Treatment of cns disorders using cns target modulators

Abstract

The invention is directed to compositions used for treating Central Nervous System (CNS) disorders. In addition, the invention provides convenient methods of treatment of a CNS disorder. Furthermore, the invention provides methods of treating sleep disorders using compositions that remain active for a discrete period of time to reduce side effects. More specifically, the invention is directed to the compositions and use of derivatized, e.g., ester or carboxylic acid derivatized, antihistamine antagonists for the treatment of sleep disorders.

1 - 232 . (canceled)  
     
     
         233 . A method of treating a sleep disorder, comprising administering to a subject an effective amount of a therapeutic compound, such that the sleep disorder is treated, wherein the therapeutic compound comprises the formula:  
         [ AH]− ( SP ) n   −[DA]   
       wherein AH is a moiety that antagonizes a histamine receptor or a collection of histamine receptors, DA is a drug activity modulating moiety that provides the ability to modulate the activity of the therapeutic compound, selected from an ester, an alcohol, or an acid, and SP is a spacer molecule, (CH 2 ) m , where m is 1 to 20, and n is 0 or 1.  
     
     
         234 . The method of  claim 233 , wherein the DA does not substantially effect the biological activity of said AH compound.  
     
     
         235 . The method of  claim 233 , wherein the DA significantly effects the biological activity of said AH compound.  
     
     
         236 . The method of  claim 235 , wherein the DA improves the biological activity of said AH compound.  
     
     
         237 . A method of treating a sleep disorder, comprising administering to a subject an effective amount of a therapeutic compound of  claim 233 , such that the sleep disorder is treated, wherein the therapeutic compound has a favorable biological property (FBP).  
     
     
         238 . The method of  claim 237 , wherein the FBP is selected from the group consisting of penetration through the blood brain barrier into the central nervous system (CNS), sequestration of the compound in the CNS as a result of in vivo hydrolysis of an ester by esterases, modification of the half-life of the therapeutic compound, and any combination thereof.  
     
     
         239 . The method of  claim 237 , wherein the favorable biological property is selected from the group consisting of alteration of charge, pharmacology-kinetics, log P by a value of 1 or more, and any combination thereof.  
     
     
         240 . The method of  claim 237 , wherein the favorable biological property is selected from the group consisting of increased receptor selectivity, reduced peripheral half-life, the ability to increase dosage, increased peripheral elimination, decreased anti-muscarinic activity, decreased anti-cholinergic, or any combination thereof, relative to the original AH compound.  
     
     
         241 . The method of  claim 237 , wherein the FBP is the discrete period of time that the therapeutic compound remains active in said subject.  
     
     
         242 . The method of  claim 237 , wherein the FBP is the induction of a discrete sleep or hypnotic state.  
     
     
         243 . The method of  claim 237 , wherein the FBP is the reduced ability of the subject to form a tolerance to the therapeutic compound.  
     
     
         244 . The method of  claim 237 , wherein the FBP is penetration through the blood brain barrier into the CNS.  
     
     
         245 . The method of  claim 244 , wherein the FBP is penetration through the blood brain barrier into the CNS due to the lipophilicity of substituents or conformational lipophilicity.  
     
     
         246 . The method of  claim 245 , wherein the conformational lipophilicity is a result of an internal salt formation between a carboxylate anion on the therapeutic compound and a protonated amine.  
     
     
         247 . The method of  claim 238 , wherein the FBP is modulation of the half-life of the therapeutic compound.  
     
     
         248 . The method of  claim 240 , wherein the favorable biological property of said AH compound is increased receptor selectivity relative to the original AH compound.  
     
     
         249 . The method of  claim 240 , wherein the favorable biological property of said AH compound is reduced peripheral half-life relative to the original AH compound.  
     
     
         250 . The method of  claim 240 , wherein the favorable biological property of said AH compound is the ability to increase dosage relative to the original AH compound.  
     
