Abstract:
Disclosed are compounds of the formula:                            
     or the pharmaceutically acceptable acid addition salts thereof, wherein: 
     R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are the same or different and represent hydrogen, C 1 -C 6  alkyl, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C 1 -C 6  alkoxy, —O 2 CR′, —NHCOR′, —COR′, —SO m R′, where R′ is C 1 -C 6  alkyl and wherein m is 0, 1 or 2; or 
     R 1 , R 2 , R 3 , R4, R 5 , R 6 , R 7 , R 8  and R 9  independently represent —CONR′R″, or —NR′R″ where R′ and R″ independently represent hydrogen or C 1 -C 6  alkyl; 
     R 10  is hydrogen or C 1 -C 6  alkyl; and 
     R represents an aminoalkyl group; 
     which compounds are useful in the treatment of affective disorders such as schizophrenia, depression, Alzheimer&#39;s disease, movement disorders such as Parkinsonism and dystonia, and other disorders which respond to dopaminergic blockade such as substance abuse and obsessive compulsive disorders. Further, compounds of this invention may be useful in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents.

Description:
This is a continuation of application Ser. No. 09/264,448 filed Mar. 8, 1999, now U.S. Pat. No. 6,025,493, which is a continuation of Ser. No. 08/994,588 filed Dec. 19, 1997, now U.S. Pat. No. 5,883,257, which is a continuation of application Ser. No. 08/619,351 filed Mar. 21, 1996, now U.S. Pat. No. 5,703,235. 
    
