Patent Publication Number: US-2007123540-A1

Title: Sexual desire enhancing medicaments comprising benzimidazolone derivatives

Description:
The invention relates to the use of benzimidazolone derivatives of formula (I) and their acid addition salts for the preparation of a medicament for the treatment of sexual desire disorders.  
     DESCRIPTION OF THE INVENTION  
      The compounds of formula (I) and their acid addition salts are disclosed in WO 01/21593 A1and have the following chemical structure:  
                 
 
 wherein R 1 , R 2 , R 3 , and R 4  denote hydrogen or hydroxy with the proviso that R 1 , R 2 , R 3 , and R 4  cannot simultaneously represent hydrogen. 
 
      Preferred compounds according to the present invention are those of general formula (I) wherein two or three of the four radicals R 1 , R 2 , R 3 , and R 4  denote hydrogen. Also preferred are those compounds of general formula (I) wherein one of the radicals R 1 , R 2 , R 3 , and R 4  denotes hydroxy, whilst the other radicals represent hydrogen.  
      Above mentioned compounds show affinity for the 5-HT1A and 5-HT2-receptor. They may be of value in the treatment of those diseases where an altered functioning of neurosignal transmission is present. Examples of these CNS disorders include depression, schizophrenia, Parkinson, anxiety, sleep disturbances, sexual and mental disorders and age associated memory impairment (WO 01/21593 A1).  
      The generic term “Sexual disorders” includes Sexual Desire Disorders, Sexual Arousal Disorders, Orgasmic Disorders, Sexual Pain Disorders, Sexual Dysfunction due to a General Medical Condition, Substance-induced Sexual Dysfunction, and Sexual Dysfunction not otherwise specified (Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision. Washington DC, American Psychiatric Association, 2000).  
      The present invention relates to the use of the compounds of formula (I), optionally in form of the pharmacologically acceptable acid addition salts thereof for the preparation of a medicament for the treatment of sexual desire disorders which are a subgroup of sexual disorders.  
      In a preferred embodiment, the present invention relates to the use of the compounds of formula (I) selected from the group consisting of  
                 
                 
                 
 
 optionally in form of the pharmacologically acceptable acid addition salts thereof for the preparation of a medicament for the treatment of sexual desire disorders. 
 
      In another preferred embodiment the invention relates to the use of the compounds of formula (I), optionally in form of the pharmacologically acceptable acid addition salts thereof for the preparation of a medicament for the treatment of disorders selected from the group consisting of hypoactive sexual desire disorder, sexual aversion disorder, loss of sexual desire, lack of sexual desire, decreased sexual desire, inhibited sexual desire, loss of libido, libido disturbance, and frigidity.  
      In another preferred embodiment the invention relates to the use of the compounds of formula (I) selected from the group consisting of the compounds (I.a), (I.b), (I.c), (I.d), (I.e), (I.f), (I.g) and (I.h), optionally in form of the pharmacologically acceptable acid addition salts thereof for the preparation of a medicament for the treatment of disorders selected from the group consisting of hypoactive sexual desire disorder, sexual aversion disorder, loss of sexual desire, lack of sexual desire, decreased sexual desire, inhibited sexual desire, loss of libido, libido disturbance, and frigidity.  
      Further preferred according to the invention is the use of the compounds of formula (I), optionally in form of the pharmacologically acceptable acid addition salts thereof for the preparation of a medicament for the treatment of disorders selected from the group consisting of hypoactive sexual desire disorder, sexual aversion disorder, loss of sexual desire, lack of sexual desire, decreased sexual desire, inhibited sexual desire.  
      Further preferred according to the invention is the use of the compounds of formula (I), selected from the group consisting of the compounds (I.a), (I.b), (I.c), (I.d), (I.e), (I.f), (I.g) and (I.h), optionally in form of the pharmacologically acceptable acid addition salts thereof for the preparation of a medicament for the treatment of disorders selected from the group consisting of hypoactive sexual desire disorder, sexual aversion disorder, loss of sexual desire, lack of sexual desire, decreased sexual desire, inhibited sexual desire.  
      In another preferred embodiment the invention relates to the use of the compounds of formula (I), optionally in form of the pharmacologically acceptable acid addition salts thereof for the preparation of a medicament for the treatment of disorders selected from the group of hypoactive sexual desire disorder and loss of sexual desire.  
      In another preferred embodiment the invention relates to the use of the compounds of formula (I), selected from the group consisting of the compounds (I.a), (I.b), (I.c), (I.d), (I.e), (I.f), (I.g) and (I.h), optionally in form of the pharmacologically acceptable acid addition salts thereof for the preparation of a medicament for the treatment of disorders selected from the group of hypoactive sexual desire disorder and loss of sexual desire.  
      The observed effects of the compounds of formula (I) and the compounds (I.a), (I.b), (I.c), (I.d), (I.e), (I.f), (I.g) and (I.h), optionally in form of the pharmacologically acceptable acid addition salts thereof can be achieved in men and women. However, according to a further aspect of the invention the use of the compounds of formula (I) and the compounds (I.a), (I.b), (I.c), (I.d), (I.e), (I.f), (I.g) and (I.h), optionally in form of the pharmacologically acceptable acid addition salts for the preparation of a medicament for the treatment of female sexual desire disorders is preferred.  
      The beneficial effects of the compounds of formula (I) and the compounds (I.a), (I.b), (I.c), (I.d), (I.e), (I.f), (I.g) and (I.h), optionally in form of the pharmacologically acceptable acid addition salts thereof can be observed regardless of whether the disturbance existed lifelong or was acquired, is of the “generalized type” or “situational type” and independent of etiologic origin (organic—both, physically and drug induced-, psychogen (due to psychological factors), a combination of organic—both, physically and drug induced-, and psychogen (due to combined factors), or unknown). The term “lifelong” refers to such sexual disorders of the present invention, which have been present since the onset of sexual functioning. The term “acquired” refers to such sexual disorders of the present invention which developed only after a period of normal sexual functioning. The “generalized type” refers to such sexual disorders of the present invention wherein the disorder is not limited to certain types of stimulation, situations, or partners. The “situational type” applies to such sexual disorders of the present invention wherein the disorder is limited to certain types of stimulation, situations, or partners. The subtype due to “psychological factors” applies when psychological factors are judged to have the major role in the onset, severity, exacerbation, or maintenance of the sexual disorder, and general medical conditions and substance play no role in the etiology of the sexual disorder. Finally the subtype due to “combined factors” applies when 1) psychological factors are judged to have a role in the onset, severity, exacerbation, or maintenance of the sexual disorder, and 2) a general medical condition or substance use is also judged to be contributory but is not sufficient to account for a sexual disorder (Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision. Washington DC, American Psychiatric Association, 2000).  
      The compounds of formula (I) and the compounds (I.a), (I.b), (I.c), (I.d), (I.e), (I.f), (I.g) and (I.h), can be used either as free base or in form of its pharmaceutically acceptable acid addition salts. The term “acceptable acid addition salts includes both organic and inorganic acids such as maleic, citric, tartaric, methanesulphonic, acetic, benzoic, succinic, gluconic, isethionic, glycinic, lactic, malic, mucoic, glutamic, sulphamic and ascorbic acid; inorganic acids include hydrochloric, hydrobromic, nitric, sulfuric, or phosphoric acid, and mixtures thereof.  
      The compounds of formula (I) and the compounds (I.a), (I.b), (I.c), (I.d), (I.e), (I.f), (I.g) and (I.h), optionally used in form of its pharmaceutically acceptable acid addition salts, may be incorporated into the conventional pharmaceutical preparation in solid, liquid or spray form. The composition may, for example, be presented in a form suitable for oral, rectal, parenteral administration or for nasal inhalation: preferred forms includes for example, capsules, tablets, coated tablets, ampoules, suppositories and nasal spray.  
      The active ingredient may be incorporated in excipients or carriers conventionally used in pharmaceutical compositions such as, for example, talc, arabic gum, lactose, gelatine, magnesium stearate, corn starch, acqueous or non acqueous vehicles, polyvynil pyrrolidone, semisynthetic glycerides of fatty acids, benzalconium chloride, sodium phosphate, EDTA, polysorbate 80. The compositions are advantageously formulated in dosage units, each dosage unit being adapted to supply a single dose of the active ingredient. The dosis range applicable per day is between 0.1 to 400, preferably between 1.0 to 300, more preferably between 2 to 200 mg. Each dosage unit may conveniently contain from 0,01 mg to 100 mg, preferably from 0,1 to 50 mg.  
      Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.  
      Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number or layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.  
      Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. of. a flavouring such as vanilline or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.  
      Solutions for injection are prepared in the usual way, e.g. of. with the addition of preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, and transferred into injection vials or ampoules.  
      Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.  
      Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.  
      The Examples which follow illustrate the present invention without restricting its scope: 
    
