# Patent

## Title
Benzimidazole and imidazopyridine derivatives and use thereof as a medicament

## Abstract

A compound of the formula




wherein the substituents are as defined in the specification and pharmaceutical salts thereof having a good affinity for sub-types of melanocortin receptors making them useful for treating diseases in which such receptors are included such as pain, inflammatory conditions, etc.

## Background
This application is a 371 of PCT/FR04/00418 filed Feb. 25, 2004.
A subject of the present application is novel derivatives of benzimidazole and imidazo-pyridine. These products have a good affinity for certain sub-types of melanocortin receptors, in particular the MC4 receptors. They are particularly useful for treating pathological conditions and diseases in which one or more melanocortin receptors are involved. The invention also relates to pharmaceutical compositions containing said products and their use for preparing a medicament.
The melanocortins represent a group of peptides which derive from the same precursor, proopiomelanocortin (POMC), and which are structurally close: the adrenocorticotropic hormone (ACTH), the α-melanocyte stimulating hormone (α-MSH), β-MSH and γ-MSH (Eipper B. A. and Mains R. E., Endocr. Rev. 1980, 1, 1-27). The melanocortins carry out numerous physiological functions. They stimulate the synthesis of the steroids by the adrenal cortex and the synthesis of eumelanine by the melanocytes. They regulate the intake of food, energetic metabolism, sexual function, neuronal regeneration, blood pressure and heart rate, as well as the perception of pain, learning, attention and memory. The melanocortins also possess anti-inflammatory and anti-pyretic properties and control the secretion of several endocrine or exocrine glands such as the sebaceous, lacrimal and mammary glands, the prostate and the pancreas (Wikberg J. E. et al. Pharmacol. Res. 2000, 42, 393-420; Abdel-Malek Z. A., Cell. Mol. Life. Sci. 2001, 58, 434-441).
The effects of the melanocortins are mediated by a family of membrane receptors specific to seven transmembrane domains and coupled to G proteins. Five sub-types of receptors, named MC1 to MC5, have been cloned and characterized to date. These receptors differ in their tissue distribution and in the affinity of different melanocortins, the MC2 receptors only recognizing the ACTH. The stimulation of the melanocortin receptors activates adenylate cyclase with production of cyclic AMP. If the specific functional roles of each of the receptors are not totally elucidated, the treatment of pathological disorders or diseases can be associated with an affinity for certain sub-types of receptors. Thus activation of the MC1 receptors has been associated with the treatment of inflammations, while blocking them has been associated with the treatment of cutaneous cancers. The treatment of nutritional disorders has been associated with the MC3 and MC4 receptors, the treatment of obesity with agonists and the treatment of cachexia and anorexia with antagonists. Other indications linked to the activation of the MC3 and MC4 receptors are problems with sexual activity, neuropathic pain, anxiety, depression and drug addiction. The activation of the MC5 receptors has been associated with the treatment of acne and dermatoses.
The Applicants have discovered that the novel compounds of general formula (I) described hereafter possess a good affinity for the melanocortin receptors. They preferably act on the MC4 receptors. Said compounds, agonists or antagonists of the melanocortin receptors, can be used for treating the pathological conditions or diseases of the metabolism, of the nervous system or dermatological diseases in which one or more melanocortin receptors are involved such as the following examples: inflammatory conditions, energetic homeostasis disorders, intake of food disorders, weight disorders (obesity, cachexia, anorexia), sexual activity disorders (erective disorders), pain and more particularly neuropathic pain. Mental health problems (anxiety, depression), drug addiction, skin diseases (acne, dermatoses, skin cancer, melanomas) can also be mentioned. These compounds can also be used to stimulate nerve regeneration.
A subject of the invention is therefore a compound 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(Ra)(Rb)—;
    X represents —CH— or —N—;
    Ra and Rb represent, independently, the hydrogen atom or a (C1-C6)alkyl radical;
    R1 represents the hydrogen atom; a (C1-C8)alkyl radical optionally substituted by hydroxy or one or more identical or different halo radicals; (C2-C6)alkenyl; or a radical of formula —(CH2)n—X1;
    R2 represents a (C1-C8)alkyl radical optionally substituted by hydroxy or one or more identical or different halo radicals; (C2-C6)alkenyl; or a radical of formula —(CH2)n—X1;
    each X1 independently represents (C1-C6)alkoxy, (C3-C7)cycloalkyl, adamantyl, heterocycloalkyl, aryl or heteroaryl,
    
        the (C3-C7)cycloalkyl, heterocycloalkyl, aryl and heteroaryl radicals being optionally substituted by one or more identical or different substituents chosen from: —(CH2)n′—V1—Y1, halo, nitro, cyano and aryl;
        V1 represents —O—, —S— or a covalent bond;
        Y1 represents a (C1-C6)alkyl radical optionally substituted by one or more identical or different halo radicals;
        n represents an integer from 0 to 6 and n′ an integer from 0 to 2 (it being understood that when n is equal to 0, then X1 does not represent the alkoxy radical);
    
    
    or R1 and R2 form together with the nitrogen atom to which they are attached, a heterobicycloalkyl or a heterocycloalkyl optionally substituted by one or more identical or different substituents chosen from: hydroxy, (C1-C6)alkyl optionally substituted by hydroxy, (C1-C6)alkoxy-carbonyl, heterocycloalkyl and —C(O)NV1′Y1′ with V1′ and Y1′ independently representing the hydrogen atom or a (C1-C6)alkyl; or R1 and R2 together form a radical of 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 represent, independently, the hydrogen atom or a (C1-C6)alkyl radical;
        Z3 represents Z3a, Z3b, Z3c, Z3d, or Z3e;
        Z3a represents a (C1-C6)alkyl radical;
        Z3b represents a (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkylamino or di((C1-C6)alkyl)amino radical;
        Z3c represents an aryl or heteroaryl radical;
        Z3d represents a (C1-C6)alkoxy-carbonyl, amino-carbonyl, (C1-C6)alkylamino-carbonyl, di((C1-C6)alkyl)amino-carbonyl, (C1-C6)alkyl-C(O)—NH—, (C3-C7)cycloalkyl, heterocycloalkyl radical;
        the (C3-C7)cycloalkyl and heterocycloalkyl radicals being optionally substituted by one or more identical or different substituents chosen from: halo, nitro, (C1-C6)alkoxy optionally substituted by one or more identical or different halo radicals, (C1-C6)alkyl optionally substituted by one or more identical or different halo radicals, (C1-C6)alkyl-carbonyl, (C1-C6)alkoxy-carbonyl, amino-carbonyl, (C1-C6)alkylamino-carbonyl, di((C-C6)alkyl)amino-carbonyl and oxy,
        the aryl and heteroaryl radicals being optionally substituted by one or more identical or different substituents chosen from: halo, cyano, nitro, azido, oxy, (C1-C6)alkoxy-carbonyl-(C1-C6)alkenyl, (C1-C6)alkylamino-carbonyl-(C1-C6)alkenyl, —SO2—NR31R32, heterocycloalkyl, heteroaryl or —(CH2)p′—V3—Y3;
        R31 and R32 form together with the nitrogen atom to which they are attached, a 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 a covalent bond;
        Y3 represents the hydrogen atom; a (C1-C6)alkyl radical optionally substituted by one or more identical or different halo radicals; an aryl radical optionally substituted by one or more identical or different substituents chosen from: halo, nitro, (C1-C6)alkyl and (C1-C6)alkoxy; or an aryl-(C1-C6)alkyl radical optionally substituted by one or more identical or different substituents chosen from: halo, nitro, (C1-C6)alkyl and (C1-C6)alkoxy;
        Z3e represents a radical of formula
    
    






    
    
        Z′3 represents an aryl radical optionally substituted by one or more identical or different substituents chosen from: halo, 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 a covalent bond;
        Y′3 represents the hydrogen atom or a (C1-C6)alkyl radical optionally substituted by one or more identical or different halo radicals;
        R′3 represents the hydrogen atom, a (C1-C6)alkyl or (C1-C6)alkoxy radical;
        p represents an integer from 1 to 4; p′ and p′′ represent, independently, an integer from 0 to 4;
    
    
    R4 represents a radical of formula —(CH2)s—R′4 
    R′4 represents the guanidine radical; a heterocycloalkyl containing at least one nitrogen atom and optionally substituted by (C1-C6)alkyl or aralkyl; a heteroaryl containing at least one nitrogen atom and optionally substituted by (C1-C6)alkyl; or a radical of formula —NW4W′4 
    
        W4 represents the hydrogen atom or (C1-C8)alkyl;
        W′4 represents a radical of formula —(CH2)s′-Z4;
        Z4 represents the hydrogen atom, (C1-C8)alkyl optionally substituted by one or more identical or different substituents chosen 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)alkyl substituents; cyclohexene; heteroaryl and aryl;
        
            the aryl and heteroaryl radicals being optionally substituted by one or more identical or different radicals chosen of formula: —(CH2)s′′—V4—Y4, hydroxy, halo, nitro and cyano;
            
                V4 represents —O—, —S—, —NH—C(O)—, —NV4′— or a covalent bond;
                Y4 represents a hydrogen atom or a (C1-C6)alkyl radical optionally substituted by one or more identical or different halo radicals;
                V4′ represents a hydrogen atom or a (C1-C6)alkyl;
                s′′ represents an integer from 0 to 4;
            
            
        
        
        or Z4 represents a radical of formula
    
    






    
    
        s and s′ represent, independently, an integer from 0 to 6;
    
    
    and i) when R3 represents —C(O)-Z′3 and R4 represents a radical of formula —(CH2)s—NW4W′4 and W4 and W′4 represent, independently, the hydrogen atom or the (C1-C6)alkyl radical, then —(CH2)s represents neither the ethylene radical nor the —(CH2)—CH((C1-C4)alkyl)- radical and ii) when R3 represents -Z3c and Z3c represents a phenyl or naphthyl radical, then phenyl and naphthyl are not substituted by cyano; and it being understood that when R3 represents -Z3d then Z3d only represents one (C3-C7)cycloalkyl or heterocycloalkyl radical; or a pharmaceutically acceptable salt thereof.


In the definitions given above, the expression halo represents the fluoro, chloro, bromo or iodo radical, preferably chloro, fluoro or bromo. The expression alkyl (unless otherwise specified), preferably represents a linear or branched alkyl radical having from 1 to 6 carbon atoms, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl or amyl, isopentyl, neopentyl, 2,2-dimethyl-propyl, hexyl, isohexyl or 1,2,2-trimethyl-propyl radicals. The term (C1-C8)alkyl designates a linear or branched alkyl radical having from 1 to 8 carbon atoms, such as the radicals containing from 1 to 6 carbon atoms as defined above but also heptyl, octyl, 1,1,2,2-tetramethyl-propyl, 1,1,3,3-tetramethyl-butyl. The term hydroxyalkyl designates the radicals in which the alkyl radical is as defined above such as for example hydroxymethyl, hydroxyethyl. By the expression alkyl substituted by hydroxy is meant any linear or branched alkyl chain, containing a hydroxy radical positioned along the chain; thus for a chain containing 3 carbon atoms and one hydroxy radical, HO—(CH2)3—, CH3—CH(OH)—CH2— and CH3—CH2—CH(OH)— can be cited as examples.
By alkenyl, unless otherwise specified, is meant a linear or branched alkyl radical containing from 1 to 6 carbon atoms and having at least one unsaturation (double bond), such as for example vinyl, allyl, propenyl, butenyl or pentenyl.
The term alkoxy designates the radicals in which the alkyl radical is as defined above such as for example the methoxy, ethoxy, propyloxy or isopropyloxy radicals but also linear, secondary or tertiary butoxy, pentyloxy. The term alkoxy-carbonyl preferably designates the radicals in which the alkoxy radical is as defined above such as for example methoxycarbonyl, ethoxycarbonyl. The term alkylthio designates the radicals in which the alkyl radical is as defined above such as for example methylthio, ethylthio.
The term guanidine represents the —NHC(═NH)NH2 radical.
The term (C3-C7)cycloalkyl designates a saturated carbon monocyclic system comprising from 3 to 7 carbon atoms, and preferably the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings. The expression heterocycloalkyl designates a 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 chosen from oxygen, sulphur or nitrogen. As an example of a heterocycloalkyl, there may be mentioned the rings containing at least one nitrogen atom such as pyrrolidine, imidazolidine, pyrrazolidine, isothiazolidine, thiazolidine, isoxazolidine, oxazolidine, piperidine, piperazine, azepane (azacycloheptane), azacyclooctane, diazepane, morpholine, decahydroisoquinoline (or decahydroquinoline) but also the rings not containing any nitrogen atom such as tetrahydrofuran or tetrahydrothiophene. As an example of cycloalkyl or heterocycloalkyl substituted by oxy, for example pyrrolidinone and imidazolidinone can be mentioned.
The term heterobicycloalkyl designates a non-condensed saturated hydrocarbon bicyclic system containing from 5 to 8 carbon atoms and at least one heteroatom chosen from nitrogen, oxygen and sulphur. As an example of heterobicycloalkyl, aza-bicycloheptane and aza-bicyclooctane such as 7-aza-bicyclo[2,2,1]heptane, 2-aza-bicyclo[2,2,2]octane or 6-aza-bicyclo[3,2,1]octane can be mentioned.
The expression aryl represents an aromatic radical, constituted by a ring or condensed rings, such as for example the phenyl, naphthyl, fluorenyl or anthryl radical. The expression heteroaryl designates an aromatic radical, constituted by a ring or condensed rings, with at least one ring containing one or more identical or different heteroatoms chosen from sulphur, nitrogen or oxygen. As an example of a heteroaryl radical, there can be mentioned the radicals containing at least one nitrogen atom such as pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl, triazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, quinioxalinyl, indolyl, dihydroindolyl, benzoxadiazoyl, carbazolyl, phenoxazinyl but also the radicals not containing a nitrogen atom such as thienyl, benzothienyl, furyl, benzofuryl dibenzofuryl, dihydrobenzofuryl, dibenzothienyl, thioxanthenyl, or pyranyl. The term aralkyl (arylalkyl) preferably designates the radicals in which the aryl and alkyl radicals are as defined above such as for example benzyl or phenethyl. As an example of an aryl or heteroaryl radical substituted by oxy, for example fluorenone, acridone, xanthenone, benzothienyl-dione, anthraquinone, thioxanthene, benzocoumarine can be mentioned.
In the present Application also, the (CH2)i radical (i integer being able to represent n, n′, p, p′, p′′, s, s′ and s′′ as defined above), represents a linear or branched hydrocarbon chain, with i carbon atoms. Thus the —(CH2)3 radical can represent —CH2—CH2—CH2— but also —CH(CH3)—CH2—, —CH2—CH(CH3)— or —C(CH3)2—.
According to the present Application also, when a radical has the formula —B-D-E with D representing for example —C(O)—NH—, this means that the carbon atom of —C(O)—NH—is bound to B and the nitrogen atom to E.
Preferably, the invention relates to compounds of formula I as defined above and characterized in that X represents —CH—; or a pharmaceutically acceptable salt thereof.
Preferably, the invention relates to compounds of formula I as defined above, characterized in that X represents —CH— and A represents —CH2, and more particularly

    
    
        R1 and R2 represent, independently, a (C1-C8)alkyl radical;
        R3 represents -Z3c, —C(RZ3)(R′Z3)-Z3c, —C(RZ3)(R′Z3)-Z3d, —C(RZ3)(R′Z3)—(CH2)p-Z3d;
        R4 represents a radical of formula —(CH2)s—R′4;
        R′4 represents a heterocycloalkyl containing at least one nitrogen atom and optionally substituted by (C1-C6)alkyl; or a radical of formula —NW4W′4;
        
            W4 represents the hydrogen atom or (C1-C8)alkyl;
            W′4 represents a radical of formula —(CH2)s′—-Z4;
            Z4 represents the hydrogen atom;
        
        
        s represents an integer from 2 to 4; s′ represents an integer from 0 to 4;

and preferably

        the heterocycloalkyl represented by R′4 is the piperidine ring;
        RZ3 and R′Z3 represent the hydrogen atom;
        Z3c represents the thienyl, furyl or phenyl radical,
        
            the phenyl radical being substituted by one or more identical or different substituents chosen from: halo and —(CH2)p′—V3—Y3;
            V3 represents —O—, —C(O)—, —C(O)—O—, —C(O)—NR′3— or a covalent bond;
            R′3 represents the hydrogen atom or a (C1-C6)alkyl radical;
            Y3 represents the hydrogen atom; a (C1-C6)alkyl radical optionally substituted by one or more identical or different halo radicals;
        
        
        Z3d represents the (C1-C6)alkoxy-carbonyl or heterocycloalkyl radical, and preferably the heterocycloalkyl is imidazolidine; or a pharmaceutically acceptable salt thereof.
    
    


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(Ra)(Rb)— with Ra and Rb representing the methyl radical; and more particularly

    
    
        R1 and R2 represent, independently, a (C1-C8)alkyl radical;
        R3 represents -Z3c, —C(RZ3)(R′Z3)-Z3c, —C(RZ3)(R′Z3)-Z3d or —C(RZ3)(R′Z3)—(CH2)p-Z3d;
        R4 represents a radical of formula —(CH2)s—R′4;
        R′4 represents a heterocycloalkyl containing at least one nitrogen atom and optionally substituted by (C1-C6)alkyl; or a radical of formula —NW4W′4;
        
            W4 represents the hydrogen atom or (C1-C8)alkyl;
            W′4 represents a radical of formula —(CH2)s′-Z4;
            Z4 represents the hydrogen atom, the phenyl radical or a heteroaryl;
            s represents an integer from 2 to 4; s′ represents an integer from 0 to 4;

and preferably

        
        
        RZ3 and R′Z3 represent, independently, the hydrogen atom;
        Z3c represents a thienyl radical optionally substituted by (C1-C6)alkoxy-carbonyl; or phenyl substituted by one or more identical or different substituents chosen from: halo, nitro or —(CH2)p′—V3—Y3;
        
            V3 represents —O—, —C(O)—, —C(O)—O—, —C(O)—NR′3— or a covalent bond;
            Y3 represents the hydrogen atom; a (C1-C6)alkyl radical optionally substituted by one or more identical or different halo radicals;
            R′3 represents the hydrogen atom;
        
        
        Z3d represents a (C1-C6)alkoxy-carbonyl radical;
        the heterocycloalkyl represented by R′4 is piperidine;
        the heteroaryl represented by Z4 is pyridine; or a pharmaceutically acceptable salt thereof.
    
    


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 particularly R3 represents —C(O)-Z′3;
    
        R1 and R2 represent, independently, a (C1-C8)alkyl radical;
        Z′3 represents a phenyl radical optionally substituted by one or more identical or different substituents chosen from: halo, nitro and —(CH2)p′′—V′3—Y′3 
        
            V′3 represents —O—, —C(O)—O— or a covalent bond;
            Y′3 represents the hydrogen atom or a (C1-C6)alkyl radical;
            p′′ represents the integer 0;
        
        
        R4 represents a radical of formula —(CH2)s—R′4 and R′4 represents a radical of formula —NW4W′4 
        
            W4 represents the hydrogen atom or (C1-C8)alkyl;
            W′4 represents a radical of formula —(CH2)s′-Z4 and Z4 represents the hydrogen atom;
            s represents an integer from 2 to 4; s′ represents an integer from 0 to 4;

or a pharmaceutically acceptable salt thereof.