    
     SUMMARY OF THE INVENTION 
     This invention provides novel compounds of Formula I which interact with dopamine receptor subtypes. Thus, the invention provides compounds of general Formula I useful in the treatment and/or prevention of various neuropsychological disorders. The invention also provides pharmaceutical compositions comprising compounds of Formula 1. 
     The invention further relates to the use of such compounds and compositions in the treatment of affective disorders such as schizophrenia, depression, Alzheimer&#39;s disease and certain movement disorders such as Parkinsonism and dystonia. Compounds of this invention are also useful in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents. Further, the compounds of the present invention are useful for the treatment of other disorders which respond to dopaminergic blockade such as substance abuse and obsessive compulsive disorder. 
     Since dopamine D 3  receptors are concentrated in the limbic system (Taubes, Science, 265: 1034 (1994)) which controls cognition and emotion, compounds which interact with these receptors also have utility in the treatment of cognitive disorders. Such disorders include cognitive deficits which are a significant component of the negative symptoms (social withdrawal and unresponsiveness) of schizophrenia. Other disorders involving memory impairment or attention deficit disorders can also be treated with the compounds of this invention that interact specifically with the dopamine D 3  receptor subtype. 
     Furthermore, compounds of this invention may be useful in treatment of depression, memory-impairment or Alzheimer&#39;s disease by modulation of D 3  receptors which selectively exist in limbic area known to control emotion and cognitive functions. The compounds of the present invention are also useful for the treatment of other disorders which respond to dopaminergic blockade such as substance abuse (Caine and Koob, Science, 260: 1814 (1993)) and obsessive compulsive disorder (Goodman et al., Clin. Psychopharmacol., 7: 35 (1992)). The interaction of the compounds of the invention with dopamine receptor subtypes is demonstrated below. This interaction results in the pharmacological activities of these compounds. 
     Accordingly, a broad embodiment of the invention is directed to a compound of Formula I:                           
     or the pharmaceutically acceptable acid addition salts thereof, wherein: 
     R 1 -R 9  are the same or different and represent hydrogen, C 1 -C 6  alkyl, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C 1 -C 6  alkoxy, —O 2 CR′, —NHCOR′, —COR′, —SO m R′, where R′ is C 1 -C 6  alkyl and wherein m is 0, 1 or 2; or 
     R 1 -R 9  independently represent —CONR′R″, or —NR′R″ where R′ and R″ independently represent hydrogen or C 1 -C 6  alkyl; 
     R 10  is hydrogen or C 1 -C 6  alkyl; and 
     R represents an arinoalkyl group. 
     Thus, the invention relates to the use of compounds of formula I in the treatment and/or prevention of neuropsychochological disorders including, but not limited to, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, memory impairment, cognitive deficits, Parkinson-like motor disorders and motion disorders related to the use of neuroleptic agents. 
     Accordingly, a broad embodiment of the invention is directed to a compound of Formula I:                           
     or the pharmaceutically acceptable acid addition salts thereof, wherein: 
     R 1 -R 9  are the same or different and represent hydrogen, C 1 -C 6  alkyl, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C 1 -C 6  alkoxy, —O 2 CR′, —NHCOR′, —COR′, —SO m R′, where R′ is C 1 -C 6  alkyl and wherein m is 0, 1 or 2; or 
     R 1 -R 9  independently represent —CONR′R″, or —NR′R″ where R′ and R″ independently represent hydrogen or C 1 -C 6  alkyl; 
     R 10  is hydrogen or C 1 -C 6  alkyl; and 
     R represents an aminoalkyl group. 
     Thus, the invention relates to the use of compounds of formula I in the treatment and/or prevention of neuropsychochological disorders including, but not limited to, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, memory impairment, cognitive deficits, Parkinson-like motor disorders and motion disorders related to the use of neuroleptic agents. 
     DETAILED DESCRIPTION OF THE INVENTION 
     In addition to compounds of general formula I described above, the invention encompasses compounds of general formula IA:                           
     wherein: 
     R 1 -R 10  are as defined above; and 
     R represents an aminoalkyl group of the formula                           
     where 
     A represents an alkylene group of 2 to 6 carbon atoms optionally substituted with one or more alkyl groups having from 1 to 4 carbon atoms, 
     Z is N or C; 
     R 11  and R 12  are the same or different and represent hydrogen or C 1 -C 6  alkyl; or 
     R 11  and R 12  together with the the 6-membered ring to which they are attached form a 5 to 8-membered ring, and 
     W is phenyl, naphthyl, 1-(5,6,7,8-tetrahydro)naphthyl or 4-(1,2-dihydro)indenyl, pyndinyl, pynmidyl, isoquinolinyl, quinolinyl, benzofuranyl, benzothienyl; each of which is optionally substituted with up to three groups independently selected from halogen, C 1 -C 6  alkyl, C 1 -C 4  alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy. 
     Preferred compounds of formula IA include those where R 1 -R 9  are hydrogen and A is alkylene of 3-5 carbon atoms. 
     In addition to compounds of general formula I described above, the invention encompasses compounds of general formula IB:                           
     wherein: 
     R 1 -R 12  are as defined above; and 
     A, Z and W are as defined above. 
     The present invention further encompasses compounds of Formula II:                           
     wherein R 1 -R 612 , A, and W are as defined above. 
     Preferred compounds of formula II are those where R 1 -R 9  are hydrogen; A is C 3 -C 5  alkylene; and W is naphthyl or phenyl optionally substituted with up to three groups independently selected from halogen, C 1 -C 6  alkyl, C 1 -C 4  alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy. More preferred compounds of formula II are those where R 1 -R 10  are hydrogen; A is C 3 -C 5  alkylene; and W is naphthyl or phenyl optionally substituted with up to two groups in the 2 and/or 3 and/or 6 positions (relative to the point of attachment of the phenyl group to the piperazine ring), the groups being independently selected from halogen, C 1 -C 4  alkyl, and C 1 -C 4  alkoxy. Particularly preferred compounds of formula II are those where R 1 -R 10  are hydrogen; A is C 4  alkylene; and W is naphthyl or phenyl optionally substituted with up to two groups in the 2 and/or 3 and/or 6 positions (relative to the point of attachment of the phenyl group to the piperazine ring), the groups being independently selected from chloro, methyl, and methoxy. 
