Methods of treating a subject using bioreversible derivatives of hydroxy n-substituted-2-aminotetralins

Abstract

Described are compositions that may be orally administered that comprise a bioreversible derivative of hydroxy N-substituted-2-aminotetralin or an enantiomer or salt or prodrug thereof, and a pharmaceutically acceptable carrier suitable for oral administration in the amount present, wherein the composition is orally bioavailable when administered to a subject. The bioreversible derivative has an intrinsic lipophilicity C log P value of about 7 to about 11.5. A method comprises oral administering such composition to a human subject in need of hydroxy N-substituted-2-aminotetralin therapy.

1 . A method of treating a subject for at least one syndrome selected from the group consisting of Parkinson's disease and restless leg syndrome, wherein the method comprising:
 orally administering a composition to the subject, wherein the composition comprises:
 a bioreversible derivative of a compound of formula (I) or an enantiomer or salt or prodrug thereof, 
   
       
         
           
           
               
               
           
         
         wherein R a  is selected from the group consisting of H, 2-thiophen-2-ylethyl, and n-propyl; and 
         a pharmaceutically acceptable carrier, 
         wherein the bioreversible derivative has an intrinsic lipophilicity C log P value of about 7 to about 11.5. 
       
     
     
         2 . The method of  claim 1 , wherein the bioreversible derivative has an intrinsic lipophilicity C log P value of about 8 to about 11, or about 8.5 to about 10.5. 
     
     
         3 . The method of  claim 1 , wherein the compound of formula (I) is selected from the group consisting of (S)-6-[propyl(2-thiophen-2-ylethyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol compound of formula (IA), (6S)-(+5-hydroxy-N-propyl-2-aminotetralin compound of formula (IB), 8-hydroxy-N,N-dipropyl-2-aminotetralin compound of formula (IC), 5-hydroxy-N,N-dipropyl-2-aminotetralin compound of formula (ID), and 7-hydroxy-N,N-dipropyl-2-aminotetralin compound of formula (1E). 
       
         
           
           
               
               
           
         
       
     
     
         4 . The method of  claim 1 , wherein the bioreversible derivative has the following structure: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, aralkyl, acyl, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acetal, ketal, —C(O)NR 2 R 3 , —C(O)NHR 2 , —S(O) 2 R 2 , —S(O) 2 OR 2 , —P(O 2 H)OR 2 ; 
         R 2  and R 3  are independently selected from the group consisting of H, C 1-16  alkyl or alkenyl or alkynyl, C 3-16  cycloalkyl or cycloalkenyl or cycloalkynl, benzyl, and phenyl. 
       
     
     
         5 . The method of  claim 1 , wherein the bioreversible derivative has the following structure: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from the group of C 6-14  alkylcarbonyl, C 3-14  cycloalkylcarbonyl, benzoyl, —C(O)NR 2 R 3 , and —C(O)NHR 2 , and 
         R 2  and R 3  are independently selected from the group consisting of C 1-12  alkylcarbonyl, and C 3-12  cycloalkylcarbonyl. 
       
     
     
         6 . The method of  claim 1 , wherein the bioreversible derivative or its salt, when administered to the subject, is cleaved, processed or metabolized to (S)-6-[propyl(2-thiophen-2-ylethyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol, or a prodrug or metabolite thereof. 
     
     
         7 .- 14 . (canceled) 
     
     
         15 . A method of treating a subject in need of (S)-6-[propyl(2-thiophen-2-ylethyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol therapy, the method comprising:
 orally administering an oral unit dosage form to the subject to provide a daily dose of the (S)-6-[propyl(2-thiophen-2-ylethyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol, or the prodrug or salt or enantiomer thereof, of about 0.5 mg to about 400 mg of the (S)-6-[propyl(2-thiophen-2-ylethyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol equivalent, based on single unit or multiple unit oral dosing,   wherein the oral unit dosage form comprises a 5-hydroxy bioreversible derivative of (S)-6-[propyl(2-thiophen-2-ylethyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol, or an enantiomer or salt or prodrug thereof and a pharmaceutically acceptable carrier, the 5-hydroxy bioreversible derivative having an intrinsic lipophilicity C log P value of about 7 to about 11.5.   
     
