only the et-C(O)-, and

R1represents a hydrogen atom, a radical (C1-C8)alkyl, optionally substituted hydroxy, (C2-C6)alkenyl or a radical of the formula -(CH2)n-X1;

R2represents the radical (C1-C8)alkyl, optionally substituted hydroxy, (C2-C6)alkenyl or a radical of the formula -(CH2)nX1;

each X1independently represents a C1-C6)alkoxy, (C3-C7)cycloalkyl, aryl or heteroaryl,

moreover, the aryl radical optionally substituted by one or more identical or different substituents chosen from -(CH2)n'-V1-Y1and halogen;

V1represents-O - or a covalent bond;

Y1represents the radical (C1-C6)alkyl, optionally substituted by one or more identical or different radicals of halogen; or aryl;

or R1and R2together with the nitrogen atom to which they are attached, form heteroseksualci, optionally substituted by one or more identical or different substituents selected from hydroxy, (C1-C6)alkyl, optionally substituted hydroxy, (C1-C6)alkoxycarbonyl, geterotsiklicheskie and-C(O)NV1'Y1'where V1' and Y1' independently represent a hydrogen atom or a (C1-C6)al the sludge

or R1and R2together form a radical of the formula:

R3represents-Z3, -C(RZ3)(R'Z3)-Z3or-C(RZ3)(R'Z3)-(CH2)p-Z3;

R4represents a radical of the formula -(CH2)s-R'4;

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

W4represents a hydrogen atom or a (C1-C8)alkyl;

W'4represents a radical of the formula -(CH2)s'-Z4;

Z4represents a hydrogen atom, (C3-C7)cycloalkyl or aryl;

s represents an integer from 0 to 5; s' represents an integer from 0 to 4;

and more specifically characterized in that they possess at least one of the following characteristics:

- radical (C3-C7)cycloalkyl presented X1is cyclopropyl;

the aryl radical represented by X1represents a phenyl radical;

- radical heteroaryl presented X1represents a pyridine;

- heteroseksualci, which is formed of R1The R 2together with the nitrogen atom to which they are attached, are selected from pyrrolidine, piperidine, azepane, azacycloheptane, research, piperazine and decahydroquinoline;

- radical heteroseksualci represented by R'4, optionally substituted (C1-C6)alkyl or benzyl, selected from pyrrolidinyl, piperidinyl, morpholinyl or piperazinil;

- radical heteroaryl represented by R'4represents a radical imidazolyl;

- cycloalkyl, presents Z4choose from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;

the aryl represented by Z4represents phenyl; or their pharmaceutically acceptable salts.

Very preferably, the invention relates to compounds of formula I, as defined above, wherein R4represents a radical of the formula -(CH2)s-R'4in which R'4is pyrrolidinyl or piperidinyl; or a radical of the formula-NW4W'4;

W4represents a hydrogen atom or a (C1-C8)alkyl;

W'4represents a radical of the formula -(CH2)s'-Z4in which Z4represents a hydrogen atom;

s represents an integer from 2 to 4; s' represents an integer from 0 to 4; or their pharmaceutically acceptable salts.

Also very preferably from retina relates to compounds of the formula I, as defined above, characterized in that, R1and R2independently represent a radical (C1-C8)alkyl; or their pharmaceutically acceptable salts.

Preferably the invention also relates to compounds of formula I, as defined above, characterized in that X represents-CH-, A is-C(O)-, and

R3represents-Z3and Z3isZ3s, Z3dor Z3e;

Z3dis (C3-C7)cycloalkyl or heteroseksualci; and more specifically

Z3sis heteroaryl selected from tanila, furil, indolyl, dihydroindole, pyridyl, benzothiazyl and benzofuran; or an aryl radical selected from phenyl, naphthyl and fluorenyl;

moreover, the radical heteroaryl optionally substituted by one or more identical or different substituents selected from (C1-C6)alkylsulphonyl and (C1-C6)alkoxycarbonyl;

the aryl radical optionally substituted by one or more identical or different substituents selected from halogen, cyano, nitro, azido, (C1-C6)alkoxycarbonyl-(C1-C6)alkenyl, hydroxy, -SO2-NR31R32, geterotsiklicheskie, heteroaryl or -(CH2)p'-V3-Y3;

R31and R32together with the nitrogen atom to which they are attached, form a number of the TSO piperidine;

V3represents-O-, -S-, -C(O)-, -C(O)-O-, -SO2-, -SO2NH-, -NR'3-, -NR'3-C(O)-, -C(O)-NR'3-, -NH-C(O)-NR'3- or a covalent bond;

Y3represents a hydrogen atom; a radical (C1-C6)alkyl, optionally substituted by one or more identical or different halogen radicals; a phenyl radical; or a benzyl radical;

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

Z3dis cyclopropyl, cyclohexyl or piperidinyl, each of which may be substituted by radical (C1-C6)alkoxycarbonyl; or their pharmaceutically acceptable salts.

Preferably the invention also relates to compounds of formula I, as defined above, characterized in that X represents-CH-, A is-C(O)-, and

R3represents-Z3and Z3is Z3c, Z3dor Z3e;

Z3dis (C3-C7)cycloalkyl or heteroseksualci;

and more specifically

Z3cis heteroaryl selected from tanila, indolyl and benzothiazyl; or an aryl radical selected from phenyl and naphthyl;

moreover, the radical heteroaryl optionally substituted by one or more hydroxy radicals;

the aryl radical optionally substituted by one or more identical or different mixing what italiani, selected from halogen, nitro, heteroaryl or -(CH2)p'-V3-Y3;

V3represents-O-, -S-, -C(O)-, -C(O)-O-, -SO2-, -SO2NH-, -NR'3-C(O)-, -C(O)-NR'3-, -NH-C(O)-NR'3- or a covalent bond;

Y3represents a hydrogen atom; a radical (C1-C6)alkyl, optionally substituted by one or more identical or different halogen radicals; a phenyl radical; or a benzyl radical;

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

Z3dis cyclopropyl or piperidinyl, each of which is optionally substituted C1-C6)alkoxycarbonyl;

and preferably

Z3is Z3cor Z3e;

Z3crepresents phenyl, optionally substituted by one or more identical or different substituents selected from nitro and -(CH2)p'-V3-Y3;

V3represents-O-, -S-, -C(O)-, -C(O)-O-, -SO2-, -SO2NH-, -NR'3-C(O)-, -C(O)-NR'3- or a covalent bond;

Y3represents a hydrogen atom; a radical (C1-C6)alkyl; a phenyl radical; or a benzyl radical;

R'3represents a hydrogen atom;

Z3eis

or their pharmaceutically acceptable salts.

Preferably the invention is e refers to compounds of the formula I, as defined above, characterized in that X represents-CH-, A is-C(O)-, R3represents-C(RZ3)(R'Z3)-Z3and Z3is Z3b, Z3s, Z3dor Z3e; or their pharmaceutically acceptable salts.

Very preferably, the invention also relates to compounds of formula I, as defined above, characterized in that X represents-CH-, A is-C(O)-, and

R3represents-C(RZ3)(R'Z3)-Z3and Z3is Z3bor Z3s;

RZ3and R'Z3represent a hydrogen atom;

and more specifically

Z3brepresents the radical (C1-C6)alkoxy;

Z3crepresents the radical heteroaryl selected from tanila, furil, pyridyl, benzothiazyl and dihydrobenzofuran; or an aryl radical selected from phenyl and naphthyl,

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

V3represents-O-, -S-, -C(O)-, -C(O)-O-, -SO2-, -SO2NH-, -NR'3-C(O)-, -C(O)-NR'3-,

Y3represents a hydrogen atom; a radical (C1-C6)alkyl, optionally substituted by one or more identical or different halogen radicals;

R'3represents a hydrogen atom;

or the pharmacist who Cesky acceptable salt.

Very preferably, the invention relates to compounds of formula I, as defined above, characterized in that X represents-CH-, A is-C(O)-, and

R3represents-C(RZ3)(R'Z3)-Z3and Z3is Z3bor Z3c;

RZ3and R'Z3represent a hydrogen atom;

and more specifically

Z3brepresents the radical (C1-C6)alkoxy;

Z3srepresents the radical heteroaryl selected from tanila, furil, dihydrobenzofuran; or a phenyl radical;

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

V3represents-O-, -S-, -C(O)-, -C(O)-O-, -SO2-, -SO2NH-, -C(O)-NR'3-,

Y3represents a hydrogen atom; or a radical (C1-C6)alkyl, optionally substituted by one or more identical or different halogen radicals;

R'3represents a hydrogen atom; and preferably

Z3is Z3s;

Z3sis furyl or phenyl,

moreover, the phenyl radical optionally substituted by one or more identical or different substituents of the formula -(CH2)p'-V3-Y3;

V3represents-O-, -S-, -C(O)-, -C(O)-O-, -SO2-, -SO2NH-, -C(O)-NR'3-,

Ysub> 3represents a hydrogen atom; or a radical (C1-C6)alkyl, optionally substituted by one or more identical or different halogen radicals;

R'3represents a hydrogen atom;

or their pharmaceutically acceptable salts.

Very preferably, the invention also relates to compounds of formula I, as defined above, characterized in that X represents-CH-, A is-C(O)-, and

R3represents-C(RZ3)(R'Z3)-Z3and Z3is Z3dor Z3e;

RZ3and R'Z3represent a hydrogen atom or a (C1-C6)alkyl;

Z3dis (C1-C6)alkoxycarbonyl, (C3-C7)cycloalkyl or heteroseksualci;

Z3eis

and more specifically

Z3dis (C1-C6)alkoxycarbonyl, cyclohexyl or tetrahydropyranyl; or their pharmaceutically acceptable salts.

Very preferably, the invention also relates to compounds of formula I, as defined above, characterized in that X represents-CH-, A is-C(O)-, and

R3represents-C(RZ3)(R'Z3)-Z3and Z3is Z3dor Z3e;

Z3drepresents the radical (C1-C6)alkoxycarbonyl;

Z3eis

and preferably Z3is Z3e

or their pharmaceutically acceptable salts.

Preferably the invention also relates to compounds of formula I, as defined above, characterized in that X represents-CH-, A is-C(O)-, R3represents-C(RZ3)(R'Z3)-(CH2)p-Z3and Z3is Z3b, Z3sor Z3d; or their pharmaceutically acceptable salts.

Very preferably, the invention relates to compounds of formula I, as defined above, characterized in that X represents-CH-, A is-C(O)-, and

R3represents-C(RZ3)(R'Z3)-(CH2)p-Z3and Z3is Z3b; and more specifically

RZ3and R'Z3independently represent a hydrogen atom or the radical (C1-C6)alkyl;

Z3bis (C1-C6)alkoxy, (C1-C6)alkylthio or radical di((C1-C6)alkyl)amino; or their pharmaceutically acceptable salts.

Very preferably, the invention also relates to compounds of formula I, as defined above, characterized in that X represents-CH-, A is-C(O)-, and

R3represents-C(RZ3)(R'Z3)-(CH2)p-Z3and Z3is Z3b;

and more specifically

<> RZ3and R'Z3independently represent a hydrogen atom or the radical (C1-C6)alkyl;

Z3bis (C1-C6)alkoxy or the radical (C1-C6)alkylthio; or their pharmaceutically acceptable salts.

Very preferably, the invention also relates to compounds of formula I, as defined above, characterized in that X represents-CH-, A is-C(O)-, and

R3represents-C(RZ3)(R'Z3)-(CH2)p-Z3and Z3is Z3cor Z3d; and more specifically

RZ3and R'Z3independently represent a hydrogen atom or the radical (C1-C6)alkyl;

Z3cis indolyl or phenyl;

moreover, the phenyl radical optionally substituted by one or more identical or different substituents selected from halogen and -(CH2)p'-V3-Y3;

V3is-SO2NH-,

Y3represents a hydrogen atom; or a radical (C1-C6)alkyl;

Z3dis (C1-C6)alkoxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, (C1-C6)alkyl-C(O)-NH-, or a radical heteroseksualci, optionally substituted hydroxy, and preferably piperidinyl, morpholinyl, pyrrolidin or imidazolidinyl; or their pharmaceutically acceptable salts.

Very prepost is positive the invention also relates to compounds of the formula I, as defined above, characterized in that X represents-CH-, A is-C(O)-, and

R3represents-C(RZ3)(R'Z3)-(CH2)p-Z3and Z3is Z3cor Z3d;

and more specifically

Z3is Z3d;

RZ3and R'Z3independently represent a hydrogen atom or the radical (C1-C6)alkyl;

Z3dis (C1-C6)alkoxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, (C1-C6)alkyl-C(O)-NH - or heteroseksualci, and preferably pyrrolidin or imidazolidin, optionally substituted by hydroxy; or their pharmaceutically acceptable salts.

In this application, the symbol -> * corresponds to the connection point of the radical. When the place of attachment of the radical is not specified, this means that the accession shall be effected on one of the seats available on this radical for such a connection.

Defining variables A, X, R1, R2, R3and R4the compounds in accordance with the present invention can be obtained in the liquid phase according to different procedures from A to G described below.

A.Obtaining according to reaction scheme A:

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

As described in scheme A, methylated derivative (1) (if X=C is a commercially available connection; when X=N - compound, obtained according to the procedureBaumgarten and others, J. Am. Chem. Soc, 1952, 74, 3828-3831, from 6-methyl-3-nitropyridine-2-amine)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 Schmelkesand others, 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 (according to the procedure Howes and others, European J. Med. Chem, 1999, 34, 225-234). Carboxylic acid (2) can be combined with a primary or secondary amine in the presence of a coupling agent such as diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) or carbonyldiimidazole (CDI) with 1-hydroxybenzotriazole (HOBt) or without an inert organic solvent such as methylene chloride, tetrahydrofuran or dimethylformamide at ambient temperature for 3-24 hours in order 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 carbonate in an inert organic races is varicela such as dimethylformamide or acetonitrile, at a temperature of 20-100°C for 2-48 hours leads to a derivative (4). The function of the nitro group of the compound (4) restored 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 to 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 mixtures of these solvents, at a temperature of 18-25°C, within 2-8 hours in order to get dianion (5). Then the derivative (5) is exposed to isothiocyanate in the presence of a coupling agent attached or not attached to the resin, such as diisopropylcarbodiimide or dicyclohexylcarbodiimide, or N-methylcyclohexylamine-N-methylpredisolone resin in an inert solvent, such as tetrahydrofuran, methylene chloride, or chloroform at a temperature of 20-70°C within 2-72 hours, to obtain the derivative (6). Alternatively, the derivative (5) can be treated with isothiocyanates in an inert solvent such as tetrahydrofuran, methylene chloride, chloroform or ethanol at a temperature of 20-80°C for 1-16 hours, then the resulting thiourea can be processed iodide stands or yellow oxide of mercury (II) in prisutstvie and catalytic amounts of sulfur in the polar solvent, such as methanol or ethanol, for 2-24 hours at a temperature of 20-80°C in order to obtain (6). The compound (6) can be distinguished either by flash chromatography on silica gel or by adding to the reaction mixture nucleophilic reagent attached to the polymer, such as, for example, aminomethylpyrimidine resin, and/or electrophilic reagent attached to the polymer such as, for example, Methylisothiazolinone resin, followed by filtration and evaporation of the filtrate.

Example A1: dihydrochloride methyl-4-[(1-(3-aminopropyl)-6-{[bis(3-methylbutyl)amino]carbonyl}-1H-benzimidazole-2-yl)amino]benzoate

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 the boil under reflux for 6 hours, then cooled to ambient temperature. The mixture is filtered on celite, and the aqueous phase is twice washed with diethyl ether (2 x 300 ml). The aqueous phase is acidified at 0°C, a solution of concentrated hydrochloric acid, then concentrated under reduced pressure at 40°C to a volume of approximately 300 ml precipitate Formed is filtered, then washed with petroleum ether and dried in order to obtain the expected compound in the form of a white t is ejogo substances (6,9 g; 58% yield).

NMR (1H, 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 a solution of THF (40 ml) was successively added 3-fluoro-4-nitrobenzoic acid (3.8 g, 1 EQ.) in a solution of anhydrous THF (30 ml). The mixture is stirred for 1 hour at a temperature of approximately 20°C, then add vitaminen (3.6 g, 1.1 EQ.) in a solution of THF (30 ml). After stirring for 16 hours at a temperature of approximately 20°C, the reaction mixture was concentrated under reduced pressure at 40°C. the Residue absorb dichloromethane (200 ml) and water (70 ml). After decantation and extraction combined organic phases are washed with salt water, dried over Na2SO4, then concentrate under reduced pressure at 40°C. Purification of compounds by flash chromatography on silica gel (eluent: heptane/ethyl acetate 9:1)gives the expected compound as a yellow oil (4.3 g; 65% yield).

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

NMR (1H, 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: tert-butyl 3-[(5-{[bis(3-methylbutyl)amino]carbonyl}-2-nitro the Nile)amino]propellernet

A mixture of 3-fluoro-N,N-bis(3-methylbutyl)-4-nitrobenzamide (1.6 g, 1 EQ.), N-Boc-1,3-diaminopropane (0.9 g, 1.2 EQ.) and potassium carbonate (1.35 g, 2 EQ.) in acetonitrile (80 ml) is heated at the boil under reflux for 5 hours, then concentrated under reduced pressure at 40°C. the Residue absorb dichloromethane (100 ml) and water (40 ml). After decantation and extraction, the combined organic phases are washed with salt water, dried over Na2SO4, then concentrate under reduced pressure at 40°C. Purification of the residue by flash chromatography on silica gel (eluent: heptane/ethyl acetate 8:2 to 6:4) gives the expected compound as a yellow oil (2.2 g; 96% yield).

MS/LC: calculated MM = 478,6; m/z = 479,2 (MH+)

NMR (1H, 400 MHz, DMSO-d6):δ of 0.68 (m, 6H), to 0.92 (m, 6H), of 1.36 (s, 9H), 1,31 was 1.69 (m, 8H), 3.0 a (m, 2H), to 3.09 (m, 2H), 3,38 (m, 4H), 6,53 (d, 1H), to 6.88 (m, 2H), 8,10 (d, 1H), compared to 8.26 (m, 1H).

Stage 4: tert-butyl 3-[(2-amino-5-{[bis(3-methylbutyl)amino] carbonyl}phenyl)amino]propellernet

Tert-butyl 3-[(5-{[bis(3-methylbutyl)amino]carbonyl}-2-nitrophenyl)amino]propylgallate (1.65 g) in solution in a mixture of ethyl acetate/ethanol 2:1 (130 ml)and 10% palladium on coal (165 mg) was injected in the autoclave. After stirring for 3 hours in an atmosphere of hydrogen (3 bar) at a temperature of approximately 20°C, the catalyst is removed by filtration on celite, and the filtrate concentrated under PON the leaders introduce pressure at 40° C in order to obtain the expected compound in the form of an oil (1.35 g; 89% yield).

MS/LC: calculated MM = 448,6; m/z = 449,2 (MH+)

NMR (1H, 400 MHz,DMSO-d6): δ 0,81 (m, 12H), to 1.37 (s, 9H), 1.32 to of 1.53 (m, 6H), to 1.70 (m, 2H), 3.0 a (m, 4H), 3,26 (m, 4H), 4,47 (m, 1H), 4,79 (s, 2H), 6,35-6,51 (m, 3H), 6,85 (m, 1H).

Stage 5: methyl-4-[(6-{[bis(3-methylbutyl)amino]carbonyl}-1-{3-[tert-butoxycarbonyl)amino]propyl}-1H-benzimidazole-2-yl)-amino]benzoate

4-ethoxycarbonylphenyl isothiocyanate (327 mg, 1.5 EQ.) and N-methylcyclohexylamine-N-methylpredisolone resin (acquired from Novabiochem; load of 1.9 mmol/g; about 1.75 g, 3 EQ.), successively added to a solution of tert-butyl 3-[(2-amino-5-{[bis(3-methylbutyl)amino]carbonyl}phenyl)amino]propylgallate (500 mg, 1 EQ.) in tetrahydrofuran (30 ml). The mixture is heated at the boil under reflux for 17 hours, then cooled to ambient temperature and add aminomethylpropanol resin (acquired from Novabiochem, 2 EQ.). After stirring for 4 hours at ambient temperature, the mixture is filtered on a Frit, and the filtrate concentrated under reduced pressure at 40°C. Purification of the residue by flash chromatography on silica gel (eluent: heptane/ethyl acetate 1:1) produces the expected compound in the form of a white solid (409 mg; 60% yield).

MS/LC: calculated MM = 607,8; m/z = 608,1 (MH+)

NMR (1H, 400 MHz,DMSO-d 6):δ 0,65-of 0.90 (m, 12H), of 1.36 (s, 9H), 1,31-of 1.44 (m, 6H), is 1.81 (m, 2H), 3.0 a (m, 2H), 3,26-3,39 (m, 4H), 3,82 (s, 3H), 4,29 (m, 2H), 6,95 (m, 1H),? 7.04 baby mortality (d, 1H), was 7.36 (s, 1H), 7,44 (d, 1H), 7,94 (AB, 2H), 8,02 (AB, 2H), 9,34 (s, 1H).