     The present invention further encompasses compounds of Formula III:                           
     wherein R 1 -R 12 , A, and W are as defined above. 
     Preferred compounds of formula III are those where R 1 -R 10  are hydrogen; A is C 3 -C 5  alkylene, more preferably butylene; and W is naphthyl or phenyl optionally substituted with up to three groups independently selected from halogen, C 1 -C 6  alkyl, C 1 -C 4  alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy. Particularly preferred compounds of formula III are those where R 1 -R 10  are hydrogen; A is C 3 -C 5  alkylene, more preferably butylene; and W is phenyl or naphthyl. 
     The invention also provides compounds of Formula IV                           
     where 
     R 10  is hydrogen or C 1 -C 4  alkyl; 
     A represents alkylene group of 2 to 6 carbon atoms; 
     Z is nitrogen or carbon; and 
     W is phenyl or naphthyl, each of which is optionally substituted with up to three groups independently selected from halogen, C 1 -C 6  alkyl, C 1 -C 4  alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy. 
     Preferred compounds of formula IV are those where R 10  is hydrogen and A is C 3 -C 5  alkylene. More preferred compounds of formula IV are those where R 10  is hydrogen; A is C 4  alkylene; Z is nitrogen; and W is naphthyl or phenyl optionally substituted with up to two groups in the 2 and/or 3 and/or 6 positions (relative to the point of attachment of the phenyl group to the 6 membered nitrogen-containing ring), the groups being independently selected from halogen, C 1 -C 4  alkyl, and C 1 -C 4  alkoxy. 
     The invention also provides compounds of Formula V                           
     where 
     R 10  is hydrogen or C 1 -C 4  alkyl; 
     A represents alkylene group of 2 to 6 carbon atoms; and 
     W is phenyl or naphthyl, each of which is optionally substituted with up to three groups independently selected from halogen, C 1 -C 6  alkyl, C 1 -C 4  alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy. 
     Preferred compounds of formula V are those where R 10  is hydrogen and A is C 3 -C 5  alkylene. More preferred compounds of formula V are those where R 10  is hydrogen; A is C 4  alkylene; and W is naphthyl or phenyl optionally substituted with up to two groups in the 2 and/or 3 positions and/or 6 positions (relative to the point of attachment of the phenyl group to the 6-membered nitrogen-containing ring), the groups being independently selected from halogen, C 1 -C 4  alkyl, and C 1 -C 4  alkoxy. 
     The invention also provides compounds of Formula VI                           
     where 
     R 10  is hydrogen or C 1 -C 4  alkyl; 
     A represents alkylene group of 2 to 6 carbon atoms; and 
     W is phenyl or naphthyl, each of which is optionally substituted with up to three groups independently selected from halogen, C 1 -C 6  alkyl, C 1 -C 4  alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy. 
     Preferred compounds of formula VI are those where R 10  is hydrogen and A is C 3 -C 5  alkylene. More preferred compounds of formula VI are those where R 10  is hydrogen; A is C 4  alkylene; and W is naphthyl or phenyl optionally substituted with up to two groups in the 2 and/or 3 positions and/or 6 positions (relative to the point of attachment of the phenyl group to the 6-membered nitrogen-containing ring), the groups being independently selected from halogen, C 1 -C 4  alkyl, and C 1 -C 4  alkoxy. 
     When a compound of the invention is obtained as a mixture of enantiomers, these enantiomers may be separated, when desired, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, for example using a chiral HPLC column. 
     Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to the compounds in Table 1 and their pharmaceutically acceptable salts. The present invention also encompasses prodrugs, e.g., acylated prodrugs, of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and prodrugs of the compounds encompassed by Formula I. 
     Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to the compounds in Table 1 and their pharmaceutically acceptable salts. Non-toxic pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tararic, maleic, hydroiodic, alkanoic such as acetic, HOOC—(CH 2 ) n —COOH where n is 0-4, and the like. Those skilled in the art will recognize a Aide variety of non-toxic pharmaceutically acceptable addition salts. 
     The following numbering system is used to identify positions on the anthracenecarboxamide portion of the compounds of the invention:                           
     By “alkyl” and “lower alkyl” is meant straight and branched chain alkyl groups having from 1-6 carbon atoms, e.g., C 1 -C 6  alkyl. 
     By “lower alkoxy” and “alkoxy” is meant straight and branched chain alkoxy groups having from 1-6 carbon atoms, e.g., C 1 -C 6  alkoxy. 
     By halogen is meant fluorine, chlorine, bromine and iodine. 
     The amino portion of the aminoalkyl group represented by R above includes groups represented by the formula Q                           
     where W is defined above. 
     Th formula Q represents saturated heterocyclic ring systems such as, for example, piperidinyl and piperazinyl, as well as unsaturated heterocyclic ring systems such as, for example, 1, 2, 3, 6-tetrahydropyindine. Preferred Q groups are the following:                           
     where W is defined above. 
     Particularly preferred W groups of the invention are phenyl optionally substituted with up to two substituents independently selected from halogen, C 1 -C 4  alkyl, and C 1 -C 4  alkoxy. These optional phenyl substituents are preferably in the 2 and/or 3 and/or 6 positions of the phenyl group relative to the point of attachment of the phenyl group to the 6-membered nitrogen containing ring. 
     Representative examples of N-Aminoalkylanthracenecarboxamides according to the invention are shown in Table 1 below. The number below each compound is its compound number. Each of these compounds may be prepared according to the general reaction Scheme I set forth below. 
     The compounds in Table 1 have the following general formula A:                           
     where R and R 10  are defined in the table. 
     