        
        
    
    


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

    
    
        R1 represents a hydrogen atom, a (C1-C8)alkyl radical optionally substituted by hydroxy, (C2-C6)alkenyl or a radical of formula —(CH2)n—X1;
        R2 represents a (C1-C8)alkyl radical optionally substituted by hydroxy, (C2-C6)alkenyl or a radical of formula —(CH2)n—X1;
        each X1 represents, independently, (C1-C6)alkoxy, (C3-C7)cycloalkyl, aryl or heteroaryl,
        
            the aryl radical being optionally substituted by one or more identical or different substituents chosen from: —(CH2)n′—V1—Y1, halo;
            V1 represents —O— or a covalent bond;
            Y1 represents a (C1-C6)alkyl radical optionally substituted by one or more identical or different halo radicals; or aryl;
        
        
        or R1 and R2 form together with the nitrogen atom to which they are attached, a heterocycloalkyl optionally substituted by one or more identical or different substituents chosen from: hydroxy, (C1-C6)alkyl optionally substituted by hydroxy, (C1-C6)alkoxy-carbonyl, heterocycloalkyl and —C(O)NV1′Y1′ with V1′ and Y1′ independently representing the hydrogen atom or a (C1-C6)alkyl,
        or R1 and R2 together form a radical of formula:
    
    






    
    
        R3 represents -Z3, —C(RZ3)(R′Z3)-Z3 or —C(RZ3)(R′Z3)—(CH2)p-Z3;
        R4 represents a radical of formula —(CH2)s—R′4 
        R′4 represents a heterocycloalkyl containing at least one nitrogen atom and optionally substituted by (C1-C6)alkyl or aralkyl; a heteroaryl containing at least one nitrogen atom and optionally substituted by (C1-C6)alkyl; or a radical of formula —NW4W′4 
        W4 represents the hydrogen atom or (C1-C8)alkyl;
        W′4 represents a radical of formula —(CH2)s′-Z4;
        Z4 represents the 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 particularly characterized in that they have at least one of the following characteristics:

        the (C3-C7)cycloalkyl radical represented by X1 is cyclopropyl;
        the aryl radical represented by X1 the phenyl radical;
        the heteroaryl radical represented by X1 is pyridine;
        the heterocycloalkyl that R1 and R2 form together with the nitrogen atom to which they are attached is chosen from: pyrrolidine, piperidine, azepane, azacyclooctane, morpholine, piperazine and decahydroisoquinoline;
        the heterocycloalkyl radical represented by R′4, optionally substituted by C1-C6)alkyl or benzyl, is chosen from: pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl;
        the heteroaryl radical represented by R′4 is the imidazolyl radical;
        the cycloalkyl represented by Z4 is chosen from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
        the aryl represented by Z4 is phenyl; or a pharmaceutically acceptable salt thereof.
    
    


Very preferably, the invention relates to compounds of formula I as defined above, characterized in that R4 represents a radical of formula —(CH2)s—R′4 with R′4 representing the pyrrolidinyl or piperidinyl radical; or a radical of formula —NW4W′4 

    
    
        W4 represents the hydrogen atom or (C1-C8)alkyl;
        W′4 represents a radical of formula —(CH2)s′-Z4 with Z4 representing the hydrogen atom;
        s represents an integer from 2 to 4; s′ represents an integer from 0 to 4; or a pharmaceutically acceptable salt thereof.
    
    


Very preferably also, the invention relates to compounds of formula I as defined above, characterized in that R1 and R2 represent, independently, a (C1-C8)alkyl radical; or a pharmaceutically acceptable salt thereof.
Preferably, the invention also relates to compounds of formula I as defined above, characterized in that X represents —CH—, A represents —C(O)—, and

    
    
        R3 represents -Z3 and Z3 represents Z3c, Z3d or Z3e;
        Z3d represents a (C3-C7)cycloalkyl or heterocycloalkyl radical;

and more particularly

        Z3c represents a heteroaryl radical chosen from thienyl, furyl, indolyl, dihydroindolyl, pyridyl, benzothienyl and benzofuryl; or an aryl radical chosen from phenyl, naphthyl and fluorenyl;
        the heteroaryl radical being optionally substituted by one or more identical or different substituents chosen from: (C1-C6)alkyl-carbonyl and (C1-C6)alkoxy-carbonyl;
        the aryl radical being optionally substituted by one or more identical or different substituents chosen from: halo, cyano, nitro, azido, (C1-C6)alkoxy-carbonyl-(C1-C6)alkenyl, oxy, —SO2—NR31R32, heterocycloalkyl, heteroaryl, or —(CH2)p′—V3—Y3;
        R31 and R32 form together with the nitrogen atom to which they are attached, the piperidine ring;
        V3 represents —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;
        Y3 represents the hydrogen atom; a (C1-C6)alkyl radical optionally substituted by one or more identical or different halo radicals; phenyl; or benzyl;
        R′3 represents the hydrogen atom, a (C1-C6)alkyl or (C1-C6)alkoxy radical;
        Z3d represents the cyclopropyl, cyclohexyl or piperidinyl radical, each being able to be substituted by a (C1-C6)alkoxy-carbonyl radical; or a pharmaceutically acceptable salt thereof.
    
    


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

    
    
        R3 represents -Z3 and Z3 represents Z3c, Z3d or Z3e;
        Z3d represents a (C3-C7)cycloalkyl or heterocycloalkyl radical;

and more particularly

        Z3c represents a heteroaryl radical chosen from thienyl, indolyl and benzothienyl; or an aryl radical chosen from phenyl and naphthyl;
        the heteroaryl radical being optionally substituted by one or more oxy radicals;
        the aryl radical being optionally substituted by one or more identical or different substituents chosen from: halo, nitro, heteroaryl or —(CH2)p′—V3—Y3;
        
            V3 represents —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;
            Y3 represents the hydrogen atom; a (C1-C6)alkyl radical optionally substituted by one or more identical or different halo radicals; a phenyl radical; or a benzyl radical;
            R′3 represents the hydrogen atom, a (C1-C6)alkyl or (C1-C6)alkoxy radical;
        
        
        Z3d represents the cyclopropyl or piperidinyl radical, each optionally substituted by (C1-C6)alkoxy-carbonyl;

and preferably

        Z3 represents Z3c or Z3e;
        Z3c represents a phenyl being optionally substituted by one or more identical or different substituents chosen from nitro and —(CH2)p′—V3—Y3;
        
            V3 represents —O—, —S—, —C(O)—, —C(O)—O—, —SO2—, —SO2NH—, —NR′3—C(O)—, —C(O)—NR′3— or a covalent bond;
            Y3 represents the hydrogen atom; a (C1-C6)alkyl radical; a phenyl radical; or a benzyl radical;
            R′3 represents the hydrogen atom;
        
        
        Z3e represents
    
    






or a pharmaceutically acceptable salt thereof.

Preferably, the invention also relates to compounds of formula I as defined above, characterized in that X represents —CH—, A represents —C(O)—, R3 represents —C(RZ3)(R′Z3)-Z3 and Z3 represents Z3b, Z3c, Z3d or Z3e; or a pharmaceutically acceptable salt thereof.
Very preferably, the invention also relates to compounds of formula I as defined above, characterized in that X represents —CH—, A represents —C(O)—, and

    
    
        R3 represents —C(RZ3)(R′Z3)-Z3 and Z3 represents Z3b or Z3c;
        RZ3 and R′Z3 represent the hydrogen atom;

and more particularly

        Z3b represents a (C1-C6)alkoxy radical;
        Z3c represents a heteroaryl radical chosen from thienyl, furyl, pyridyl, benzothienyl and dihydrobenzofuryl; or an aryl radical chosen from phenyl and naphthyl,
        the aryl radical being optionally substituted by one or more identical or different substituents chosen from: halo or —(CH2)p′—V3—Y3;
        V3 represents —O—, —S—, —C(O)—, —C(O)—O—, —SO2—, —SO2NH—, —NR′3—C(O)—, —C(O)—NR′3—,
        Y3 represents the hydrogen atom; a (C1-C6)alkyl radical optionally substituted by one or more identical or different halo radicals;
        R′3 represents the hydrogen atom;

or a pharmaceutically acceptable salt thereof.

    
    


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

    
    
        R3 represents —C(RZ3)(R′Z3)-Z3 and Z3 represents Z3b or Z3c;
        RZ3 and R′Z3 represent the hydrogen atom;

and more particularly

        Z3b represents a (C1-C6)alkoxy radical;
        Z3c represents a heteroaryl radical chosen from thienyl, furyl, dihydrobenzofuryl; or a phenyl radical;
        the phenyl radical being optionally substituted by one or more identical or different substituents chosen from: nitro or —(CH2)p′—V3—Y3;
        V3 represents —O—, —S—, —C(O)—, —C(O)—O—, —SO2—, —SO2NH—, —C(O)—NR′3—,
        Y3 represents the hydrogen atom; or a (C1-C6)alkyl radical optionally substituted by one or more identical or different halo radicals;
        R′3 represents the hydrogen atom;

and preferably

    
    


Z3 represents Z3c;

    
    
        Z3c represents a furyl or phenyl radical,
        the phenyl radical being optionally substituted by one or more identical or different substituents of formula —(CH2)p′—V3—Y3;
        V3 represents —O—, —S—, —C(O)—, —C(O)—O—, —SO2—, —SO2NH—, —C(O)—NR′3—,
        Y3 represents the hydrogen atom; or a (C1-C6)alkyl radical optionally substituted by one or more identical or different halo radicals;
        R′3 represents the hydrogen atom;

or a pharmaceutically acceptable salt thereof.

    
    


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

    
    
        R3 represents —C(RZ3)(R′Z3)-Z3 and Z3 represents Z3d or Z3e;
        RZ3 and R′Z3 represent the hydrogen atom or (C1-C6)alkyl;
        Z3d represents a (C1-C6)alkoxy-carbonyl, (C3-C7)cycloalkyl or heterocycloalkyl radical;
        Z3e represents
    
    






and more particularly

    
    
        Z3d represents a (C1-C6)alkoxy-carbonyl, cyclohexyl or a tetrahydrofuranyl radical; or a pharmaceutically acceptable salt thereof.
    
    


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

    
    
        R3 represents —C(RZ3)(R′Z3)-Z3 and Z3 represents Z3d or Z3e;
        Z3d represents a (C1-C6)alkoxy-carbonyl radical;
        Z3e, represents
    
    






and preferably Z3 represents Z3e





or a pharmaceutically acceptable salt thereof.

Preferably, the invention also relates to compounds of formula I as defined above, characterized in that X represents —CH—, A represents —C(O)—, R3 represents —C(RZ3)(R′Z3)—(CH2)p-Z3 and Z3 represents Z3b, Z3c or Z3d; or a pharmaceutically acceptable salt thereof.
Very preferably, the invention relates to compounds of formula I as defined above, characterized in that X represents —CH—, A represents —C(O)—, and

    R3 represents —C(RZ3)(R′Z3)—(CH2)p-Z3 and Z3 represents Z3b;

and more particularly
    
        RZ3 and R′Z3 represent, independently, the hydrogen atom or a (C1-C6)alkyl radical;
        Z3b represents a (C1-C6)alkoxy, (C1-C6)alkylthio or di((C1-C6)alkyl)amino radical; or a pharmaceutically acceptable salt thereof.
    
    


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

    
    
        R3 represents —C(RZ3)(R′Z3)—(CH2)p-Z3 and Z3 represents Z3b;

and more particularly

        RZ3 and R′Z3 represent, independently, the hydrogen atom or a (C1-C6)alkyl radical;
        Z3b represents a (C1-C6)alkoxy or (C1-C6)alkylthio radical; or a pharmaceutically acceptable salt thereof.
    
    


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

    
    
        R3 represents —C(RZ3)(R′Z3)—(CH2)p-Z3 and Z3 represents Z3c or Z3d;

and more particularly

        RZ3 and R′Z3 represent, independently, the hydrogen atom or a (C1-C6)alkyl radical;
        Z3c represents an indolyl or phenyl radical;
        
            the phenyl radical being optionally substituted by one or more identical or different substituents chosen from: halo and —(CH2)p′—V3—Y3;
            V3 represents —SO2NH—,
            Y3 represents the hydrogen atom; or a (C1-C6)alkyl radical;
        
        
        Z3d represents a (C1-C6)alkoxy-carbonyl, amino-carbonyl, (C1-C6)alkyl-amino-carbonyl, (C1-C6)alkyl-C(O)—NH—, or heterocycloalkyl radical optionally substituted by oxy, and preferably piperidinyl, morpholinyl, pyrrolidine or imidazolidinyl; or a pharmaceutically acceptable salt thereof.
    
    


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

    
    
        R3 represents —C(RZ3)(R′Z3)—(CH2)p-Z3 and Z3 represents Z3c or Z3d;

and more particularly

        Z3 represents Z3d;
        RZ3 and R′Z3 represent, independently, the hydrogen atom or a (C1-C6)alkyl radical;
        Z3d represents a (C1-C6)alkoxy-carbonyl, amino-carbonyl, (C1-C6)alkylamino-carbonyl, (C1-C6)alkyl-C(O)—NH— or heterocycloalkyl radical, and preferably pyrrolidine or imidazolidine, optionally substituted by oxy; or a pharmaceutically acceptable salt thereof.
    
    


In the present Application, the symbol ->* corresponds to the attachment point of the radical. When the attachment site is not specified on the radical, this means that the attachment is carried out on one of the sites available on this radical for such an attachment.
Following the definitions of the variable groups A, X, R1, R2, R3 and R4, the compounds according to the invention can be prepared in liquid phase according to the different procedures A to G described below.
A. Preparation According to Reaction Diagram A:
The compounds of formula (I) according to the invention in which A represents —C(O)—, can be prepared according to the following diagram A:




As described in diagram A, the methylated derivative (1) (for X═C commercial compound; for X═N compound prepared according to the procedure of Baumgarten et al, J. Am. Chem. Soc, 1952, 74, 3828-3831, from 6-methyl-3-nitro-pyridin2-amine) can be oxidized to carboxylic acid (2) by an aqueous solution of potassium permanganate at a temperature of 100° C. for 3 to 6 hours (according to procedure of Schmelkes et al., J. Am. Chem. Soc, 1944, 1631), or by an aqueous solution of sodium dichromate in the presence of sulphuric acid at a temperature of 20-90° C. for 1 to 3 hours (according to procedure of Howes et al., European J. Med. Chem, 1999, 34, 225-234). The carboxylic acid (2) can be coupled with a primary or secondary amine in the presence of a coupling agent such as diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), 1,3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) or carbonyldiimidazole (CDI) with or without 1-hydroxybenzotriazole (HOBt) in an inert organic solvent such as methylene chloride, tetrahydrofuran or dimethylformamide at ambient temperature for 3 to 24 hours in order to produce the corresponding amide (3). Treatment of the fluorinated or chlorinated derivative (3) by a primary amine in the presence of an inorganic base such as caesium or potassium carbonate in an inert organic solvent such as dimethylformamide or acetonitrile at a temperature of 20-100° C. for 2 to 48 hours leads to derivative (4). The nitro function of compound (4) is reduced by treatment with dihydrate tin chloride 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 carbon in an inert solvent such as methanol, ethanol, ethyl acetate or a mixture of these solvents, at a temperature of 18-25° C., for 2 to 8 hours in order to produce the dianiline (5). The derivative (5) is then treated with an isothiocyanate in the presence of a coupling agent supported or not supported on a resin such as diisopropylcarbodiimide or dicyclohexylcarbodiimide or N-methylcyclohexylcarbodiimide N-methyl polystyrene resin in an inert solvent such as tetrahydrofuran, methylene chloride, or chloroform at a temperature of 20-70° C. for 2 to 72 hours in order to produce derivative (6). Alternatively, the derivative (5) can be treated with an isothiocyanate 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 resultant thiourea can be treated by methyl iodide or yellow mercury (II) oxide in the presence of a catalytic quantity of sulphur in a polar solvent such as methanol or ethanol for 2 to 24 hours at a temperature of 20-80° C. in order to produce (6). Compound (6) can be isolated either by flash chromatography on silica gel, or by addition to the reaction mixture of a nucleophilic reagent supported on a polymer such as for example an aminomethylpolystyrene resin and/or an electrophilic reagent supported on a polymer such as for example methylisothiocyanate-polystyrene resin, followed by filtration and evaporation of the filtrate.