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

A solution of hydrogen chloride in dioxane (4n., 2 ml) was added to a solution of methyl-4-[(6-{[bis(3-methylbutyl)amino]carbonyl}-1-{3-[(tert-butoxycarbonyl)amino]propyl}-1H-benzimidazole-2-yl)-amino]benzoate (180 mg) in ethyl acetate (2 ml). After stirring for 1 hour at a temperature of approximately 20°C the mixture is concentrated under reduced pressure at 40°C. the Obtained solid is washed with ethyl ether and dried (165 mg; 96% yield).

MS/LC: calculated MM = 507,7; m/z = 508,3 (MH+)

NMR (1H, 400 MHz,DMSO-d6): δ 0,63-and 0.98 (m, 12H), of 1.45 (m, 6H), of 2.08 (m, 2H), 2,98 (m, 2H), 3,12 is-3.45 (m, 4H), 3,85 (s, 3H), 4,59 (m, 2H), 7,20 (m, 1H), 7,46 (d, 1H), to 7.67 (s, 1H), of 7.90 (m, 2H), 8,01-8,07 (m, 5H), 11,08 (m, 1H).

Example A2: the dihydrochloride of 2-[(4-acetylphenyl)amino]-N,N-bis(3-methylbutyl)-1-(3-piperidine-1-ylpropyl)-1H-benzimidazole-6-carboxamide

Stage 1: 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, obtained in accordance with Example A1), 3-piperidinophenyl (212 mg, 1.1 EQ.) and the carbonate is potassium (365 mg, 2 EQ.) in acetonitrile (10 ml) is heated at the boil under reflux for 3 hours, then concentrated under reduced pressure at 40°C. the Residue absorb dichloromethane (50 ml) and water (20 ml). After decantation and extraction, the combined organic phases are washed with salt water, dried over Na2SO4, then concentrate under reduced pressure at 40°C. Purification of the residue by flash chromatography on silica gel (eluent: ethyl acetate 100%), gives the expected compound as a yellow oil (460 mg, 78% yield).

MS/LC: calculated MM = 446,6; m/z = 447,3 (MH+)

NMR (1H, 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 2: the dihydrochloride of 2-[(4-acetylphenyl)amino]-N,N-bis(3-methylbutyl)-1-(3-piperidine-1-ylpropyl)-1H-benzimidazole-6-carboxamide

N,N-bis(3-methylbutyl)-4-nitro-3-[(3-piperidine-1-ylpropyl)-amino]benzamide (44 mg) in a solution mixture of ethyl acetate/ethanol 2:1 (1.5 ml)and 10% palladium on coal (5 mg) is introduced into the tube hemolysis, placed in the autoclave. After stirring for 3 hours in an atmosphere of hydrogen (3 bar) at a temperature of approximately 20°C catalyst is removed by filtration on celite and the filtrate concentrated under reduced pressure at 40°C. 4-acetylphenothiazine (27 mg, 1.5 EQ.) and N-methylcyclohex incarnational-N-methylpredisolone resin (acquired from Novabiochem; load of 1.9 mmol/g; 158 mg, 3 EQ.), consistently add to aniline obtained, thus, in a solution of tetrahydrofuran (2 ml). The mixture is heated at the boil under reflux for 18 hours, then cooled to ambient temperature and add aminomethylpropanol resin (acquired from Novabiochem, 2 EQ.). After stirring for 4 hours at ambient temperature the mixture is filtered on a Frit and the filtrate concentrated under reduced pressure at 40°C. Purification of the residue by flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/methanol 9:1) produces the expected compound in the form of a Foundation. The corresponding salt is a hydrochloride is obtained by adding 1N. solution of hydrogen chloride in a simple ether. The precipitate is filtered and dried in order to obtain the expected dihydrochloride connection.

MS/LC: calculated MM = 559.8 M.; m/z = 560,3 (MH+)

NMR (1H, 400 MHz, DMSO-d6): δ of 0.68 (m, 6H), were 0.94 (m, 6H), 1,31-of 1.56 (m, 6H), 1.57 in-1,90 (m, 6H), 2,28 (m, 2H), 2,60 (s, 3H), of 2.86 (m, 2H), 3,21 (m, 4H), 3,40 (m, 4H), to 4.62 (t, 2H), 7,24 (AB, 1H), 7,47 (AB, 1H), 7,76 (s, 1H), 7,81 (m, 2H), 8,07 (m, 2H), the 10.40 (s, 1H), 11,64 (m, 1H).

Example A3: the dihydrochloride of 2-(cyclohexylamino)-1-[3-(dimethylamino)propyl]-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamide

Stage 1: 3-{[3-(dimethylamino)propyl]amino}-N,N-bis(3-methylb the Teal)-4-nitrobenzamide

A mixture of 3-fluoro-N,N-bis(3-methylbutyl)-4-nitrobenzamide (2.5 g, 1 EQ, obtained in accordance with Example A1), 3-diethylaminopropylamine (877 mg, 1.1 EQ.) and potassium carbonate (2,13 g, 2 EQ.) in acetonitrile (80 ml) is heated at the boil under reflux for 5 hours, then concentrated under reduced pressure at 40°C. the Residue absorb dichloromethane (130 ml) and water (50 ml). After decantation and extraction combined organic phases are washed with salt water, dried over Na2SO4, then concentrate under reduced pressure at 40°C. Purification of the residue by flash chromatography on silica gel (eluent: dichloromethane/methanol 9:1) produces the expected compound in the form of a yellow oil (2.1 g; 68% yield).

MS/LC: calculated MM = 406,6; m/z = 407,3 (MH+)

NMR (1H, 400 MHz,DMSO-d6): δ of 0.68 (d, 6H), to 0.92 (d, 6H), 1,31-is 1.51 (m, 5H), to 1.59 (m, 1H), 1,74 (m, 2H), and 2.14 (s, 6H), 2,31 (t, 2H), 3,11 (m, 2H), 3,39 (m, 4H), 6,53 (d, 1H), 6.90 to (s, 1H), of 8.09 (d, 1H), to 8.57 (t, 1H).

Stage 2: the dihydrochloride of 2-(cyclohexylamino)-1-[3-(dimethylamino)propyl]-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamide

3-{[3-(dimethylamino)propyl]amino}-N,N-bis(3-methylbutyl)-4-nitrobenzamide (81 mg) in a solution mixture of ethyl acetate/ethanol 2:1 (4 ml)and 10% palladium on coal (8 mg) is introduced into the tube hemolysis, placed in the autoclave. After stirring for 3 hours in an atmosphere of hydrogen (3 bar) at a temperature in listello 20° C the catalyst is removed by filtration on celite and the filtrate concentrated under reduced pressure at 40°C. Cyclohexylstyrene (58 mg, 2 EQ.) consistently add to aniline obtained, thus, in a solution of tetrahydrofuran (2 ml). The mixture is heated at the boil under reflux for 3 hours, then cooled to ambient temperature and concentrate under reduced pressure. Yellow oxide of mercury (II) (87 mg, 2 EQ.) and sulfur (1.4 mg) are successively added to the thiourea is formed, thus, in ethanol (3 ml). The mixture is heated at the boil under reflux for 17 hours, then cooled to ambient temperature and filtered over a microfibre paper. The filtrate is concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: 100%dichloromethane to dichloromethane/methanol 9:1) produces the expected compound in the form of a Foundation. Appropriate cleaners containing hydrochloride salt is obtained by adding 1N. solution of hydrogen chloride in a simple ether. The precipitate is filtered and dried in order to obtain the expected dihydrochloride compound (87 mg, 78% yield).

MS/LC: calculated MM = 483,7; m/z = 484,4 (MH+)

NMR (1H, 400 MHz, DMSO-d6): δ 0,58-of 1.03 (m, 12H), of 1.18 (m, 1H), 1.30 and 1,71 (m, 11H), of 1.80 (m, 2H), 2,01 (m, 4H), by 2.73 (s, 6H), 3,14 (m, 4H), of 3.25 (m, 2H), 3,71 (m, H), 4,32 (m, 2H), 7,16 (m, 1H), 7,39 (m, 1H), 7,54 (m, 1H), 8,42 (m, 1H), the 10.40 (m, 1H), 13,41 (m, 1H).

Getting not commercially available isothioscyanates:

The primary amine can be converted to isothiocyanate by processing thiophosgene in the presence of a tertiary base, such as triethylamine, in an aprotic solvent such as dichloromethane or tetrahydrofuran, at a temperature of 0-20°C for 0.3 to 2 hours, or, alternatively, by treatment with carbon disulfide and cyclohexylcarbodiimide attached or not attached to the resin, in an aprotic solvent such as dichloromethane or tetrahydrofuran, at a temperature of 0-70°C for 0.3 to 15 hours.

N-(4-isothiocyanates)ndimethylacetamide

Thiophosgene high (0.56 ml, 1.1 EQ.) added dropwise into a solution of N-(4-AMINOPHENYL)ndimethylacetamide (1 g, 1 EQ.) triethylamine (2.8 ml, 3 EQ.) in tetrahydrofuran (130 ml), cooled to 0°C. the Mixture is stirred for 30 minutes at 0°C, then remove the cold bath and continue stirring for another 30 minutes. The mixture was added water (70 ml) and diethyl ether (150 ml). After decantation and extraction the combined organic phases are washed with salt water, dried over Na2SO4, then concentrate under reduced pressure at 40°C. the Obtained solid substance perakis alsovisit from a mixture of dichloromethane/petroleum ether (0.95 g; 75% yield).

NMR (1H, 400 MHz, DMSO-d6): δ 2,04 (s, 3H), 7,35 (AB, 2H), 7,63 (AB, 2H), 10,14 (s, 1H).

The following isothiocyanates received in accordance with the same procedure described for N-(4-isothiocyanates)ndimethylacetamide:

Obtain N-(4-isothiocyanates)-N'-1-methoxylation

Carbonyldiimidazole (1,62 g, 2 EQ.) add a solution of tert-butyl 4-aminophenylalanine(1.04 g) in anhydrous dichloromethane (100 ml), cooled to 0°C. the Mixture is brought to a temperature of 20°C and stirred at this temperature for 15 hours. The triethylamine (7 ml, 10 equiv.) and then the hydrochloride of O-methylhydroxylamine (4,2 g, 10 EQ.) successively added to the reaction medium cooled to 0°C. After stirring for 3 hours at a temperature of approximately 20°C the mixture was added water, saturated sodium bicarbonate and chloroform. After decantation and extraction combined organic phases are washed with salt water, dried over Na2SO4, then concentrate under reduced pressure at 40°C in order to get thetert-butyl 4-{[(methoxyamino)carbonyl]amino}phenylcarbamate (1,33 g). Through the suspension of this derivative in ethyl acetate insure flow razoobrazny the th hydrogen chloride until while the reaction is not completed. Formed precipitate was filtered, then washed with diethyl ether and dried in order to obtain the hydrochloride of N-(4-AMINOPHENYL)-N'-methoxymetopon (1 g).

Thiophosgene (0,38 ml, 1.1 EQ.) added dropwise into a solution of the hydrochloride of N-(4-AMINOPHENYL)-N'-methoxymetopon (1 g) and triethylamine (3.2 ml, 5 EQ.) in tetrahydrofuran (90 ml), cooled to 0°C. the Mixture is stirred for 15 minutes at 0°C, then add water and diethyl ether. After decantation and extraction the combined organic phases are washed with salt water, dried over Na2SO4, then concentrate under reduced pressure at 40°C. Purification by flash chromatography on silica gel (eluent: heptane/ethyl acetate 7:3-3:7) gives the expected compound (630 mg, 62% yield).

NMR (1H, 400 MHz,DMSO-d6): δ 3,61 (s, 3H), 7,34 (AB, 2H), to 7.67 (AB, 2H), 9,11 (s, 1H), 9,65 (s, 1H).

Getting not commercially available arylisocyanates:

Arylisocyanate can be obtained on the basis of the acid chlorides of the corresponding acid by treatment with potassium thiocyanate in an aprotic solvent such as acetonitrile, at a temperature of 0-60°C for 0.2-5 hours.

Methyl-4-isothiocyanatobenzene:

The potassium thiocyanate (1.08 g) is added to a solution of methyl-4-chlorocarbonyl is soata (2 g) in acetonitrile (30 ml). After stirring for 1 hour at approximately 20°C the mixture is filtered and the filtrate concentrated under reduced pressure at 40°C. the Obtained solid is purified by flash chromatography on silica gel (eluent: heptane/ethyl acetate 1:1) to obtain the expected compound (2.1 g; 95% yield).

NMR (1H, 400 MHz,DMSO-d6): δ 3,88 (s, 3H), 8,0 (m, 4H).

The following isothiocyanates received in accordance with the same procedure described for methyl-4-isothiocyanatobenzene:

In accordance with reaction scheme A and in a manner analogous to the procedure described for the synthesis dihydrochloride methyl-4-[(1-(3-aminopropyl)-6-{[bis(3-methylbutyl)amino]carbonyl}-1H-benzimidazole-2-yl)amino]benzoate, the dihydrochloride of 2-[(4-acetylphenyl)amino]-N,N-bis(3-methylbutyl)-1-(3-piperidine-1-ylpropyl)-1H-benzimidazole-6-carboxamide or dihydrochloride of 2-(cyclohexylamino)-1-[3-(dimethylamino)propyl]-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamide, obtained the following compounds:

in which R1R2N represents one of the radicals below:

and R3represents one of the radicals below:

and R 4represents one of the radicals below:

B.Obtaining according to the reaction scheme B:

The compounds of formula (I) in accordance with the present invention, in which A represents-C(O)-, can also be obtained according to the following scheme B:

As described in scheme B, carboxylic acid (2) can be converted to methyl ester (7) or by treatment with a solution trimethylsilyldiazomethane at a temperature of 0-20°C, either through education carboxylate salts using inorganic bases, such as the dihydrate lithium hydroxide, or cesium carbonate, at ambient temperature for 30 minutes to 2 hours, in an inert organic solvent, such as tetrahydrofuran, followed by adding dimethylsulfate at ambient temperature under stirring at boiling within 5-15 hours. Fluorinated or chlorinated derivative (7) can be treated by 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 for 2-48 hours in order to derive (8). The function of the nitro group of compound (8) can restore the houtem processing dihydrate 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 mixtures of these solvents, at a temperature of 18-25°C, within 2-8 hours in order to get dianiline (9). Then the derivative (9) is treated with isothiocyanates in the presence of a coupling agent such as diisopropylcarbodiimide or dicyclohexylcarbodiimide, in an inert solvent, such as tetrahydrofuran, methylene chloride or chloroform, at a temperature of 20-70°C within 2-72 hours in order to derive (10). Alternatively, the derivative (9) can be treated with isothiocyanates in an inert solvent, such as tetrahydrofuran, methylene chloride, chloroform or ethanol, at a temperature of 20-80°C for 1-16 hours, then the resulting thiourea can be treated with methyliodide or yellow oxide of mercury (II) in the presence of catalytic amounts of sulfur in a polar solvent such as methanol or ethanol, for 2-24 hours at a temperature of 20-80°C, in order to obtain (10). Methyl ether (10) can be subjected to a saponification reaction in the presence of inorganic bases, such as the dihydrate lithium hydroxide in a mixture of polar solvents such as water and tetr hydrofuran, at a temperature of 20-70°C for 3-17 hours. The resulting carboxylic acid (11) can be combined with a primary or secondary amine in the presence of a coupling agent, such as diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) or carbonyldiimidazole (CDI), 1-hydroxybenzotriazole (HOBt) or without it, in an inert organic solvent such as methylene chloride, tetrahydrofuran or dimethylformamide at ambient temperature for 3-24 hours, in order to obtain the corresponding amide (6), which can be distinguished either by flash chromatography on silica gel or by adding to the reaction mixture nucleophilic reagent attached to the polymer, such as, for example, aminomethylpyrimidine resin, and an electrophilic reagent attached to the polymer, such as, for example, Methylisothiazolinone resin, followed by filtration and vypadeniem filtrate.

Example B1: dihydrochloride of 1-(3-aminopropyl)-6-(piperidine-1-ylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-1H-benzimidazole-2-amine

Stage 1: methyl 3-fluoro-4-nitrobenzoate

The solution trimethylsilyldiazomethane (2M in hexane, 50 ml, 4 EQ.) slowly add a solution of 3-fluoro-4-nitrobenzoic acid (4.7 g, 1 EQ.) in Meath is zero (70 ml) as long until the evolution of gas ceases. Excess trimethylsilyldiazomethane removed by adding acetic acid dropwise until then, until the solution becomes colourless. The mixture is then concentrated under reduced pressure at a temperature of about 40°C. To the residue is added water (200 ml) and dichloromethane (300 ml). After decantation and extraction combined organic phases are washed with salt water, dried over Na2SO4, then concentrate under reduced pressure at 40°C. the Obtained solid is washed with petroleum ether and dried (4.4 g; 87% yield).

NMR (1H, 400 MHz,CDCl3): δ 4,0 (s, 3H), of 7.97 (m, 2H), 8,11 (d, 1H).

Stage 2: methyl-3-({3-[(tert-butoxycarbonyl)amino]propyl}-amino)-4-nitrobenzoate

A mixture of methyl 3-fluoro-4-nitrobenzoate (5.8 g, 1 EQ.), N-Boc-1,3-diaminopropane (5.75 g, 1.1 EQ.) and potassium carbonate (8,04 g, 2 EQ.) in acetonitrile (200 ml) is heated at the boil under reflux for 2 hours, then concentrated under reduced pressure at 40°C. the Residue absorb dichloromethane (200 ml) and water (100 ml). After decantation and extraction combined organic phases are washed with salt water, dried over Na2SO4, then concentrate under reduced pressure at 40°C. the Obtained solid is washed with petroleum ether and dried (10.2 g; 99% yield).

NMR (1H, 400 MHz, CDCl3): δ 1,45 (s, 9H), of 1.95 (m, 2H), 3,30 (m, 2H), 3,44 (m, 2H), 3,95 (s, 3H), of 4.67 (m, 1H), 7,25 (m, 1H), 7,55 (s, 1H), 8,04 (m, 1H), they were 8.22 (m, 1H).

Stage 3: methyl-4-amino-3-({3-[(tert-butoxycarbonyl)amino]-propyl}amino)benzoate

Methyl-3-({3-[(tert-butoxycarbonyl)amino]propyl}amino)-4-nitrobenzoate (10.2 g) in a solution mixture of ethyl acetate/methanol 3:1 (300 ml)and 10% palladium on coal (1,02 g) is introduced into the autoclave. After stirring for 4 hours in an atmosphere of hydrogen (3 bar) at a temperature of approximately 20°C, the catalyst is removed by filtration on celite, and the filtrate concentrated under reduced pressure at 40°C in order to obtain the expected compound in the form of oil (of 7.75 g; 83% yield).

MS/LC: calculated MM = 323,4; m/z = 324,2 (MH+)

NMR (1H, 400 MHz, CDCl3): δ 1,45 (s, 9H), of 1.85 (m, 2H), 3,24 (m, 2H), 3,30 (m, 2H), 3,86 (m, 5H), and 4.68 (m, 1H), of 6.68 (d, 1H), 7,34 (s, 1H), 7,45 (d, 1H).

Stage 4: methyl-1-{3-[(tert-butoxycarbonyl)amino]propyl}-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-6-carboxylate

3,4,5-trimethoxyphenethylamine (6.6 g, 1.2 EQ.) and diisopropylcarbodiimide (9,1 g, 3 EQ.) successively added to a solution of methyl-4-amino-3-({3-[(tert-butoxycarbonyl)amino]-propyl}amino)benzoate (of 7.75 g, 1 EQ.) in tetrahydrofuran (130 ml). The mixture is heated at the boil under reflux for 16 hours, then cooled to ambient temperature and concentrate under reduced pressure and at 40° C. To the obtained residue, add water (100 ml) and dichloromethane (200 ml). After decantation and extraction combined organic phases are washed with salt water, dried over Na2SO4, then concentrate under reduced pressure at 40°C. Purification of the residue by flash chromatography on silica gel (eluent: heptane/ethyl acetate 8:2-3:7), gives the expected compound in the form of a solid, which was washed with ether (4.4 g; 36% yield).

MS/LC: calculated MM = 514,5; m/z = 515,3 (MH+)

NMR (1H, 400 MHz, CDCl3): and 1.54 (s, 9H), 2,11 (m, 2H), 3,26 (m, 2H), 3,83 (m, 3H), 3,90 (s, 3H), 3,93 (s, 6H), 4,22 (m, 2H), to 5.03 (m, 1H), 7.23 percent (s, 2H), 7,53 (d, 1H), of 7.90 (s, 1H), 7,92 (d, 1H), 9,12 (m, 1H).