     
         251 . The method of  claim 240 , wherein the favorable biological property of said AH compound is increased peripheral elimination relative to the original AH compound.  
     
     
         252 . The method of  claim 237 , wherein the DA of said therapeutic compound is an acid, and has an FBP that includes increased concentration within the CNS for a discrete period of time as a result of the existence of an ionic bond that includes the carboxylate ion of the corresponding carboxylic acid.  
     
     
         253 . The method of  claim 237 , wherein the DA of said therapeutic compound is an ester and has an FBP that includes increased concentration within the CNS for a discrete period of time as a result of a slower rate of conversion to the corresponding carboxylic acid by in vivo esterase activity within the CNS as compared with the periphery.  
     
     
         254 . The method of  claim 253 , wherein said acid is not a therapeutically active agent for treating disorders.  
     
     
         255 . The method of  claim 237 , wherein the DA of said compound is an ester or an alcohol, and is more active as a therapeutic agent for treating disorders than said compound having an acid DA.  
     
     
         256 . The method of  claim 242 , wherein the therapeutic compound induces a discrete sleep or hypnotic state by penetration into the Central Nervous System (CNS).  
     
     
         257 . The method of  claim 233 , wherein the sleep disorder is selected from the group consisting of insomnia, hypersomnia, narcolepsy, sleep apnea syndromes, parasomnia, restless leg syndrome, and circadian rhythm abnormality.  
     
     
         258 . The method of  claim 233 , wherein the sleep disorder is insomnia.  
     
     
         259 . The method of  claim 233 , wherein the sleep disorder is hypersomnia.  
     
     
         260 . The method of  claim 233 , wherein the sleep disorder is narcolepsy.  
     
     
         261 . The method of  claim 233 , wherein the sleep disorder is circadian rhythm abnormality.  
     
     
         262 . The method of  claim 261 , wherein the circadian rhythm abnormality is selected from the group consisting of jet lag, shift-work disorders, and delayed or advanced sleep phase syndrome.  
     
     
         263 . The method of  claim 233 , wherein the (CH 2 ) m  spacer molecule is substituted with one or more substituents.  
     
     
         264 . The method of  claim 263 , wherein the spacer molecule is disubstituted.  
     
     
         265 . The method of  claim 264 , wherein the spacer molecule is geminally-dialkylated.  
     
     
         266 . The method of  claim 265 , wherein the spacer molecule is geminally-dimethylated.  
     
     
         267 . The method of  claim 263 , wherein the spacer molecule is singly substituted with a substituent other than a noncyclic alkyl group.  
     
     
         268 . The method of  claim 263 , wherein the spacer molecule is substituted with a heteroatom or a cyclic substituent.  
     
     
         269 . The method of  claim 268 , wherein the cyclic substituent is a cyclic alkyl or a cyclic ether.  
     
     
         270 . The method of  claim 233 , further comprising administering the therapeutic compound in a pharmaceutically acceptable vehicle.  
     
     
         271 . The method of  claim 233 , wherein said therapeutic compound is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       wherein a is 0 through 5, b is 0 through 5, and R is H or any group which imparts properties to the therapeutic compound to promote penetration into the CNS and to modify the half-life of the compound.  
     
     
         272 . The method of  claim 233 , wherein said therapeutic compound is:  
       
         
           
           
               
               
           
         
       
       wherein d is 0 through 5, e is 0 through 4, the dashed line represents a single or double bond, and R is H or any group which imparts properties to the therapeutic compound to promote penetration into the CNS and to modify the half-life of the compound.  
     
     
         273 . The method of  claim 233 , wherein said therapeutic compound is:  
       
         
           
           
               
               
           
         
         wherein f is 0 through 5, the dashed line represents a single or double bond, and R is H or any group which imparts properties to the therapeutic compound to promote penetration into the CNS and to modify the half-life of the compound.  
       