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




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) is heated under reflux for 6 hours then cooled down to ambient temperature. The mixture is filtered on celite and the aqueous phase is washed twice with diethyl ether (2×300 ml). The aqueous phase is acidified, at 0° C., with a solution of concentrated hydrochloric acid then concentrated under reduced pressure at 40° C. to a volume of approximately 300 ml. The precipitate formed is filtered then washed with petroleum ether and dried in order to produce the expected compound in the form of a white solid (6.9 g; 58% yield).
NMR (1H, 400 MHz, DMSO-d6): δ 7.93 (m, 2H), 8.25 (m, 1H), 13.95 (m, 1H).
Stage 2: 3-fluoro-N,N-bis(3-methylbutyl)-4-nitrobenzamide
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (4.4 g, 1.1 eq) in solution in chloroform (25 ml) and 1-hydroxybenzotriazole (HOBt) (3.05 g, 1.1 eq) in solution in THF (40 ml) are added successively to 3-fluoro-4-nitrobenzoic acid (3.8 g, 1 eq) in solution in anhydrous THF (30 ml). The mixture is stirred for 1 hour at a temperature of approximately 20° C. then diisoamylamine (3.6 g, 1.1 eq) in solution in THF (30 ml) is added. After stirring for 16 hours at a temperature of approximately 20° C., the reaction mixture is concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (200 ml) and water (70 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the compound by flash chromatography on silica gel (eluent: heptane/ethyl acetate 9:1) produces the expected compound in the form of a yellow oil (4.3 g; 65% yield).
MS/LC: calculated MM=324.4; m/z 325.2 (MH+) NMR (1H, 400 MHz, DMSO-d6): δ 0.69 (m, 6H), 0.93 (m, 6H), 1.35-1.60 (m, 6H), 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-nitrophenyl)amino]propylcarbamate
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 under reflux for 5 hours then concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (100 ml) and water (40 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated 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) produces the expected compound in the form of 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 0.68 (m, 6H), 0.92 (m, 6H), 1.36 (s, 9H), 1.31-1.69 (m, 8H), 3.0 (m, 2H), 3.09 (m, 2H), 3.38 (m, 4H), 6.53 (d, 1H), 6.88 (m, 2H), 8.10 (d, 1H), 8.26 (m, 1H).
Stage 4: tert-butyl 3-[(2-amino-5-{[bis(3-methylbutyl)amino]carbonyl}phenyl)amino]propylcarbamate
Tert-butyl 3-[(5-{[bis(3-methylbutyl)amino]carbonyl}-2-nitrophenyl)amino]propylcarbamate (1.65 g) in solution in a mixture of ethyl acetate/ethanol 2:1 (130 ml), and 10% palladium on carbon (165 mg) are introduced into an autoclave. After stirring for 3 hours under a hydrogen atmosphere (3 bar) at a temperature of approximately 20° C., the catalyst is eliminated by filtration on celite and the filtrate is concentrated under reduced pressure at 40° C. in order to produce 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), 1.37 (s, 9H), 1.32-1.53 (m, 6H), 1.70 (m, 2H), 3.0 (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-benzimidazol-2-yl)amino]benzoate
4-methoxycarbonylphenyl isothiocyanate (327 mg, 1.5 eq) and N-methylcyclohexylcarbodiimide-N-methyl-polystyrene resin (acquired from Novabiochem; charge 1.9 mmol/g; 1.75 g, 3 eq) are added successively to a solution of tert-butyl-3-[(2-amino-5-{[bis(3-methylbutyl)amino]carbonyl}phenyl)amino]propylcarbamate (500 mg, 1 eq) in tetrahydrofuran (30 ml). The mixture is heated under reflux for 17 hours then cooled down to ambient temperature and aminomethylpolystyrene resin (acquired from Novabiochem, 2 eq) is added. After stirring for 4 hours at ambient temperature, the mixture is filtered on frit and the filtrate is 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-d6): δ 0.65-0.90 (m, 12H), 1.36 (s, 9H), 1.31-1.44(m, 6H), 1.81 (m, 2H), 3.0 (m, 2H), 3.26-3.39 (m, 4H), 3.82 (s, 3H), 4.29 (m, 2H), 6.95 (m, 1H), 7.04 (d, 1H), 7.36 (s, 1H), 7.44 (d, 1H), 7.94 (AB, 2H), 8.02 (AB, 2H), 9.34 (s, 1H).
Stage 6: methyl 4-[(1-(3-aminopropyl)-6-{[bis(3-methylbutyl)amino]carbonyl}-1H-benzimidazol-2-yl)amino]benzoate dihydrochloride
A solution of hydrochloric acid in dioxane (4N, 2 ml) is added to a solution of methyl 4-[(6-{[bis(3-methylbutyl)amino]carbonyl}-1-{3-[(tert-butoxycarbonyl)amino]propyl}-1H-benzimidazol-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 solid obtained 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 0.63-0.98 (m, 12H), 1.45 (m, 6H), 2.08 (m, 2H), 2.98 (m, 2H), 3.12-3.45 (m, 4H), 3.85 (s, 3H), 4.59 (m, 2H), 7.20 (d, 1H), 7.46 (d, 1H), 7.67 (s, 1H), 7.90 (m, 2H), 8.01-8.07 (m, 5H), 11.08 (m, 1H).
EXAMPLE A2
2-[(4-acetylphenyl)amino]-N,N-bis(3-methylbutyl)-1-(3-piperidin-1-ylpropyl)-1H-benzimidazole-6-carboxamide dihydrochloride




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

A mixture of 3-fluoro-N,N-bis(3-methylbutyl)-4-nitrobenzamide (430 mg, 1 eq, prepared according to Example A1), 3-piperidino-propylamine (212 mg, 1.1 eq) and potassium carbonate (365 mg, 2 eq) in acetonitrile (10 ml) is heated under reflux for 3 hours then concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (50 ml) and water (20 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: ethyl acetate 100%) produces the expected compound in the form of 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 0.68 (d, 6H), 0.92 (d, 6H), 1.31-1.69 (m, 12H), 1.74 (m, 2H), 2.32 (m, 6H), 3.10 (m, 2H), 3.38 (m, 4H), 6.53 (d, 1H), 6.91 (m, 1H), 8.09 (d, 1H), 8.44 (t, 1H).
Stage 2: 2-[(4-acetylphenyl)amino]-N,N-bis(3-methylbutyl)-1-(3-piperidine-1-ylpropyl)-1H-benzimidazole-6-carboxamide dihydrochloride
N,N-bis(3-methylbutyl)-4-nitro-3-[(3-piperidin-1-yl-propyl)amino]benzamide (44 mg) in solution in a mixture of ethyl acetate/ethanol 2:1 (1.5 ml), and 10% palladium on carbon (5 mg) are introduced into a haemolysis tube placed in an autoclave. After stirring for 3 hours under a hydrogen atmosphere (3 bar) at a temperature of approximately 20° C., the catalyst is eliminated by filtration on celite and the filtrate is concentrated under reduced pressure at 40° C. 4-acetylphenyl isothiocyanate (27 mg, 1.5 eq) and N-methylcyclohexylcarbodiimide-N-methyl-polystyrene resin (acquired from Novabiochem; charge 1.9 mmol/g; 158 mg, 3 eq) are added successively to the aniline thus obtained, in solution in tetrahydrofuran (2 ml). The mixture is heated under reflux for 18 hours then cooled down to ambient temperature and aminomethylpolystyrene resin (acquired from Novabiochem, 2 eq) is added. After stirring for 4 hours at ambient temperature, the mixture is filtered on frit and 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 a base. The corresponding hydrochloride salt is formed by adding a 1N solution of hydrochloric acid in ether. The precipitate obtained is filtered and dried in order to produce the expected dihydrochloride compound.
MS/LC: calculated MM=559.8; m/z=560.3 (MH+) NMR (1H, 400 MHz, DMSO-d6): 50.68 (m, 6H), 0.94 (m, 6H), 1.31-1.56 (m, 6H), 1.57-1.90 (m, 6H), 2.28 (m, 2H), 2.60 (s, 3H), 2.86 (m, 2H), 3.21 (m, 4H), 3.40 (m, 4H), 4.62 (t, 2H), 7.24 (AB, 1H), 7.47 (AB, 1H), 7.76 (s, 1H), 7.81 (m, 2H), 8;07 (m, 2H), 10.40 (s, 1H), 11.64 (m, 1H).
EXAMPLE A3
2-(cyclohexylamino)-1-[3-(dimethylamino)propyl]-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamide dihydrochloride




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

A mixture of 3-fluoro-N,N-bis(3-methylbutyl)-4-nitrobenzamide (2.5 g, 1 eq, prepared according to Example A1), 3-diethylamino-propylamine (877 mg, 1.1 eq) and potassium carbonate (2.13 g, 2 eq) in acetonitrile (80 ml) is heated under reflux for 5 hours then concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (130 ml) and water (50 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated 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 mg; 68% yield).
MS/LC: calculated MM=406.6; m/z=407.3 (MH+) NMR (1H, 400 MHz, DMSO-d6): δ 0.68 (d, 6H), 0.92 (d, 6H), 1.31-1.51 (m, 5H), 1.59 (m, 1H), 1.74 (m, 2H), 2.14 (s, 6H), 2.31 (t, 2H), 3.11 (m, 2H), 3.39 (m, 4H), 6.53 (d, 1H), 6.90 (s, 1H), 8.09 (d, 1H), 8.57 (t, 1H).
Stage 2: 2-(cyclohexylamino)-1-[3-(dimethylamino)propyl]-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamide dihydrochloride
3-{[3-(dimethylamino)propyl]amino}-N,N-bis(3-methylbutyl)-4-nitrobenzamide (81 mg) in solution in a mixture of ethyl acetate/ethanol 2:1 (4 ml), and 10% palladium on carbon (8 mg) are introduced into a haemolysis tube placed in an autoclave. After stirring for 3 hours under a hydrogen atmosphere (3 bar) at a temperature of approximately 20° C., the catalyst is eliminated by filtration on celite and the filtrate is concentrated under reduced pressure at 40° C. Cyclohexyl isothiocyanate (58 mg, 2 eq) is successively added to the aniline thus obtained, in solution in tetrahydrofuran (2 ml). The mixture is heated under reflux for 3 hours then cooled down to ambient temperature and concentrated under reduced pressure. Yellow mercury (II) oxide (87 mg, 2 eq) and sulphur (1.4 mg) are successively added to the thiourea thus formed in solution in ethanol (3 ml). The mixture is heated for 17 hours under reflux then cooled down to ambient temperature and filtered on 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 base. The corresponding hydrochloride salt is formed by adding a 1N solution of hydrochloric acid in ether. The precipitate obtained is filtered and dried in order to produce 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 0.58-1.03 (m, 12H), 1.18 (m, 1H), 1.30-1.71 (m, 11H), 1.80 (m, 2H), 2.01 (m, 4H), 2.73 (s, 6H), 3.14 (m, 4H), 3.25 (m, 2H), 3.71 (m, 1H), 4.32 (m, 2H), 7.16 (m, 1H), 7.39 (m, 1H), 7.54 (m, 1H), 8.42 (m, 1H), 10.40 (m, 1H), 13.41 (m, 1H).
Preparation of Non-commercial Isothiocyanates:




A primary amine can be converted to isothiocyanate, by treatment with 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 disulphide and cyclohexylcarbodiimide supported or not supported on a 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-isothiocyanatophenyl)acetamide




Thiophosgene (0.56 ml, 1.1 eq) is added dropwise to a solution cooled down to 0° C., of N-(4-aminophenyl)acetamide (1 g, 1 eq) and triethylamine (2.8 ml, 3 eq) in tetrahydrofuran (130 ml). The mixture is stirred for 30 minutes at 0° C. then the cold bath is removed and the stirring is continued for another 30 minutes. Water (70 ml) and diethyl ether (150 ml) are added to the mixture. After decantation and extractions, the organic phases are combined, washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. The solid obtained is recrystallized from a dichloromethane/petroleum ether mixture (0.95 g; 75% yield).
NMR (1H, 400 MHz, DMSO-d6): δ 2.04 (s, 3H), 7.35 (AB, 2H), 7.63 (AB, 2H), 110.14 (s, 1H).
The following isothiocyanates were prepared according to the same procedure as that described for N-(4-isothiocyanatophenyl)acetamide:






















Preparation of N-(4-isothiocyanatophenyl)-N′-methoxyurea





Carbonyl-di-imidazole (1.62 g, 2 eq) is added to a solution cooled down to 0° C., of tert-butyl 4-aminophenylcarbamate (1.04 g) in anhydrous dichloromethane (100 ml). The mixture is taken to a temperature of 20° C. and is stirred at this temperature for 15 hours. Triethylamine (7 ml, 10 eq) followed by O-methylhydroxylamine hydrochloride (4.2 g, 10 eq) are successively added to the reaction medium cooled down to 0° C. After stirring for 3 hours at a temperature of approximately 20° C., water saturated with sodium hydrogen carbonate and chloroform is added to the mixture. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. in order to produce tert-butyl 4-{[(methoxyamino)carbonyl]amino}phenylcarbamate (1.33 g). A current of gaseous hydrochloric acid is passed through a suspension of this derivative in ethyl acetate until the reaction is complete. The precipitate obtained is filtered then washed with diethyl ether and dried in order to produce N-(4-aminophenyl)-N′-methoxyurea hydrochloride (1 g).
Thiophosgene (0.38 ml, 1.1 eq) is added dropwise to a solution cooled down to 0° C., of N-(4-aminophenyl)-N′-methoxyurea hydrochloride (1 g) and triethylamine (3.2 ml, 5 eq) in tetrahydrofuran (90 ml). The mixture is stirred for 15 min at 0° C. then water and diethyl ether are added. After decantation and extractions, the phases organic are combined, washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification by flash chromatography on silica gel (eluent: heptane/ethyl acetate 7:3 to 3:7) produces the expected compound (630 mg; 62% yield).
NMR (1H, 400 MHz, DMSO-d6): δ 3.61 (s, 3H), 7.34 (AB, 2H), 7.67 (AB, 2H), 9.11 (s, 1H), 9.65 (s, 1H).
Preparation of Non-Commercial Acyl-isothiocyanates:




Acyl-isothiocyanates can be prepared starting from the corresponding acid chlorides 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-isothiocyanatocarbonylbenzoate:




Potassium thiocyanate (1.08 g) is added to a solution of methyl 4-chlorocarbonylbenzoate (2 g) in acetonitrile (30 ml). After stirring for 1 hour at approximately 20° C., the mixture is filtered and the filtrate is concentrated under reduced pressure at 40° C. The solid obtained is purified by flash chromatography on silica gel (eluent: heptane/ethyl acetate 1:1) in order to produce 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 were prepared according to the same procedure as that described for the methyl 4-isothiocyanatocarbonylbenzoate:




According to reaction diagram A and in a fashion analogous to the procedure described for the synthesis of methyl 4-[(1-(3-aminopropyl)-6-{[bis(3-methylbutyl) amino]carbonyl}-1H-benzimidazol-2-yl)amino]benzoate dihydrochloride, 2-[(4-acetylphenyl)amino]-N,N-bis(3-methylbutyl)-1-(3-piperidin-1-ylpropyl)-1H-benzimidazole-6-carboxamide dihydrochloride or 2-(cyclohexylamino)-1-[3-(dimethylamino)propyl]-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamide dihydrochloride, the following compounds were prepared:




in which R1R2N represents one of the radicals below:





and R3 represents one of the radicals below:

    
    
        1 or more substitutions chosen from:
    
    






U=H, F, Cl, Br, I, NO2, N2, OMe, OEt, SMe, Me, Et, iPr, tBu, CF3, OCF3, SCF3, C(O)OMe, C(O)OEt, C(O)Me, C(O)Et, C(O)Ph, NHC(O)NHMe, C(O)N(Me)2, C(O)NH2, NHC(O)NHMe, NHC(O)NHOMe, S(O)2Me, S(O)2NH2, S(O)2NHMe, S(O)2piperdine, NHphenyl, phenyl, phenoxy, benzyloxy








    
    
        1 or more substitutions chosen from:
    
    






V=H, F, Cl, Br, I, NO2, OMe, SMe, Me, Et, iPr, CF3, OCF3, SCF3, C(O)OMe, C(O)OEt, C(O)Me, C(O)Et, C(O)NHMe, S(O)2Me, S(O)2NH2








and R4 represents one of the radicals below:





B. Preparation According to Reaction Diagram B:

The compounds of formula (I) according to the invention in which A represents —C(O)—, can also be prepared according to the following diagram B:




As described in diagram B, the carboxylic acid (2) can be converted to methyl ester (7) either by treatment with a solution of trimethylsilyl-diazomethane at a temperature of 0-20° C., or by formation of a carboxylate salt using an inorganic base such as lithium hydroxide dihydrate or caesium carbonate, at ambient temperature for 30 minutes to 2 hours, in an inert organic solvent such as tetrahydrofuran, followed by the addition of dimethylsulphate at ambient temperature and stirring under reflux for 5 to 15 hours. The fluorinated or chlorinated derivative (7) can be treated with a primary amine in the presence of an inorganic base such as caesium or potassium carbonate in an inert organic solvent such as dimethylformamide or acetonitrile at a temperature of 20-100° C. for 2 to 48 hours in order to produce derivative (8). The nitro function of compound (8) can be reduced by treatment with tin chloride dihydrate 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 carbon in an inert solvent such as methanol, ethanol, ethyl acetate or a mixture of these solvents, at a temperature of 18-25° C., for 2 to 8 hours, in order to produce the dianiline (9). The derivative (9) is then treated with an isothiocyanate 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. for 2 to 72 hours in order to produce derivative (10). Alternatively, derivative (9) can be treated with an isothiocyanate 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 resultant thiourea can be treated with methyl iodide or yellow mercury (II) oxide in the presence of a catalytic quantity of sulphur in a polar solvent such as methanol or ethanol for 2 to 24 hours at a temperature of 20-80° C. in order to produce (10). The methyl ester (10) can then be saponified in the presence of an inorganic base such as lithium hydroxide dihydrate in a mixture of polar solvents such as water and tetrahydrofuran at a temperature of 20 to 70° C. for 3 to 17 hours. The resultant carboxylic acid (11) can be coupled with a primary or secondary amine in the presence of a coupling agent such as diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) or carbonyldiimidazole (CDI), with or without 1-hydroxybenzotriazole (HOBt) in an inert organic solvent such as methylene chloride, tetrahydrofuran or dimethylformamide at ambient temperature for 3 to 24 hours in order to produce the corresponding amide (6) which can be isolated, either by flash chromatography on silica gel, or by the addition to the reaction mixture of a nucleophilic reagent supported on a polymer such as for example an aminomethylpolystyrene resin and an electrophilic reagent supported on a polymer such as for example methylisothiocyanate-polystyrene resin, followed by filtration and evaporation of the filtrate.
EXAMPLE B1
1-(3-aminopropyl)-6-(piperidin-1-ylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-1H-benzimidazol-2-amine dihydrochloride




Stage 1: methyl 3-fluoro-4-nitrobenzoate

A solution of trimethylsilyldiazomethane (2M in hexane, 50 ml, 4 eq) is slowly added to a solution of 3-fluoro-4-nitrobenzoic acid (4.7 g, 1 eq) in methanol (70 ml) until the gas evolution ceases. The excess trimethylsilyldiazomethane is consumed by the dropwise addition of acetic acid until the solution becomes discoloured. The mixture is then concentrated under reduced pressure at a temperature of approximately 40° C. Water (200 ml) and dichloromethane (300 ml) are added to the residue. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. The solid obtained is washed with petroleum ether and dried (4.4 g; 87% yield).
NMR (1H, 400 MHz, CDCl3): δ 4.0 (s, 3H), 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 under reflux for 2 hours then concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (200 ml) and water (100 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. The solid obtained is washed with petroleum ether and dried (10.2 g; 99% yield).
NMR (1H, 400 MHz, CDCl3): δ1.45 (s, 9H), 1.95 (m, 2H), 3.30 (m, 2H), 3.44 (m, 2H), 3.95 (s, 3H), 4.67 (m, 1H), 7.25 (m, 1H), 7.55 (s, 1H), 8.04 (m, 1H), 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 solution in a mixture of ethyl acetate/methanol 3:1 (300 ml), and 10% palladium on carbon (1.02 g) are introduced into an autoclave. After stirring for 4 hours under a hydrogen atmosphere (3 bar) at a temperature of approximately 20° C., the catalyst is eliminated by filtration on celite and the filtrate is concentrated under reduced pressure at 40° C. in order to produce the expected compound in the form of an oil (7.75 g; 83% yield).
MS/LC: calculated MM=323.4; m/z=324.2 (MH+) NMR (1H, 400 MHz, CDCl3): 1.45 (s, 9H), 1.85 (m, 2H), 3.24 (m, 2H), 3.30 (m, 2H), 3.86 (m, 5H), 4.68 (m, 1H), 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-trimethoxyphenyl isothiocyanate (6.6 g, 1.2 eq) and diisopropylcarbodiimide (9.1 g, 3 eq) are successively added to a solution of methyl 4-amino-3-({3-[(tert-butoxycarbonyl)amino]propyl}amino)benzoate (7.75 g, 1 eq) in tetrahydrofuran (130 ml). The mixture is heated under reflux for 16 hours then cooled down to ambient temperature and concentrated under reduced pressure at 40° C. Water (100 ml) and dichloromethane (200 ml) are added to the residue obtained. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: heptane/ethyl acetate 8:2 to 3:7) produces the expected compound in the form of a solid which is washed with ether (4.4 g; 36% yield).
MS/LC: calculated MM=514.5; m/z=515.3 (MH+) NMR (1H, 400 MHz, CDCl3): 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), 5.03 (m, 1H), 7.23 (s, 2H), 7.53 (d, 1H), 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
Lithium hydroxide (2.18 g, 6 eq) is added to 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 under reflux for 18 hours then cooled down to ambient temperature and concentrated under reduced pressure at 40° C. Dichloromethane (150 ml) and water (100 ml) are added to the residue. The mixture is acidified by the addition of acetic acid to pH 5. After decantation and extractions, the combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The solid obtained is washed with ethyl ether (3.95 g; 93%).
MS/LC: calculated MM=500.5; m/z=501.3 (MH+) NMR (1H, 400 MHz, DMSO-d6): 1.37 (s, 9H), 1.83 (m, 2H), 3.03 (m, 2H), 3.61 (s, 3H), 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: 1-(3-aminopropyl)-6-(piperidin-1-ylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-1H-benzimidazol-2-amine dihydrochloride
A solution of carbonyldiimidazole (CDI) (18 mg, 1.1 eq) in chloroform (0.2 ml) is 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 a solution of piperidine (17 mg, 2 eq) in tetrahydrofuran (0.2 ml) is added. After stirring for 18 hours at a temperature of approximately 20° C., the mixture is diluted with dichloromethane (3 ml), and aminomethylpolystyrene resin (2 eq), TBD-methyl-polystyrene resin (2 eq) and methylisothiocyanate-polystyrene resin (4 eq) are added. After stirring for 6 hours at approximately 20° C., the mixture is filtered and the filtrate is concentrated under reduced pressure at 40° C. The residue obtained is dissolved in ethyl acetate (0.5 ml) and a solution of hydrochloric acid (1N in diethyl ether, 3 ml) is added. After stirring for 1 hour at a temperature of approximately 20° C., the precipitate obtained is filtered and dried in order to produce the expected compound (35 mg, 65%).
MS/LC: calculated MM=467.56; m/z=467.9 (MH+) NMR (1H, 400 MHz, DMSO-d6): 1.48-1.63 (m, 6H), 2.05 (m, 2H), 2.90 (m, 2H), 3.50 (m, 4H), 3.65 (s, 3H), 3.79 (s, 6H), 4.45 (m, 2H), 7.10-7.60 (m, 5H), 7.54 (m, 1H), 7.94 (m, 3H), 8.41 (m, 1H), 14.3 (m, 1H).
According to reaction diagram B and in a fashion analogous to the procedure described for the synthesis of 1-(3-aminopropyl)-6-(piperidin-1-ylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-1H-benzimidazol-2-amine dihydrochloride, the following compounds were prepared:




in which R1R2N represents one of the radicals below:








R3 represents the radical below:





and R4 represents one of the radicals below:





C. Preparation According to Reaction Diagram C:





As described in diagram C, the derivative (12), prepared according to reaction diagrams A or B can be treated with an organic or inorganic acid such as trifluoroacetic acid or hydrochloric acid (aqueous or in gaseous form) in an aprotic solvent such as dichloromethane, diethyl ether or ethyl acetate at a temperature of 0-20° C. for 0.5 to 5 hours, in order to produce the amine (13). The amine (13) can react with an aldehyde in a protic or aprotic solvent, such as dichloromethane, tetrahydrofuran or methanol, for 1 to 15 hours at a temperature of 0-50° C. The resultant imine is then reduced in situ by a reducing agent supported or not supported on a resin, preferably sodium triacetoxyborohydride, sodium cyanoborohydride or borohydride supported on a resin, with or without the presence of an acid such as acetic acid, at a temperature of 20 to 50° C. for a duration of 0.2 to 5 hours, in order to produce compound (14). The secondary amine (14) can optionally undergo a second reducing amination under the same operating conditions as those described previously in order to produce the tertiary amine (14′).
EXAMPLE C1
N,N-diisobutyl-1-[3-(neopentylamino)propyl]-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-6-carboxamide dihydrochloride




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

A current of dry HCl is passed through a solution of tert-butyl 3-{6-[(diisobutylamino)carbonyl]-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazol-1-yl}propylcarbamate (350 mg; prepared according to diagram A) in ethyl acetate (30 ml), cooled down to 0° C., until TLC (eluent: 100% ethyl acetate) shows the total disappearance of the starting product. The mixture is then concentrated under reduced pressure at 40° C. The solid obtained is triturated in ethyl ether then filtered, washed with dichloromethane and dried. The dihydrochloride obtained is taken up in dichloromethane and water saturated with sodium hydrogen carbonate. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. in order to produce 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 0.82 (m, 12H), 1.87 (m, 4H), 2.58 (m, 2H), 3.21 (m, 4H), 3.62 (s, 3H), 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: N,N-diisobutyl-1-[3-(neopentylamino)propyl]-2-[(3,4,5-trimethoxyphenyl) amino]-1H-benzimidazole-6-carboxamide dihydrochloride
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 sodium triacetoxyborohydride is added (41 mg, 2 eq). After 1 hour at a temperature of approximately 20° C., dichloromethane (20 ml) and water saturated with sodium hydrogen carbonate (10 ml) are added to the mixture. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then 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 base. The corresponding hydrochloride salt is formed by adding a 1N solution of hydrochloric acid in ether. The precipitate obtained is filtered and dried in order to produce 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 0.67 (m, 6H), 0.95 (m, 6H), 0.99 (s, 9H), 1.82 (m, 1H), 2.06 (m, 1H), 2.27 (m, 2H), 2.71 (m, 2H), 3.10 (m, 4H), 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).
Preparation According to Reaction Diagram C′:
The compounds (14) for which s=3 can also be prepared according to the following diagram C′:




As described in diagram C′, the derivative (15) prepared according to reaction diagram A can be treated either with an organic acid such as pyridinium tosylate or paratoluenesulphonic acid in an aprotic solvent such as acetone in the presence of water, at a temperature of 20-70° C. for 2 to 12 hours, or by an inorganic acid such as aqueous hydrogen chloride in an aprotic solvent such as tetrahydrofuran at a temperature of 0-20° C. for 6 to 18 hours in order to produce compound (16). The aldehyde (16) can then be treated with an amine in a protic or aprotic solvent such as dichloromethane, tetrahydrofuran or methanol for 1 to 18 hours at a temperature of 20° C. The resultant imine is then reduced in situ by a reducing agent, preferably sodium triacetoxyborohydride or sodium cyanoborohydride, in the presence or absence of an acid such as acetic acid, at a temperature of 20-50° C. for a duration of 0.2 to 6 hours, in order to produce compound (17). The secondary amine (17) can optionally undergo a second reducing amination under the same operating conditions as those described previously in order to produce the tertiary amine (17′).
EXAMPLE C1′
2-[(4-acetylphenyl)amino]-1-{3-[cyclohexylmethyl amino]propyl}-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamide dihydrochloride




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

A mixture of 3-fluoro-N,N-bis(3-methylbutyl)-4-nitrobenzamide prepared according to Example A1 (1.86 g, 1 eq), 2-(2-aminoethyl)-1,3-dioxolane (0.8 g, 1.2 eq) and potassium carbonate (1.58 g, 2 eq) in acetonitrile (150 ml) is heated under reflux for 3 hours then concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (150 ml) and water (60 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated 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) produces 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 0.68 (d, 6H), 0.92 (d, 6H), 1.31-1.50 (m, 5H), 1.61 (m, 1H), 1.97 (m, 2H), 3.10 (m, 2H), 3.37-3.48 (m, 4H), 3.80 (m, 2H), 3.91 (m, 2H), 4.94 (t, 1H), 6.55 (d, 1H), 6.89 (s, 1H), 8.10 (d, 1H), 8.39 (t, 1H).
Stage 2: 4-amino-3-{[2-(1,3-dioxolan-2-yl)ethyl]amino}-N,N-bis(3-methylbutyl) benzamide
3-{[2-(1,3-dioxolan-2-yl)ethyl]amino}-N,N-bis(3-methylbutyl)-4-nitrobenzamide (2.4 g) in solution in a mixture of ethyl acetate/methanol 2:1 (100 ml), and 10% palladium on carbon (240 mg) are introduced into an autoclave. After stirring for 4 hours under a hydrogen atmosphere (3 bar) at a temperature of approximately 20° C., the catalyst is eliminated by filtration on celite and the filtrate is concentrated under reduced pressure at 40° C. in order to produce the expected compound in the form of an oil (2.02 g; 89% yield).
MS/LC: calculated MM=391.5; m/z=392.2 (MH+) NMR (1H, 400 MHz, DMSO-d6): δ 0.80 (m, 12H), 1.40 (m, 6H), 1.90 (m, 2H), 3.10 (m, 2H), 3.29 (m, 4H), 3.77 (m, 2H), 3.90 (m, 2H), 4.54 (m, 1H), 4.78 (s, 2H), 4.93 (t, 1H), 6.36-6.52 (m, 1H).
Stage 3: 2-[(4-acetylphenyl)amino]-1-[2-(1,3-dioxolan-2-yl)ethyl]-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamide
4-acetylphenyl isothiocyanate (1.1 g, 1.2 eq) and diisopropylcarbodiimide (1.95 g, 3 eq) are successively added to a solution of 4-amino-3-{[2-(1,3-dioxolan-2-yl)ethyl]amino}-N,N-bis(3-methylbutyl)benzamide (2 g, 1 eq) in tetrahydrofuran (50 ml). The mixture is heated under reflux for 18 hours then cooled down to ambient temperature and concentrated under reduced pressure at 40° C. Water (100 ml) and dichloromethane (200 ml) are added to the residue obtained. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: heptane/ethyl acetate 4:6) produces the expected compound in the form of 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 0.80 (m, 12H), 1.44 (m, 6H), 2.01 (m, 2H), 2.52 (s, 3H), 3.30 (t, 4H), 3.72 (t, 2H), 3.85 (m, 2H), 4.39 (t, 2H), 4.83 (t, 1H), 7.05 (AB, 1H), 7.30 (s, 1H), 7.44 (AB, 1H), 7.96 (s, 4H), 9.37 (s, 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-dioxolan-2-yl)ethyl]-N,N-bis(3-methylbutyl)-1H-benzimidazole-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 extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. in order to produce 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 0.68-0.99 (m, 12H), 1.35 (m, 6H), 2.39 (m, 2H), 2.64 (s, 3H), 3.10-3.49 (m, 4H), 3.72 (n, 2H), 4.15 (m, 1H), 4.50 (m, 1H), 5.54 (s, 1H), 7.27 (AB, 1H), 7.39 (AB, 1H), 7.64 (s, 1H), 7.82 (AB, 1H), 8.15 (AB, 1H).
Stage 5: 2-[(4-acetylphenyl)amino]-1-{3-[(cyclohexylmethyl)amino]propyl}-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamide dihydrochloride
A solution of 2-[(4-acetylphenyl)amino]-N,N-bis(3-methylbutyl)-1-(3-oxopropyl)-1H-benzimidazole-6-carboxamide (100 mg, 1 eq) and aminomethylcyclohexane (46 mg, 2 eq) is stirred for 4 hours at a temperature of approximately 20° C. The mixture is diluted with methanol (1 ml), then sodium triacetoxyborohydride (86 mg, 2 eq) and a few drops of acetic acid are added to produce a pH of 5. After 1 hour at a temperature of approximately 20° C., dichloromethane (20 ml) and water saturated with sodium hydrogen carbonate (10 ml) are added to the mixture. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then 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 base. The corresponding hydrochloride salt is formed by adding a 1N solution of hydrochloric acid in ether. The precipitate obtained is filtered and dried in order to produce 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 0.68-0.99 (m, 14H), 1.19 (m, 3H), 1.29-1.82 (m, 12H), 2.59 (s, 3H), 2.73 (m, 2H), 3.07 (t, 2H), 3.21 (m, 2H), 3.43 (m, 2H), 4.64 (t, 2H), 7.24 (AB, 1H), 7.47 (AB, 1H), 7.37 (s, 1H), 7.84 (d, 2H), 8.06 (d, 2H), 8.89 (m, 2H), 11.42 (m, 1H).
According to reaction diagram C or C′ and in a fashion analogous to the procedure described for the synthesis of N,N-diisobutyl-1-[3-(neopentylamino)propyl]-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-6-carboxamide dihydrochloride or 2-[(4-acetylphenyl)amino]-1-{3-[(cyclohexylmethyl)amino]propyl}-N,N-bis(3-methyl butyl)-1H-benzimidazole-6-carboxamide dihydrochloride, the following compounds were prepared:




in which R3 represents one of the radicals below:





and R4 represents one of the radicals below:











D. Preparation According to the Reaction Diagram D:





As described in diagram D, the derivative (18) prepared according to reaction diagram A, can be saponified in the presence of an inorganic base such as lithium hydroxide dihydrate in a mixture of polar solvents such as water and tetrahydrofuran at a temperature of 20 to 70° C. for 3 to 17 hours. The resultant carboxylic acid (19) can be coupled with a primary or secondary amine in the presence of a coupling agent such as diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) or carbonyldiimidazole (CDI), with or without 1-hydroxybenzotriazole (HOBt) in an inert organic solvent such as methylene chloride, tetrahydrofuran or dimethylformamide at ambient temperature for 3 to 24 hours in order to produce compound (20).
EXAMPLE D1
1-(3-aminopropyl)-2-({4-[(methylamino)carbonyl]phenyl}amino)-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamide dihydrochloride




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

Lithium hydroxide (141 mg, 5 eq) is added to methyl 4-[(6-{[bis(3-methylbutyl)amino]carbonyl}-1-{3-[(tert-butoxycarbonyl)amino]propyl}-1H-benzimidazol-2-yl)amino]benzoate prepared according to reaction diagram A, Example A1, (405 mg, 1 eq) in a mixture of tetrahydrofuran (4 ml) and water (3 ml). The mixture is heated under reflux for 18 hours then cooled down to ambient temperature and concentrated under reduced pressure at 40° C. Dichloromethane (50 ml) and water (20′ ml) are added to the residue. The mixture is acidified by the addition of acetic acid to pH 5. After decantation and extractions, the combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The solid obtained is taken up in ethyl ether in order to produce the expected compound (309 mg; 79%).
MS/LC: calculated MM=593.8; m/z=594.3 (MH+) NMR (1H, 400 MHz, DMSO-d6): 0.77 (m, 12H), 1.22-1.55 (m, 6H), 1.36 (s, 9H), 1.83 (m, 2H), 3.03 (m, 2H), 3.33 (m, 4H), 4.28 (m, 2H), 6.95-7.90 (m, 8H), 9.24 (s, 1H).
Stage 2: 1-(3-aminopropyl)-2-({4-[(methylamino)carbonyl]phenyl}amino)-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamide dihydrochloride
A solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (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-benzimidazol-2-yl)amino]benzoic acid (50 mg, 1 eq) in anhydrous tetrahydrofuran (1 ml). The mixture is stirred for 1 hour at a temperature of approximately 20° C. then the methylamine is added (2M in THF; 0.86 ml, 2 eq). After stirring for 17 hours at a temperature of approximately 20° C., the mixture is diluted with dichloromethane (3 ml) followed by the addition of aminomethylpolystyrene resin (2 eq), TBD-methyl polystyrene resin (2 eq) and methylisothiocyanate-polystyrene resin (4 eq). After stirring for 6 hours at approximately 20° C., the mixture is filtered and the filtrate is concentrated under reduced pressure at 40° C. The residue obtained is dissolved in dichloromethane (3 ml) and washed with a saturated aqueous solution of sodium hydrogen carbonate. The organic phase is dried over sodium sulphate and concentrated at a temperature of approximately 40° C. The residue obtained is dissolved in ethyl acetate (0.5 ml) and a solution of hydrochloric acid (4N in dioxane, 2 ml) is added. After stirring for 1 hour a temperature of approximately 20° C., the precipitate obtained is filtered and dried in order to produce 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), 1.46 (m, 6H), 2.0 (m, 2H), 2.77 (d, 3H), 2.89 (m, 2H), 3.33 (m, 4H), 4.45 (m, 2H), 7.07 (d, 1H), 7.43 (d, 1H), 7.48 (s, 1H), 7.84 (m, 5H), 7.97 (m, 2H), 8.28 (m, 2H), 9.49 (m, 1H).
According to reaction diagram D and in a fashion analogous to the procedure described for the synthesis of 1-(3-aminopropyl)-2-({4-[(methylamino)carbonyl]phenyl}amino)-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamide dihydrochloride, the following compounds were prepared




in which R3 represents one of the radicals below:





E. Preparation According to Reaction Diagram E:





As described in diagram E, the derivative (21) prepared according to reaction diagram A, can be reduced by treatment with tin chloride dihydrate 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 carbon in an inert solvent such as methanol, ethanol, ethyl acetate or a mixture of these solvents, at a temperature of 18-25° C., for 2 to 8 hours, in order to produce aniline (22). Compound 23 can be treated with an isocyanate in an aprotic solvent such as dichloromethane or tetrahydrofuran at a temperature of 20-60° C. for 2 to 24 hours or alternatively with carbonyldiimidazole (CDI) in an aprotic solvent such as dichloromethane or tetrahydrofuran at a temperature of 0-60° C. for 6 to 24 hours, followed by a primary amine at a temperature of 20-60° C. for 2 to 24 hours, in order to produce the urea (23).
EXAMPLE E1
1-(3-aminopropyl)-2-[(4-{[(methylamino)carbonyl]amino}phenyl)amino]-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamide




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

4-nitrophenyl isothiocyanate (305 mg, 1.5 eq) and N-methylcyclohexylcarbodiimide-N-methyl-polystyrene resin (acquired from Novabiochem; charge 1.9 mmol/g; 1.75 g, 3 eq) are successively added to a solution of tert-butyl-3-[(2-amino-5-{[bis(3-methylbutyl)amino]carbonyl}phenyl)amino]propylcarbamate prepared according to Example A1 (500 mg, 1 eq) in tetrahydrofuran (30 ml). The mixture is heated under reflux for 18 hours then cooled down to ambient temperature and filtered on 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 0.64-0.95 (m, 12H), 1.36 (s, 9H), 1.31-1.65 (m, 6H), 1.82 (m, 2H), 3.0 (m, 2H), 3.15-3.39 (m, 4H), 4.32 (t, 2H), 6.95 (m, 1H), 7.05 (d, 1H), 7.40 (s, 1H), 7.48 (d, 1H), 8.11 (AB, 2H), 8.26 (AB, 2H), 9.71 (s, 1H).
Stage 2: tert-butyl 3-(2-[(4-aminophenyl)amino]-6-{[bis(3-methylbutyl)amino]carbonyl}-1H-benzimidazol-1-yl)propylcarbamate
Tert-butyl 3-{6-{[bis(3-methylbutyl)amino]carbonyl}-2-[(4-nitrophenyl)amino]-1H-benzimidazol-1-yl}propylcarbamate (580 mg) in solution in a mixture of ethyl acetate/methanol 3:1 (40 ml), and 10% palladium on carbon (58 mg) are introduced into an autoclave. After stirring for 15 hours under a hydrogen atmosphere (3 bar) at a temperature of approximately 20° C., the catalyst is eliminated by filtration on celite and the filtrate is concentrated under reduced pressure at 40° C. in order to produce the expected compound in the form of a 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), 1.37 (s, 9H), 1.31-1.58 (m, 6H), 1.79 (m, 2H), 3.01 (m, 2H), 3.15-3.39 (m, 4H), 4.15 (t, 2H), 4.80 (m, 2H), 6.56 (m, 2H), 6.94 (d, 2H), 7.21 (AB, 2H), 7.40 (AB, 2H), 8.45 (s, 1H)
Stage 3: tert-butyl 3-{6-{[bis(3-methylbutyl)amino]carbonyl}-2-[(4-{[(methylamino)carbonyl]amino}phenyl)amino]-1H-benzimidazol-1-yl}propyl carbamate dihydrochloride
A solution of 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-benzimidazol-1-yl)propylcarbamate (50 mg, 1 eq) in dichloromethane (2 ml). The mixture is stirred for 18 hours at a temperature of approximately 20° C. then methylamine is added (2M in THF, 0.440 ml, 10 eq). The mixture is stirred for 4 hours at a temperature of approximately 20° C. then concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (7 ml) and a saturated aqueous solution of sodium hydrogen carbonate (3 ml). After decantation and extractions the combined organic phases are washed with salt water then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: heptane/ethyl acetate 1:1 to 1:9) produces a compound in the form of foam which is dissolved in ethyl acetate (0.5 ml). A solution of hydrochloric acid (2N in diethyl ether, 2 ml) is added and the mixture is stirred for 1 hour at a temperature of approximately 20° C. then the precipitate obtained is filtered and dried in order to produce the expected compound (28 mg, 55% yield).
MS/LC: calculated MM=521.7; m/z=522.3 (MH+)
According to reaction diagram E and in a fashion analogous to the procedure described for the synthesis of tert-butyl 3-{6-{[bis(3-methylbutyl)amino]carbonyl}-2-[(4-{[(methylamino)carbonyl]amino}phenyl)amino]-1H-benzimidazol-1-yl}propyl carbamate dihydrochloride, the following compounds were prepared:




in which R3 represents one of the radicals below:





and R4 represents one of the radicals below:





F. Preparation According to Reaction Diagram F:

The compounds of formula (I) according to the invention in which A represents —CH2—, can be prepared according to the following diagrams F and F′:




As described in diagram F, the derivative (4) prepared according to reaction diagram A, can be reduced to compound (24) using borane or lithium aluminium hydride in an aprotic solvent such as tetrahydrofuran or diethyl ether at a temperature of 0 to 70° C., for 18 to 24 hours. The dianiline (24) can then be treated by an isothiocyanate in the presence of a coupling agent supported or not supported on a resin such as diisopropylcarbodiimide or dicyclohexylcarbodiimide or N-methylcyclohexylcarbodiimide N-methyl polystyrene resin in an inert solvent such as tetrahydrofuran, methylene chloride, or chloroform at a temperature of 20-70° C. for 2 to 72 hours in order to produce derivative (25).
Preparation According to Reaction Diagram F′:
The compounds (25) can also be prepared according to the following diagram F′:




As described in diagram F′, the amide (6) prepared according to reaction diagrams A or B, can be reduced to the corresponding amine (25) using borane or lithium aluminium 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
6-{[bis(3-methylbutyl)amino]methyl}-1-[3-(dimethylamino)propyl]-N-(4-methoxyphenyl)-1H-benzimidazol-2-amine hydrochloride




A solution of lithium aluminium hydride (0.785 ml; 1 M in THF) is added dropwise to a solution cooled down to 0° C. of 1-[3-(dimethylamino)propyl]-2-[(4-methoxyphenyl) amino]-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamide prepared according to reaction diagram A (80 mg, 1 eq) in anhydrous tetrahydrofuran (2 ml). The mixture is taken to a temperature of 20° C. then heated at 60° C. for 3 hours. After cooling down to 0° C., the reaction medium is hydrolyzed. After the addition of ethyl acetate, decantation and extractions, the combined organic phases are washed with salt water, dried over sodium sulphate and concentrated 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 base. The corresponding hydrochloride salt is formed by adding a 1N solution of hydrochloric acid 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 0.83 (m, 12H), 1.50-1.72 (m, 6H), 2.29 (m, 2H), 2.78 (m, 6H), 2.99 (m, 4H), 3.30 (m, 2H), 3.80 (s, 3H), 4.41 (m, 4H), 6.90-8.50 (m, 7H), 10.5 (m, 1H), 10.85 (m, 1H), 12.9 (m, 1H).
The following compounds were prepared according to reaction diagrams F or F′:




in which R1R2N represents one of the radicals below:





in which R3 represents one of the radicals below:





and R4 represents one of the radicals below:





G. Preparation According to Reaction Diagram G:

The compounds of formula (I) according to the invention in which A represents —C(O)—C(Ra)(Rb)—, can be prepared according to the following diagram G:




As described in diagram G, the derivative (26) can be alkylated in the presence of a strong base such as potassium tertbutylate, by an α-chloroester derivative, in an aprotic polar solvent such as dimethylformamide at a temperature of 0-20° C. for 0.5-2 hours, in order to produce compound (27). The derivative (27) can be optionally alkylated in the presence of a strong base such as sodium hydride and an alkylating agent such as an alkyl iodide in an aprotic solvent such as dimethylformamide at a temperature of 0-20° C. for 1-4 hours, in order to produce compound (28). The ester (28) can be saponified in the presence of an inorganic base such as lithium 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 resultant carboxylic acid (29) can be coupled with a primary or secondary amine in the presence of a coupling agent such as diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) or carbonyldiimidazole (CDI), with or without 1-hydroxybenzotriazole (HOBt) in an inert organic solvent such as methylene chloride, tetrahydrofuran or dimethylformamide at ambient temperature for 3 to 24 hours. Alternatively the acid (29) can be treated with thionyl or oxalyl chloride in an aprotic solvent such as dichloromethane or toluene at a temperature of 40-60° C. for 2-16 hours then the acid chloride thus obtained 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. over 0.5-4 hours in order to produce the amide (30). Treatment of the fluorinated or chlorinated derivative (30) with a primary amine in the presence of an inorganic base such as caesium or potassium carbonate in an inert organic solvent such as dimethylformamide or acetonitrile at a temperature of 20-100° C. for 2 to 48 hours leads to the derivative (31). The nitro function of compound (31) is reduced by treatment with tin chloride dihydrate 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 carbon in an inert solvent such as methanol, ethanol, ethyl acetate or a mixture of these solvents, at a temperature of 18-25° C., for 2 to 8 hours in order to produce the dianiline (32). The derivative (32) is then treated with an isothiocyanate in the presence of a coupling agent supported or not supported on a resin such as diisopropylcarbodiimide or dicyclohexylcarbodiimide or N-methylcyclohexylcarbodiimide N-methyl polystyrene resin in an inert solvent such as tetrahydrofuran, methylene chloride, or chloroform at a temperature of 20-70° C. for 2 to 72 hours in order to produce the derivative (33). Alternatively, the derivative (32) can be treated with an isothiocyanate 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 resultant thiourea can be treated with methyl iodide or yellow mercury (II) oxide in the presence of a catalytic quantity of sulphur in a polar solvent such as methanol or ethanol for 2 to 24 hours at a temperature of 20-80° C. in order to produce (33). Compound (6) can be isolated either by flash chromatography on silica gel, or by the addition to the reaction mixture of a nucleophilic reagent supported on a polymer such as for example an aminomethylpolystyrene resin and/or an electrophilic reagent supported on a polymer such as for example methylisothiocyanate-polystyrene resin, followed by filtration and evaporation of the filtrate.
EXAMPLE G1
2-{2-[(4-acetylphenyl)amino]-1-[3-(dimethylamino)propyl]-1H-benzimidazol-6-yl}-N,N-diisobutyl-2-methylpropanamide dihydrochloride




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

Potassium tert-butylate (11.22 g, 2 eq) is added to a solution of DMF (80 ml) cooled down to 0° C. A solution of 1-chloro-2-nitrobenzene (7.87 g, 1 eq) and ethyl 2-chloropropanoate (7 ml, 1.1 eq) is added dropwise over 45 minutes to the mixture whilst keeping the reaction temperature below 5° C. At the end of the addition, stirring is maintained for 2 hours at 0° C., then the mixture is hydrolyzed at this temperature with a 1N solution of hydrochloric acid and ethyl acetate is added. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluent: heptane/dichloromethane 8:2 to 6:4) produces the expected compound in the form of a yellow oil (8.28 g; 64% yield).
NMR (1H, 400 MHz, DMSO-d6): δ 1.14 (t, 3H), 1.42 (d, 3H), 3.99 (q, 1H), 4.08 (m, 2H), 7.52 (AB, 1H), 7.71 (s, 1H), 8.05 (AB, 1H).
Stage 2: ethyl 2-(3-chloro-4-nitrophenyl)-2-methylpropanoate
A solution of ethyl 2-(3-chloro-4-nitrophenyl)propanoate (14.1 g) is added dropwise to a suspension of sodium hydride (60% in oil, 2.4 g, 1.1 eq) in DMF (15 ml), cooled down to 0° C. After stirring for 1 hour at this temperature, a solution of methyl iodide (3.72 ml, 1.1 eq) in DMF (40 ml) is added dropwise to the mixture. Stirring is continued for 3 hours at ambient temperature. The reaction medium is cooled down to 0° C. then ethyl acetate, water saturated with sodium hydrogen carbonate are added dropwise, then water. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 and concentrated under reduced pressure in order to produce the expected compound in the form of an oil which crystallizes. The crystals are washed with heptane and dried (13.8 g; 94% yield).
NMR (1H, 400 MHz, DMSO-d6): δ 1.12 (t, 3H), 1.54 (s, 6H), 4.09 (q, 1H), 7.50 (AB, 1H), 7.66 (s, 1H), 8.04 (AB, 1H).
Stage 3: 2-(3-chloro-4-nitrophenyl)-2-methylpropanoic acid
A 2N solution of potassium hydroxide (18 ml) is added at a temperature of approximately 20° C. to a solution of ethyl 2-(3-chloro-4-nitrophenyl)-2-methylpropanoate (1 g) in methanol (20 ml). The mixture is then heated at 80° C. for 1.5 hours then cooled down to ambient temperature. The methanol is evaporated by concentration of the mixture under reduced pressure. The remaining aqueous phase is washed with dichloromethane then cooled down to 0° C. and acidified with acetic acid. After the addition of dichloromethane, decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 and concentrated under reduced pressure in order to produce the expected compound in the form of an oil which crystallizes (852 mg, 95% yield).
NMR (1H, 400 MHz, DMSO-d6): δ 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) is added to a solution of 2-(3-chloro-4-nitrophenyl)-2-methylpropanoic acid (500 mg) in dichloromethane (1 ml). The mixture is heated under reflux for 16 hours then cooled down to ambient temperature. The solvent is evaporated off under reduced pressure at 40° C. (co-evaporation with toluene). Diisopropylethylamine (0.42 ml, 1.2 eq) and diisobutylamine (0.36 ml, 1 eq) are successively added to a solution of the acid chloride thus obtained in dichloromethane (1 ml), cooled down to 0° C. At the end of the addition, stirring is continued for 3 hours at ambient temperature then the mixture is concentrated under reduced pressure at 40° C. The residue is dissolved in ethyl ether and the organic phase is washed successively with 1N soda, a saturated solution of sodium hydrogen carbonate, salt water then dried over Na2SO4 and concentrated under reduced pressure at 40° C. Purification by flash chromatography on silica gel (eluent: heptane/ethyl acetate 8:2 to 7:3) produces 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), 0.90 (d, 6H), 1.58 (m, 6H), 1.74 (m, 1H), 1.95 (m, 1H), 2.65 (d, 2H), 3.27 (d, 2H), 7.30 (AB, 1H), 7.44 (s, 1H), 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) is heated under reflux for 3 hours then cooled down to ambient temperature. The residue is taken up in ethyl acetate (20 ml) and water (8 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/methanol 8:2) produces the expected compound in the form of a yellow oil (44 mg; 48% yield).
MS/LC: calculated MM=420.6; m/z=421.3 (MH+) NMR (1H, 400 MHz, CDCl3): δ 0.60 (d, 6H), 0.90 (d, 6H), 1.57 (m, 6H), 1.75 (m, 1H), 1.88 (m, 2H), 1.97 (m, 1H), 2.28 (s, 6H), 2.45 (t, 1H), 2.75 (d, 2H), 3.26 (d, 2H), 3.34 (m, 2H), 6.57 (m, 1H), 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 carbon (5 mg) are introduced into an autoclave. After stirring for 4 hours under a hydrogen atmosphere (3 bar) at a temperature of approximately 20° C., the catalyst is eliminated by filtration on celite and the filtrate is concentrated under reduced pressure at 40° C. in order to produce the expected compound in the form of an 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), 1.36 (s, 6H), 1.65 (m, 1H), 1.72 (m, 2H), 1.87 (m, 1H), 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 (AB, 1H), 6.48 (AB, 1H).
Stage 7: 2-{2-[(4-acetylphenyl)amino]-1-[3-(dimethylamino)propyl]-1H-benzimidazol-6-yl}-N,N-diisobutyl-2-methylpropanamide dihydrochloride
4-acetylphenyl isothiocyanate (14 mg, 1.2 eq) and N-methylcyclohexylcarbodiimide-N-methyl-polystyrene resin (acquired from Novabiochem; charge 1.9 mmol/g; 210 mg, 4 eq) are successively added to a solution of 2-(4-amino-3-{[3-(dimethylamino)propyl]amino}phenyl)-N,N-diisobutyl-2-methylpropanamide (39 mg, 1 eq) in tetrahydrofuran (2 ml). The mixture is heated under reflux for 17 hours then cooled down 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 form of a base (409 mg; 60% yield). The corresponding hydrochloride salt is formed by adding a 1N solution of hydrochloric acid in ether. The precipitate obtained is filtered and dried in order to produce 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 0.40 (m, 6H), 0.82 (m, 6H), 1.53 (s, 6H), 1.64 (m, 1H), 1.89 (m, 1H), 2.21 (m, 2H), 2.59 (s, 3H), 2.75 (m, 8H), 3.15 (m, 2H), 3.25 (m, 2H), 4.60 (t, 2H), 7.10 (AB, 1H), 7.41 (AB, 1H), 7.56 (s, 1H), 7.82 (m, 2H), 8.05 (m, 2H), 10.79 (m, 1H), 11.4 (m, 1H).
According to reaction diagram G, the following compounds were prepared:




in which R1R2N represents one of the radicals below:





R3 represents one of the radicals below:





and R4 represents one of the radicals below:





A subject of the invention is also a process for the preparation of a compound of formula (I) as defined above, characterized, in that the compound of general formula:




in which A, X, R1, R2, R4 have the meaning indicated above, is treated with an isothiocyanate of general formula R3N═C═S in which R3 has the meaning indicated above, in the presence of a coupling agent or of yellow mercury (II) oxide in the presence of sulphur, for a period of 3 to 48 hours, in a protic or aprotic solvent, at a temperature of 50 to 80° C.

The coupling agent can be supported such as N-methylcyclohexyl carbodiimide N-methyl polystyrene resin or not supported such as diisopropylcarbodiimide, diethylcarbodiimide or dicyclohexylcarbodiimide. A protic solvent such as methanol or ethanol or an aprotic solvent such as tetrahydrofuran or acetonitrile can be used.
A subject of the invention is also a compound of general formula (II)




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

    A represents —CH2—, —C(O)—, —C(O)—C(Ra)(Rb)—;
    X represents —C— or —N—;
    Ra and Rb represent, independently, the hydrogen atom or a (C1-C6)alkyl radical;
    R1 and R2 represent, independently, the hydrogen atom, a (C1-C8)alkyl radical optionally substituted by hydroxy, (C2-C6)alkenyl or a radical of formula —(CH2)n—X1;
    X1 represents (C1-C6)alkoxy, (C3-C7)cycloalkyl, adamantyl, heterocycloalkyl, aryl or heteroaryl,
    
        the (C3-C7)cycloalkyl, heterocycloalkyl, aryl and heteroaryl radicals being optionally substituted by one or more identical or different substituents chosen from: —(CH2)n′—V1—Y1, halo, nitro and cyano;
        V1 represents —O—, —S— or a covalent bond;
        Y1 represents a (C1-C6)alkyl radical optionally substituted by one or more identical or different halo radicals; or aryl;
        n represents an integer from 0 to 6 and n′ an integer from 0 to 2 (it being understood that when n is equal to 0, then X1 represents neither the hydroxy radical nor the alkoxy radical);
    
    
    or R1 and R2 form together with the nitrogen atom to which they are attached, a heterobicycloalkyl or a heterocycloalkyl optionally substituted by one or more identical or different substituents chosen from: hydroxy, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy-carbonyl, —C(O)NV1′Y11 with V1 and Y1′ independently representing the hydrogen atom or a (C1-C6)alkyl, and heterocycloalkyl; or R1 and R2 form together a radical of formula:






    R3 represents —(CH2)p-Z3 or —C(O)-Z′3 
    
        Z3 represents a (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C1-C6)alkoxy-carbonyl, (C3-C7)cycloalkyl, heterocycloalkyl, aryl or heteroaryl radical,
        the (C3-C7)cycloalkyl and heterocycloalkyl radicals being optionally substituted by (C1-C6)alkyl,
        the aryl radical being optionally substituted by one or more identical or different substituents chosen from: halo, nitro, azido or —(CH2)p′—V3—Y3;
        V3 represents —O—, —S—, —C(O)—, —C(O)—O—, —NH—C(O)—, —C(O)—NR′3—, —NH—C(O)—NR′3— or a covalent bond;
        Y3 represents the hydrogen atom or a (C1-C6)alkyl radical optionally substituted by one or more identical or different halo radicals;
        or Z3 represents a radical of formula
    
    






    
    
        Z′3 represents an aryl radical optionally substituted by one or more identical or different substituents chosen from: halo, nitro and —(CH2)p′′—V′3—Y′3;
        V′3 represents —O—, —C(O)—, —C(O)—O—, —C(O)—NR′3—, —NH—C(O)—, —NH—C(O)—NR′3— or a covalent bond;
        Y′3 represents the hydrogen atom or a (C1-C6)alkyl radical optionally substituted by one or more identical or different halo radicals;
        R′3 represents the hydrogen atom, a (C1-C6)alkyl or (C1-C6)alkoxy radical;
        p, p′ and p′′ represent, independently, an integer from 0 to 4;
    
    
    R4 represents a radical of formula —(CH2)s—R′4 
    R′4 represents a heterocycloalkyl containing at least one nitrogen atom and optionally substituted by (C1-C6)alkyl or aralkyl; a heteroaryl containing at least one nitrogen atom and optionally substituted by (C1-C6)alkyl; or a radical of formula —NW4W′4 
    
        W4 represents the hydrogen atom or (C1-C8)alkyl;
        W′4 represents a radical of formula —(CH2)s′-Z4;
        Z4 represents the hydrogen atom, (C1-C8)alkyl optionally substituted by one or more identical or different substituents chosen 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)alkyl substituents; cyclohexene; heteroaryl; aryl optionally substituted by one or more identical or different radicals chosen from: —(CH2)s′′—V4—Y4, hydroxy, halo, nitro and cyano;
        