Stage 5: 1-{3-[(tert-butoxycarbonyl)amino]propyl}-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-6-carboxylic acid

The lithium hydroxide (2,18 g, 6 EQ.) add a solution of methyl 1-{3-[(tert-butoxycarbonyl)amino]propyl}-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-6-carboxylate (4.4 g, 1 EQ.) in a mixture of tetrahydrofuran (40 ml) and water (30 ml). The mixture is heated at the boil under reflux for 18 hours, then cooled to ambient temperature and concentrate under reduced pressure at 40°C. To the residue is added dichloromethane (150 ml) and water (100 ml). The mixture is acidified by adding acetic acid to pH 5. After decantation and extraction combined organic phases are dried over sulfate is the atrium, and concentrate under reduced pressure. The obtained solid is washed with diethyl ether (3,95 g; 93%).

MS/LC: calculated MM = 500,5; m/z = 501,3 (MH+)

NMR (1H, 400 MHz,DMSO-d6): of 1.37 (s, 9H)and 1.83 (m, 2H), 3,03 (m, 2H), 3,61 (s, 3H), of 3.80 (s, 6H), 4,27 (m, 2H), 7,0 (m, 1H), 7,31 (s, 2H), 7,35 (d, 1H), 7,71 (d, 1H), 7,87 (s, 1H), 8,97 (s, 1H).

Stage 6: dihydrochloride of 1-(3-aminopropyl)-6-(piperidine-1-ylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-1H-benzimidazole-2-amine

The solution carbonyldiimidazole (CDI) (18 mg, 1.1 EQ.) in chloroform (0.2 ml) are added to a solution of 1-{3-[(tert-butoxycarbonyl)amino]propyl}-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-6-carboxylic acid (50 mg, 1 EQ.) in tetrahydrofuran (0.45 ml) and dimethylformamide (0.05 ml). The mixture is stirred for 16 hours at a temperature of approximately 20°C, then add a solution of piperidine (17 mg, 2 EQ.) in tetrahydrofuran (0.2 ml). After stirring for 18 hours at a temperature of approximately 20°C mixture is diluted with dichloromethane (3 ml) and add aminomethylpropanol resin (2 EQ.), TBD-methylpredisolone resin (2 EQ.) and Methylisothiazolinone resin (4 EQ.). After stirring for 6 hours at approximately 20°C the mixture is filtered, and concentrate the filtrate under reduced pressure at 40°C. the resulting residue is dissolved in ethyl acetate (0.5 ml) and add a solution of hydrogen chloride (1N in diethyl ether, 3 ml). After paramasivan what I'm in for 1 hour at a temperature of approximately 20° C the precipitate is filtered and dried in order to obtain the expected compound (35 mg, 65%).

MS/LC: calculated MM = 467,56; m/z = 467,9 (MH+)

NMR (1H, 400 MHz, DMSO-d6): δ 1,48-to 1.63 (m, 6H), was 2.05 (m, 2H), 2,90 (m, 2H), 3,50 (m, 4H), of 3.65 (s, 3H), 3,79 (s, 6H), of 4.45 (m, 2H), 7,10-of 7.60 (m, 5H), 7,54 (m, 1H), 7,94 (m, 3H), to 8.41 (m, 1H), 14,3 (m, 1H).

According to the reaction scheme B and in a manner analogous to the procedure described for the synthesis of dihydrochloride of 1-(3-aminopropyl)-6-(piperidine-1-ylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-1H-benzimidazole-2-amine, obtained the following compounds:

in which R1R2N represents one of the radicals below:

R3is radical, to the following:

and R4represents one of the radicals below:

C.Obtaining according to the reaction scheme C:

As described in scheme C, the derivative (12), obtained according to the reaction scheme A or B, you can handle organic or inorganic acid, such as triperoxonane acid or hydrochloric acid (aqueous or gaseous form), in an aprotic solvent such as dichloromethane, diethyl ether or ethyl acetate, at a temperature of 0-20°C, for 0.5-5 hours to get AMI is (13). Amin (13) can react with the aldehyde in a proton or an aprotic solvent such as dichloromethane, tetrahydrofuran or methanol, for 1 to 15 hours, at a temperature of 0-50°C. the Resulting Imin then restore in situ reducing agent, attached or not attached to the resin, preferably triacetoxyborohydride sodium, lamborghini.com sodium borohydride or attached to the resin, in the presence or in the absence of acid, such as acetic acid, at a temperature of 20-50°C for 0.2 to 5 hours, to obtain compound (14). Secondary amine (14) can optionally be subjected to a second recovery aminating under the same reaction conditions as previously described, in order to obtain a tertiary amine(14').

Example C1: the dihydrochloride of N,N-Diisobutyl-1-[3-(neopentylene)propyl]-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-6-carboxamide

Stage 1: 1-(3-aminopropyl)-N,N-Diisobutyl-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-6-carboxamide

A stream of anhydrous HCl is bubbled through a solution of tert-butyl 3-{6-[(diisobutylamine)carbonyl]-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-1-yl}propylgallate (350 mg; obtained according to the scheme A) in ethyl acetate (30 ml), cooled to 0°C, up until TLC (eluent: 100% ethyl acetate) does not show is the comprehensive disappearance of the original product. The mixture is then concentrated under reduced pressure at 40°C. the Obtained solid is ground to powder in diethyl ether, filtered, washed with dichloromethane and dried. The resulting dihydrochloride absorb dichloromethane and water, saturated with sodium bicarbonate. After decantation and extraction combined organic phases are washed with salt water, dried over Na2SO4, then concentrate under reduced pressure at 40°C in order to obtain the expected compound in the form of the free base (275 mg; 94% yield).

MS/LC: calculated MM = 511,6; m/z = 512,3 (MH+)

NMR (1H, 400 MHz,DMSO-d6): δ of 0.82 (m, 12H), to 1.87 (m, 4H), 2,58 (m, 2H), 3,21 (m, 4H), 3,62 (s, 3H), of 3.78 (s, 6H), 4,25 (t, 2H), 7,0 (AB, 1H), 7,20 (s, 2H), 7,26 (s, 1H), 7,34 (AB, 1H).

Stage 2: the dihydrochloride of N,N-Diisobutyl-1-[3-(neopentylene)propyl]-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-6-carboxamide

A solution of 1-(3-aminopropyl)-N,N-Diisobutyl-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-6-carboxamide (100 mg, 1 EQ.) and trimethylacetaldehyde (25 mg, 1.5 EQ.) in dichloromethane (1 ml) is stirred for 4 hours at a temperature of approximately 20°C. the Mixture is diluted with methanol (1 ml), then add triacetoxyborohydride sodium (41 mg, 2 EQ.). After 1 hour at a temperature of approximately 20°C the mixture was added dichloromethane (20 ml), and water, saturated bicarbonate is m sodium (10 ml). After decantation and extraction combined organic phases are washed with salt water, dried over Na2SO4, then concentrate under reduced pressure at 40°C. Purification of the residue by flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/methanol 9:1) produces the expected compound in the form of a Foundation. Appropriate cleaners containing hydrochloride salt is formed by adding 1N. solution of hydrogen chloride in a simple ether. The precipitate is filtered and dried in order to obtain the expected dihydrochloride compound (83 mg, 65% yield).

MS/LC: calculated MM = 581,8; m/z = 582,3 (MH+)

NMR (1H, 400 MHz,DMSO-d6): δ to 0.67 (m, 6H), of 0.95 (m, 6H), 0,99 (s, 9H), is 1.82 (m, 1H), 2.06 to (m, 1H), and 2.27 (m, 2H), 2,71 (m, 2H), 3,10 (m, 4H), of 3.28 (m, 2H), 3,70 (s, 3H), 3,81 (s, 6H), 4,58 (t, 2H), 6,99 (m, 2H), 7,22 (AB, 1H), 7,41 (AB, 1H), 7,69 (s, 1H), 8,72 (m, 2H), 11,42 (m, 1H), 13,02 (m, 1H).

Obtaining according to the reaction scheme C':

Connection (14)for which s=3 can also be obtained according to the following scheme C':

As shown in the diagram C', derived (15)obtained according to reaction scheme A, can be processed or organic acid, such as toilet pyridinium or paratoluenesulfonyl acid, in an aprotic solvent, such as acetone, in the presence of water at a temperature of 20-70°C for 2-12 hours or inorganic acid, such to the water-hydrogen chloride in an aprotic solvent such as tetrahydrofuran, at a temperature of 0-20°C for 6-18 hours in order to obtain the compound (16). The aldehyde (16) can then be treated with the amine in a proton or an aprotic solvent such as dichloromethane, tetrahydrofuran or methanol, for 1-18 hours, at a temperature of 20°C. the Resulting Imin then restore in situ reducing agent, preferably triacetoxyborohydride sodium or lamborghini.com sodium, in the presence or in the absence of acid, such as acetic acid, at a temperature of 20-50°C, for 0.2 to 6 hours, to obtain compound (17). In order to obtain a tertiary amine (17'), secondary amine (17) can optionally be subjected to a second recovery aminating under the same conditions that were described earlier.

Example C1': the dihydrochloride of 2-[(4-acetylphenyl)amino]-1-{3-[cyclohexylethylamine]propyl}-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamide

Stage 1: 3-{[2-(1,3-dioxolane-2-yl)ethyl]amino}-N,N-bis(3-methylbutyl)-4-nitrobenzamide

A mixture of 3-fluoro-N,N-bis(3-methylbutyl)-4-nitrobenzamide obtained in accordance with example A1 (1.86 g, 1 EQ.), 2-(2-amino-ethyl)-1,3-dioxolane (0.8 g, 1.2 EQ.) and potassium carbonate (1,58 g, 2 EQ.) in acetonitrile (150 ml) is heated at the boil under reflux for 3 hours, then concentrated under reduced is the t at 40° C. the Residue absorb dichloromethane (150 ml) and water (60 ml). After decantation and extraction combined organic phases are washed with salt water, dried over Na2SO4, then concentrate under reduced pressure at 40°C. Purification of the residue by flash chromatography on silica gel (eluent: heptane/ethyl acetate 8:2 to 7:3) gives the expected compound in the form of an orange-yellow oil (2.4 g; 98% yield).

MS/LC: calculated MM = 421,5; m/z = 422,2 (MH+)

NMR (1H, 400 MHz,DMSO-d6): δ of 0.68 (d, 6H), to 0.92 (d, 6H), 1,31 of 1.50 (m, 5H), to 1.61 (m, 1H), of 1.97 (m, 2H), 3,10 (m, 2H), 3,37-of 3.48 (m, 4H), 3,80 (m, 2H), 3,91 (m, 2H), 4,94 (t, 1H), 6,55 (d, 1H), 6.89 in (s, 1H), 8,10 (d, 1H), 8,39 (t, 1H).

Stage 2: 4-amino-3-{[2-(1,3-dioxolane-2-yl)ethyl]amino}-N,N-bis(3-methylbutyl)benzamide

3-{[2-(1,3-dioxolane-2-yl)ethyl]amino}-N,N-bis(3-methylbutyl)-4-nitrobenzamide (2.4 g) in a solution mixture of ethyl acetate/methanol 2:1 (100 ml)and 10% palladium on coal (240 mg) contribute to the autoclave. After stirring for 4 hours in an atmosphere of hydrogen (3 bar) at a temperature of approximately 20°C catalyst is removed by filtration on celite, and the filtrate concentrated under reduced pressure at 40°C in order to obtain the expected compound in the form of oil (2,02 g; 89% yield).

MS/LC: calculated MM = 391,5; m/z = 392,2 (MH+)

NMR(1H, 400 MHz,DMSO-d6): δ to 0.80 (m, 12H), of 1.40 (m, 6H), 1,90 (m, 2H), 3,10 (m, 2H), 3,29 (m, 4H), of 3.77 (m, 2H), 3,90 (m, 2H), 4,54 (m, 1H), 4,78 (s, H), is 4.93 (t, 1H), 6,36-of 6.52 (m, 1H).

Stage 3: 2-[(4-acetylphenyl)amino]-1-[2-(1,3-dioxolane-2-yl)ethyl]-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamide

4-acetylphenothiazine (1.1 g, 1.2 EQ.) and diisopropylcarbodiimide (1,95 g, 3 EQ.) successively added to a solution of 4-amino-3-{[2-(1,3-dioxolane-2-yl)ethyl]amino}-N,N-bis(3-methylbutyl)benzamide (2 g, 1 EQ.) in tetrahydrofuran (50 ml). The mixture is heated at the boil under reflux for 18 hours, then cooled to ambient temperature and concentrate under reduced pressure at 40°C. To the obtained residue, add water (100 ml) and dichloromethane (200 ml). After decantation and extraction combined organic phases are washed with salt water, dried over Na2SO4, then concentrate under reduced pressure at 40°C. Purification of the residue by flash chromatography on silica gel (eluent: heptane/ethyl acetate 4:6) gives the expected compound as a white foam (1.8 g; 66% yield).

MS/LC: calculated MM = 534,7; m/z = 535,3 (MH+)

NMR (1H, 400 MHz,DMSO-d6): δ to 0.80 (m, 12H), of 1.44 (m, 6H), for 2.01 (m, 2H), 2,52 (s, 3H), 3,30 (t, 4H), and 3.72 (t, 2H), 3,85 (m, 2H), 4,39 (t, 2H), a 4.83 (t, 1H), 7,05 (AB, 1H), 7,30 (s, 1H), 7,44 (AB, 1H), of 7.96 (s, 4H), 9,37 (, 1H).

Stage 4: 2-[(4-acetylphenyl)amino]-N,N-bis(3-methylbutyl)-1-(3-oxopropyl)-1H-benzimidazole-6-carboxamide

A solution of 2-[(4-acetylphenyl)amino]-1-[2-(1,3-dioxolane-2-yl)ethyl]-N,N-bis(3-methylbutyl)-1H-Ben is an imidazole-6-carboxamide (900 mg) in a mixture of tetrahydrofuran (30 ml) and aqueous hydrochloric acid (3n., 40 ml) is stirred for 18 hours at a temperature of approximately 20°C then concentrated under reduced pressure at 40°C. Dichloromethane (100 ml) is added to the remaining aqueous phase. After decantation and extraction combined organic phases are washed with salt water, dried over Na2SO4, then concentrate under reduced pressure at 40°C in order to obtain the expected compound in the form of a beige foam (820 mg, 99% yield).

MS/LC: calculated MM = 490,6; m/z = 491,3 (MH+)

NMR (1H, 400 MHz,DMSO-d6): δ 0,68 is 0.99 (m, 12H), of 1.35 (m, 6H), 2,39 (m, 2H), 2,64 (s, 3H), 3,10-to 3.49 (m, 4H), and 3.72 (m, 2H), 4,15 (m, 1H), 4,50 (m, 1H), 5,54 (s, 1H), 7,27 (AB, 1H), 7,39 (AB, 1H), to 7.64 (s, 1H), 7,82 (AB, 1H), 8,15 (AB, 1H).

Stage 5: the dihydrochloride of 2-[(4-acetylphenyl) amino]-1-{3-[(cyclohexylmethyl)amino]propyl}-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamide

A solution of 2-[(4-acetylphenyl)amino]-N,N-bis(3-methylbutyl)-1-(3-oxopropyl)-1H-benzimidazole-6-carboxamide (100 mg, 1 EQ.) and aminometilbensana (46 mg, 2 EQ.) stirred for 4 hours at a temperature of approximately 20°C. the Mixture is diluted with methanol (1 ml), then add triacetoxyborohydride sodium (86 mg, 2 EQ.) and a few drops of acetic acid to obtain a pH of 5. After 1 hour at a temperature of approximately 20°C the mixture was added dichloromethane (20 ml) and water saturated with sodium bicarbonate (10 ml). After the cantali and extraction combined organic phases are washed with salt water, dried over Na2SO4, then concentrate under reduced pressure at 40°C. Purification of the residue by flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/methanol 9:1) produces the expected compound in the form of a Foundation. Appropriate cleaners containing hydrochloride salt is formed by adding 1N. solution of hydrogen chloride in a simple ether. The precipitate is filtered and dried in order to obtain the expected dihydrochloride compound (83 mg, 62% yield).

MS/LC: calculated MM = 587,8; m/z = 588,3 (MH+)

NMR(1H, 400 MHz,DMSO-d6): δ 0,68 is 0.99 (m, 14H), 1,19 (m, 3H), 1,29-to 1.82 (m, 12H), at 2.59 (s, 3H), by 2.73 (m, 2H), of 3.07 (t, 2H), 3,21 (m, 2H), 3.43 points (m, 2H), with 4.64 (t, 2H), 7,24 (AB, 1H), 7,47 (AB,1H), 7,37 (s, 1H), to 7.84 (d, 2H), of 8.06 (d, 2H), 8,89 (m, 2H), 11,42 (m, 1H).

According to reaction scheme C or C' and in a manner analogous to the procedure described for the synthesis of the dihydrochloride of N,N-Diisobutyl-1-[3-(neopentylene)propyl]-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-6-carboxamide or a dihydrochloride of 2-[(4-acetylphenyl)amino]-1-{3-[(cyclohexylmethyl)amino]propyl}-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamide, obtained the following connection:

in which R3represents one of the radicals below:

and R4represents one of the radicals below:

D.Obtaining according to the reaction scheme D:

As shown in scheme D, the derivative (18), obtained according to the reaction scheme A, can be subjected to a saponification reaction in the presence of inorganic bases, such as the dihydrate lithium hydroxide, in a mixture of polar solvents such as water and tetrahydrofuran, at a temperature of 20-70°C for 3-17 hours. The resulting carboxylic acid (19) can be combined with a primary or secondary amine in the presence of a coupling agent, such as diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) or carbonyldiimidazole (CDI), 1-hydroxybenzotriazole (HOBt) or without an inert organic solvent such as methylene chloride, tetrahydrofuran or dimethylformamide, at ambient temperature, within 3-24 hours to obtain the compound (20).

Example D1: dihydrochloride of 1-(3-aminopropyl)-2-({4-[(methylamino)carbonyl]phenyl}amino)-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamide

Stage 1: 4-[(6-{[bis(3-methylbutyl)amino]carbonyl}-1-{3-[(tert-butoxycarbonyl)amino]propyl}-1H-benzimidazole-2-yl)amino]benzoic acid

The lithium hydroxide (141 mg, 5 EQ.) added to methyl 4-[(6-{[bis(3-methylbutyl)amino]carbonyl}-1-{3-[(Trets the-butoxycarbonyl)amino]propyl}-1H-benzimidazole-2-yl)amino]-benzoate, obtained according to the reaction scheme A, example A1 (405 mg, 1 EQ.) in a mixture of tetrahydrofuran (4 ml) and water (3 ml). The mixture is heated at the boil under reflux for 18 hours, then cooled to ambient temperature and concentrate under reduced pressure at 40°C. To the residue is added dichloromethane (50 ml) and water (20 ml). The mixture is acidified by adding acetic acid to pH 5. After decantation and extraction combined organic phases are dried over sodium sulfate and concentrate under reduced pressure. The obtained solid substance absorb diethyl ether in order to obtain the expected compound (309 mg; 79%).

MS/LC: calculated MM = of 593.8; m/z = 594,3 (MH+)

NMR (1H, 400 MHz,DMSO-d6): 0,77 (m, 12H), 1,22-of 1.55 (m, 6H), of 1.36 (s, 9H)and 1.83 (m, 2H), 3,03 (m, 2H), 3.33 and (m, 4H), 4,28 (m, 2H), 6,95-of 7.90 (m, 8H), 9,24 (s, 1H).

Stage 2: dihydrochloride of 1-(3-aminopropyl)-2-({4-[(methylamino)carbonyl]phenyl}amino)-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamide

A solution of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (18 mg, 1.1 EQ.) in chloroform (1 ml) and a solution of 1-hydroxybenzotriazole (HOBt) (13 mg, 1.1 EQ.) in tetrahydrofuran (1 ml) are successively added to 4-[(6-{[bis(3-methylbutyl)amino]carbonyl}-1-{3-[(tert-butoxycarbonyl)-amino]propyl}-1H-benzimidazole-2-yl)amino]benzoic acid (50 mg, 1 EQ.) in anhydrous tetrahydrofuran (1 ml). The mixture is displaced is more for 1 hour at a temperature of approximately 20° C, then added methylamine (2M in THF; 0,86 ml, 2 EQ.). After stirring for 17 hours at a temperature of approximately 20°C mixture is diluted with dichloromethane (3 ml) followed by the addition aminomethylpropanol resin (2 EQ.), TBD-methylpredisolone resin (2 EQ.) and Methylisothiazolinone resin (4 EQ.). After stirring for 6 hours at approximately 20°C the mixture is filtered, and the filtrate concentrated under reduced pressure at 40°C. the resulting residue is dissolved in dichloromethane (3 ml) and washed with saturated aqueous sodium bicarbonate. The organic phase is dried over sodium sulfate and concentrated at a temperature of about 40°C. the resulting residue is dissolved in ethyl acetate (0.5 ml) and add a solution of hydrogen chloride (4n. in dioxane, 2 ml). After stirring for 1 hour at a temperature of approximately 20°C the precipitate is filtered and dried in order to obtain the expected compound (29 mg; 60% yield).