    
     EXAMPLES OF PHARMACEUTICAL FORMULATIONS  
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                   
               
               
                   
                 A) Tablets 
                 per tablet 
               
               
                   
                   
               
             
            
               
                   
                 compound (I. a) 
                 100 mg 
               
               
                   
                 lactose 
                 240 mg 
               
               
                   
                 corn starch 
                 340 mg 
               
               
                   
                 polyvinylpyrrolidone 
                  45 mg 
               
               
                   
                 magnesium stearate 
                  15 mg 
               
               
                   
                   
                 740 mg 
               
               
                   
                   
               
            
           
         
       
     
      The finely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the remaining corn starch and the magnesium stearate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size.  
                                                   B) Tablets   per tablet                          compound (I. b)   80 mg           corn starch   190 mg            lactose   55 mg           microcrystalline cellulose   35 mg           polyvinylpyrrolidone   15 mg           sodium-carboxymethyl starch   23 mg           magnesium stearate    2 mg               400 mg                       
 
      The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened. The sodium-carboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.  
                                                   C) Coated tablets   per coated tablet                          compound (I. c)   5 mg           corn starch   41.5 mg             lactose   30 mg            polyvinylpyrrolidone   3 mg           magnesium stearate   0.5 mg                 80 mg                       
 
      The active substance, corn starch, lactose and polyvinylpyrrolidone are thoroughly mixed and moistened with water. The moist mass is pushed through a screen with a 1 mm mesh size, dried at about 45° C. and the granules are then passed through the same screen. After the magnesium stearate has been mixed in, convex tablet cores with a diameter of 6 mm are compressed in a tablet-making machine. The tablet cores thus produced are coated in known manner with a covering consisting essentially of sugar and talc. The finished coated tablets are polished with wax.  
                                                   D) Capsules   per capsule                          compound (I. d)   150 mg           Corn starch   268.5 mg             Magnesium stearate    1.5 mg               420 mg                      
 
      The substance and corn starch are mixed and moistened with water. The moist mass is screened and dried. The dry granules are screened and mixed with magnesium stearate. The finished mixture is packed into size 1 hard gelatine capsules.  
                                               E) Ampoule solution                                                    compound (I. e)   50 mg           sodium chloride   50 mg           water for inj.    5 ml                      
 
      The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion.  
                                               F) Suppositories                                                    compound (I. f)    50 mg           solid fat   1650 mg               1700 mg                      
 
      The hard fat is melted. At 40° C. the ground active substance is homogeneously dispersed. It is cooled to 38° C. and poured into slightly chilled suppository moulds.