            V4 represents —O—, —S—, —NH—C(O)—, —NV4′— or a covalent bond;
            Y4 represents a hydrogen atom or a (C1-C6)alkyl radical optionally substituted by one or more identical or different halo radicals;
            V4′ represents a hydrogen atom or a (C1-C6)alkyl;
            s′′ represents an integer from 0 to 4;
        
        
        or Z4 represents a radical of formula
    
    






    
    
        s and s′ represent, independently, an integer from 0 to 6;
    
    
    and when R3 represents —C(O)-Z′3 and R4 represents a radical of formula —(CH2)s—NW4W′4 and W4 and W′4 represent, independently, the hydrogen atom or the (C1-C6)alkyl radical, then —(CH2)s represents neither the ethylene radical nor the —(CH2)—CH((C1-C4)alkyl)- radical;


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

    A represents —C(O)— and X represents —C—;
    R1 and R2 represent, independently, a hydrogen atom, a (C1-C8)alkyl radical optionally substituted by hydroxy, (C2-C6)alkenyl or a radical of formula —(CH2)n—X1;
    X1 represents (C1-C6)alkoxy, (C3-C7)cycloalkyl, aryl or heteroaryl,
    
        the aryl radical being optionally substituted by one or more identical or different substituents chosen from: —(CH2)n′—V1—Y1, halo;
        V1 represents —O— or a covalent bond;
        Y1 represents a (C1-C6)alkyl radical optionally substituted by one or more identical or different halo radicals; or aryl;
    
    
    or R1 and R2 form together with the nitrogen atom to which they are attached, a heterocycloalkyl optionally substituted by one or more identical or different substituents chosen from: hydroxy, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy-carbonyl, —C(O)NV1′Y1′ with V1′ and Y1′ independently representing the hydrogen atom or a (C1-C6)alkyl, and heterocycloalkyl; or R1 and R2 form together a radical of formula:






    R3 represents —(CH2)p-Z3 or —C(O)-Z′3 
    
        Z3 represents a (C1-C6)alkoxy-carbonyl, (C3-C7)cycloalkyl, heteroaryl, or aryl radical optionally substituted by one or more identical or different substituents chosen from: halo, nitro or —(CH2)p′—V3—Y3;
        V3 represents —O—, —S—, —C(O)—, —C(O)—O—, —C(O)—NR′3—, —NH—C(O)—, —NH—C(O)—NR′3— or a covalent bond;
        Y3 represents the hydrogen atom or a (C1-C6)alkyl radical optionally substituted by one or more identical or different halo radicals;
        or Z3 represents a radical of formula
    
    






    
    
        Z′3 represents an aryl radical optionally substituted by one or more identical or different substituents chosen from: halo, nitro and —(CH2)p′′—V′3—Y′3;
        V′3 represents —O— or a covalent bond;
        Y′3 represents the hydrogen atom or a (C1-C6)alkyl radical optionally substituted by one or more identical or different halo radicals;
        R′3 represents the hydrogen atom, a (C1-C6)alkyl or (C1-C6)alkoxy radical;
        p is equal to 0 or 1, and p′ and p′′ are equal to 0;
    
    
    R4 represents a radical of formula —(CH2)s—R′4 
    
        R′4 represents a heterocycloalkyl containing at least one nitrogen atom and optionally substituted by (C1-C6)alkyl or benzyl; a heteroaryl containing at least one nitrogen atom; or a radical of formula —NW4W′4;
        W4 represents the hydrogen atom or (C1-C8)alkyl;
        W′4 represents a radical of formula —(CH2)s′-Z4;
        Z4 represents the hydrogen atom, (C1-C8)alkyl, (C3-C7)cycloalkyl or aryl;

and more particularly

    
    
    the cycloalkyl radical is chosen from the cyclopropyl, cyclohexyl and cycloheptyl radicals,
    the heterocycloalkyl radical is chosen from the pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azacycloheptyl, azacyclooctyl and decahydro-isoquinolinyl radicals,
    the aryl radical is the phenyl radical,
    the heteroaryl radical is chosen from the furyl, pyridyl and imidazolyl radicals,

or a pharmaceutically acceptable salt thereof.



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

    A represents —C(O)— and X represents —C—;
    R1 and R2 represent, independently, a (C1-C8)alkyl radical;
    R3 represents —(CH2)p-Z3 
    
        Z3 represents a phenyl radical optionally substituted by one or more identical or different substituents chosen from: nitro or —(CH2)p′—V3—Y3;
        V3 represents —O—, —C(O)—, —C(O)—O—, —C(O)—NR′3—, NH—C(O)—, —NH—C(O)—NR′3—;
        Y3 represents the hydrogen atom or a (C1-C6)alkyl radical;
        R′3 represents the hydrogen atom or a (C1-C6)alkoxy radical;
        p is equal to 0 or 1; p′ is equal to 0;
    
    
    R4 represents a radical of formula —(CH2)s—R′4 
    R′4 represents a heterocycloalkyl containing at least one nitrogen atom and optionally substituted by (C1-C6)alkyl; or a radical of formula —NW4W′4;
    
        W4 represents the hydrogen atom or (C1-C8)alkyl;
        W′4 represents a radical of formula —(CH2)s′-Z4;
        Z4 represents the hydrogen atom or (C3-C7)cycloalkyl;
        s represents an integer from 2 to 4; s′ represents an integer from 0 to 4;
    
    
    and more particularly the heterocycloalkyl radical represented by R′4 is the pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl radical, and the cycloalkyl represented by Z4 is cyclohexyl;

or a pharmaceutically acceptable salt thereof.



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

    A represents —C(O)—C(Ra)(Rb)—; X represents —C—;
    Ra and Rb represent, independently, a (C1-C6)alkyl radical;
    R1 and R2 represent, independently, a (C1-C8)alkyl radical;
    R3 represents —(CH2)p-Z3 
    
        Z3 represents a phenyl radical optionally substituted by one or more identical or different substituents of formula —(CH2)p′—V3—Y3;
        V3 represents —O—, —C(O)—, —C(O)—O—, —C(O)—NR′3—, —NH—C(O)—NR′3—;
        Y3 represents the hydrogen atom or a (C1-C6)alkyl radical;
        R′3 represents a (C1-C6)alkyl or (C1-C6)alkoxy radical;
        p and p′ are equal to 0;
    
    
    R4 represents a radical of formula —(CH2)s—R′4 
    R′4 represents a heterocycloalkyl containing at least one nitrogen atom and optionally substituted by (C1-C6)alkyl; or a radical of formula —NW4W′4 
    
        W4 represents the hydrogen atom or (C1-C8)alkyl;
        W′4 represents a radical of formula —(CH2)s′-Z4;
        Z4 represents the hydrogen atom, the phenyl radical or a heteroaryl;
        s represents an integer from 2 to 4; s′ represents an integer from 0 to 4;

or a pharmaceutically acceptable salt thereof.

    
    


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

    A represents —CH2—; X represents —C—;
    R1 and R2 represent, independently, a (C1-C8)alkyl radical;
    R3 represents —(CH2)p-Z3 
    
        Z3 represents a phenyl radical optionally substituted by one or more identical or different substituents of formula —(CH2)p′—V3—Y3;
        V3 represents —O—, —C(O)—, —C(O)—O—, —C(O)—NR′3—, —NH—C(O)—NR′3—;
        Y3 represents the hydrogen atom or a (C1-C6)alkyl radical;
        R′3 represents a (C1-C6)alkyl or (C1-C6)alkoxy radical;
        p and p′ are equal to 0;
    
    
    R4 represents a radical of formula —(CH2)s—R′4 
    R′4 represents a heterocycloalkyl containing at least one nitrogen atom and optionally substituted by (C1-C6)alkyl; or a radical of formula —NW4W′4 
    
        W4 represents the hydrogen atom or (C1-C8)alkyl;
        W′4 represents a radical of formula —(CH2)s′-Z4;
        Z4 represents the hydrogen atom;
        s represents an integer from 2 to 4; s′ represents an integer from 0 to 4;

or a pharmaceutically acceptable salt thereof.

    
    


The compounds I and II of the present invention have useful pharmacological properties. It has thus been discovered that the compounds I and II of the present invention have a good affinity for certain sub-types of melanocortin receptors, in particular the MC4 receptors.
The compounds of the present invention can thus be used in different therapeutic applications. They can advantageously be used for treating the pathological states or diseases in which one or more melanocortin receptors are involved such as inflammatory conditions, weight disorders (obesity, cachexia, anorexia), sexual activity disorders (erective disorders), pain, but also mental health problems (anxiety, depression), drug addiction, skin diseases (acne, dermatoses, melanomas). Hereafter, in the experimental part, an illustration will be found of the pharmacological properties of the compounds of the invention.
A subject of the present Application is also pharmaceutical compositions containing, as active ingredient, at least one product of formula I as defined above, as well as the pharmaceutically acceptable salts of said product of formula I, in combination with a pharmaceutically acceptable support.
By pharmaceutically acceptable salt, is understood in particular addition salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, diphosphate and nitrate or of organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulphonate, p-toluenesulphonate, pamoate and stearate. Also within the scope of the present invention, when they can be used, the salts forested from bases such as sodium or potassium hydroxide. For other examples of pharmaceutically acceptable salts, reference can be made to “Salt selection for basic drugs”, Int. J. Pharm. (1986), 33, 201-217.
A subject of the present Application is also the use of the compounds according to the present invention, for the preparation of a medicament for the treatment of weight disorders such as obesity, cachexia and more particularly cancerous cachexia, AIDS cachexia, old-age cachexia, cardiac cachexia, renal cachexia, cachexia in rheumatoid arthritis, and anorexia, the treatment of pain and more particularly neuropathic pain, mental health problems such as anxiety and depression, sexual activity disorders such as erective disorders.
The pharmaceutical composition can be in the form of a solid, for example, powders, granules, tablets, gelatin capsules or suppositories. Appropriate solid supports can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.
A subject of the present invention is also the use of a compound 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(Ra)(Rb)—;
    X′ represents —CH—;
    Ra and Rb represent, independently, the hydrogen atom or a (C1-C6)alkyl radical;
    R′, represents the hydrogen atom; a (C1-C8)alkyl radical optionally substituted by hydroxy or one or more identical or different halo radicals; (C2-C6)alkenyl; or a radical of formula —(CH2)n—X1;
    R′2 represents a (C1-C8)alkyl radical optionally substituted by hydroxy or one or more identical or different halo radicals; (C2-C6)alkenyl; or a radical of formula —(CH2)n—X1;
    each X1 independently represents (C1-C6)alkoxy, (C3-C7)cycloalkyl, adamantyl, heterocycloalkyl, aryl or heteroaryl,
    
        the (C3-C7)cycloalkyl, heterocycloalkyl, aryl and heteroaryl radicals being optionally substituted by one or more identical or different substituents chosen from: —(CH2)n′—V1—Y1, halo, nitro, cyano and aryl;
        V1 represents —O—, —S— or a covalent bond;
        Y1 represents a (C1-C6)alkyl radical optionally substituted by one or more identical or different halo radicals;
        n represents an integer from 0 to 6 and n′ an integer from 0 to 2 (it being understood that when n is equal to 0, then X1 does not represent the alkoxy radical)
        or R1 and R2 form together with the nitrogen atom to which they are attached, a heterobicycloalkyl or a heterocycloalkyl optionally substituted by one or more identical or different substituents chosen from: hydroxy, (C1-C6)alkyl optionally substituted by hydroxy, (C1-C6)alkoxy-carbonyl, heterocycloalkyl and —C(O)NV1′Y1′ with V1 and Y1′ independently representing the hydrogen atom or a (C1-C6)alkyl; or R1 and R2 form together a radical of formula:
    
    






    R′3 represents -Z3, C(RZ3)(R′Z3)-Z3, —C(RZ3)(R′Z3)—(CH2)p-Z3 or —C(O)-Z′3 
    
        RZ3 and R′Z3 represent, independently, the hydrogen atom or a (C1-C6)alkyl radical;
        Z3 represents Z3a, Z3b, Z3c, Z3d, or Z3e;
        Z3a represents a (C1-C6)alkyl radical;
        Z3b represents a (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkylamino or di((C1-C6)alkyl)amino radical;
        Z3c represents an aryl or heteroaryl radical;
        Z3d represents a (C1-C6)alkoxy-carbonyl, amino-carbonyl, (C1-C6)alkylamino-carbonyl, di((C1-C6)alkyl)amino-carbonyl, (C1-C6)alkyl-C(O)—NH—, (C3-C7)cycloalkyl, heterocycloalkyl radical;
        the (C3-C7)cycloalkyl and heterocycloalkyl radicals being optionally substituted by one or more identical or different substituents chosen from: halo, nitro, (C1-C6)alkoxy optionally substituted by one or more identical or different halo radicals, (C1-C6)alkyl optionally substituted by one or more identical or different halo radicals, (C1-C6)alkyl-carbonyl, (C1-C6)alkoxy-carbonyl, amino-carbonyl, (C1-C6)alkylamino-carbonyl, di((C1-C6)alkyl)amino-carbonyl and oxy,
        the aryl and heteroaryl radicals being optionally substituted by one or more identical or different substituents chosen from: halo, cyano, nitro, azido, oxy, (C1-C6)alkoxy-carbonyl-(C1-C6)alkenyl, (C1-C6)alkylamino-carbonyl-(C1-C6)alkenyl, —SO2—NR3, R32, heterocycloalkyl, heteroaryl or —(CH2)p′—V3—Y3;
        R31 and R32 form together with the nitrogen atom to which they are attached, a 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 a covalent bond;
        Y3 represents the hydrogen atom; a (C1-C6)alkyl radical optionally substituted by one or more identical or different halo radicals; an aryl radical optionally substituted by one or more identical or different substituents chosen from: halo, nitro, (C1-C6)alkyl and (C1-C6)alkoxy; or an aryl-(C1-C6)alkyl radical optionally substituted by one or more identical or different substituents chosen from: halo, nitro, (C1-C6)alkyl and (C1-C6)alkoxy;
        Z3e represents a radical of formula
    
    






    
    
        Z′3 represents an aryl radical optionally substituted by one or more identical or different substituents chosen from: halo, 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 a covalent bond;
        Y′3 represents the hydrogen atom or a (C1-C6)alkyl radical optionally substituted by one or more identical or different halo radicals;
        R′3 represents the hydrogen atom, a (C1-C6)alkyl or (C1-C6)alkoxy radical;
        p represents an integer from 1 to 4; p′ and p′′ represent, independently, an integer from 0 to 4;
    
    
    R4 represents a radical of formula —(CH2)s—R′4;
    R′4 represents the guanidine radical; a heterocycloalkyl containing at least one nitrogen atom and optionally substituted by (C1-C6)alkyl or aralkyl; a heteroaryl containing at least one nitrogen atom and optionally substituted by (C1-C6)alkyl; or a radical of formula —NW4W′4 
    
        W4 represents the hydrogen atom or (C1-C8)alkyl;
        W′4 represents a radical of formula —(CH2)s′-Z4;
        Z4 represents the hydrogen atom, (C1-C8)alkyl optionally substituted by one or more identical or different substituents chosen 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)alkyl substituents; cyclohexene; heteroaryl and aryl;
        
            the aryl and heteroaryl radicals being optionally substituted by one or more identical or different radicals chosen from formula —(CH2)s′′—V4—Y4, hydroxy, halo, nitro and cyano;
            
                V4 represents —O—, —S—, —NH—C(O)—, —NV′4 or a covalent bond;
                Y4 represents a hydrogen atom or a (C1-C6)alkyl radical optionally substituted by one or more identical or different halo radicals;
                V4′ represents a hydrogen atom or a (C1-C6)alkyl;
                s′′ represents an integer from 0 to 4;
            
            
        
        
        or Z4 represents a radical of formula
    
    






    
    
        
        
            s and s′ represent, independently, an integer from 0 to 6; or a pharmaceutically acceptable salt thereof;

for the preparation of a medicament for the treatment of weight disorders, mental health problems, pain, or sexual activity disorders.

        
        
    
    


A subject of the present invention is more particularly the use of a compound of general formula (I′) as defined above, characterized in that

    
    
        R1 and R2 represent, independently, a (C1-C8)alkyl radical;
        R3 represents Z3c and Z3c represents a phenyl or naphthyl radical, each substituted at least by cyano;
        R4 represents a radical of formula —(CH2)s—R′4 with R′4 representing the pyrrolidinyl or piperidinyl radical; or a radical of formula —NW4W′4;
        
            W4 represents the hydrogen atom or (C1-C8)alkyl;
            W′4 represents a radical of formula —(CH2)s′-Z4 with Z4 representing the hydrogen atom;
            s represents an integer from 2 to 4; s′ represents an integer from 0 to 4;

or a pharmaceutically acceptable salt thereof.

        
        
    
    


The pharmaceutical compositions containing a compound of the invention can also be presented in liquid form, for example, solutions, emulsions, suspensions or syrups. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or the glycols, as well as their mixtures, in varying proportions, in water, added to pharmaceutically acceptable oils or greases. The sterile liquid compositions can be used for intramuscular, intraperitoneal or sub-cutaneous injections and the sterile compositions can also be administered by intravenous route.
All the technical and scientific terms used in the present text have the meaning known to a person skilled in the art. Moreover, all the patents (or patent applications) as well as the other bibliographical references are incorporated by way of reference.
Experimental Part:
The compounds according to the invention obtained according to the procedures of Examples A, B, C, C′, D, E, F, F′ and G described previously, are set out in the table below.
The compounds are characterized by their retention times (rt) and their molecular peak determined by mass spectrometry (MH+).
For the mass spectrometry, a single quadripole mass spectrometer (Micromass, Platform model) equipped with an electrospray source is used with a resolution of 0.8 Da at 50% valley. A calibration is carried out monthly between the masses 80 and 1000 Da using a calibrating mixture of sodium iodide and rubidium iodide in solution in an isopropanol/water mixture (1/1 Vol.).
For the liquid chromatography, a Waters system including an in-line degasser, a Waters 600 quaternary pump, a Gilson 233 plate sampling injector and a Waters PAD 996 UV detector, is used.
The elution conditions used are the following:
Eluent: A water+0.04% trifluoroacetic acid; B acetonitrile












T (minutes)
A %
B %

















1
95
5


8.5
 5
95 


10.5
 5
95 


10.6
95
5


14.9
95
5


15.0
95
5









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 procedures above and should in no event be considered as a limit to the scope of the invention.