MS/LC: calculated MM = 506,7; m/z = 507,2 (MH+)

NMR (1H, 400 MHz,DMSO-d6): 0,78 (m, 12H), of 1.46 (m, 6H), 2.0 (m, 2H), 2,77 (d, 3H), 2,89 (m, 2H), 3.33 and (m, 4H), of 4.45 (m, 2H), 7,07 (d, 1H), 7,43 (d, 1H), of 7.48 (s, 1H), to 7.84 (m, 5H), of 7.97 (m, 2H), 8,28 (m, 2H), 9,49 (m, 1H).

According to the reaction scheme D, and in a manner analogous to the procedure described for the synthesis of dihydrochloride of 1-(3-aminopropyl)-2-({4-[(methylamino)carbonyl]phenyl}am the but)-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamide, received the following connections

in which R3represents one of the radicals below:

E.Obtaining according to the reaction scheme E:

As disclosed in scheme E, the derivative (21), obtained according to the reaction scheme A, can be restored 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 to 15 hours, or by catalytic hydrogenation in the presence of 10% palladium on charcoal, in an inert solvent, such as methanol, ethanol, ethyl acetate or a mixture of these solvents, at a temperature of 18-25°C, within 2-8 hours in order to obtain aniline (22). Compound 23 can be treated with the isocyanate in an aprotic solvent such as dichloromethane or tetrahydrofuran, at a temperature of 20-60°C for 2-24 hours, or, alternatively, carbonyl diimidazol (CDI) in an aprotic solvent such as dichloromethane or tetrahydrofuran at a temperature of 0-60°C for 6-24 hours, followed by obrabotki primary amine at a temperature of 20-60°C for 2-24 hours in order to obtain urea (23).

Example E1: 1-(3-aminopropyl)-2-[(4-{[(methylamino)carbonyl]-amino}phenyl)amino]-N,N-bis(3-methylbutyl)-1H-benzo is imidazol-6-carboxamide

Stage 1: tert-butyl 3-{6-{[bis(3-methylbutyl)amino]carbonyl}-2-[(4-nitrophenyl)amino]-1H-benzimidazole-1-yl}propellernet

4-nitrophenylacetylene (305 mg, 1.5 EQ.) and N-methylcyclohexylamine-N-methylpredisolone resin (acquired from Novabiochem; load of 1.9 mmol/g; about 1.75 g, 3 EQ.), successively added to a solution of tert-butyl 3-[(2-amino-5-{[bis(3-methylbutyl)amino]carbonyl}phenyl)amino]propellerblade obtained according to Example A1 (500 mg, 1 EQ.) in tetrahydrofuran (30 ml). The mixture is heated at the boil under reflux for 18 hours, then cooled to ambient temperature and filtered on a Frit. The filtrate is concentrated under reduced pressure at 40°C. Purification of the residue by flash chromatography on silica gel (eluent: heptane/ethyl acetate 7:3 to 2:8) produces the expected compound in the form of a yellow solid (584 mg; 88% yield).

MS/LC: calculated MM = 594,7; m/z = 595,3 (MH+)

NMR (1H, 400 MHz,DMSO-d6): δ of 0.64 to 0.95 (m, 12H), of 1.36 (s, 9H), 1,31-of 1.65 (m, 6H), is 1.82 (m, 2H), 3.0 a (m, 2H), 3,15-3,39 (m, 4H), 4,32 (t, 2H), 6,95 (m, 1H), 7,05 (d, 1H), 7,40 (s, 1H), of 7.48 (d, 1H), 8,11 (AB, 2H), compared to 8.26 (AB, 2H), 9,71 (s, 1H).

Stage 2: tert-butyl 3-(2-[(4-AMINOPHENYL)amino]-6-{[bis(3-methylbutyl)amino]carbonyl}-1H-benzimidazole-1-yl)propellernet

Tert-butyl 3-{6-{[bis(3-methylbutyl)amino]carbonyl}-2-[(4-nitrophenyl)amino]-1H-benzimidazole-1-yl}replicable (580 mg) in a solution mixture of ethyl acetate/methanol 3:1 (40 ml), and 10% palladium on coal (58 mg) was injected in the autoclave. After stirring for 15 hours in an atmosphere of hydrogen (3 bar) at a temperature of approximately 20°C catalyst is removed by filtration on celite and the filtrate concentrated under reduced pressure at 40°C in order to obtain the expected compound in the form of foam (480 mg, 87% yield).

MS/LC: calculated MM = 564,7; m/z = 565,3 (MH+)

NMR (1H, 400 MHz,DMSO-d6): δ 0,86 (m, 12H), to 1.37 (s, 9H), 1,31 is 1.58 (m, 6H), to 1.79(m, 2H), 3,01 (m, 2H), 3,15-3,39 (m, 4H), to 4.15 (t, 2H), 4,80 (m, 2H), 6,56 (m, 2H), 6,94 (d, 2H), 7,21 (AB, 2H), 7,40 (AB, 2H), to 8.45 (s, 1H).

Stage 3: dihydrochloride tert-butyl-3-{6-{[bis(3-methylbutyl)-amino]carbonyl}-2-[(4-{[(methylamino)carbonyl]amino}phenyl)amino]-1H-benzimidazole-1-yl}propellerblade

The solution carbonyldiimidazole (CDI) (29 mg, 2 EQ.) in dichloromethane (2 ml) is added to a solution of tert-butyl 3-(2-[(4-AMINOPHENYL)amino]-6-{[bis(3-methylbutyl)amino]carbonyl}-1H-benzimidazole-1-yl)propylgallate (50 mg, 1 EQ.) in dichloromethane (2 ml). The mixture is stirred for 18 hours at a temperature of approximately 20°C, then added methylamine (2M in THF, 0,440 ml, 10 EQ.). The mixture is stirred for 4 hours at a temperature of approximately 20°C, then concentrate under reduced pressure at 40°C. the Residue absorb dichloromethane (7 ml) and saturated aqueous sodium hydrogen carbonate (3 ml). After decantation and extraction about the United organic phases are washed with salt water, then concentrate under reduced pressure at 40°C. Purification of the residue by flash chromatography on silica gel (eluent: heptane/ethyl acetate 1:1-1:9), gives compound in the form of a foam, which was dissolved in ethyl acetate (0.5 ml). Add a solution of hydrogen chloride (2H. in diethyl ether, 2 ml), and stirred the mixture for 1 hour at a temperature of approximately 20°C, then the precipitate is filtered and dried in order to obtain the expected compound (28 mg, 55% yield).

MS/LC: calculated MM = 521,7; m/z = 522,3 (MH+)

According to the reaction scheme E, and in a manner analogous to the procedure described for the synthesis dihydrochloride tert-butyl 3-{6-{[bis(3-methylbutyl)amino]carbonyl}-2-[(4-{[(methylamino)carbonyl]amino}-phenyl)amino]-1H-benzimidazole-1-yl}propylgallate, received the following connections:

in which R3represents one of the radicals below:

and R4represents one of the radicals below:

F.Obtaining according to the reaction scheme F:

The compounds of formula (I) in accordance with the present invention, in which A represents A-CH2-, can be obtained according to the following schemes F and F':

As described in scheme F, the derivative (4)obtained according to the Hema reaction A, can be restored to a connection (24) using borane or lithium aluminum hydride in an aprotic solvent such as tetrahydrofuran or diethyl ether, at a temperature of 0-70°C for 18-24 hours. Then dianiline (24) can be treated with isothiocyanates in the presence of a coupling agent attached or not attached to the resin, such as diisopropylcarbodiimide or dicyclohexylcarbodiimide, or N-methylcyclohexylamine-N-methylpredisolone resin in an inert solvent, such as tetrahydrofuran, methylene chloride, or chloroform at a temperature of 20-70°C, within 2-72 hours in order to derive (25).

Obtaining according to the reaction scheme F':

Compound (25) can also be obtained according to the following scheme F':

As disclosed in scheme F', amide (6)obtained according to reaction scheme A or B, can be restored to the corresponding amine (25) using borane or lithium aluminum hydride in an aprotic solvent such as tetrahydrofuran or diethyl ether, at a temperature of 0 to 70°C, for 1 to 6 hours.

Example F'1: hydrochloride of 6-{[bis(3-methylbutyl)amino]methyl}-1-[3-(dimethylamino)propyl]-N-(4-methoxyphenyl)-1H-benzimidazole-2-amine

A solution of lithium aluminum hydride (0,785 ml; 1 M in THF) is added dropwise to a cooled to 0#x000B0; C to a solution of 1-[3-(dimethylamino)-propyl]-2-[(4-methoxyphenyl)amino]-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamide, obtained according to the reaction scheme A (80 mg, 1 EQ.) in anhydrous tetrahydrofuran (2 ml). The mixture is brought to a temperature of 20°C, then heated at 60°C for 3 hours. After cooling to 0°C hydrolyzing reaction medium. After adding ethyl acetate, decantation and extraction, the combined organic phases are washed with salt water, dried over sodium sulfate and concentrate under reduced pressure. Purification by flash chromatography on silica gel (eluent: 100%dichloromethane to dichloromethane/methanol 9:1) produces the expected compound in the form of a Foundation. Appropriate cleaners containing hydrochloride salt is formed by adding 1N. solution of hydrogen chloride in diethyl ether (61 mg; 55% yield).

MS/LC: calculated MM = 493,7; m/z = 494,4 (MH+)

NMR (1H, 400 MHz,DMSO-d6): δ or 0.83 (m, 12H), 1,50-1,72 (m, 6H), to 2.29 (m, 2H), 2,78 (m, 6H), 2,99 (m, 4H), 3,30 (m, 2H), 3,80 (s, 3H), to 4.41 (m, 4H), 6.90 to-8,50 (m, 7H), 10,5 (m, 1H), 10,85 (m, 1H), 12,9 (m, 1H).

The following compounds were obtained according to the reaction scheme F or F':

in which R1R2N represents one of the radicals below:

in which R3represents one of the radicals below:

and R4represents one of the radicals below:

G.Obtaining according to the reaction scheme G:

The compounds of formula (I) in accordance with the present invention, in which A represents-C(O)-C(Rand)(Rb)-, can be obtained according to the following scheme G:

As shown in scheme G, the derivative (26) can be alkilirovanii in the presence of a strong base such as tert-butyl potassium,derived complex α-glorifier, in an aprotic polar solvent such as dimethylformamide, at a temperature of 0-20°C for 0.5-2 hours to obtain the compound (27). Derivative (27) can optionally be alkilirovanii 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 to obtain the compound (28). Ester (28) can be subjected to a saponification reaction 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 (29) can be combined with a primary or secondary amine in the presence of a coupling agent, tcog is how diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) or carbonyldiimidazole (CDI), 1-hydroxybenzotriazole (HOBt) or without an inert organic solvent such as methylene chloride, tetrahydrofuran or dimethylformamide at ambient temperature for 3-24 hours. Alternatively, the acid (29) can handle tional or oxalylamino in an aprotic solvent such as dichloromethane or toluene, at a temperature of 40-60°C for 2-16 hours, then, the thus obtained acid chloride of the acid can react with a primary or secondary 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 in order to obtain the amide (30). Processing of fluorinated or chlorinated derivative (30) 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 a derivative (31). The function of the nitro group of the compound (31) restored by treatment with chloride dihydrate tin in an inert solvent, such as ethyl acetate, or digitiform the Ministry of foreign Affairs, 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 mixtures of these solvents, at a temperature of 18-25°C, within 2-8 hours in order to get dianion (32). Then the derivative of (32) is treated with isothiocyanates in the presence of a coupling agent attached or not attached to the resin such as diisopropylcarbodiimide or dicyclohexylcarbodiimide or N-methylcyclohexylamine-N-methylpredisolone resin, in an inert solvent, such as tetrahydrofuran, methylene chloride, or chloroform, at a temperature of 20-70°C within 2-72 hours in order to derive (33). In the alternative, the derivative of (32) can be treated with isothiocyanates in an inert solvent, such as tetrahydrofuran, methylene chloride, chloroform or ethanol, at a temperature of 20-80°C for 1-16 hours, then the resulting thiourea can be processed methyl iodide or yellow oxide of mercury (II) in the presence of catalytic amounts of sulfur in a polar solvent such as methanol or ethanol, for 2-24 hours at a temperature of 20-80°C in order to obtain (33). The compound (6) can be distinguished either by flash chromatography on silica gel or by adding in the reactions is nnow mixture of nucleophilic reagent, attached to the polymer, such as, for example, aminomethylpyrimidine resin, and/or electrophilic reagent attached to the polymer, such as, for example, Methylisothiazolinone resin, followed by filtration and evaporation of the filtrate.

Example G1:the dihydrochloride of 2-{2-[(4-acetylphenyl)amino]-1-[3-(dimethylamino)propyl]-1H-benzimidazole-6-yl}-N,N-Diisobutyl-2-methylpropanamide

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

Tert-butyl potassium (11,22 g, 2 EQ.) add in a solution of DMF (80 ml), cooled to 0°C. a Solution of 1-chloro-2-nitrobenzene (7,87 g, 1 EQ.) and ethyl-2-chloropropanol (7 ml, 1.1 EQ.) add to the mixture dropwise over 45 minutes, keeping the reaction temperature below 5°C. At the end of the addition stirring is maintained for 2 hours at 0°C, then at this temperature the mixture was hydrolized 1H. 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 by flash chromatography on silica gel (eluent: heptane/dichloromethane 8:2-6:4) gives the expected compound as a yellow oil (8,28 g; 64% yield).

NMR (1H, 400 MHz, DMSO-d6): δ 1,14(t, 3H), of 1.42 (d, 3H), 3,99 (kV, 1H), 4,08 (m, 2H), 7,52 (AB, 1H), 7,71 (s, 1H), 8,05 (AB, 1H).

Stage 2ethyl-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 of methyliodide (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 0°C, then added dropwise ethyl acetate, water, saturated sodium bicarbonate, then water. After decantation and extraction combined organic phases are washed with salt water, dried over Na2SO4and concentrate under reduced pressure to obtain the expected compound in the form of oil, which crystallizes. The crystals are washed with heptane and dried (13.8 g; 94% yield).

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

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

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

NMR (1H, 400 MHz,DMSO-d6): δ of 1.52 (s, 6H), 7,53 (AB, 1H), 7,66 (s, 1H), 8,04 (AB, 1H), 12,72 (s, 1H).

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

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

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

NMR (1H, 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 (s, 1H), to $ 7.91 (AB, 1H).

Stage 5: 2-(3-{[3-(dimethylamino)propyl]amino}-4-nitrophenyl)-N,N-Diisobutyl-2-methylpropanamide

A mixture of 2-(3-chloro-4-nitrophenyl)-N,N-Diisobutyl-2-methylpropanamide (78 mg, 1 EQ.), 3-dimethylaminopropylamine (45 mg, 2 EQ.) and potassium carbonate (62 mg, 2 EQ.) in DMF (2 ml) are heated at the boil under reflux for 3 hours, then cooled to ambient temperature. The remainder is absorbed by ethyl acetate (20 ml) and water (8 ml). After decantation and extraction combined organic phases are washed with salt water, dried over Na2SO4, then concentrate under reduced pressure at 40°C. Purification of the residue by flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/methanol 8:2) yields the desired compound as a yellow oil (44 mg; 48% yield).

MS/LC: calculated MM = 420,6; m/z = 421,3 (MH+)

NMR (1H, 400 MG IS, CDCl3): δ 0,60 (d, 6H), of 0.90 (d, 6H), of 1.57 (m, 6H), of 1.75 (m, 1H), of 1.88 (m, 2H), of 1.97 (m, 1H), 2,28 (s, 6H), of 2.45 (t, 1H), 2,75 (d, 2H), 3,26 (d, 2H), 3,34 (m, 2H), to 6.57 (m, 1H), of 6.68 (s, 1H), 8,15 (m, 1H), 8,49 (m, 1H).

Stage 6: 2-(4-amino-3-{[3-(dimethylamino)propyl]amino}phenyl)-N,N-Diisobutyl-2-methylpropanamide

2-(3-{[3-(dimethylamino)propyl]amino}-4-nitrophenyl)-N,N-Diisobutyl-2-methylpropanamide (44 mg) in solution in a mixture of ethyl acetate/ethanol 2:1 (3 ml)and 10% palladium on coal (5 mg) contribute to the autoclave. After stirring for 4 hours in an atmosphere of hydrogen (3 bar) at a temperature of approximately 20°C catalyst is removed by filtration on celite and the filtrate concentrated under reduced pressure at 40°C in order to obtain the expected compound in the form of oil (39 mg; 95% yield).

MS/LC: calculated MM = 390,6; m/z = 391,3 (MH+)

NMR (1H, 400 MHz,DMSO-d6): δ 0,49 (m, 6H), 0,81 (m, 6H), of 1.36 (s, 6H), of 1.65 (m, 1H), 1,72 (m, 2H), 1,87 (m, 1H), measuring 2.20 (s, 6H), 2,39 (t, 2H), 2,81 (m, 2H), 2,97 (t, 2H), 3,11 (m, 2H), 4,56 (m, 2H), 6,18 (s, 1H), 6.30-in (AB, 1H), 6.48 IN (AB, 1H).

Stage 7: the dihydrochloride of 2-{2-[(4-acetylphenyl)amino]-1-[3-(dimethylamino)propyl]-1H-the benzimidazole-6-yl}-N,N-Diisobutyl-2-methylpropanamide

4-acetylphenothiazine (14 mg, 1.2 EQ.) and N-ethylcyclohexylamine-N-methylpredisolone resin was obtained from Novabiochem; load of 1.9 mmol/g; 210 mg, 4 equiv.) successively added to a solution of 2-(4-amino-3-{[3-(dimethylamino)propyl]amino}phenyl)-N,N-Diisobutyl-methylpropanamide (39 mg, 1 EQ.) in tetrahydrofuran (2 ml). The mixture is heated at the boil under reflux for 17 hours, then cooled to ambient temperature and filtered. The filtrate is concentrated under reduced pressure at 40°C. Purification of the residue by flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/methanol 9:1) produces the expected compound in the form of the base (409 mg; 60% yield). Appropriate cleaners containing hydrochloride salt is formed by adding 1N. solution of hydrogen chloride in a simple ether. The precipitate is filtered and dried in order to obtain the expected dihydrochloride compound (51 mg, 85% yield).

MS/LC: calculated MM = 533,7; m/z = 534,4 (MH+)

NMR (1H, 400 MHz,DMSO-d6): δ, and 0.40 (m, 6H), of 0.82 (m, 6H), of 1.53 (s, 6H), of 1.64 (m, 1H), 1,89 (m, 1H), of 2.21 (m, 2H), 2,59 (s, 3H), of 2.75 (m, 8H), 3.15 in (m, 2H), 3,25 (m, 2H), 4,60 (t, 2H), 7,10 (AB, 1H), 7,41 (AB, 1H), 7,56 (, 1H), 7,82 (m, 2H), with 8.05 (m, 2H), 10,79 (m, 1H), 11,4 (m, 1H).

According to the reaction scheme G received the following connections:

in which R1R2N represents one of the radicals below:

R3represents one of the radicals below:

and R4represents one of the radicals below:

The subject of this image is etenia is also a method of obtaining the compounds of formula (I), as defined above, characterized in that the compound of the General formula:

in which A, X, R1,R2, R4have the meanings indicated above, is treated with isothiocyanates General formula R3N=C=S, where R3matter mentioned above, in the presence of a coupling agent or yellow oxide of mercury (II) in the presence of sulfur, for 3-48 hours, proton or an aprotic solvent, at a temperature of 50-80°C.

The binding agent may be on a substrate, such as N-methylcyclohexylamine-N-methylpredisolone resin, or free, such as diisopropylcarbodiimide, diethylcarbamazine or dicyclohexylcarbodiimide. You can use proton solvent, such as methanol or ethanol, or an aprotic solvent, such as tetrahydrofuran or acetonitrile.