     
     
         274 . The method of  claim 233 , wherein said therapeutic compound is:  
       
         
           
           
               
               
           
         
       
       wherein 
 the dashed line represents a single or double bond;  
 R is H or any group which imparts properties to the therapeutic compound to promote penetration into the CNS and to modify the half-life of the compound;  
 R 1 ═H, OH, CH 2 OH, CH 2 CH 2 OH;  
 R 2 ═H, CH 3 , CF 3 , Cl, Br; and  
 n is 1, 2, or 3.  
 
     
     
         275 . The method of  claim 274 , wherein the (CH 2 ) n  spacer molecule to the carboxyl group is substituted with one or more substituents.  
     
     
         276 . The method of  claim 275 , wherein the spacer molecule is disubstituted.  
     
     
         277 . The method of  claim 275 , wherein the spacer molecule is geminally-dialkylated.  
     
     
         278 . The method of  claim 275 , wherein the spacer molecule is geminally-dimethylated.  
     
     
         279 . The method of  claim 275 , wherein the spacer molecule is singly substituted with a substituent other than a noncyclic alkyl group.  
     
     
         280 . The method of  claim 279 , wherein the spacer molecule is substituted with a heteroatom or a cyclic substituent.  
     
     
         281 . The method of  claim 280 , wherein the cyclic substituent is a cyclic alkyl or a cyclic ether.  
     
     
         282 . The method of  claim 233 , wherein said therapeutic compound is:  
       
         
           
           
               
               
           
         
       
       wherein c is 0 through 5, and R is H or any group which imparts properties to the therapeutic compound to promote penetration into the CNS and to modify the half-life of the compound.  
     
     
         283 . The method of  claim 271 , wherein a is 0 or 1 and b is 0 or 1.  
     
     
         284 . The method of  claim 272 , wherein d is 0 or 1 and e is 0 or 1.  
     
     
         285 . The method of  claim 273 , wherein f is 0 or 1.  
     
     
         286 . The method of  claim 282 , wherein c is 0 or 1.  
     
     
         287 . The method of  claim 271 , wherein R is selected from the group consisting of hydrocarbons and perfluorocarbons.  
     
     
         288 . The method of  claim 287 , wherein the hydrocarbons are selected from the group consisting of linear, branched, cyclic, aromatic, and a combination of aliphatic and aromatic, which are optionally substituted with O, N, S, or halogens.  
     
     
         289 . The method of  claim 287 , wherein the hydrocarbons contain from 1 to 10 carbons.  
     
     
         290 . The method of  claim 271 , wherein R is selected from the group consisting of a methyl, an ethyl, an n-propyl, an isopropyl, a cyclopropyl, a t-butyl, an isobutyl, a cyclopentyl, a cyclohexyl, a cycloheptyl, and a benzyl group.  
     
     
         291 . A sleep disorder target modulator having a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       wherein a is 0 through 5, b is 0 through 5, and R is H or any group which imparts properties to the therapeutic compound to promote penetration into the CNS and to modify the half-life of the compound.  
     
     
         292 . A sleep disorder target modulator having the formula:  
       
         
           
           
               
               
           
         
       
       wherein d is 0 through 5, e is 0 through 4, the dashed line represents a single or double bond, and R is H or any group which imparts properties to the therapeutic compound to promote penetration into the CNS and to modify the half-life of the compound.  
     
     
         293 . A sleep disorder target modulator having the formula:  
       
         
           
           
               
               
           
         
       
       wherein f is 0 through 5, the dashed line represents a single or double bond, and R is H or any group which imparts properties to the therapeutic compound to promote penetration into the CNS and to modify the half-life of the compound.  
     
     
         294 . A sleep disorder target modulator having the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 the dashed line represents a single or double bond;  
 R is H or any group which imparts properties to the therapeutic compound to promote penetration into the CNS and to modify the half-life of the compound;  
 R 1 ═H, OH, CH 2 OH, CH 2 CH 2 OH;  
 R 2 ═H, CH 3 , CF 3 , Cl, Br; and  
 n is 1, 2, or 3.  
 