Examples
Molecular structures
[M + H]+
rt (min)


















1




512.3
7.8


 


2




582.3
8.0


 


3




490.5
7.5


 


4




491.4
6.9


 


5




508.4
7.6


 


6




574.4
8.0


 


7




566.4
8.1


 


8




626.4
8.2


 


9




540.3
8.2


 


10




454.3
7.2


 


11




467.9
7.3


 


12




482.3
7.4


 


13




496.1
7.5


 


14




484.5
7.0


 


15




484.3
7.0


 


16




498.3
7.1


 


17




482.3
7.5


 


18




496.2
7.6


 


19




470.2
7.0


 


20




498.3
7.2


 


21




469.1
6.2


 


22




537.1
6.8


 


23




551.0
6.9


 


24




540.2
7.4


 


25




540.0
7.4


 


26




541.0
7.3


 


27




566.9
7.3


 


28




526.0
7.2


 


29




522.3
7.7


 


30




452.2
7.2


 


31




466.1
7.3


 


32




452.3
7.8


 


33




422.3
7.7


 


34




440.3
7.8


 


35




490.3
8.3


 


36




464.3
8.0


 


37




468.3
7.9


 


38




458.3
8.0


 


39




490.3
8.9


 


40




482.3
7.9


 


41




466.3
7.8


 


42




467.3
8.3


 


43




436.3
7.8


 


44




436.3
7.8


 


45




450.3
8.0


 


46




490.3
8.2


 


47




497.3
8.5


 


48




464.3
8.1


 


49




468.3
8.0


 


50




462.4
8.0


 


51




452.4
7.8


 


52




450.4
8.0


 


53




500.2
8.2


 


54




514.3
8.2


 


55




484.2
8.7


 


56




484.2
9.1


 


57




484.2
9.0


 


58




495.3
8.9


 


59




464.3
8.7


 


60




464.3
8.9


 


61




480.3
8.7


 


62




464.3
8.9


 


63




450.3
8.7


 


64




484.2
8.4


 


65




528.2
8.5


 


66




468.3
8.2


 


67




464.3
8.1


 


68




495.3
9.1


 


69




480.3
8.1


 


70




496.3
8.3


 


71




518.2
9.0


 


72




534.2
8.7


 


73




492.3
8.4


 


74




508.3
8.5


 


75




525.3
8.9


 


76




478.2
8.5


 


77




522.2
8.6


 


78




522.2
8.4


 


79




506.2
8.2


 


80




492.2
8.5


 


81




508.2
8.6


 


82




522.3
8.8


 


83




494.2
8.7


 


84




529.3
8.5


 


85




543.3
8.7


 


86




545.3
8.6


 


87




506.3
8.5


 


88




507.3
7.9


 


89




543.3
8.5


 


90




557.3
8.7


 


91




559.3
8.7


 


92




558.3
8.0


 


93




494.3
8.1


 


94




507.2
8.0


 


95




521.2
8.0


 


96




549.3
8.2


 


97




522.3
8.6


 


98




564.3
8.9


 


99




564.3
9.1


 


100




562.3
8.8


 


101




562.3
8.8


 


102




576.3
8.9


 


103




590.3
9.0


 


104




578.3
8.7


 


105




591.3
8.5


 


106




456.2
8.0


 


107




500.1
8.0


 


108




440.2
7.7


 


109




490.2
8.4


 


110




478.3
8.2


 


111




548.1
8.1


 


112




479.2
7.6


 


113




478.2
8.1


 


114




637.3
8.8


 


115




653.3
9.0


 


116




547.3
8.8


 


117




563.3
9.0


 


118




610.4
9.1


 


119




626.4
9.3


 


120




520.3
8.5


 


121




534.3
8.7


 


122




536.3
8.6


 


123




550.3
8.2


 


124




535.3
8.0


 


125




506.3
8.4


 


126




548.3
8.6


 


127




548.3
8.8


 


128




546.3
8.6


 


129




546.3
8.6


 


130




560.3
8.6


 


131




574.3
8.7


 


132




562.3
8.5


 


133




575.3
8.3


 


134




522.3
8.2


 


135




521.2
8.1


 


136




563.2
8.2


 


137




563.2
8.3


 


138




561.2
8.2


 


139




561.2
8.2


 


140




575.2
8.2


 


141




589.2
8.3


 


142




577.2
8.1


 


143




594.4
8.8


 


144




535.4
8.0


 


145




564.4
9.5


 


146




588.4
9.2


 


147




456.2
7.2


 


148




484.3
7.5


 


149




512.2
7.8


 


150




470.3
7.3


 


151




470.2
7.4


 


152




498.3
7.6


 


153




540.2
8.1


 


154




496.3
7.6


 


155




480.3
7.4


 


156




516.0
7.0


 


157




516.2
7.2


 


158




522.3
7.9


 


159




590.2
8.0


 


160




608.5
9.2


 


161




624.5
9.4


 


162




623.5
8.5


 


163




534.3
8.7


 


164




533.3
8.0


 


165




535.4
8.0


 


166




564.4
9.5


 


167




508.2
8.2


 


168




474.3
8.0


 


169




484.4
8.2


 


170




498.4
8.4


 


171




526.3
8.4


 


172




540.3
8.5


 


173




482.3
8.1


 


174




566.4
8.1


 


175




520.2
8.6


 


176




534.2
8.7


 


177




534.2
8.7


 


178




560.2
8.9


 


179




574.2
9.0


 


180




588.2
9.1


 


181




532.2
8.6


 


182




494.4
7.5


 


183




534.4
8.1


 


184




504.4
8.4


 


185




562.2
8.9


 


186




546.2
8.7


 


187




562.2
8.9


 


188




508.2
8.2


 


189




494.4
7.5


 


190




474.3
8.0


 


191




484.4
8.2


 


192




498.4
8.4


 


193




526.3
8.4


 


194




540.3
8.5


 


195




482.3
8.1


 


196




566.4
8.1


 


197




602.3
9.2


 


198




550.3
8.1


 


199




549.3
7.8


 


200




564.4
8.1


 


201




606.4
8.2


 


203




611.4
7.4


 


204




478.4
7.5


 


205




492.4
7.5


 


206




508.3
7.6


 


207




507.3
7.3


 


208




522.3
7.4


 


209




610.3
8.7


 


210




624.4
8.7


 


211




640.4
8.8


 


212




639.3
8.3


 


213




654.4
8.5


 


214




514.4
8.2


 


215




528.4
8.2


 


216




560.4
8.2


 


217




592.4
8.1


 


218




594.3
8.1


 


219




590.4
8.4


 


220




532.3
8.4


 


221




548.2
8.6


 


222




547.4
8.0


 


223




550.4
8.5


 


224




542.4
8.2


 


225




604.5
8.3


 


226




528.4
7.9


 


227




556.5
8.1


 


228




556.5
8.0


 


229




590.4
8.4


 


230




532.4
8.6


 


231




546.4
8.6


 


232




548.3
8.5


 


233




547.4
7.9


 


234




533.4
7.9


 


235




532.5
8.7


 


236




548.4
8.8


 


237




547.5
8.1


 


238




533.4
8.0


 


239




532.4
8.1


 


240




548.4
8.3


 


241




547.4
7.7


 


242




533.4
7.7


 


243




632.5
8.3


 


244




556.4
8.1


 


245




570.4
8.1


 


246




584.5
8.2


 


247




548.4
7.5


 


248




472.4
7.2


 


249




486.4
7.3


 


250




500.4
7.3


 


251




618.5
8.7


 


252




602.5
8.6


 


253




617.5
8.1


 


254




603.5
8.1


 


255




534.4
7.6


 


256




518.4
7.5


 


257




533.4
7.3


 


258




519.4
7.2


 


259




518.4
8.1


 


260




534.4
8.2


 


261




533.4
7.7


 


262




519.4
7.7


 


263




562.4
7.8


 


264




486.3
7.6


 


265




500.4
7.6


 


266




514.4
7.7


 


267




562.4
8.2


 


268




546.4
8.1


 


269




561.4
7.8


 


270




547.4
7.8


 


271




570.4
8.7


 


272




542.4
8.7


 


273




554.4
8.6


 


274




513.4
8.3






















Examples
Molecular structures
[M + H]+
rt (min)


















275




527.4
8.4


 


276




556.4
8.6


 


277




556.4
8.8


 


278




576.4
7.9


 


279




500.4
7.6


 


280




514.4
7.6


 


281




528.5
7.7


 


282




548.4
8.7


 


283




597.4
8.9


 


284




570.4
8.9


 


285




597.4
8.7


 


286




567.4
8.5


 


287




554.4
8.4


 


288




538.3
8.7


 


289




522.4
8.6


 


290




562.4
8.5


 


291




592.4
8.6


 


292




574.4
8.6


 


293




560.4
8.7


 


294




600.3
9.2


 


295




562.4
8.5


 


296




546.3
8.9


 


297




562.3
9.1


 


298




561.3
8.5


 


299




547.3
8.5


 


300




576.4
8.6


 


301




500.4
8.4


 


302




514.4
8.4


 


303




528.4
8.4


 


304




590.4
8.5


 


305




575.4
8.1


 


306




589.4
8.2


 


307




534.5
7.7


 


308




534.5
7.8


 


309




562.5
7.9


 


310




546.5
7.8


 


311




556.4
8.2


 


312




508.5
7.7


 


313




524.3
7.5


 


314




556.4
7.5


 


315




540.3
7.5


 


316




539.5
7.9


 


317




510.4
8.1


 


318




494.4
8.0


 


319




542.4
8.1


 


320




526.4
7.8


 


321




528.4
8.3


 


322




500.4
8.4


 


323




514.4
8.4


 


324




570.4
8.8


 


325




506.4
7.3


 


326




506.4
7.3


 


327




534.4
7.4


 


328




518.4
7.3


 


329




528.3
7.6


 


330




548.3
7.3


 


331




486.3
7.0


 


332




480.4
7.1


 


333




592.4
8.1


 


334




634.3
9.2


 


335




577.4
9.0


 


336




584.3
8.4


 


337




591.4
8.3


 


338




610.3
8.4


 


339




518.4
7.4


 


340




534.3
7.5


 


341




533.3
7.2


 


342




519.3
7.1


 


343




544.3
7.8


 


344




486.3
8.1


 


345




506.5
7.3


 


346




518.5
7.5


 


347




544.4
7.9


 


348




528.4
7.7


 


349




506.5
7.4


 


350




534.4
7.4


 


351




518.4
7.4


 


352




534.4
7.6


 


353




533.5
7.3


 


354




519.4
7.3


 


355




486.4
7.2


 


356




500.4
7.2


 


357




528.5
7.3


 


358




548.4
7.4


 


359




496.4
7.3


 


360




538.5
8.3


 


361




522.5
8.2


 


362




494.5
8.0


 


363




510.5
8.1


 


364




562.5
8.1


 


365




520.5
8.1


 


366




569.4
8.2


 


367




561.5
7.9


 


368




574.5
9.0


 


369




589.6
8.3


 


370




562.5
8.4


 


371




589.6
8.1


 


372




646.4
9.9


 


373




524.4
8.7


 


374




496.4
8.3


 


375




566.4
9.9


 


376




534.4
8.2


 


377




561.4
7.9


 


378




524.4
8.4


 


379




506.4
8.1


 


380




518.4
8.4


 


381




532.4
8.6


 


382




534.4
8.5


 


383




519.4
7.9


 


384




533.4
7.9


 


385




547.4
7.9


 


386




555.3
8.2


 


387




482.5
8.2


 


388




482.3
8.0


 


389




496.4
8.1


 


390




582.4
10.3


 


391




556.5
8.4


 


392




534.4
8.4


 


393




560.4
9.0


 


394




547.4
8.2


 


395




583.4
8.5


 


396




548.4
8.4


 


397




576.4
8.4


 


398




575.5
8.1


 


399




508.4
8.3


 


400




524.4
8.4


 


401




540.4
8.1


 


402




553.5
8.1


 


403




530.4
8.4


 


404




502.4
8.1


 


405




520.4
8.2


 


406




548.4
8.2


 


407




547.4
7.9


 


408




480.4
8.0


 


409




496.4
8.1


 


410




512.4
7.8


 


411




525.4
7.9


 


412




548.4
8.6


 


413




560.4
8.6


 


414




576.4
8.8


 


415




562.4
8.5


 


416




611.4
8.3


 


417




561.4
8.2


 


418




546.6
8.1


 


419




560.6
8.3


 


420




532.6
8.0


 


421




574.4
8.3


 


422




564.6
8.7


 


423




618.6
9.9


 


424




602.6
9.1


 


425




596.6
8.9


 


426




610.7
8.3


 


427




665.7
9.6


 


428




558.7
8.7


 


429




562.6
8.4


 


430




576.6
8.5


 


431




568.6
8.6


 


432




557.6
8.5


 


433




590.3
9.3


 


434




562.3
8.6


 


435




610.3
9.0


 


436




624.4
9.0


 


437




594.3
9.1


 


438




543.3
9.3


 


439




563.2
9.7


 


440




561.3
8.4


 


441




559.3
8.8


 


442




582.3
8.8


 


443




576.2
8.5


 


444




558.3
8.6


 


445




526.3
8.3


 


446




585.3
8.6


 


447




625.4
8.3


 


448




618.4
9.6


 


449




552.4
8.8


 


450




536.4
8.5


 


451




596.3
8.9


 


452




589.5
8.2


 


453




616.5
9.1


 


454




603.5
8.3


 


455




584.5
8.0


 


456




585.4
8.6


 


457




557.4
8.5


 


458




600.4
8.5


 


459




622.4
9.1


 


460




601.4
8.7


 


461




623.4
9.0


 


462




594.4
8.6


 


463




573.4
8.3


 


464




595.3
8.7


 


465




519.4
8.1


 


466




548.4
8.4


 


467




548.4
8.5


 


468




576.4
9.1


 


469




596.4
8.9


 


470




549.3
9.5


 


471




582.3
8.8


 


472




596.4
8.2


 


473




597.4
8.2


 


474




602.4
9.0


 


475




571.4
8.5


 


476




562.4
8.4


 


477




568.3
8.3


 


478




582.3
8.5


 


479




535.4
9.1


 


480




547.3
7.8


 


481




557.4
8.2


 


482




582.3
7.9


 


483




583.3
7.8


 


484




548.4
8.2


 


485




534.4
8.2


 


486




525.4
7.6


 


487




527.5
7.5


 


488




541.4
7.5


 


489




562.4
8.7


 


490




534.4
8.2


 


491




588.4
8.7


 


492




538.3
8.3


 


493




588.3
8.5


 


494




546.4
8.2


 


495




588.3
8.5


 


496




573.4
7.9


 


497




581.4
8.5


 


498




555.4
8.4


 


499




556.3
8.2


 


500




566.4
8.7


 


501




596.4
8.6


 


502




560.3
8.3


 


503




592.3
8.8


 


504




505.4
7.7


 


505




491.4
7.9


 


506




560.3
8.4


 


507




550.3
8.3


 


508




596.4
8.7


 


509




540.3
8.5


 


510




566.3
8.5


 


511




616.4
8.7


 


512




616.4
8.7


 


513




578.3
8.6


 


514




624.4
9.0


 


515




601.4
8.1


 


516




609.4
8.8


 


517




583.4
8.7


 


518




584.4
8.4


 


519




533.4
7.8


 


520




574.4
8.4


 


521




588.3
8.5


 


522




588.3
8.6


 


523




568.4
8.7


 


524




620.4
9.1


 


525




610.4
9.0


 


526




622.4
9.0


 


527




611.4
8.7


 


528




582.3
8.7


 


529




594.4
8.6


 


530




583.3
8.3


 


531




475.3
8.7


 


532




493.3
8.0


 


533




465.3
7.8


 


534




575.3
8.1


 


535




541.5
8.0









Pharmacological Study

The affinity of the compounds of the present invention for the different sub-types of melanocortin receptors was measured according to procedures analogous to those described below for the MC4 receptors.
Study of the Affinity of the Compounds for the MC4 Receptors of Melanocortins:
The affinity of the compounds of the invention for the MC4 receptors is determined by measuring the inhibition of the binding of [125I]-[Nle4, D-Phe7]-α-MSH to membrane preparations of transfected CHO—K1 cells.
The CHO—K1 cells expressing in a stable fashion the human MC4 receptors are cultured in an RPMI 1640 medium containing 10% of foetal calf serum, 2 mM of glutamine, 100 U/ml of penicillin, 0.1 mg/ml of streptomycin and 0.5 mg/ml of G418. The cells are collected with 0.5 mM of EDTA and centrifuged at 500 g for 5 minutes at 4° C. The pellet is resuspended in a phosphate buffered saline (PBS) medium and centrifuged at 500 g for 5 minutes at 4° C. The pellet is resuspended in a Tris 50 mM buffer medium at pH 7.4 and centrifuged at 500 g for 5 minutes at 4° C. The cells are lysed by sonication and centrifuged at 39,000 g for 10 minutes at 4° C. The pellet is resuspended in the Tris 50 mM buffer medium at pH 7.4 and centrifuged at 50,000 g for 10 min at 4° C. The membranes obtained in this last pellet are stored at −80° C.
The measurement of the competitive inhibition of the binding of [125I]-[Nle4, D-Phe7]-α-MSH to the MC4 receptors is carried out in duplicate using polypropylene 96-well plates. The cell membranes (50 μg of proteins/well) are incubated with [125I]-[Nle4, D-Phe7]-α-MSH (0.5 nM) for 90 minutes at 37° C. in a Tris-HCl 50 mM buffer medium, pH 7.4, comprising 0.2% of bovine serum albumin (BSA), 5 mM of MgCl2, and 0.1 mg/ml of bacitracin.
The bonded [125I]-[Nle4, D-Phe7]-α-MSH is separated from the free [125I]-[Nle4, D-Phe7]-α-MSH by filtration through GF/C glass fibre filters (Unifilter, Packard) pre-impregnated with 0.1% of polyethylenimine (P.E.I.), using a Filtermate 196 (Packard). The filters are washed with Tris-HCl 50 mM buffer, pH 7.4 at 0-4° C. and the radioactivity present is determined using a counter (Packard Top Count).
The specific binding is obtained by subtracting the non-specific binding (determined in the presence of 0.1 μM of Nle4, D-Phe7-α-MSH) from the total binding. The data are analyzed by computer-aided non-linear regression (MDL) and the values of the inhibition constants (Ki) are determined.
The agonist or antagonist activity of the MC4 receptors of the compounds of the present invention was determined by measuring the production of cyclic AMP by the CHO-K1 cells transfected by the MC4 receptor.
Measurement of the Production of Intracellular Cyclic AMP via the MC4 Receptors:
The CHO—K1 cells expressing the MC4 receptors of the melanocortins are cultured in 384-well plates in an RPMI 1640 medium with 10% of foetal calf serum and 0.5 mg/ml of G418. The cells are washed twice with 50 μl of RPMI medium comprising 0.2% BSA and 0.5 mM of 3-isobutyl-1-methylxanthine (IBMX).
In order to measure the agonist effect of a compound, the cells are incubated for 5 minutes at 37° C. in the presence of 0.5 mM of IBMX, then stimulation of the production of cyclic AMP is obtained by adding the compound at concentrations comprised between 1 pM and 10 μM in duplicate for 20 minutes at 37° C. The antagonist effect of a compound is measured by inhibiting stimulation of the production of cyclic AMP induced by Nle4, D-Phe7-α-MSH at concentrations comprised between 1 pM and 10 μm, in the presence of the compound to be tested, at concentrations comprised between 1 nM and 10 μM in duplicate for 20 minutes at 37° C.
The reaction medium is eliminated and 80 μl of lysis buffer is added. The intracellular cyclic AMP level is measured by a competition test with fluorescent cyclic AMP (CatchPoint, Molecular Devices).