The object of the present invention is also a compound of the General formula (II)

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

A represents A-CH2-, -C(O)-, -C(O)-C(Rand)(Rb)-;

X is-C - or-N-;

Randand Rbindependently represent a hydrogen atom or the radical (C1-C6)alkyl;

R1and R2independently represent a hydrogen atom, a radical (C1-C8 )alkyl, optionally substituted hydroxy, (C2-C6)alkenyl or a radical of the formula -(CH2)n-X1;

X1is (C1-C6)alkoxy, (C3-C7)cycloalkyl, substituted, heteroseksualci, aryl or heteroaryl,

moreover, the radicals (C3-C7)cycloalkyl, heteroseksualci, aryl and heteroaryl optionally substituted by one or more identical or different substituents chosen from -(CH2)n'-V1-Y1, halogen, nitro and cyano;

V1represents-O-, -S - or a covalent bond;

Y1represents the radical (C1-C6)alkyl, optionally substituted by one or more identical or different radicals of halogen; or aryl;

n represents an integer from 0 to 6 and n' an integer from 0 to 2 (and it should be understood that, if n is equal to 0, then X1is neither a hydroxy radical or an alkoxy 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 substituents selected from hydroxy, (C1-C6)alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)alkoxycarbonyl, -C(O)NV1'Y1'where V1' and Y1' independently presented Aut a hydrogen atom or a (C 1-C6)alkyl, and geterotsiklicheskie; or R1and R2together form a radical of the formula:

R3represents -(CH2)p-Z3or-C(O)-Z'3

Z3is(C1-C6)alkyl,(C2-C6)alkenyl,(C1-C6)alkoxy,(C1-C6)alkoxycarbonyl,(C3-C7)cycloalkyl, heteroseksualci, aryl or heteroaryl,

moreover, the radicals (C3-C7)cycloalkyl and heteroseksualci optionally substituted C1-C6)alkyl,

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

V3represents-O-, -S-, -C(O)-, -C(O)-O-, -NH-C(O)-, -C(O)-NR'3-, -NH-C(O)-NR'3- or a covalent bond;

Y3represents a hydrogen atom or the radical (C1-C6)alkyl, optionally substituted by one or more identical or different halogen radicals;

or Z3represents a radical of the formula

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

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

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

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

p, p' and p independently represent an integer from 0 to 4;

R4represents a radical of the formula -(CH2)s-R'4;

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

W4represents a hydrogen atom or a (C1-C8)alkyl;

W'4represents a radical of the formula -(CH2)s'-Z4;

Z4represents a hydrogen atom, (C1-C8)alkyl, optionally substituted by one or more identical or different substituents selected from (C1-C6)alkoxy, (C1-C6)alkylthio and hydroxy; (C2-C6)alkenyl; (C3-C7)cycloalkyl, optionally substituted by one or more identical or different (C1-C6)alkilani; cyclohexen heteroaryl; aryl, optionally substituted by one or more identical or different radicals selected from -(CH2)s-V4-Y4, hydroxy, halogen, nitro and cyano;

V4represents-O-, -S-, -NH-C(O)-, -NV4'- or a covalent bond;

Y4represents a hydrogen atom or the radical (C1-C6)alkyl, optionally substituted by one or more identical or different halogen radicals;

V4' represents a hydrogen atom or a (C1-C6)alkyl;

s" represents an integer from 0 to 4;

or Z4represents a radical of the formula

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

and if R3represents-C(O)-Z'3and R4represents a radical of the formula -(CH2)sNW4W'4and W4and W'4independently represent a hydrogen atom or the radical (C1-C6)alkyl, then -(CH2)srepresents neither the ethylene radical or the radical -(CH2)-CH((C1-C4)alkyl)-;

Preferably the invention relates to compounds of formula II, as defined above, in which

A represents-C(O)- and X is-C-;

R1and R2independently represent a hydrogen atom, a radical (C1-C8)alkyl, optionally substituted hydroxy, (C2-C6)alkenyl or radical Faure the uly -(CH 2)n-X1;

X1is (C1-C6)alkoxy, (C3-C7)cycloalkyl, aryl or heteroaryl,

moreover, the aryl radical optionally substituted by one or more identical or different substituents chosen from -(CH2)n'-V1-Y1and halogen;

V1represents-O - or a covalent bond;

Y1represents the radical (C1-C6)alkyl, optionally substituted by one or more identical or different radicals of halogen; or aryl;

or R1and R2together with the nitrogen atom to which they are attached, form heteroseksualci, optionally substituted by one or more identical or different substituents selected from hydroxy,(C1-C6)alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)alkoxycarbonyl, -C(O)NV1'Y1'where V1' and Y1'independently represent a hydrogen atom or a (C1-C6)alkyl, and geterotsiklicheskie; or R1and R2together form a radical of the formula:

R3represents -(CH2)p-Z3or-C(O)-Z'3

Z3is (C1-C6)alkoxycarbonyl, (C3-C7)cycloalkyl, heteroaryl, or aryl radical, optionally substituted by one or more identical or R is slishnimi substituents, selected from halogen, nitro or -(CH2)p'-V3-Y3;

V3represents-O-, -S-, -C(O)-, -C(O)-O-, -C(O)-NR'3-, -NH-C(O)-, -NH-C(O)-NR'3- or a covalent bond;

Y3represents a hydrogen atom or the radical (C1-C6)alkyl, optionally substituted by one or more identical or different halogen radicals;

orZ3represents a radical of the formula

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

V'3represents-O - or a covalent bond;

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

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

p equals 0 or 1, and p' and p" are equal to 0;

R4represents a radical of the formula -(CH2)s-R'4;

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

W4represents a hydrogen atom or a (C1-C8)alkyl;

W'4represents a radical of the formula -(CH2)s'-Z4;

Z4represents a hydrogen atom, (C1-C8)alkyl, (C3-C7)cycloalkyl or aryl; and more specifically

radical cycloalkyl chosen from radicals of cyclopropyl, cyclohexyl and cycloheptyl,

radical heteroseksualci chosen from radicals of pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, azacycloheptane, azacyclonol and decahydroquinoline,

the aryl radical is a phenyl radical,

radical heteroaryl Vybrat from radicals of furil, pyridinyl and imidazolyl,

or their pharmaceutically acceptable salts.

Very preferably, the invention also relates to compounds of the formula II as defined above and in which

A represents-C(O)- and X is-C-;

R1and R2independently represent a radical (C1-C8)alkyl;

R3represents -(CH2)p-Z3

Z3represents a phenyl radical, optionally substituted by one or more identical or different substituents selected from nitro or -(CH2)p'-V3-Y3;

V3represents-O-, -C(O)-, -C(O)-O-, -C(O)-NR'3-, NH-C(O)-, -NH-C(O)-NR'3-;

Y3represents a hydrogen atom and the and (C 1-C6)alkyl;

R'3represents a hydrogen atom or a (C1-C6)alkoxy;

p is 0 or 1; p' 0;

R4represents a radical of the formula - (CH)s-R'4

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

W4represents a hydrogen atom or a (C1-C8)alkyl;

W'4represents a radical of the formula -(CH2)s'-Z4;

Z4represents a hydrogen atom or a (C3-C7)cycloalkyl;

s represents an integer from 2 to 4; s' represents an integer from 0 to 4;

and more specifically radical heteroseksualci represented by R'4is pyrrolidinyl, piperidinyl, morpholinyl or piperazinil, and cycloalkyl, presents Z4represents cyclohexyl;

or their pharmaceutically acceptable salts.

Also preferably, the invention relates to compounds of formula II, as defined above, in which

A represents-C(O)-C(Rand)(Rb)-; X represents-C;

Randand Rbindependently represent a radical (C1-C6)alkyl;

R1and R2independently represent a radical (C1-C8)alkyl;

R3represents -(CH2)p-Z3

Z3represents a phenyl radical, optionally substituted by one or more identical or different substituents of the formula -(CH2)p'-V3-Y3;

V3represents-O-, -C(O)-, -C(O)-O-, -C(O)-NR'3-, -NH-C(O)-NR'3-;

Y3represents a hydrogen atom or the radical (C1-C6)alkyl;

R'3is (C1-C6)alkyl or (C1-C6)alkoxy;

p and p' are equal to 0;

R4represents a radical of the formula -(CH2)s-R'4;

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

W4represents a hydrogen atom or a (C1-C8)alkyl;

W'4represents a radical of the formula -(CH2)s'-Z4;

Z4represents a hydrogen atom, a phenyl radical or heteroaryl;

s represents an integer from 2 to 4; s' represents an integer from 0 to 4;

or their pharmaceutically acceptable salts.

Preferably also, the invention relates to compounds of formula II, as defined above, in which

A represents-CH2-; X represents-C;

R1and R2independently represent a radical (C1-C8)alkyl;

R3represents -(CH2)p-Z3;

Z32)p'-V3-Y3;

V3represents-O-, -C(O)-, -C(O)-O-, -C(O)-NR'3-, -NH-C(O)-NR'3-;

Y3represents a hydrogen atom or the radical (C1-C6)alkyl;

R'3is(C1-C6)alkyl or (C1-C6)alkoxy;

p and p' are equal to 0;

R4represents a radical of the formula -(CH2)s-R'4;

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

W4represents a hydrogen atom or a (C1-C8)alkyl;

W'4represents a radical of the formula -(CH2)s'-Z4;

Z4represents a hydrogen atom;

s represents an integer from 2 to 4; s' represents an integer from 0 to 4;

or their pharmaceutically acceptable salts.

The compounds I and II in accordance with the present invention possess useful pharmacological properties. So, it has been found that the compounds I and II in accordance with the present invention have a good affinity to certain subtypes of melanocortin receptors, in particular to the MC4 receptor.

Thus, the compounds in accordance with this image is emeniem can be used in various therapeutic options for use. They can be used successfully for the treatment of pathological conditions or diseases that involve one or more melanocortin receptors, such as inflammatory conditions, disorders weight (obesity, cachexia, anorexia), disorders of sexual activity (erectile dysfunction), pain, and mental health problems (anxiety, depression), drug dependency, skin diseases (inflammation of the sebaceous glands, dermatitis, melanoma). Below, in the experimental part, an illustration of the pharmacological properties of the compounds in accordance with the present invention.

The subject of this application are also pharmaceutical compositions containing as active ingredient at least one product of formula I, as defined above, and pharmaceutically acceptability of salt specified product of formula I in combination with a pharmaceutically acceptable carrier.

Under a pharmaceutically acceptable salt should be understood, in particular, additive salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, diphosphate and nitrate or organic acids, such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluensulfonate, pamoate and stearate. In the scope of the present invention salts derived from bases, so the x as sodium hydroxide or potassium, if you can use them. For other examples of pharmaceutically acceptable salts is possible to make reference to "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217.

The subject of this application is also the use of compounds in accordance with the present invention for obtaining a medicinal product for treating disorders weight, such as obesity, cachexia and, more specifically, malignant cachexia, AIDS cachexia, geriatric cachexia, cardiac cachexia, renal cachexia, cachexia in rheumatoid arthritis and anorexia, the treatment of pain and, more specifically, neuropathic pain, mental health problems, such as anxiety and depression, lack of sexual activity, such as erectile dysfunction.

The pharmaceutical composition may be in the form of a solid, for example powders, granules, tablets, gelatin capsules or suppositories. Suitable solid carriers can, for example, be a calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.

The object of the present invention is also the use of compounds of General formula (I')

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

<> A' represents-CH2-, -C(O)-, -C(O)-C(Rand)(Rb)-;

X' is-CH-;

Randand Rbindependently represent a hydrogen atom or the radical (C1-C6)alkyl;

R'1represents a hydrogen atom; a radical (C1-C8)alkyl, optionally substituted by hydroxy or one or more identical or different halogen radicals; (C2-C6)alkenyl; or a radical of the formula -(CH2)nX1;

R'2represents the radical (C1-C8)alkyl, optionally substituted by hydroxy or one or more identical or different halogen radicals; (C2-C6)alkenyl; or a radical of the formula -(CH2)n-X1;

each X1independently represents a C1-C6)alkoxy, (C3-C7)cycloalkyl, substituted, heteroseksualci, aryl or heteroaryl,

moreover, the radicals (C3-C7)cycloalkyl, heteroseksualci, aryl and heteroaryl optionally substituted by one or more identical or different substituents chosen from -(CH2)n'-V1-Y1, halogen, nitro, cyano and aryl;

V1represents-O-, -S - or a covalent bond;

Y1represents the radical (C1-C6)alkyl, optionally substituted by one or more identical or different halogen radicals;

n represents an integer h is the layer from 0 to 6 and n' - an integer from 0 to 2 (it should be understood that, if n is equal to 0, then X1does not represent a radical alkoxy),

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 substituents selected from hydroxy, (C1-C6)alkyl, optionally substituted by a hydroxy-group, (C1-C6)alkoxycarbonyl, heterocyclization and-C(O)NV1'Y1'where V1' and Y1' independently represent a hydrogen atom or a (C1-C6)alkyl; or R1and R2together form a radical of the formula:

R3' is-Z3, -C(RZ3)(R'Z3)-Z3, -C(RZ3)(R'Z3)-(CH2)p-Z3or-C(O)-Z'3;

RZ3and R'Z3independently represent a hydrogen atom or the radical (C1-C6)alkyl;

Z3isZ3a,Z3b,Z3c,Z3dorZ3e;

Z3arepresents the radical (C1-C6)alkyl;

Z3bis (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkylamino or di((C1-C6)alkyl)amino;

Z3crepresents aryl or heteroaryl;

Z3dp is establet (C 1-C6)alkoxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, di((C1-C6)alkyl)aminocarbonyl, (C1-C6)alkyl-C(O)-NH-, (C3-C7)cycloalkyl, heteroseksualci;

moreover, the radicals (C3-C7)cycloalkyl and heteroseksualci optionally substituted by one or more identical or different substituents selected from halogen, nitro, (C1-C6)alkoxy, optionally substituted by one or more identical or different radicals halogen, (C1-C6)alkyl, optionally substituted by one or more identical or different radicals halogen, (C1-C6)alkylcarboxylic, (C1-C6)alkoxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, di((C1-C6)alkyl)aminocarbonyl and hydroxy,

the aryl radicals and heteroaryl optionally substituted by one or more identical or different substituents selected from halogen, cyano, nitro, azido, hydroxy, (C1-C6)alkoxycarbonyl-(C1-C6)alkenyl, (C1-C6)alkylaminocarbonyl-(C1-C6)alkenyl, -SO2-NR31R32, geterotsiklicheskie, heteroaryl or -(CH2)p'-V3-Y3;

R31and R32together with the nitrogen atom to which they are attached, form heteroseksualci;

V3represents-O-, -S-, -C(O)-, -C(O)-O-, -O-C(O)-,-SO2-, -SO2NH-, -NR'3-SO2-, -NR'3-, -NR'3-C(O)-, -C(O)-NR'3-, -NH-C(O)-NR'3- or a covalent bond;

Y3represents a hydrogen atom; a radical (C1-C6)alkyl, optionally substituted by one or more identical or different halogen radicals; aryl radical, optionally substituted by one or more identical or different substituents selected from halogen, nitro, (C1-C6)alkyl and (C1-C6)alkoxy; or a radical aryl-(C1-C6)alkyl, optionally substituted by one or more identical or different substituents selected from halogen, nitro, (C1-C6)alkyl and (C1-C6)alkoxy;

Z3erepresents a radical of the formula

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

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

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

R'3represents a hydrogen atom, (C1-C6/sub> )alkyl or (C1-C6)alkoxy;

p represents an integer from 1 to 4; p' and p independently represent an integer from 0 to 4;

R4represents a radical of the formula -(CH2)s-R'4;

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

W4represents a hydrogen atom or a (C1-C8)alkyl;

W'4represents a radical of the formula -(CH2)s'-Z4;

Z4represents a hydrogen atom, (C1-C8)alkyl, optionally substituted by one or more identical or different substituents selected from (C1-C6)alkoxy, (C1-C6)alkylthio and hydroxy; (C2-C6)alkenyl; (C3-C7)cycloalkyl, optionally substituted by one or more identical or different (C1-C6)alkilani; cyclohexene; heteroaryl and aryl;

and aryl radicals and heteroaryl optionally substituted by one or more identical or different radicals selected from: the formula -(CH2)s-V4-Y4, hydroxy, halogen, nitro and cyano;

V4represents-O-, -S-, -NH-C(O)-, -NV4'- or a covalent bond;

Y4represents a hydrogen atom or the radical (C1-C6)alkyl, optionally substituted by one or more identical or different halogen radicals;

V4' represents a hydrogen atom or a (C1-C6)alkyl;

s" represents an integer from 0 to 4;

or Z4represents a radical of the formula

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

to obtain drugs for treatment of disorders of weight, mental health problems, pain or disorders of sexual activity.

The object of the present invention more specifically is the use of compounds of General formula (I')as defined above, characterized in that

R1and R2independently represent a radical (C1-C8)alkyl;

R3is Z3sand Z3srepresents phenyl or naphthyl, each substituted at least cyano;

R4represents a radical of the formula -(CH2)s-R'4in which R'4represents the radical pyrrolidinyl or piperidinyl; or a radical of the formula-NW4W'4;

W4represents a hydrogen atom or a (C1-C8)alkyl;

W'4represents a radical of the formula -(CH2)s'-Z 4in which Z4represents a hydrogen atom;

s represents an integer from 2 to 4; s' represents an integer from 0 to 4;

or its pharmaceutically acceptable salt.

Pharmaceutical compositions containing the compound in accordance with the present invention, can also be presented in liquid form, for example in the form of solutions, emulsions, suspensions or syrups. Suitable liquid carriers may, for example be a water, organic solvents such as glycerol or glycols, as well as their mixtures, 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 by.

All technical and scientific terms used herein have the meaning known to the person skilled in the art. In addition, all patents (or patent applications) as well as other bibliographic references included in this description by reference.

Experimental part:

Compounds in accordance with the present invention, obtained in accordance with the procedures of Examples A, B, C, C', D, E, F, F' and G, described above, are presented in the table below.

Join the nature of the technology at times retention (rt) and molecular peaks, defined using mass spectrometry (MH+).

For mass spectrometry using mono-quadrupole mass spectrometer (Micromass, Platform model), equipped withsource elektrorazpredelenie with a resolution of 0.8 Yes 50% minimum. Calibration performed monthly in the mass range from 80 to 1000 Yes using a calibration mixture of sodium iodide and rubidium iodide in solution in a mixture of isopropanol/water (1/1 by vol.).

For liquid chromatography using the system of Waters, including flow degasser, Quaternary pump Waters 600, Gilson 233 flat sample injector and detector Waters PAD 996 UV.

Used the following elution conditions:

Eluent:Andwater + 0,04% triperoxonane acid;Bacetonitrile

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

Flow rate: 1 ml/min; Injection: 10 μl; Column: Uptisphere ODS 3 µm 75×4.6 mm i.d.

These examples are presented in order to illustrate the procedure, above, and under no circumstances should the race is to atreatise as limiting the scope of the present invention.