     
         16 . The method of  claim 15 , wherein the oral unit dosage form provides a mean serum rotigotine or its metabolite Cmax value in the subject of at least about 0.04 ng/ml after single dose. 
     
     
         17 . The method of  claim 15 , wherein the oral unit dosage form provides a mean serum rotigotine or its metabolite Cmax/mg value in the subject of at least about 1.0×10 −10  ml −1 . 
     
     
         18 . The method of  claim 15 , wherein the oral unit dosage form provides a mean Css-max/mg value in the subject of at least about 2.5×10 −10  ml −1 . 
     
     
         19 . The method of  claim 15 , wherein the oral unit dosage form provides a serum rotigotine or its metabolite Cavg value in the subject of at least about 0.04 ng/ml. 
     
     
         20 . The method of  claim 15 ,
 wherein the dosage form provides a mean serum AUC 0-24  of (S)-6-[propyl(2-thiophen-2-ylethyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol of at least about 0.5 ng·hr·ml −1  after a single dose oral administration with a meal.   
     
     
         21 . The method of  claim 15 , wherein the oral unit dosage form provides a mean serum (S)-6-[propyl(2-thiophen-2-ylethyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol AUC 0-24  per mg of the 5-hydroxy bioreversible derivative equivalent administered of at least about 1.25×10 −9  hr. ml −1 . 
     
     
         22 . The method of  claim 15 , wherein
 the oral unit dosage form provides a mean serum AUC 0-24  of (S)-6-[propyl(2-thiophen-2-ylethyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol of no greater than about 94 ng·hr·ml −1 , upon single dose oral administration to the mammal subject.   
     
     
         23 . The method of  claim 15 , wherein the oral unit dosage form is orally administered to the subject with a meal that comprises at least about 15 g of fat. 
     
     
         24 . A method of treating a subject for at least one of the following symptoms: depression, pain, anxiety disorders, sexual dysfunctions, glaucoma, cognitive disorders, restless leg syndrome, restless limb disorder, neurodevelopmental type disorder, attention deficit hyperactivity syndrome (ADHS), attention deficit hyperactivity disorder (ADHD), hyperkinetic disorder, obsessive compulsive disorder, impulsive disorder, hyperprolactinemia, hyperprolactinoma, eating disorders, neurodegenerative disorder, Parkinson-associated movement disorders, dopa- and neuroleptic-induced/sensitive movement disorders, galactorrhea, ovarian hyperstimulation disorder, neuroleptic-induced (tardive) dyskinesia, dystonia, akathisia, Parkinson plus syndrome, and addiction to cocaine, alcohol, opiate or nicotine, the method comprising:
 orally administering a composition to the subject, wherein the composition comprises:
 a bioreversible derivative of hydroxy N-substituted-2-aminotetralin, or an enantiomer, or salt or prodrug thereof; and 
 a pharmaceutically acceptable carrier, 
 wherein the bioreversible derivative has an apparent lipophilicity log D 7.4  value at pH 7.4 of about 4 to about 9, and 
 wherein upon oral administration of the composition to the subject, at least about 1% of the hydroxy N-substituted-2-aminotetralin equivalent dose is bioavailable as hydroxy N-substituted-2-aminotetralin to the subject. 
   
     
     
         25 . The method of  claim 24 , wherein the hydroxy N-substituted-2-aminotetralin is selected from the group consisting of (S)-6-[propyl(2-thiophen-2-ylethyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol, (6S)-(−)-5-hydroxy-N-propyl-2 amino tetralin, 5-hydroxy-N,N-dipropyl-2-aminotetralin (5-OH-DPAT), 8-hydroxy-N,N-dipropyl-2-aminotetralin (8-OH-DPAT), and 7-hydroxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT). 
     
     
         26 .- 28 . (canceled) 
     
     
         29 . The method of  claim 24 , wherein the composition is administered with a meal. 
     
     
         30 . The method of  claim 24 , wherein the composition is administered with a meal that comprises at least about 15 g of fat.