## Claims

1. A compound of the formula




in racemic, enantiomeric form or any combinations of these forms wherein
A is —C(O)—;
X is —CH═;
Ra and Rb are independently selected from the group consisting of hydrogen or (C1-C6)alkyl;
R1 is selected from the group consisting of hydrogen, (C1-C8)alkyl optionally substituted by hydroxy or at least one halo; (C1-C6)alkenyl and —(CH2)n—X1;
R2 is selected from the group consisting of (C1-C8)alkyl optionally substituted by hydroxy or at least one halo; (C2-C4alkenyl and —(CH2)n—X1;
each X1 independently is selected from the group consisting of (C1-C6)alkoxy, (C3-C7)cycloalkyl, adamantyl, heterocycloalkyl, aryl and heteroaryl,
the (C3-C7)cycloalkyl, heterocycloalkyl, aryl and heteroaryl being unsubstituted or substituted by at least one member selected from the group consisting of —CH2n—V1—Y1, halo, nitro, cyano and aryl;

V1 is —O—, —S— or a covalent bond;
Y1 is (C1-C6)alkyl optionally substituted by at least one halo;
n is an integer from 0 to 6 and n′ is an integer from 0 to 2 (it being understood that when n is equal to 0, then X1 is not alkoxy);

or R1 and R2 form together with the nitrogen atom to which they are attached, a heterobicycloalkyl or a heterocycloalkyl optionally substituted by at least one member selected from the group consisting of hydroxy, (C1-C6)alkyl optionally substituted by hydroxy, (C1-C6)alkoxy-carbonyl, heterocycloalkyl and —C(O)NV1′Y1′, V1′ and Y1′ independently are hydrogen or (C1-C6)alkyl; or R1 and R2 together form a member selected from the group consisting of




R3 is selected from the group consisting of -Z3, —C(RZ3)(R′Z3)-Z3, —C(RZ3)(R′Z3)—(CH2)p—Z3 or —C(O)-V′3 
RZ3 and R′Z3 are independently hydrogen or (C1-C6) alkyl,
Z3 is selected from the group consisting of Z3a, Z3b, Z3c, Z3d, or Z3e;
Z3a is (C1-C6)alkyl;
Z3b is selected from the group consisting of (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkylamino or di((C1-C6)alkyl)amino;
Z3c is aryl or heteroaryl;
Z3d is selected from the group consisting of (C1-C6) alkoxy-carbonyl, amino-carbonyl, C1-C6)alkylamino-carbonyl, di((C1-C6)alkyl)amino-carbonyl, (C1-C6)alkyl-C(O)—NH—, (C3-C7)cycloalkyl, heterocycloalkyl;
the (C3-C7)cycloalkyl and heterocycloalkyl being optionally substituted by at least one member selected from the group consisting of halo, nitro, (C1-C6)alkoxy optionally substituted by at least one halo, (C1-C4alkyl optionally substituted by at least one halo, (C1-C6)alkyl-carbonyl, (C1-C6)alkoxy-carbonyl, amino-carbonyl, (C1-C6)alkylamino-carbonyl, di((C1-C6)alkyl)amino-carbonyl and oxy,
the aryl and heteroaryl radicals being optionally substituted by at least one member selected from the group consisting of halo, cyano, nitro, azido, oxy, (C1-C6)alkoxy-carbonyl-(C1-C6)alkenyl, (C1-C6)alkylamino-carbonyl-(C1-C6)alkenyl, —SO2—NR31R32, heterocycloalkyl, heteroaryl or —(CH2)p—V3Y3;
R31, and R32 form together with the nitrogen atom to which they are attached, a heterocycloalkyl;
V3 is selected from the group consisting of —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;
Y3 is selected from the group consisting of hydrogen; (C1-C6)alkyl optionally substituted by at least one halo; aryl optionally substituted by at least one member selected from the group consisting of halo, nitro, (C1-C6)alkyl and (C1-C6)alkoxy; aryl-(C1C4)alkyl optionally substituted by at least one member selected from the group consisting of halo, nitro, (C1-C6)alkyl and (C1-C1)alkoxy;
Z3e is






Z′3 is aryl optionally substituted by one member selected from the group consisting of halo, nitro and —(CH2)p′—V′3—Y′3;
V′3 is selected from the group consisting of —O—, —C(O)—, [—C(O)—], —C(O)—O—, —C(O)—NR′3—, —NH—C(O)—NR′3—or a covalent bond;
Y′3 is hydrogen or (C1-C6)alkyl optionally substituted by at least one halo;
R′3 is selected from the group consisting of hydrogen, (C1-C6)alkyl or (C1-C6)alkoxy;
p is selected from the group consisting of an integer from 1 to 4; p′ and p′′ are independently an integer from 0 to 4;

R′4 is —(CH2)—R′4 
R′4 is selected from the group consisting of guanidine; heterocycloalkyl containing at least one nitrogen atom and optionally substituted by (C1-C6)alkyl or aralkyl; a heteroaryl containing at least one nitrogen atom and optionally substituted by (C1-C6)alkyl; or —NW4W′4 
W4 is hydrogen or (C1-C8)alkyl;
W′4 is —(CH2)s′-Z4;
Z4 is selected from the group consisting of hydrogen, (C1-C8)alkyl optionally substituted by at least one member selected from the group consisting of (C1 -C6)alkoxy, (C1-C6)alkylthio, hydroxy; (C2-C6)alkenyl; (C3-C7)cycloalkyl optionally substituted by at least one (C1-C6)alkyl; cyclohexene; heteroaryl and aryl;
the aryl and heteroaryl radicals being optionally substituted by at least one member selected from the group consisting of —(CH2)s′′—V4—Y4, hydroxy, halo, nitro and cyano;
V4 is selected from the group consisting of —O—, —S—, —NH—C(O)—, —NV4′— or a covalent bond;
Y4 is hydrogen or (C1-C6)alkyl optionally substituted by at least one halo;
V4′ is hydrogen or (C1-C6)alkyl;
s′′ is an integer from 0 to 4;


or Z4 is






s and s′ are independently an integer from 0 to 6;
and i) when R3 is —C(O)-Z′3 and R4 is —(CH2)s—NW4W′4 and W4 and W′4 are independently hydrogen or (C1-C6)alkyl, then —(CH2)s is neither ethylene nor —(CH2)—CH((C1-C4alkyl)-, ii) when R3 is -Z′3c and Z′3c is phenyl or naphthyl, ten phenyl and naphthyl are not substituted by cyano; and it being understood that when R3 is -Z3d then Z3d only is one (C1-C7) cycloalkyl or heterocycloalkyl;
and iii) when A is —C(O)—; X═—CH—, Z3═—C(O)-Z′3-, R4 is —(CH2)s—R′4 and s is an integer from 1 to 6, either R1 is hydrogen or alkenyl and R2 is alkenyl, or R1 is —CH2)n—X1and R2 is —(CH,)n—X1;

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 wherein R3 is —C(O)-Z′3;
R1 and R2 are independently (C1-C8)alkyl;
Z′3 is phenyl optionally substituted by at least one member selected from the group consisting of halo, nitro and —(CH2)p′′—V′3—Y′3 
V′3 is selected from the group consisting of —O—, —C(O)—O— or a covalent bond;
V′3 is hydrogen or (C1 -C6)alkyl;
p′ is 0;

R4 is —(CH2)s—R′4 and R′4—NW4W′4 
W4 is hydrogen or (C1-C8)alkyl;
W′4 is —(CH2)s′-Z4 and Z4 is hydrogen;
s is an integer from 2 to 4; s′ is an integer from 0 to 4;

or a pharmaceutically acceptable salt thereof.

3. A compound of claim 1 wherein
R1 is selected from the group consisting of hydrogen, (C1-C8)alkyl optionally substituted by hydroxy, (C2-C6)alkenyl or —(CH2)n—X1;
R2 is selected from the group consisting of (C1-C8)alkyl optionally substituted by hydroxy, (C2-C6)alkenyl or —(CH2)n—X1;
each X1 is independently selected from the group consisting of (C1-C6)alkoxy, (C3-C7)cycloalkyl, aryl or heteroaryl,
the aryl being optionally substituted by at least one —(CH2)n′—V1—Y1 or halo;
V1 is —O— or a covalent bond;
Y1 is (C1-C6)alkyl optionally substituted by at least one halo or aryl;
or R1 and R2 form together with the nitrogen atom to which they are attached, a heterocycloalkyl optionally substituted by at least one member selected from the group consisting of hydroxy, (C1-C6)alkyl optionally substituted by hydroxy, (C1-C6)alkoxy-carbonyl, heterocycloalkyl and —C(O)NV1′Y1′, V1′ and Y1′ independently are hydrogen or (C1-C6)alkyl,
or R1 and R2 together form a member selected from the group consisting of




R3 is selected from the group consisting of -Z3, —C(RZ3)(R′Z3)-Z3 or —C(RZ3)(RZ3)—(CH2)p-Z3;
R4 is —(CH2)s—R′4 
R′4 is selected from the group consisting of heterocycloalkyl containing at least one nitrogen atom and optionally substituted by (C1-C6)alkyl or aralkyl; a heteroaryl containing at least one nitrogen atom and optionally substituted by (C1-C6)alkyl; or —NW4W′4 
W4 is hydrogen or (C1-C8)alkyl;
W′4 is —(CH2)s′-Z4;

Z4 is selected from the group consisting of hydrogen, (C3-C7)cycloalkyl or aryl;

s is an integer from 0 to 5; s′ is an integer from 0 to 4; or a pharmaceutically acceptable salt thereof.

4. A compound of claim 3 wherein having at least one of the following characteristics:
(C3-C7)cycloalkyl of X1 is cyclopropyl
aryl of X1 is phenyl;
heteroaryl of X1 is pyridine;
heterocycloalkyl that R1 and R2 form together with the nitrogen atom to which they are attached is selected from the group consisting of pyrrolidine, piperidine, azepane, azacyclooctane, morpholine, piperazine and decahydroisoquinoline;
heterocycloalkyl of R′4, optionally substituted by (C1-C6)alkyl or benzyl, is selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl;
heteroaryl of R′4 is imidazolyl;
cycloalkyl of Z4 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
aryl of Z4 is phenyl; or a pharmaceutically acceptable salt thereof.

5. A compound of claim 3, wherein R4 is —(CH2)s—R′4, R′4 is pyrrolidinyl or piperidinyl; or —NW4W′4 
W4 is hydrogen or (C1-C8)alkyl;
W′4 is —(CH2)s-Z4 and Z4 is hydrogen;
s is an integer from 2 to 4; s′ is an integer from 0 to 4; or a pharmaceutically acceptable salt thereof.

6. A compound of claim 3 wherein R1 and R2 are independently (C1-C8)alkyl; or a pharmaceutically acceptable salt thereof.

7. A compound of claim 3 wherein
R3 is -Z3 and Z3 is Z3c, Z3d or Z3e;
Z3d is (C3-C7)cycloalkyl or heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

8. A compound of claim 7, wherein
Z3c is a heteroaryl selected from the group consisting of thienyl, furyl, indolyl, dihydroindolyl, pyridyl, benzothienyl and benzofuryl; or an aryl selected from the group consisting of phenyl, naphthyl and fluorenyl;
the heteroaryl being optionally substituted by at least one (C1-C6)alkyl-carbonyl or (C1-C6)alkoxy-carbonyl;
the aryl being optionally substituted by at least one member selected from the group consisting of halo, cyano, nitro, azido, (C1-C6)alkoxy-carbonyl-(C1-C6)alkenyl, oxy, —SO2—NR31R32, heterocycloalkyl, heteroaryl, or —(CH2)p′—V3—Y3;
R31 and R32 form together with the nitrogen atom to which they are attached piperidine;
V3 is selected from the group consisting of —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;
Y3 is selected from the group consisting of hydrogen; (C1-C6)alkyl optionally substituted by at least one halo, phenyl; or benzyl;
R′3 is selected from the group consisting of hydrogen, (C1-C6)alkyl or (C1-C6)alkoxy;
Z3d is cyclopropyl, cyclohexyl or piperidinyl, each being unsubstituted or substituted by (C1-C6)alkoxy-carbonyl; or a pharmaceutically acceptable salt thereof.

9. A compound of claim 7, wherein
R3 is -Z3 and Z3 is Z3c, Z3d or Z3e;
Z3c is heteroaryl selected from the group consisting of thienyl, indolyl and benzothienyl; or aryl is phenyl or naphthyl;
the heteroaryl being optionally substituted by at least one oxy;
the aryl radical being optionally substituted by at least one member selected from the group consisting of halo, nitro, heteroaryl or —(CH2)p′—V3—Y3;
V3 is selected from the group consisting of —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;
Y3 is selected from the group consisting of hydrogen; (C1-C6)alkyl optionally substituted by at least one halo, phenyl; or benzyl;
R′3 is selected from the group consisting of hydrogen, (C1-C6)alkyl or (C1-C6)alkoxy;

Z3d is cyclopropyl or piperidinyl, each optionally substituted by (C1-C6)alkoxy-carbonyl; or a pharmaceutically acceptable salt thereof.

10. A compound of claim 9, wherein
Z3 is Z3c or Z3e; 
Z3c is phenyl optionally substituted by at least one-member selected from the group consisting of nitro or —(CH2)p′—V3—Y3;
V3 is selected from the group consisting of —O—, —S—, —C(O)—, —C(O)—O—, —SO2—, —SO2NH—, —NR′3C(O)—, —C(O)—NR′3— or a covalent bond;
Y3 is selected from the group consisting of hydrogen; (C1-C6)alkyl; phenyl; or benzyl;
R′3 is hydrogen;

Z3e is





or a pharmaceutically acceptable salt thereof.

11. A compound of claim 3 wherein R3 is —C(RZ3)(R′Z3)-Z3 and Z3 is Z3b, Zc, Z3d or Z3e; or a pharmaceutically acceptable salt thereof.

12. A compound of claim 11, wherein
R3 is —C(RZ3)(R′Z3)-3Z; and Z3 is Z3b or R3c;
R23 and R23′ are hydrogens;

or a pharmaceutically acceptable salt thereof.

13. A compound of claim 12 wherein
Z3b is (C1-C6)alkoxy;
Z3c is heteroaryl selected from the group consisting of thienyl, furyl, pyridyl, benzothienyl and dihydrobenzofuryl; or phenyl or naphthyl,
the aryl being optionally substituted by at least one of halo or —(CH2)p′—V3Y3;
V3 is selected from the group consisting of —O—, —O—, —C(O)—, —C(O)—O—, —SC2—, SO2NH—, —NR′3—C(O)—or —C(O)—NR′3,
Y3 is selected from the group consisting of hydrogen (C1-C6)alkyl optionally substituted by at least one halo;
R+3 is hydrogen;

or a pharmaceutically acceptable salt thereof.

14. A compound of claim 12, wherein
R3 is —C(RZ3)(R′Z3)-Z3, Z3 is Z3b or Z3c;
Z3b is (C1-C6)alkoxy;
Z3c, is heteroaryl selected from the group consisting of thienyl, furyl, dihydrobenzofuryl; or phenyl;
the phenyl being optionally substituted by at least one of nitro or —(CH2)p′—V3—Y3;
V3 is selected from the group consisting of —O—, —S—, —C(O)—, —C(O)—O—, —SO2—, SO2NH or —C(O)—NR′3—,
Y3 is hydrogen or (C1-C6)alkyl optionally substituted by at least one halo;
R′3 is hydrogen;

or a pharmaceutically acceptable salt thereof.

15. A compound of claim 14, wherein
Z3 is Z3c;
Z3c, is furyl or phenyl unsubstituted or substituted by at least one —(CH)p′—V3—Y3;
V3 is selected from the group consisting of —O—, —S—, —C(O)—, —C(O)—O—, —SO2—, —SO2NH— or —C(O)—NR′3—,
Y3 is hydrogen; or (C1-C6)alkyl optionally substituted by at least one halogen;
R′3 is hydrogen;

or a pharmaceutically acceptable salt thereof.

16. A compound of claim 11, wherein
R3 is —C(RZ3)(R′Z3)-Z3, Z3 is Z3d or Z3e;
RZ3 and R′Z3 are hydrogen or (C1-C6)alkyl;
Z3d is (C1-C6)alkoxy-carbonyl, (C3-C7)cycloalkyl or heterocycloalkyl;
Z3c is





or a pharmaceutically acceptable salt thereof.

17. A compound of claim 16 wherein
Z3d is selected from the group consisting of (C1-C6)alkoxy-carbonyl, cyclohexyl or tetrabydrofuranyl,

or a pharmaceutically acceptable salt thereof.

18. A compound of claim 16 wherein Z3 is Z3d or Z3e;
Z3d is (C1-C6)alkoxy-carbonyl;
Z3c is





or a pharmaceutically acceptable salt thereof.

19. A compound of claim 18 wherein Z3 is




or a pharmaceutically acceptable salt thereof.

20. A compound of claim 3 wherein R3 is —C(RZ3)(R′Z3)—(CH2)p-Z3 and Z3 is Z3b, Z3c or Z3d; or a pharmaceutically acceptable salt thereof.

21. A compound of claim 20, wherein R3 is —C(RZ3)(R′Z3)—(CH2)p-Z3 and Z3 is Z3b; or a pharmaceutically acceptable salt thereof.

22. A compound of claim 21, wherein RZ3 and R′Z3 are independently hydrogen or (C1-C6)alkyl;
Z3b is (C1-C6)alkoxy, (C1-C6)alkylthio or di((C1-C6)alkyl)amino; or a pharmaceutically acceptable salt thereof.

23. A compound of claim 21, wherein
RZ3 and R′Z3 are independently hydrogen or (C1-C6)alkyl;
Z3b is (C1-C6)alkoxy or (C1-C6)alkylthio; or a pharmaceutically acceptable salt thereof.

24. A compound of claim 20, wherein R3 is —C(RZ3)(R′Z3)—(CH2)p-Z3 and Z3 is Z3c or Z3d; or a pharmaceutically acceptable salt thereof.

25. A compound of claim 24, wherein
RZ3 and R′ZZ3 are independently hydrogen or (C1-C6)alkyl,
Z3c is indolyl or phenyl unsubstituted or substituted by at least one of halo or —(CH2)p′—V3—Y3;
V3 is —SO2NH—,
Y3 is hydrogen; or (C1-C6)alkyl,

Z3d is selected from the group consisting of (C1-C6)alkoxy-carbonyl, amino-carbonyl, (C1-C6)alkyl-amino-carbonyl, (C1-C6)alkyl-C(O)—NH—, or piperidinyl, morpholinyl, pyrrolidine or imidazolidinyl; or a pharmaceutically acceptable salt thereof.

26. A compound of claim 24, wherein
Z3 is Z3d;
RZ3 and R′Z3 are independently hydrogen or (C1-C6)alkyl;
Z3d is selected from the group consisting of (C1-C6)alkoxy-carbonyl, amino-carbonyl, (C1-C6)alkylamino-carbonyl, (C1-C6)alkyl-C(O)—NH— or heterocycloalkyl, optionally substituted by oxy; or a pharmaceutically acceptable salt thereof.

27. A process for the preparation of a compound of claim 1 comprising reacting a compound of the formula




in which A, X, R1, R2, R4 have the meaning of claim 1, with an isothiocyanate of the formula R3N═C═S in which R3 has the meaning indicated in claim 1, in the presence of a coupling agent or yellow mercury (II) oxide in the presence of sulfur, for a period of 3 to 48 hours, in a protic or aprotic solvent, at a temperature of 50 to 80° C.

28. A pharmaceutical composition comprising at least one compound of claim 1, in combination with a pharmaceutically acceptable carrier.