7,4
ExamplesMolecular structure[M+H]+rt (min)
1512,37,8
2582,38,0
3490,57,5
4491,46,9
5508,47,6
6574,48,0
7566,48,1
8626,48,2
9540,38,2
10of 454.37,2
11467,97,3
12482,3
13496,17,5
14484,57,0
15484,37,0
16498,37,1
17482,37,5
18496,27,6
19470,27,0
20498,37,2
21469,16,2
22537,16,8
23551,06,9
24540,27,4
25540,07,4
26 541,07,3
27566,97,3
28526,07,2
29522,37,7
30452,27,2
31466,17,3
32452,37,8
33422,37,7
34440,37,8
35490,38,3
36rub464.38,0
37468,37,9
38458,38,0
39 490,38,9
40482,37,9
41466,37,8
42467,38,3
43436,37,8
44436,37,8
45450,38,0
46490,38,2
47497,38,5
48rub464.38,1
49468,38,0
50462,48,0
51452,47,8
52450,4 8,0
53500,28,2
54514,38,2
55484,28,7
56484,29,1
57484,29,0
58495,38,9
59rub464.38,7
60rub464.38,9
61480,38,7
62rub464.38,9
63450,38,7
64484,28,4
65528,28,5
66 468,38,2
67rub464.38,1
68495,39,1
69480,38,1
70496,38,3
71518,29,0
72534,28,7
73492,38,4
74508,38,5
75525,38,9
76478,28,5
77522,28,6
78522,28,4
79 506,28,2
80492,28,5
81508,28,6
82522,38,8
83494,28,7
84529,38,5
85543,38,7
86545,38,6
87506,38,5
88507,37,9
89543,38,5
90557,38,7
91559,38,7
92558,3 8,0
93494,38,1
94507,28,0
95521,28,0
96549,38,2
97522,38,6
98made 564.38,9
99made 564.39,1
100562,38,8
101562,38,8
102576,38,9
103590,39,0
104578,38,7
105591,38,5
16 456,28,0
107500,18,0
108440,27,7
109490,28,4
110478,38,2
111548,18,1
112479,27,6
113478,28,1
114637,38,8
115653,39,0
116547,38,8
117563,39,0
118610,49,1
119 626,49,3
120520,38,5
121534,38,7
122536,38,6
123550,38,2
124535,38,0
125506,38,4
126548,38,6
127548,38,8
128546,38,6
129546,38,6
130560,38,6
131574,38,7
13252,3 8,5
133575,38,3
134522,38,2
135521,28,1
136563,28,2
137563,28,3
138561,28,2
139561,28,2
140575,28,2
141589,28,3
142577,28,1
143594,48,8
144535,48,0
145564,49,5
146588,49,2
147456,27,2
148484,37,5
149512,27,8
150470,37,3
151470,27,4
152498,37,6
153540,28,1
154496,37,6
155480,37,4
156516,07,0
157516,27,2
158522,37,9
159 590,28,0
160608,59,2
161624,59,4
162623,58,5
163534,38,7
164533,38,0
165535,48,0
166564,49,5
167508,28,2
168474,38,0
169484,48,2
170498,48,4
171526,38,4
172 540,38,5
173482,38,1
174566,48,1
175520,28,6
176534,28,7
177534,28,7
178560,28,9
179574,29,0
180588,29,1
181532,28,6
182494,47,5
183534,48,1
184504,48,4
18552,2 8,9
186546,28,7
187562,28,9
188508,28,2
189494,47,5
190474,38,0
191484,48,2
192498,48,4
193526,38,4
194540,38,5
195482,38,1
196566,48,1
197to 602.39,2
198550,38,1
199549,37,8
200564,48,1
201606,48,2
203611,47,4
204478,47,5
205492,47,5
206508,37,6
207507,37,3
208522,37,4
209610,38,7
210624,48,7
211640,48,8
212639,38,3
213 654,48,5
214514,48,2
215528,48,2
216560,48,2
217592,48,1
218594,38,1
219590,48,4
220532,38,4
221548,28,6
222547,48,0
223550,48,5
224542,48,2
225604,58,3
226 528,47,9
227556,58,1
228556,58,0
229590,48,4
230532,48,6
231546,48,6
232548,38,5
233547,47,9
234533,47,9
235532,58,7
236548,48,8
237547,58,1
238533,48,0
23952,4 8,1
240548,48,3
241547,47,7
242533,47,7
243632,58,3
244556,48,1
245570,48,1
246584,58,2
247548,47,5
248472,47,2
249486,47,3
250500,47,3
251exports, as against 618.58,7
252602,58,6
253617,58,1
254603,58,1
255534,47,6
256518,47,5
257533,47,3
258519,47,2
259518,48,1
260534,48,2
261533,47,7
262519,47,7
263562,47,8
264486,37,6
265500,47,6
266 514,47,7
267562,48,2
268546,48,1
269561,47,8
270547,47,8
271570,48,7
272542,48,7
273554,48,6
274513,48,3
275527,48,4
276556,48,6
277556,48,8
278576,47,9
279 500,47,6
280514,47,6
281528,57,7
282548,48,7
283597,48,9
284570,48,9
285597,48,7
286567,48,5
287554,48,4
288538,38,7
289522,48,6
290562,48,5
291592,48,6
29254,4 8,6
293560,48,7
294600,39,2
295562,48,5
296546,38,9
297562,39,1
298561,38,5
299547,38,5
300576,48,6
301500,48,4
302514,48,4
303528,48,4
304590,48,5
305575,48,1
306589,48,2
307534,57,7
308534,57,8
309562,57,9
310546,57,8
311556,48,2
312508,57,7
313524,37,5
314556,47,5
315540,37,5
316539,57,9
317510,48,1
318494,48,0
319 542,48,1
320to 526.47,8
321528,48,3
322500,48,4
323514,48,4
324570,48,8
325506,47,3
326506,47,3
327534,47,4
328518,47,3
329consists 528.37,6
330548,37,3
331486,37,0
332 480,47,1
333592,48,1
334634,39,2
335577,49,0
336584,38,4
337591,48,3
338610,38,4
339518,47,4
340534,37,5
341533,37,2
342519,37,1
343to 544.37,8
344486,38,1
34556,5 7,3
346518,57,5
347544,47,9
348528,47,7
349506,57,4
350534,47,4
351518,47,4
352534,47,6
353533,57,3
354519,47,3
355486,47,2
356500,47,2
357528,57,3
358548,47,4
359496,47,3
360538,58,3
361522,58,2
362of 494.58,0
363to 510.58,1
364562,58,1
365520,58,1
366569,48,2
367561,57,9
368574,59,0
369589,68,3
370562,58,4
371589,68,1
372 646,49,9
373524,48,7
374496,48,3
375566,49,9
376534,48,2
377561,47,9
378524,48,4
379506,48,1
380518,48,4
381532,48,6
382534,48,5
383519,47,9
384533,47,9
385 547,47,9
386555,38,2
387482,58,2
388482,38,0
389496,48,1
390582,410,3
391556,58,4
392534,48,4
393560,49,0
394547,48,2
395583,48,5
396548,48,4
397576,48,4
39875,5 8,1
399508,48,3

400524,48,4
401540,48,1
402553,58,1
403530,48,4
404502,48,1
405520,48,2
406548,48,2
407547,47,9
408480,48,0
409496,48,1
410512,47,8
411 525,47,9
412548,48,6
413560,48,6
414576,48,8
415562,48,5
416611,48,3
417561,48,2
418546,68,1
419560,68,3
420532,68,0
421574,48,3
422564,68,7
423618,69,9
42462,6 9,1
425596,68,9
426610,78,3
427665,79,6
428558,78,7
429562,68,4
430576,68,5
431568,68,6
432557,68,5
433590,39,3
434562,38,6
435610,39,0
436624,49,0
437594,39,1
438543,39,3
439563,2the 9.7
440561,38,4
441559,38,8
442582,38,8
443576,28,5
444558,38,6
445526,38,3
446585,38,6
447625,48,3
448618,49,6
449552,48,8
450536,48,5
451 596,38,9
452589,58,2
453616,59,1
454603,58,3
455584,58,0
456585,48,6
457557,48,5
458600,48,5
459622,49,1
460601,48,7
461623,49,0
462594,48,6
463RUB 573.48,3
464 595,38,7
465519,48,1
466548,48,4
467548,48,5
468576,49,1
469596,48,9
470549,39,5
471582,38,8
472596,48,2
473597,48,2
474602,49,0
475571,48,5
476562,48,4
47758,3 8,3
478582,38,5
479535,49,1
480547,37,8
481557,48,2
482582,37,9
483583,37,8
484548,48,2
485534,48,2
486525,47,6
487527,57,5
488541,47,5
489562,48,7
490534,48,2
491588,48,7
492538,38,3
493588,38,5
494546,48,2
495588,38,5
496RUB 573.47,9
497581,48,5
498555,48,4
499556,38,2

500566,48,7
501596,48,6
502560,38,3
503 592,38,8
504505,47,7
505491,47,9
506560,38,4
507550,38,3
508596,48,7
509540,38,5
510566,38,5
511616,48,7
512616,48,7
513578,38,6
514624,49,0
515601,48,1
516609,48,8/td>
517583,48,7
518584,48,4
519533,47,8
520574,48,4
521588,38,5
522588,38,6
523568,48,7
524620,49,1
525610,49,0
526622,49,0
527611,48,7
528582,38,7
529594,48,6
530/td> 583,38,3
531475,38,7
532493,38,0
533465,37,8
534575,38,1
535to 541.58,0

Pharmacological research

The affinity of compounds in accordance with the present invention for different subtypes of melanocortin receptors was measured according to the procedure similar to that described below for the MC4 receptor.

Study of the affinity of compounds for receptor melanocortin MC4:

The affinity of compounds of the invention for the MC4 receptor is determined by measuring inhibition of binding of [125I]-[Nle4, D-Phe7]-α-MSH with membrane preparations of transfected cells CHO-K1.

Cells CHO-K1, stably expressing the human MC4 receptor, 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/G418. Cells are harvested using 0.5 mm EDTA and centrifuged at 500 g for 5 minutes at 4°C. the Precipitate by centrifugation resuspended environment zbuffering phosphate saline (PBS) and centrifuged at 500 g for 5 minutes at 4°C. the Precipitate by centrifugation resuspended in an environment of 50 mm Tris buffer at pH 7.4 and centrifuged at 500 g for 5 minutes at 4°C. the Cells are lysed by ultrasound and centrifuged at 39 000 g for 10 minutes at 4°C. the Precipitate by centrifugation resuspended in an environment of 50 mm Tris buffer at pH 7.4 and centrifuged at 50 000 g for 10 minutes at 4°C. the Membranes obtained in this last precipitate by centrifugation, stored at -80°C.

Measurement of competitive inhibition of binding of [125I]-[Nle4, D-Phe7]-α-MSH with MC4 receptors perform in the 2xreplays using polypropylene 96-well plates. Cell membranes (50 μg protein per well) are incubated with [125I]-[Nle4, D-Phe7]-α-MSH (0.5 nm) for 90 minutes at 37°C in an environment of 50 mm buffer Tris-HCl, pH of 7.4, containing 0.2% 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, Packard), will precede the flax soaked in 0.1% polyethylenimine (P.E.I.), using Filtermate 196 (Packard). The filters are washed with 50 mm buffer Tris-HCl, pH to 7.4 at 0-4°C and present the radioactivity determined using a counter (Packard Top Count).

Specific binding is obtained by subtracting nonspecific binding (determined in the presence of 0.1 μm Nle4, D-Phe7-α-MSH) from the full link. Data analyzed with an automated non-linear regression (MDL) and determine the values of the constants of inhibition (Ki).

The activity of the agonist or antagonist of the receptor MC4 connections in accordance with the present invention is determined by the production of cyclic AMP cells CHO-K1, transfitsirovannykh the MC4 receptor.

Measurement of the production of intracellular cyclic AMP through MC4 receptors:

Cells CHO-K1 expressing the MC4 receptors of melanocortins, cultured in 384-well tablets in medium RPMI 1640 with 10% fetal calf serum and 0.5 mg/ml G418. Cells are washed twice with 50 μl of RPMI medium containing 0.2% BSA and 0.5 mm 3-isobutyl-1-methylxanthines (IBMX).

In order to measure the agonistic activity of the compounds, the cells are incubated for 5 minutes at 37°C in the presence of 0.5 mm IBMX, and then double-stimulate the production of cyclic AMP by adding compounds at concentrations ranging from 1 PM to 10 μm for 20 minutes at 37� C. Antagonistic effect of the compounds was measured by inhibiting the stimulation of the production of cyclic AMP induced Nle4, D-Phe7-α-MSH at concentrations ranging from 1 PM to 10 μm in the presence of test compounds at concentrations between 1 nm and 10 μm for 20 minutes at 37°C in two repetitions.

Reaction medium was removed and add 80 ál of lysis buffer. The level of intracellular cyclic AMP measured by research competition with fluorescent cyclic AMP (CatchPoint, Molecular Devices).

1. Compounds of General formula (I)

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

where a represents-CH2-, -C(O)-, -C(O)-C(Ra)(Rb)-;

X is-CH-;

Raand Rbindependently represent a hydrogen atom or a radical (C1-With6)alkyl;

R1represents a hydrogen atom; a radical (C1-C8)alkyl, optionally substituted by hydroxy or one or more identical or different halogen radicals; and (C2-C6)alkenyl or a radical of the formula -(CH2)n-X1;

R2represents the radical (C1-C8)alkyl, optionally substituted by hydroxy or one or more identical or different'm glad the Kalami halogen; (C2-C6)alkenyl or a radical of the formula -(CH2)n-X1;

each X1independently represents a (C1-C6)alkoxy, (C3-C7)cycloalkyl, aryl or heteroaryl,

moreover, the radicals (C3-C7)cycloalkyl, aryl and heteroaryl optionally substituted by one or more identical or different substituents selected from: -(CH2)n′-V1-Y1, halogen and aryl;

V1represents-O-, -S - or a covalent bond;

Y1represents the radical (C1-C6)alkyl, optionally substituted by one or more identical or different halogen radicals; n represents an integer from 0 to 6 and n′ is an integer from 0 to 2 (and it should be understood that if n is 0, then X1does not represent a radical alkoxy);

or R1and R2form together with the nitrogen atom to which they are attached, heterobicyclic or heteroseksualci, optionally substituted by one or more identical or different substituents selected from: hydroxy, (C1-C6)alkyl, optionally substituted hydroxy, (C1-C6)alkoxycarbonyl, heterocyclization and-C(O)NV1′Y1′where V1′and Y1′ independently represent a hydrogen atom or (C1-the 6)alkyl; or R1and R2together form a radical of the formula

R3represents-Z3, -C(RZ3)(RZ3)-Z3, -C(RZ3)(R′Z3)-(CH2)p-Z3or-C(O)Z′3;

RZ3and RZ3independently represent a hydrogen atom or a radical (C1-C6)alkyl;

Z3is Z3b, Z3c, Z3dor Z3e;

Z3bis (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkylamino or radical di((C1-C6)alkyl)amino;

Z3crepresents aryl or the radical heteroaryl;

Z3dis (C1-C6)alkoxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, di((C1-C6)alkyl)aminocarbonyl, (C1-C6)alkyl-C(O)-NH-, (C3-C7)cycloalkyl, heteroseksualci;

moreover, the radicals (C3-C7)cycloalkyl and heteroseksualci optionally substituted by one or more identical or different substituents selected from: (C1-C6)alkoxy, (C1-C6)alkylsulphonyl, (C1-C6)alkoxycarbonyl and hydroxy, aryl radicals and heteroaryl optionally substituted one is m or more identical or different substituents, selected from: halogen, cyano, nitro, azido, hydroxy, (C1-C6)alkoxycarbonyl-(C1-C6)alkenyl, (C1-C6)alkylaminocarbonyl-(C1-C6)alkenyl, -SO2-NR31R32, geterotsiklicheskie, heteroaryl or -(CH2)p-V3-Y3;

R31and R32form together with the nitrogen atom to which they are attached, heteroseksualci;

V3represents-O-, -S-, -C(O)-, -C(O)-O-, -O-C(O)-, -SO2-, -SO2NH-, -NR′3-SO2-, -NR′3-, -NR′3-C(O)-, -C(O)-NR′3-, -NH-C(O)-NR′3- or a covalent bond;

Y3represents a hydrogen atom; a radical (C1-C6)alkyl, optionally substituted by one or more identical or different halogen radicals; and the aryl radical or the radical aryl-(C1-C6)alkyl;

Z3erepresents a radical of the formula

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

V′3represents-O-, -C(O)-, -C(O)-O-, -C(O)-NR′3-,-NH-C(O)-NR′3- or a covalent bond;

Y′3before the hat a hydrogen atom or a radical (C 1-C6)alkyl, optionally substituted by one or more identical or different halogen radicals;

R′3represents a hydrogen atom, (C1-C6)alkyl or the radical (C1-C6)alkoxy;

p represents an integer from 1 to 4; R′ and R′′ independently represent an integer from 0 to 4;

R4represents a radical of the formula -(CH2)s-R′4;

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

W4represents a hydrogen atom or (C1-C8)alkyl;

W′4represents a radical of the formula -(CH2)s′-Z4;

Z4represents a hydrogen atom, (C1-C8)alkyl, (C3-C7)cycloalkyl, heteroaryl and aryl;

s and s′ independently represent an integer from 0 to 6;

and (i) if R3represents-C(O)-Z′3and R4represents a radical of the formula -(CH2)sNW4W′4and W4and W′4independently represent at the m hydrogen or a radical (C 1-C6)alkyl, then -(CH2)srepresents neither the ethylene radical or the radical -(CH2)-CH((C1-C4)alkyl) and (ii)if R3represents-Z3cand Z3crepresents phenyl or naphthyl, then the phenyl and naphthyl are not substituted by cyano; and it should be understood that if R3represents-Z3dthen Z3dis only one (C3-C7)cycloalkyl or heteroseksualci,

or their pharmaceutically acceptable salt.

2. Compounds according to claim 1, wherein a represents-CH2-,

or their pharmaceutically acceptable salt.

3. Compounds according to claim 2, characterized in that

R1and R2independently represent a radical (C1-C8)alkyl;

R3represents-Z3c, -C(RZ3)(R′Z3)-Z3c, -C(RZ3)(R′Z3)-Z3d, -C(RZ3)(R′Z3)-(CH2)p-Z3d;

R4represents a radical of the formula -(CH2)s-R′4;

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

W4represents a hydrogen atom or (C1-C8)alkyl;

W′4represents a radical of the formula -(CH2)s2 -Z4;

Z4represents a hydrogen atom;

s represents an integer from 2 to 4; s′ represents an integer from 0 to 4, or its pharmaceutically acceptable salt.

4. Compounds according to claim 3, characterized in that

heteroseksualci, presents R′4represents piperidino ring;

RZ3and R′Z3represent a hydrogen atom;

Z3cis thienyl, furyl or phenyl,

moreover, the phenyl radical substituted by one or more identical or different substituents selected from: halogen and -(CH2)p-V3-Y3;

V3represents-O-, -C(O)-, -C(O)-Oh, -C(O)-NR′3- or a covalent bond;

R′3represents a hydrogen atom or a radical (C1-C6)alkyl;

Y3represents a hydrogen atom; a radical (C1-C6)alkyl, optionally substituted by one or more identical or different halogen radicals;

Z3dis (C1-C6)alkoxycarbonyl or heteroseksualci and preferably heteroseksualci is imidazolidin,

or their pharmaceutically acceptable salt.

5. Compounds according to claim 1, characterized in that a represents-C(O)-C(Ra)(Rb)-, in which Raand Rbrepresent the radical is ethyl,

or their pharmaceutically acceptable salt.

6. Compounds according to claim 5, characterized in that

R1and R2independently represent a radical (C1-C8)alkyl;

R3represents-Z3c, -C(RZ3)(R′Z3)-Z3c, -C(RZ3)(R′Z3)-Z3dor-C(RZ3)(RZ3)-(CH2)p-Z3d;

R4represents a radical of the formula -(CH2)s-R′4;

R4is heteroseksualci containing at least one nitrogen atom and optionally substituted (C1-C6)alkyl; or a radical of the formula-NW4W′4;

W4represents a hydrogen atom or (C1-C8)alkyl;

W′4represents a radical of the formula -(CH2)s′-Z4;

Z4represents a hydrogen atom, a phenyl radical or heteroaryl;

s represents an integer from 2 to 4; s′ represents an integer from 0 to 4,

or their pharmaceutically acceptable salt.

7. Compounds according to claim 6, characterized in that

RZ3and R′Z3independently represent a hydrogen atom;

Z3crepresents the radical thienyl, optionally substituted (C1-C6)alkoxycarbonyl; or phenyl substituted by one or more identical or different substituent and, selected from: halogen, nitro or -(CH2)p′-V3-Y3;

V3represents-O-, -C(O)-, -C(O)-Oh, -C(O)-NR′3- or a covalent bond;

Y3represents a hydrogen atom; a radical (C1-C6)alkyl, optionally substituted by one or more identical or different halogen radicals;

R′3represents a hydrogen atom;

Z3drepresents the radical (C1-C6)alkoxycarbonyl;

heteroseksualci, presents R′4represents piperidine;

heteroaryl, presents Z4represents a pyridine,

or their pharmaceutically acceptable salt.

8. Compounds according to claim 1, characterized in that a represents-C(O)-, or their pharmaceutically acceptable salt.

9. Connection of claim 8, wherein R3represents-C(O)-Z′3; R1and R2independently represent a radical (C1-C8)alkyl;

Z′3represents a phenyl radical, optionally substituted by one or more identical or different substituents selected from: halogen, nitro and -(CH2)p′-V′3-Y′3;

V3represents-O-, -C(O)-O - or a covalent bond;

Y′3represents a hydrogen atom or a radical (C1-C 6)alkyl;

R′′ represents the integer 0;

R4represents a radical of the formula -(CH2)s-R′4and R′4represents a radical of the formula-NW4W′4;

W4represents a hydrogen atom or (C1-C8)alkyl;

W′4represents a radical of the formula -(CH2)s′-Z4and Z4represents a hydrogen atom;

s represents an integer from 2 to 4; s′ represents an integer from 0 to 4,

or their pharmaceutically acceptable salt.

10. Connection of claim 8, characterized in that

R1represents a hydrogen atom; a radical (C1-C8)alkyl, optionally substituted by hydroxy; and (C2-C6)alkenyl; or a radical of the formula -(CH2)n-X1;

R2represents the radical (C1-C8)alkyl, optionally substituted by hydroxy; and (C2-C6)alkenyl; or a radical of the formula -(CH2)n-X1;

each X1independently represents a (C1-C6)alkoxy, (C3-C7)cycloalkyl, aryl or heteroaryl,

moreover, the aryl radical optionally substituted by one or more identical or different substituents selected from: -(CH2)n′-V1-Y1and halogen;

V1represents-O - Il is a covalent bond;

Y1represents the radical (C1-C6)alkyl, optionally substituted by one or more identical or different radicals of halogen; or aryl; or R1and R2form together with the nitrogen atom to which they are attached, heteroseksualci, optionally substituted by one or more identical or different substituents selected from: hydroxy, (C1-C6)alkyl, optionally substituted hydroxy, (C1-C6)alkoxycarbonyl, heterocyclization and-C(O)NV1′Y1′where V1′ and Y1′ independently represent a hydrogen atom or (C1-C6)alkyl,

or R1and R2together form a radical of the formula

R3represents-Z3, -C(RZ3)(R′Z3)-Z3or-C(RZ3)(R′Z3)-(CH2)p-Z3;

R4represents a radical of the formula -(CH2)s-R′4;

R′4is heteroseksualci containing at least one nitrogen atom, and optionally substituted (C1-C6)alkyl or aralkyl; heteroaryl containing at least one nitrogen atom, and optionally substituted (C1-C6)alkyl; and a radical of the formula-NW 4W′4;

W4represents a hydrogen atom or (C1-C8)alkyl;

W′4represents a radical of the formula -(CH2)s′-Z4;

Z4represents a hydrogen atom, (C3-C7)cycloalkyl or aryl;

s represents an integer from 0 to 5; s′ represents an integer from 0 to 4,

or their pharmaceutically acceptable salt.