       
         
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                 Co- 
                   
                   
               
               
                 mound 
               
               
                 Number 
                 R 5   
                 R 
               
               
                   
               
             
             
               
                 1 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 2 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 3 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 4 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 5 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 6 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 7 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
     Particular compounds according to the invention include: 
     N-{4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butyl}-2-anthracenecarboxamide hydrochloride 
     N-{4-[4-(1-Naphthyl)-1-piperazinyl]butyl}-2-anthracenecarboxamide hydrochloride 
     N-{4-[4-(2,3-Dimethylphenyl)-1-piperazinyl]butyl}-2-anthracenecarboxamide hydrochloride 
     N-{4-[4-(2-Methylphenyl)-1-piperazinyl]butyl}1-2-anthracenecarboxamide hydrochloride 
     N-{4-[4-(2-Chlorophenyl)-1-piperazinyl]butyl}-2-anthracenecarboxamide hydrochloride 
     N-{4-[4-(2-Methoxyphenyl)-1-piperazinyl]butyl}-2-anthracenecarboxamide hydrochloride 
     N-{4-[4-(8-Isoquinolinyl)-1-piperazinyl]butyl}-2-anthracenecarboxamide hydrochloride 
     N-{4-[4-Phenyl-1-(1,2,3,6tetrahydropyridinyl)]butyl}-2-anthracenecarboxamide hydrochloride 
     N-{4-[4(3-Chloro-2-methylphenyl)-1-piperazinyl]butyl}-2-anthracenecarboxamide hydrochloride 
     N-{4-[4(1-Naphthyl)-1-(1,2,3,6tetrahydropyridinyl)]butyl}-2-anthracene-carboxamide hydrochloride 
     N-{4-[4-Phenyl-1-piperidinyl)]butyl}-2-anthracenecarboxamide hydrochloride 
     The invention also pertains to the use of compounds of general Formula I in the treatment of neuropsychological disorders. The pharmaceutical utility of compounds of this invention are indicated by the following assays for dopamine receptor subtype affinity. 
     Assay for D 2  AND D 3  Receptor Binding Activity 
     Pellets of COS cells containing recombinantly produced D 2  or D 3  receptors from African Green monkey were used for the assays. The sample is homogenized in 100 volumes (w/vol) of 0.05 M Tris HCl buffer at 4° C. and pH 7.4. The sample is then centrifuged at 30,000×g and resuspended and rehomogenized. The sample is then centrifuged as described and the final tissue sample is frozen until use. The tissue is resuspended 1:20 (wt/vol) in 0.05 M Tris HCl buffer containing 100 mM NaCl. 
     Incubations are carried out at 48° C. and contain 0.4 ml of tissue sample, 0.5 nM  3 H-YM 09151-2 and the compound of interest in a total incubation of 1.0 ml. Nonspecific binding is defined as that binding found in the presence of 1 mM spiperone; without further additions, nonspecific binding is less than 20% of total binding. The binding characteristics of representative compounds of the invention for D 2  and D 3  receptor subtypes are shown in Table 2 for rat striatal homogenates. 
     