     
     
         295 . The method of  claim 294 , wherein the (CH 2 ) n  spacer molecule to the carboxyl group is substituted with one or more substituents.  
     
     
         296 . The method of  claim 295 , wherein the spacer molecule is disubstituted.  
     
     
         297 . The method of  claim 295 , wherein the spacer molecule is geminally-dialkylated.  
     
     
         298 . The method of  claim 295 , wherein the spacer molecule is geminally-dimethylated.  
     
     
         299 . The method of  claim 295 , wherein the spacer molecule is singly substituted with a substituent other than a noncyclic alkyl group.  
     
     
         300 . The method of  claim 299 , wherein the spacer molecule is substituted with a heteroatom or a cyclic substituent.  
     
     
         301 . The method of  claim 300 , wherein the cyclic substituent is a cyclic alkyl or a cyclic ether.  
     
     
         302 . A sleep disorder target modulator having the formula:  
       
         
           
           
               
               
           
         
       
       wherein c is 0 through 5, and R is H or any group which imparts properties to the therapeutic compound to promote penetration into the CNS and to modify the half-life of the compound.  
     
     
         303 . The sleep disorder target modulator of  claim 291 , wherein a is 0 or 1 and b is 0 or 1.  
     
     
         304 . The sleep disorder target modulator of  claim 292 , wherein d is 0 or 1 and e is 0 or 1.  
     
     
         305 . The sleep disorder target modulator of  claim 293 , wherein f is 0 or 1.  
     
     
         306 . The sleep disorder target modulator of  claim 302 , wherein c is 0 or 1.  
     
     
         307 . The sleep disorder target modulator of  claim 291 , wherein R is selected from the group consisting of hydrocarbons and perfluorocarbons.  
     
     
         308 . The sleep disorder target modulator of  claim 307 , wherein the hydrocarbons are selected from the group consisting of linear, branched, cyclic, aromatic, and a combination of aliphatic and aromatic, which are optionally substituted with O, N, S, or halogens.  
     
     
         309 . The sleep disorder target modulator of  claim 307 , wherein the hydrocarbons contain from 1 to 10 carbons.  
     
     
         310 . The sleep disorder target modulator of  claim 291 , wherein R is selected from the group consisting of a methyl, an ethyl, an n-propyl, an isopropyl, a cyclopropyl, a t-butyl, an isobutyl, a cyclopentyl, a cyclohexyl, a cycloheptyl, and a benzyl group.  
     
     
         311 . The sleep disorder target modulator of  claim 294 , wherein R 1  and R 2  are not both H when the alkylene spacer molecule is unsubstituted.  
     
     
         312 . The sleep disorder target modulator of  claim 294 , with the proviso that the compound is not a compound of Formula VI when the alkylene spacer molecule is unsubstituted, and R 1  and R 2  are selected from the group consisting of H, halogen CF 3 , OH, C 1-6  alkyl, C 1-6  alkoxy.  
     
     
         313 . The sleep disorder target modulator of  claim 294 , wherein n is not 2 or 3 when the spacer molecule is unsubstituted.  
     
     
         314 . The sleep disorder target modulator of  claim 291 , wherein R is a bulky alkyl group.  
     
     
         315 . The sleep disorder target modulator of  claim 314 , wherein the bulky alkyl group is a Type B alkyl of Table 1.  
     
     
         316 . The sleep disorder target modulator of  claim 314 , wherein the bulky alkyl group is a Type A alkyl of Table 1.  
     
     
         317 . A sleep disorder target modulator selected from the compounds depicted in Table 2 and Table 3.  
     
     
         318 . The method of  claim 233 , wherein the therapeutic compound is selected from the group consisting of the compounds in Table 2.  
     
     
         319 . The method of  claim 233 , wherein the therapeutic compound is selected from the group consisting of the compounds in Table 3.