11. Connection of claim 10, characterized in that they possess at least one of the following characteristics:

the radical (C3-C7)cycloalkyl presented X1is cyclopropyl;

the aryl radical represented by X1represents a phenyl radical;

radical heteroaryl presented X1represents a pyridine;

heteroseksualci, which is formed of R1and R2together with the nitrogen atom to which they are attached, are selected from: pyrrolidine, piperidine, azepane, azacycloheptane, research, piperazine and decahydroquinoline;

radical heteroseksualci, presents R′4, optionally substituted (C1-C6)alkyl or benzyl, selected from: pyrrolidinyl, piperidinyl, morpholinyl or piperazinil;

radical heteroaryl, presents R′4represents a radical is imidazolyl;

cycloalkyl, presents Z4choose from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;

the aryl represented by Z4represents phenyl,

or their pharmaceutically acceptable salt.

12. Connection of claim 10, wherein R4represents a radical of the formula -(CH2)s-R′4in which R′4represents the radical pyrrolidinyl or piperidinyl; or a radical of the formula-NW4W′4;

W4represents a hydrogen atom or (C1-C8)alkyl;

W′4represents a radical of the formula -(CH2)s′-Z4in which Z4represents a hydrogen atom;

s represents an integer from 2 to 4; s′ represents an integer from 0 to 4,

or their pharmaceutically acceptable salt.

13. Compounds according to any one of p-12, characterized in that R1and R2independently represent a radical (C1-C8)alkyl,

or their pharmaceutically acceptable salt.

14. Connection of claim 10, characterized in that

R3represents-Z3and Z3is Z3c, Z3dor Z3e;

Z3dis (C3-C7)cycloalkyl or heteroseksualci,

or their pharmaceutically acceptable salt.

15. Soy is inane on 14 characterized in that

Z3crepresents the radical heteroaryl selected from: tanila, furil, indolyl, dihydroindole, pyridyl, benzothiazyl and benzofuran; or an aryl radical, selected from: phenyl, naphthyl and fluorenyl;

moreover, the radical heteroaryl optionally substituted by one or more identical or different substituents selected from: (C1-C6)alkylsulphonyl and (C1-C6)alkoxycarbonyl;

the aryl radical optionally substituted by one or more identical or different substituents selected from: halogen, cyano, nitro, azido, (C1-C6)alkoxycarbonyl-(C1-C6)alkenyl, hydroxy, -SO2-NR31R32, geterotsiklicheskie, heteroaryl or -(CH2)p′-V3-Y3;

R31and R32form together with the nitrogen atom to which they are attached, piperidine ring;

V3represents-O-, -S-, -C(O)-, -C(O)-O-, -SO2-, -SO2NH-, -NR′3, -NR′3-C(O)-, -C(O)-NR′3-, -NH-C(O)-NR′3- or a covalent bond;

Y3represents a hydrogen atom; a radical (C1-C6)alkyl, optionally substituted by one or more identical or different halogen radicals; a phenyl radical or a benzyl radical;

R′3represents a hydrogen atom, the radical (sub> 1-C6)alkyl or (C1-C6)alkoxy; Z3drepresents the radical cyclopropyl, cyclohexyl or piperidinyl, each of which may be substituted by radical (C1-C6)alkoxycarbonyl,

or their pharmaceutically acceptable salt.

16. Connection 14, characterized in that

R3represents-Z3and Z3is Z3c, Z3dor Z3e;

Z3crepresents the radical heteroaryl selected from: tanila, indolyl and benzothiazyl; or an aryl radical selected from phenyl and naphthyl;

moreover, the radical heteroaryl optionally substituted by one or more hydroxy radicals;

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

V3represents-O-, -S-, -C(O)-, -C(O)-O, -SO2-, -SO2NH-, -NR′3-C(O)-, -C(O)-NR′3, -NH-C(O)-NR′3- or a covalent bond;

Y3represents a hydrogen atom; a radical (C1-C6)alkyl, optionally substituted by one or more identical or different halogen radicals; a phenyl radical or a benzyl radical;

R′3represents a hydrogen atom, the radical (C1-C6)alkyl or (C1-C6)al is hydroxy;

Z3drepresents the radical cyclopropyl or piperidinyl, each of which is optionally substituted (C1-C6)alkoxycarbonyl,

or their pharmaceutically acceptable salt.

17. Compounds according to item 16, characterized in that Z3is Z3cor Z3e;

and Z3crepresents a phenyl radical, optionally substituted by one or more identical or different substituents selected from: nitro and -(CH2)p′-V3-Y3;

V3represents-O-, -S-, -C(O)-, -C(O)-O, -SO2-, -SO2NH-, -NR′3-C(O)-, -C(O)-NR′3- or a covalent bond;

Y3represents a hydrogen atom; a radical (C1-C6)alkyl; phenyl or benzyl;

R′3represents a hydrogen atom;

Z3eis

or their pharmaceutically acceptable salt.

18. Connection of claim 10, wherein R3represents-C(RZ3)(R′Z3)-Z3and Z3is Z3b, Z3c, Z3dor Z3e,

or their pharmaceutically acceptable salt.

19. Connection p, characterized in that

R3represents-C(RZ3)(R′Z3)-Z3and Z3is Z3bor Z3c;

RZ3and R′Z3 represent a hydrogen atom,

or their pharmaceutically acceptable salt.

20. Compounds according to claim 19, characterized in that Z3brepresents the radical (C1-C6)alkoxy;

Z3crepresents the radical heteroaryl selected from: tanila, furil, pyridyl, benzothiazyl and dihydrobenzofuran; or an aryl radical selected from phenyl and naphthyl,

moreover, the aryl radical optionally substituted by one or more identical or different substituents selected from: halogen or -(CH2)p′-V3-Y3;

V3represents-O-, -S-, -C(O)-, -C(O)-O-, -SO2-, -SO2NH-, -NR′3C(O)-, -C(O)-NR′3-,

Y3represents a hydrogen atom; a radical (C1-C6)alkyl, optionally substituted by one or more identical or different halogen radicals;

R′3represents a hydrogen atom,

or their pharmaceutically acceptable salt.

21. Compounds according to claim 19, characterized in that

R3represents-C(RZ3)(R′Z3)-Z3and Z3is Z3bor Z3c;

Z3brepresents the radical (C1-C6)alkoxy;

Z3crepresents the radical heteroaryl selected from: tanila, furil, dihydrobenzofuran; or a phenyl radical;

moreover, the phenyl radical is obazatelno substituted by one or more identical or different substituents, selected from: nitro, or -(CH2)p′-V3-Y3;

V3represents-O-, -S-, -C(O)-, -C(O)-O, -SO2-, -SO2NH-, -C(O)-NR′3-,

Y3represents a hydrogen atom or a radical (C1-C6)alkyl, optionally substituted by one or more identical or different halogen radicals;

R′3represents a hydrogen atom,

or their pharmaceutically acceptable salt.

22. Compounds according to item 21, characterized in that

Z3is Z3c;

Z3cis furyl or phenyl,

moreover, the phenyl radical optionally substituted by one or more identical or different substituents of the formula -(CH2)p′-V3-Y3;

V3represents-O-, -S-, -C(O)-, -C(O)-O-, -SO2-, -SO2NH-, -C(O)-NR′3-,

Y3represents a hydrogen atom or a radical (C1-C6)alkyl, optionally substituted by one or more identical or different halogen radicals;

R′3represents a hydrogen atom,

or their pharmaceutically acceptable salt.

23. Connection p, characterized in that

R3represents-C(RZ3)(R′Z3)-Z3and Z3is Z3dor Z3e;

RZ3and R′Z3not only is jut a hydrogen atom or (C 1-C6)alkyl;

Z3dis (C1-C6)alkoxycarbonyl, (C3-C7)cycloalkyl or heteroseksualci;

Z3eis

or their pharmaceutically acceptable salt.

24. Compounds according to item 23, characterized in that

Z3dis (C1-C6)alkoxycarbonyl, cyclohexyl or tetrahydropyranyl,

or their pharmaceutically acceptable salt.

25. Compounds according to item 23, wherein Z3is Z3dor Z3E;

Z3drepresents the radical (C1-C6)alkoxycarbonyl;

Z3eis

or their pharmaceutically acceptable salt.

26. Connection A.25, characterized in that Z3is Z3e

or their pharmaceutically acceptable salt.

27. Connection of claim 10, wherein R3represents-C(RZ3)(R′Z3)-(CH2)p-Z3and Z3is Z3b, Z3cor Z3d,

or their pharmaceutically acceptable salt.

28. Compounds according to item 27, wherein R3represents-C(RZ3)(R′Z3)-(CH2)p′-Z3and Z3the submitted the Z 3b,

or their pharmaceutically acceptable salt.

29. Connection p, characterized in that

RZ3and R′Z3independently represent a hydrogen atom or a radical (C1-C6)alkyl;

Z3bis (C1-C6)alkoxy, (C1-C6)alkylthio or di((C1-C6)alkyl)amino,

or their pharmaceutically acceptable salt.

30. Connection p, characterized in that

RZ3and R′Z3independently represent a hydrogen atom or a radical (C1-C6)alkyl;

Z3bis (C1-C6)alkoxy or (C1-C6)alkylthio,

or their pharmaceutically acceptable salt.

31. Compounds according to item 27, wherein R3represents-C(RZ3)(R′Z3)-(CH2)p-Z3and Z3is Z3cor Z3d,

or their pharmaceutically acceptable salt.

32. Connection p, characterized in that

RZ3and R′Z3independently represent a hydrogen atom or a radical (C1-C6)alkyl;

Z3cis indolyl or phenyl;

and phenyl optionally substituted by one or more identical or different substituents selected from halogen and -(CH2)p′-V3-Y3;

V3 2NH-,

Y3represents a hydrogen atom; or a radical (C1-C6)alkyl;

Z3dis (C1-C6)alkoxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, (C1-C6)alkyl-C(O)-NH - or heteroseksualci, optionally substituted hydroxy, and preferably piperidinyl, morpholinyl, pyrrolidin or imidazolidinyl,

or their pharmaceutically acceptable salt.

33. Connection p, characterized in that

Z3is Z3d;

RZ3and R′Z3independently represent a hydrogen atom or a radical (C1-C6)alkyl;

Z3dis (C1-C6)alkoxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, (C1-C6)alkyl-C(O)-NH - or heteroseksualci and preferably pyrrolidin or imidazolidin, optionally substituted hydroxy,

or their pharmaceutically acceptable salt.

34. The method of obtaining the compounds of formula (I) according to any one of the preceding paragraphs, characterized in that the compound of General formula

in which A, X, R1R2, R4have the meanings indicated in claim 1,

treated with isothiocyanates General formula

R3N=C=S,

in which R3matter, the decree is installed in claim 1,

in the presence of a coupling agent or yellow oxide of mercury (II) in the presence of sulfur for 3-48 h proton or an aprotic solvent at a temperature of 50-80°C.

35. Pharmaceutical composition having activity against receptors MS and containing as active ingredient at least one compound according to any one of claims 1 to 33 in combination with a pharmaceutically acceptable carrier.

36. The use of compounds according to any one of claims 1 to 33 for receiving medicines to treat disorders of weight, mental health problems or disorders of sexual activity.

37. Use p for treating disorders weight such as anorexia and cachexia, and more specifically, cancer cachexia, AIDS cachexia, geriatric cachexia, cardiac cachexia, renal cachexia, cachexia in rheumatoid arthritis.

38. Use p for the treatment of pain and, more specifically, neuropathic pain.

39. Use p for the treatment of mental health problems such as anxiety and depression.

40. The use of compounds of General formula (I′)

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

where A′ represents-CH2-, -C(O)-, -C(O)-C(Ra)(Rb)-;

X′ is-CH-;

RaThe R bindependently represent a hydrogen atom or a radical (C1-C6)alkyl; R′1represents a hydrogen atom; a radical (C1-C8)alkyl independently substituted by hydroxy or one or more identical or different halogen radicals; and (C2-C6)alkenyl; or a radical of the formula -(CH2)n-X1;

R′2represents the radical (C1-C8)alkyl, optionally substituted by hydroxy or one or more identical or different halogen radicals; and (C2-C6)alkenyl or a radical of the formula -(CH2)n-X1;

each X1independently represents a (C1-C6)alkoxy, (C3-C7)cycloalkyl, aryl or heteroaryl,

moreover, the radicals (C3-C7)cycloalkyl, aryl and heteroaryl optionally substituted by one or more identical or different substituents selected from: -(CH2)n′-V1-Y1, halogen and aryl;

V1represents-O-, -S - or a covalent bond;

Y1represents the radical (C1-C6)alkyl, optionally substituted by one or more identical or different halogen radicals;

n represents an integer from 0 to 6 and n′ is an integer from 0 to 2 (and it should be understood that if n is 0, then X1not present is employed, an alkoxy radical),

or R1and R2form together with the nitrogen atom to which they are attached, heterobicyclic or heteroseksualci, optionally substituted by one or more identical or different substituents selected from: hydroxy, (C1-C6)alkyl, optionally substituted hydroxy, (C1-C6)alkoxycarbonyl, heterocyclization and-C(O)NV1′Y1′where V1′ and Y1′ independently represent a hydrogen atom or (C1-C6)alkyl; or R1and R2together form a radical of the formula

R3′ represents-Z3, -C(RZ3)(R′Z3)-Z3, -C(RZ3)(R′Z3)-(CH2)p-Z3or-C(O)-Z′3; RZ3and R′Z3independently represent a hydrogen atom or a radical (C1-C6)alkyl;

Z3is Z3b, Z3c, Z3dor Z3e;

Z3brepresents the radical (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkylamino or di((C1-C6)alkyl)amino;

Z3crepresents an aryl radical or heteroaryl;

Z3dis (C1-C6)alkoxycarbonyl, aminocarbonyl (C 1-C6)alkylaminocarbonyl, di((C1-C6)alkyl)aminocarbonyl, (C1-C6)alkyl-C(O)-NH-, (C3-C7)cycloalkyl, heteroseksualci;

moreover, the radicals (C3-C7)cycloalkyl and heteroseksualci optionally substituted by one or more identical or different substituents selected from: (C1-C6)alkoxy, (C1-C6)alkylsulphonyl, (C1-C6)alkoxycarbonyl and hydroxy,

the aryl radicals and heteroaryl optionally substituted by one or more identical or different substituents selected from: halogen, cyano, nitro, azido, hydroxy, (C1-C6)alkoxycarbonyl-(C1-C6)alkenyl, (C1-C6)alkylaminocarbonyl-(C1-C6)alkenyl, -SO2-NR31R32, geterotsiklicheskie, heteroaryl or -(CH2)p′-V3-Y3;

R31and R32form together with the nitrogen atom to which they are attached, heteroseksualci;

V3represents-O-, -S-, -C(O)-, -C(O)-O-, -O-C(O)-, -SO2-, -SO2NH-, -NR′3-SO2-, -NR′3, -NR′3-C(O)-, -C(O)-NR′3-, -NH-C(O)-NR′3- or a covalent bond;

Y3represents a hydrogen atom; a radical (C1-C6)alkyl, optionally substituted by one or more identical or different R is dialami halogen; the aryl radical or the radical aryl-(C1-C6)alkyl;

Z3erepresents a radical of the formula

Z′3represents an aryl radical, optionally substituted by one or more identical or different substituents selected from: halogen, nitro and -(CH2)P′′-V′3-Y′3;

V3represents-O-, -C(O)-, -C(O)-O-, -C(O)-NR′3, -NH-C(O)-NR′3or a covalent bond;

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

R′3represents a hydrogen atom, (C1-C6)alkyl or (C1-C6)alkoxy;

p represents an integer from 1 to 4; R′ and R′′ independently represent an integer from 0 to 4;

R4represents a radical of the formula -(CH2)S-R′4;

R′4represents the radical guanidine; heteroseksualci containing at least one nitrogen atom and optionally substituted (C1-C6)alkyl or aralkyl; heteroaryl containing at least one nitrogen atom and optionally substituted (C1-C6)alkyl or the radical of f is rmula NW 4W′4;

W4represents a hydrogen atom or (C1-C8)alkyl;

W′4represents a radical of the formula -(CH2)S′-Z4;

Z4represents a hydrogen atom, (C1-C8)alkyl, (C3-C7)cycloalkyl, heteroaryl and aryl;

s and s′ independently represent an integer from 0 to 6,

or its pharmaceutically acceptable salt

to obtain drugs for treatment of disorders of weight, mental health problems, pain, or violations of sexual activity.

41. Use p, where

R1and R2independently represent a radical (C1-C8)alkyl;

R3is Z3cand Z3crepresents phenyl or naphthyl, each substituted at least cyano;

R4represents a radical of the formula -(CH2)s-R′4in which R′4represents the radical pyrrolidinyl or piperidinyl; or a radical of the formula-NW4W′4;

W4represents a hydrogen atom or (C1-C8)alkyl;

W′4represents a radical of the formula -(CH2)s′-Z4in which Z4represents a hydrogen atom;

s represents an integer from 2 to 4; s′ represents an integer from 0 to 4,

or their pharmaceutically acceptable salts.



 

Same patents:

The invention relates to a derivative phthalazine General formula (I) or their pharmaceutically acceptable salts, or hydrates, where R1and R2are the same or different from each other and each represents a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, a hydroxyl group or a C1-C4alkoxygroup, which may be substituted by a halogen atom, or cyano; X represents a cyano, a halogen atom, hydroxyimino, optional O-substituted C1-C4alkyl group, or a heteroaryl group selected from thiazoline, thienyl, pyrazolidine, triazolinones and tetrazolyl groups that may be substituted WITH1-C4alkyl group; Y represents a cyclic amino group (i) - (v) described in paragraph 1 of the claims; (vi) etinilnoy or ethyl group substituted WITH1-C4alkyl group, which, in turn, replaced by a number of deputies referred to in paragraph 1 of the claims; (vii) optionally substituted phenyl group; (viii) pyridyloxy or thiazolidine group

FIELD: chemistry.

SUBSTANCE: invention relates to the tetrahydroquinolin derivatives with the common formula (I) or their pharmaceutically acceptable salts, where R1 and R2 are H or Me; R3 is H, hydroxy or (1-4C)alkoxi; R4 is H, OH, (1-4C)alkoxi; R5 is OH, (1-4C)alkoxi or R7; provided the R4 is H, then R5 differs from OH or (1-4C)alkoxi; R6 is (2-5C)heteroaryl, not necessarily substituted with one or more substitutes, selected from (1-4C)alkyla, bromine or chlorine; (6C)aryl, not necessarily substituted with one or more substitutes, selected from (1-4C)alkyla, (1-4)C-alkoxi, bromine, chlorine, phenyl or (1-4C) (di)alkylamino; (3-8C)cycloalkyl, (2-6C)heterocycloalkyl or (1-6C)-alkyl; R7 is amino, (di)(1-4C)alkylamino, (6C)arylcarbonylamino, (2-5C)heteroarylcarbonylamino, (2-5C)heteroaryl-carbonylokxi, R8-(2-4C)alkoxi, R9-methylamino or R9-methoxi; R8 is amino, (1-4C)alkoxi, (di)(1-4C)-alkylamino, (2-6C)-heterocycloalkyl, (2-6C)heterocycloalkylcarbonylamino or (1-4C)-alkoxicarbonylamino; and R9 is aminocarbonyl, (di)(1-4C)alkylaminocarbonyl, (2-5C)heteroaryl or (6C)aryl. The invention also relates to the pharmaceutical composition which contains the said derivatives, and to the application of the derivatives in fertility modulating.

EFFECT: novel tetrahydroquinolin derivatives with follicle-stimulating hormone receptors modulating activity are obtained.

15 cl, 51 dwg

FIELD: chemistry.

SUBSTANCE: invention refers to new pyridazine -3 (2H) derivatives, the chemical formula of which corresponds to the general formula , in which R1, R2, R3, R4 and R5 have values indicated in the formula of the invention. The compounds of the formula (I) are effective and selective inhibitors of phosphodiesterase 4. The invention also refers to the method of their preparation, pharmaceutical composition which includes these compounds, and to the application for medicine preparation for treatment of disease state or disease which medicable by meance of phosphodiesterase 4 inhibition. Besides, the object of the invention is the method of disease state and disease treatment by means of phosphodiesterase 4 inhibition.

EFFECT: new compounds have effective biological properties.