       
         
               
               
               
             
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                 Compound Number 1   
                 D 3  K i  (nM) 
                 D 2  K i  (nM) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 7 
                 1089 
               
               
                 2 
                 1.2 
                  550 
               
               
                   
               
               
                   1 Compound numbers relate to compounds shown above in Table 1.  
               
             
          
         
       
     
     The compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. 
     Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a lime delay material such as glyceryl monosterate or glyceryl distearate may be employed. 
     Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil. 
     Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. 
     Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid 
     Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. 
     Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid par or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the and partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents. 
     Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitor or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or weting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer&#39;s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. 
     The compounds of general Formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. 
     Compounds of general Formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. 
     Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient. 
     It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy. 
     Preparation of N-Aminoalkanthracenecarboxamides 
     The compounds of Formula I, and the pharmaceutically acceptable acid addition salts thereof, may be prepared according to the reactions shown below in Scheme 1.                           
     wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , A, Z and W are as defined above for Formula IA. 
     As shown, a compound of Formula VII may be activated by 1,1′-carbonyldiimidazole (CDI) or thionyl chloride (SOCl 2 ) or the like in solvents such as tetrahydrofuran or dichioromethane at room temperature. The resulting activated species may be subsequently reacted with the required compound of Formula VIII to afford a compound of Formula I as the desired product. 
     Where they are not commercially available, the compounds of Formula VII may be prepared by literature procedures or procedures analogous to those described in literature. The compounds of Formula VIII are either known or capable of being prepared by various methods known in the art. 
     Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention, as demonstrated by the following examples. In some cases protection of certain reactive functionalities may be necessary to achieve some of the above transformations. In general the need for such protecting groups will be apparent to those skilled in the art of organic synthesis as well as the conditions necessary to attach and remove such groups. 
     The disclosures in this application of all articles and references, including patents, are incorporated herein by reference. 
     The invention is illustrated further by the following examples which are not to be construed as limiting the invention in scope or spirit to the specific procedures described in them. These examples illustrate the presently preferred methods for preparing the compounds of the invention. 
    
    
     EXAMPLE 1 
     
       
                 
         
             
             
         
      
     
     N-{4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butyl}1-2-anthracenecarboxamide 
     A mixture of 2-anthracenecarboxylic acid (100 mg, 0.45 mmol) and 1,1′-carbonyldiimidazole (82 mg, 0.5 mmol) in 10 mL of anhydrous tetrahydrofuran is stirred for 8 hours. A solution of 4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-1-aminobutane (150 mg, 0.5 mmol) in 1 mL of tetrahydrofuran is added and the resulting mixture is stirred for 30 minutes. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is washed with aqueous Na 2 CO 3 , dried (Na 2 SO 4 ) and concentrated in vacuo to give the title compound (183 mg, 80%). The hydrochloride salt is prepared by treating the free base with ethyl acetate-HCl. The hydrochloride salt of the tide compound has a melting point of 245-247° C. 
     EXAMPLE 2 
     The following compounds of Formula I are prepared essentially according to the procedures set forth in Example 1 above. 
     (a) N-{4-[4-(1-Naphthyl)-1-piperazinyl]butyl}-2-anthracenecarboxamide hydrochloride (mp 236-238° C.) 
     (b) N-{4-[4(2,3-Dimethylphenyl)-1-piperazinyl]butyl}-2-anthracenecarboxamide hydrochloride (mp 244-246° C.) 
     (c) N-{4-[4(2-Methylphenyl)-1-piperazinyl]butyl}-2-anthracenecarboxamide hydrochloride (mp 213-215° C.) 
     (d) N-{4-[4(2-Chlorophenyl)-1-piperazinyl]butyl}-2-anthracenecarboxamide hydrochloride (mp 218-220° C.) 
     (e) N-{4-[4-(2-Methoxyphenyl)-1-piperazinyl]butyl}-2-anthracenecarboxamide dihydrochloride (mp 253-255° C.) 
     (f) N-{4-[4(8-Isoquinolinyl)-1-piperazinyl]butyl}-2-anthracenecarboxamide dihydrochloride (mp 235-237° C.) 
     (g) N-{4-[4-Phenyl-1-(1,2,3,6-tetrahydropyridinyl]butyl} -2-anthracenecarboxamide hydrochloride (mp 248-250° C.) 
     (h) N-{4-[4-(3-Chloro-2-methylphenyl)-1-piperazinyl]butyl}-2-anthracenecarboxamide dihydrochloride (mp 247-249° C.) 
     (i) N-{4-[4-(1-Naphthyl)-1-(1,2,3,6tetrahydropyridinyl)]butyl}-2-anthracene-carboxamide hydrochloride (mp 233-236° C.) 
     (j) N-{4-[4-Phenyl-1-piperidinyl)]butyl}-2-anthracenecarboxamide hydrochloride (mp 225-227° C.)