19 cl, 25 tbl, 278 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of N-form hydroxylamine of the formula (I) where X means -CH2-, -CH(OH)-, -CH(OR)-,-CF2- or -CH(F) - where R meansC1-C7alkyl, R1 means phenyl, quinoline, izo quinoline, pyridyl oxypyridyl, unessentially replaced by substitutesR6, R7, R8, R9, or means a structural fragment of the formula where each of R10 and R11 independently means H, halogen; everyoneR2, R3, R4, R5 independently means H, C1-C7alkyl, n is equal to 0-2 provided that if n is equal to 0 Xmeans-CH2 everyone of R6, R7, R8, R9 H, OH independently means, halogen, C1-C7alkyl, replaced by halogen C1-C7alkyl, C1-C7alkoxy, phenyl or its pharmaceutically acceptable salt.

EFFECT: compounds display high anti-bacteria activity.

12 cl, 1 tbl, 50 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to drugs and concerns using (2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3-ylmethyl]-amino}-methyl)-chroman-4-ol or its pharmaceutically acceptable salts or solvates used for production of a drug for treatment of catalepsy. Also, invention proposes a pharmaceutical composition for treatment of catalepsy that comprises (2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3-ylmethyl]-amino}-methyl)-chroman-4-ol as an active component taken in the pharmaceutically effective amount in combination with one or some pharmaceutically acceptable excipients.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

3 cl, 15 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of compound of the formula (I): wherein R1 represents para-nitrobenzyl or allyl; X represents halogen atom. Method involves: (1) interaction of compound of the formula (IVa): wherein R1 represents para-nitrobenzyl or allyl, and R2 represents benzyl or substituted benzyl with P(OR3)3 in a solvent medium to yield compound of the formula (III): wherein R1 represents para-nitrobenzyl or allyl; R2 represents benzyl or substituted benzyl; R3 represents (C1-C6)-alkyl and (2) the following heating compound of the formula (III) in a solvent in the presence of LiCl and organic soluble base to form compound of the formula (II): wherein R1 represents para-nitrobenzyl or allyl; R2 represents benzyl or substituted benzyl, and (3) interaction of compound of the formula (II) with R4-OH and PX5 to form compounds of the formula (I) that is an intermediate compound in synthesis of cephalosporin.

EFFECT: improved method of synthesis.

14 cl, 5 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of aniline of the general formula (I): and their pharmaceutically acceptable salts and isomeric forms possessing properties of phosphodiesterase-4 inhibitors. Compounds can be used, fore example, for enhancing cognitive ability. In compounds of the general formula (I) R1 means linear or branched (C1-C4)-alkyl that can be unsubstituted or substituted with one or more halogen atoms; R2 means linear or branched (C1-C4)-alkyl that can be unsubstituted or substituted with one or more substitutes of the following order: halogen atom, (C1-C4)-alkoxy or their combinations, (C3-C10)-cycloalkyl, (C4-C16)-cycloalkylalkyl wherein alkyl fragment comprises from 1 to 4 carbon atoms, (C7-C11)-arylalkyl wherein aryl fragment comprises 6 carbon atoms, and alkyl fragment that can be linear or branched and comprises from 1 to 5 carbon atoms and wherein radical arylalkyl can be unsubstituted or substituted in aryl fragment with one or more substitutes of the following order: halogen atom, alkoxy group comprising from 1 to 4 carbon atoms or their combinations, and in alkyl fragment one group -CH2CH2- is optionally replaced for group -CH=CH-, and one group -CH2- is optionally replaced for -O- for -NH-, partially unsaturated carbocyclic group comprising from 5 to 9 carbon atoms that can comprise condensed benzene ring, heterocyclic group that can be saturated, partially saturated or unsaturated and comprises from 5 to 6 carbon atoms in cycle including one atom chosen from oxygen (O), or heterocyclylalkyl group wherein heterocyclic fragment can be saturated, partially saturated or unsaturated and comprises from 5 to 6 carbon atoms in cycle including 1-2 atoms chosen from nitrogen (N) or sulfur (S) atoms, and alkyl fragment that can be linear or branched comprises from 1 to 5 carbon atoms; R3 means partially unsaturated carbocyclylalkyl group wherein carbocyclic fragment comprises from 5 to 6 carbon atoms, and linear or branched alkyl fragment comprises from 1 to 5 carbon atoms, (C7-C11)-arylalkyl wherein aryl fragment comprises 6 carbon atoms, and linear or branched alkyl fragment comprises from 1 to 5 carbon atoms and wherein arylalkyl radical can be linear or substituted in aryl fragment with one or more substitutes of the following group: trifluoromethyl, (C1-C4)-alkyl, (C1-C4)-alkoxy or their combinations, heterocyclylalkyl group wherein heterocyclic fragment can be aromatic, partially or completely saturated and comprises from 5 to 10 atoms in cycle including 1-2 atoms chosen from N, O or S, and linear or branched alkyl fragment comprises from 1 to 5 carbon atoms and wherein heterocyclylalkyl group can be linear or substituted in heterocyclic fragment with one or more substitutes of the following order: halogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxy or their combinations; R4 means (C6-C12)-aryl that can be linear or substituted with one or more substitutes of the following order: halogen atom, (C1-C4)-alkyl, (C2-C4)-alkenyl, hydroxy, (C1-C4)-alkoxy, (C2-C4)-alkoxyalkoxy, nitro, trifluoromethyl, -OCF3, amino group, aminoalkyl, aminoalkoxy, hydroxy-(C1-C4)-alkyl, hydroxamic acid, tetrazol-5-yl, 2-(heterocyclyl)-tetrazol-5-yl, carboxy, alkoxycarbonyl, cyano, acyl, alkylsulfonyl, phenoxy, trialkyloxy, R5-L or their combinations, or heteroaryl comprising from 5 to 10 atoms in cycle including 1-2 atoms chosen from N wherein heteroaryl can be linear or substituted with one or more substitutes of the following order: (C1-C4)-alkyl, (C1-C4)-alkoxy, carboxy, alkoxycarbonyl or their combinations; R5 means hydrogen atom, (C1-C8)-alkyl, (C3-C10)-cycloalkyl, C6-aryl, heterocyclic group that can be saturated, partially saturated or unsaturated and comprises from 5 to 10 atoms in cycle from which at least atom means N or O, and wherein heterocyclic group can be linear or substituted with one or more (C1-C4)-alkyls, or group heterocyclylalkyl, and others. Also, invention relates to intermediates compounds and to a method for enhancing the cognitive ability.

EFFECT: valuable biological and biochemical property of compounds.

49 cl, 8 sch, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrrolidinium of the general formula (I): possessing antagonistic effect with respect to muscarinic receptors M3 wherein B means phenyl or thienyl group; each radical among R1, R2 and R means independently hydrogen, fluorine, chlorine atom or hydroxyl; n means a whole number from 0 to 1; A means group chosen from groups -CH2 and -O-; m means a whole number from 0 to 6; R means (C1-C8)-alkyl; X- represents a pharmaceutically acceptable anion of mono- or multibasic acid, and involving all separate stereoisomers and their mixtures. Also, invention relates to methods for synthesis of such compounds, pharmaceutical compositions containing such compounds and to their using in therapy as antagonists of muscarinic receptors M3.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

17 cl, 51 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to N-[(4-phenyl-1-piperazinyl)alkyl]-substituted heteroarene carboxamide of the general formula (I): and structurally similar 2-ferrocenyl compounds of the general formula (II): showing activity with respect to neuroreceptors and wherein R means hydrogen atom, (C1-C6)-alkyl, halogen atom; R1, R2 and R3 are chosen independently from hydrogen atom, hydroxy group, (C1-C6)-alkyl, (C1-C4)-alkoxy group, halogen atom, trifluoromethyl and cyano group; X can represent sulfur atom (S), oxygen atom (O), -NH or Te. Proposed compounds can be used in treatment of the central nervous system diseases. Also, invention describes methods for synthesis of these compounds, a pharmaceutical composition based on thereof and using for preparing a drug used in treatment of the central nervous system diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of synthesis.

26 cl, 2 tbl, 25 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel benzofuran derivatives comprising group of carbamoyl type of the formula [1]: wherein cycle Z represents group of the formula or A represents a simple bond or group of the formula -NH-; Y represents lower alkylene group, cycloalkanediyl group, phenyl group or piperidyl group; R4 and R5 are similar or different, and each represents hydrogen atom, unsubstituted lower alkyl group, lower alkyl group substituted with amino group optionally substituted with 1-2 lower alkyl groups, lower alkyl group substituted with hydroxyl group, lower alkyl group substituted with lower alkoxy group, or lower alkyl group substituted with pyridyl group; or R4 and R5 represent tetrahydropyranyl; or R4 and R are bound by ends to form in common with adjacent nitrogen atom and represent pyrrolidinyl group, morpholinyl group, pyrrolidinyl group substituted with (hydroxy)(lower alkyl) group, pyrrolidinyl group substituted with hydroxyl group, thiomorpholinyl group, piperidinyl group, piperdinyl group substituted with hydroxyl group, piperazinyl group substituted with (hydroxy)(lower alkyl) group, piperidinyl group substituted with (hydroxy)(lower alkyl) group, piperazinyl group substituted with lower alkyl group, pyrrolidinyl group substituted with lower alkoxycarbonylamino group, piperidinyl group substituted with amino group optionally substituted with 1-2 lower alkyl groups, or piperidinyl group substituted with lower alkoxycarbonyl group; R1 represents hydrogen atom, halogen atom or lower alkyl group; cycle B of the formula: represents benzene cycle optionally substituted with one or two groups chosen independently from halogen atom, optionally substituted lower alkyl group, hydroxy group, lower alkoxy group optionally substituted with alkoxycarbonyl group or amino group; carbonyl group optionally substituted with lower alkoxy group, hydroxyl group, amino group optionally substituted with 1-2 alkyl groups, morpholinyl or pyrrolidyl group; optionally substituted amino group; R3 represents hydrogen atom or lower alkyl group. Also, invention relates to it's a pharmaceutically acceptable salt that are useful as Fxa inhibitors. Also, invention relates to a pharmaceutical composition based on these compounds and their using in treatment of thrombosis.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

18 cl, 22 tbl, 143 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention elates to novel derivatives of imidazolidine of the formula (I): , wherein symbols B, E, W, Y, R, R2, R3, R30, e and h have values given in claim 1 of the invention. Compounds of the formula (I) represent pharmaceutically active substances. Compounds of the formula (I) relates to inhibitors of adhesion and migration of leukocytes and/or antagonists of adhesion receptor VLA-4 that relates to group of integrins. Proposed compounds can be used in treatment of diseases that are induced or associated with undesirable degree of leukocyte adhesion and/or migration of leukocytes, or wherein interaction between cells or between cells and matrix are very significant and important and these interactions are based on interaction of VLA-4 receptors and ligands. Except for, invention relates to methods for synthesis of compounds of the formula (I) and pharmaceutical compositions containing compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of synthesis and preparing.

12 cl, 19 ex

FIELD: chemistry.

SUBSTANCE: new derivatives of benzotriazol of folrmula I are described where Rl-R8-H, and one of residues R2 or R3 (IT) can designate Br, CI,CH3, CN,NH2, NO2,CF3, OCH3, phenoxy, benzoil, CH(OH)-phenyl, S-cyclohexyl,CO-OCH3; or two substitutors from this series designate Rl=Cl andR3=CF3 or R2=F and R3=Cl; n - an integer 0, 1 or 2; and one of substitutors R6 or R7 can designate R6 - CH3; R7 - CH3, C2H5; CH (CH3)2, C(CH3)3, CF3, Br, Cl, benzil or CO-OC2H5; or R6 and R7 both designate CH3; or the ring instead of R6 and R7 can contain double bond, or R5 and R6, or R6 and R7 can designate together with atoms C to which they are bonded, benzanilated ring, or in case of n=0 also cyclohexandiil, here, in case of ring formation of R6/R7, this substitutor can be unitary replaced by ofNH2 orNO2,if required, or one-twiceOCH3 and R7 and R8 together designate cyclopenthyl, diazepin or CH2; except for compounds, where R1-R5 and R8=H, n=l and R6/R7=benzanilated ring, and Rl, R3-R8=H,R2=CH3 and n=1, the method of their production and a pharmaceutical for treatment of not achrestic diabetes or a diabetic syndrome.

EFFECT: new compounds possess useful biological properties.

12 cl, 55 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to therapeutic agents showing effectiveness in treatment of pain, cancer, cerebrospinal sclerosis, Parkinson's disease, Huntington's chorea and/or Alzheimer's disease. Invention describes compound of the formula (I): or its pharmaceutically acceptable salts wherein RF1 and RF2 represent independently electron-acceptor groups; Z is chosen from O=; R1 is chosen from (C1-C10)-alkyl, heterocyclyl-(C1-C6)-alkyl, substituted heterocyclyl-(C1-C6)-alkyl; R2 is chosen from (C1-C6)-alkyl; X represents bivalent (C1-C10)-group that separates groups added to it by one or two atoms; Ar represents bivalent (C4-C12)-aromatic group, and Y is chosen from =CH=. Also, invention describes fields wherein compounds of the formula (I) are used, a pharmaceutical composition based on thereof, and methods for their synthesis. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 35 ex

FIELD: organic chemistry, medicine, pharmacy, chemical technology.

SUBSTANCE: invention relates to novel substituted esters of 1H-indol-3-carboxylic acids of the general formula (1): or their racemates, or their optical isomers, or their pharmaceutical acceptable salts and/or hydrates. Compounds can be used in treatment of such diseases as infectious hepatitis, human immunodeficiency, atypical pneumonia and avian influenza. In compound of the general formula (1) R1, R41 and R42 each represents independently of one another a substitute of amino group chosen from hydrogen atom, optionally linear or branched alkyl comprising 3-12 carbon atoms, optionally substituted cycloalkyl comprising 3-10 carbon atoms, optionally substituted aryl or optionally substituted and possibly an annelated heterocyclyl that can be aromatic or nonaromatic and comprising from 3 to 10 carbon atom in ring with one or some heteroatoms chosen from nitrogen oxygen or sulfur atoms; or R41 and R42 in common with nitrogen atom to which they are bound form 5-10-membered azaheterocycle or guanidyl through R41 and R42; R2 represents an alkyl substitute chosen from hydrogen atom, optionally substituted mercapto group, optionally substituted amino group, optionally substituted hydroxyl; R3 represents lower alkyl; R5 represents a substitute of cyclic system chosen from hydrogen atom, halogen atom, cyano group, optionally substituted aryl or optionally substituted and possibly an annelated heterocycle that can be aromatic or nonaromatic and comprising from 3 to 10 atoms in ring with one or some heteroatoms chosen from nitrogen, oxygen or sulfur atoms. Also, invention relates to methods for treatment, drugs and pharmaceutical compositions using compounds of this invention.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of synthesis.

22 cl, 3 tbl, 8 dwg, 6 ex

FIELD: chemical technology.

SUBSTANCE: invention relates to a method for synthesis of α-polymorphous eletriptane bromohydrate that involves the following steps: (a) treatment of eletriptane solution in 2-butanone with hydrobromic acid and (b) distillation of azeotropic mixture 2-butanone/water up to termination of formation of anhydrous α-polymorphous eletriptane bromohydrate. Also, invention relates to a method for preparing crystalline α-polymorphous form of eletriptane bromohydrate involving the following steps: (a) treatment of the parent eletriptane bromohydrate substance solution in mixture of 2-butanone and water, and (b) distillation of azeotropic mixture 2-butanone/water up to termination of formation of anhydrous α-polymorphous eletriptane bromohydrate. Product synthesized by claimed methods represents exclusively anhydrous eletriptane bromohydrate and prepared with the high yield, i. e. formation of other polymorphous forms or eletriptane bromohydrate solvates in realization of claimed methods do not occur. Invention provides decreasing working ability of the method in synthesis of α-polymorphous eletriptane bromohydrate provides high yield of α-polymorphous eletriptane bromohydrate.

EFFECT: improved method of synthesis.

11 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivative of 1-[(indole-3-yl)carbonyl]piperazine of the formula (I): wherein R means substitute chosen from hydrogen atom (H), (C1-C4)-alkyl, (C1-C4)-alkyloxy-group (optionally substituted with halogen atom), halogen atom, -OH, -NH2, -CN and -NO2; R1 means (C5-C8)-cycloalkyl or (C5-C8)-cycloalkenyl; R2 means H, methyl or ethyl; radicals R3, R'3, R4, R'4, R5, R'5 and R'6 means independently hydrogen atom or (C1-C4)-alkyl optionally substituted with halogen atom or -OH; R6 means hydrogen atom or (C1-C4)-alkyl optionally substituted with (C1-C4)-alkoxy-group or halogen atom; or R6 in common with R7 forms 5-6-membered saturated heterocyclic ring; R7 means H, (C1-C4)-alkyl optionally substituted with -OH, halogen atom or (C1-C4)-alkoxy- group, or (C3-C5)-cycloalkyl, or its pharmaceutically acceptable salt. Compounds of the formula (I) possess agonistic activity with respect to CB1 receptors. Also, invention describes pharmaceutical composition possessing agonistic activity with respect to CB1 receptors and using compound of the formula (I) for preparing a drug used in pain treatment.

EFFECT: valuable medicinal and pharmacological properties of compounds and pharmaceutical composition.

9 cl, 1 tbl, 21 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (IA): or the formula (IB): wherein B means hydrogen atom or lower alkyl; A means an unsubstituted or substituted cyclic group chosen from compounds of the following formulae: (a) (b) (c) (d) (e) (f) (g) (h) (i) (j) and (k) wherein R1-R4 mean independently of one another hydrogen atom, halogen atom, -CF3, -CHF2, -C(CH3)F2, (C3-C6)-cycloalkyl, lower alkoxy-group, lower alkyl, -OCF3 or phenyl; R5-R10 means independently of one another hydrogen atom, halogen atom, lower alkoxy-group, lower alkyl or -CHF2; R11-R16 mean independently of one another hydrogen atom, halogen atom, alkoxy-group or lower alkyl; R17 means halogen atom or -CHF2; R18-R20 mean independently of one another hydrogen atom, lower alkoxy-group or lower alkyl, and to their pharmaceutically acceptable acid-additive salts. Also, invention relates to a medicinal agent possessing the selective effect of blockers of NMDA receptors of subtype 2B. Invention provides synthesis of novel biologically active compounds and medicinal agents based on thereof.

EFFECT: valuable medicinal properties of compounds and drugs.

6 cl, 180 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of indoline of the formula (I): wherein (i) R1 means hydrogen atom (H), (C1-C4)-alkyl; R2 means -A1-NR5R6 wherein each substitute R5 and R6 means independently H, (C1-C4)-alkyl; A1 means -(CH2)m, -(CH2)n-A2-(CH2)p or -(CH2CH2O)qCH2CH2 wherein m means a whole number from 2 to 10; each n and p means a whole number from 1 to 6; A2 means -CH=CH, phenylene, biphenylene, cyclohexylene or piperazinylene; q = 1, 2 or 3; (ii) R1 and R2 represent in common -A3-NR7-A4 wherein each A3 and A4 means independently -(CH2)r or -(CH2CH2O)sCH2CH2 wherein r means a whole number from 2 to 6; s = 1, 2 or 3; R7 means H, (C1-C4)-alkyl; (iii) R1 and R2 in common with nitrogen atom to which they are bound form piperidinyl that comprises a substitute of the formula: -A5-R8 at 4 position wherein A5 represents (C1-C4)-alkylene, and R8 represents piperidin-4-yl; or (iv) R1 and R2 in common with nitrogen atom to which they are bound form piperidinyl, and each R3 and R4 means independently H, or its pharmaceutically acceptable salt. Proposed compounds inhibit tyrosine kinase receptors that allow their using as components of pharmaceutical compositions for treatment. Also, invention describes methods for synthesis of compounds of the formula (I).

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical compositions.

15 cl, 1 tbl, 24 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of imidazolyl derivative of the general formula (I) wherein each Ra and Rb represents independently (C1-C6)-alkyl, (C1-C6)-alkoxyalkyl, optionally substituted aryl or heteroaryl, or wherein Ra and Rb form in common additional homocyclic or heterocyclic system comprising one or some rings; each Ra' and Rb' represents hydrogen atom, or they in common form a carbon-carbon double bond wherein indicated carbon-carbon double bond is optionally part of aromatic system; Rc represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkoxyalkyl or halogen atom; Rd represents hydrogen atom or (C1-C4)-alkyl; Re represents hydrogen atom or (C1-C4)-alkyl; m = 1 or 2; R1 represents hydrogen atom or (C1-C4)-alkyl, and its salts after addition of acid and wherein compound of the general formula (II) wherein values Ra, Ra', Rb, and Rb' are given above is subjected for interaction with compound of the formula (III) wherein R represents hydrogen atom, (C1-C4)-alkyl group optionally substituted with hydroxy-group, or optionally substituted aryl group; each R', R'', R''' and R'''' represents independently hydrogen atom or (C1-C4)-alkyl group followed by interaction with compound of the formula (IV) wherein R, Rd and Re have values given above and the following optional interaction with the corresponding acid. Proposed method shows high effectiveness for synthesis of ondansetron and cilansetron.

EFFECT: improved method of synthesis.

10 cl, 10 ex

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