US2008318997A1PendingUtilityA1

Novel 4-phenyl substituted tetrahydroisoquinolines and therapeutic use thereof

Assignee: AMR TECHNOLOGY INCPriority: Jul 11, 2000Filed: Aug 18, 2008Published: Dec 25, 2008
Est. expiryJul 11, 2020(expired)· nominal 20-yr term from priority
A61P 25/16C07D 493/04C07D 491/04C07D 495/04A61P 25/24A61P 25/00A61P 25/34A61P 25/22A61P 25/14C07D 491/048
63
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Claims

Abstract

Compounds are provided that, by way of their selective neurotransmitter binding useful for the treatment of various neurological and psychological disorders, e.g., ADHD. Such compounds are 4-phenyl substituted tetrahydroisoquinolines having the Formula IA, IB, IIA, IIB, IIIA or IIIC as set forth herein.

Claims

exact text as granted — not AI-modified
1 . A method of treating a subject with a neurological or psychological disorder selected from the group consisting of attention deficit-hyperactivity disorder, anxiety, post-traumatic stress disorder, supranuclear palsy, feeding disorders, obsessive compulsive disorder, analgesia, smoking cessation, panic attacks, Parkinson's and phobia, said method comprising,
 administering to the subject a compound of Formula IA, IB, IIA, IIB, IIIA, or IIIB,   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein: 
           is a single or double bond; 
         R 1  is selected from the group consisting of C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 4 -C 7  cycloalkylalkyl and benzyl, each of which is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C 1 -C 3  alkyl, halogen, —CN, —OR 8  and —NR 8 R 9 ; 
         R 2  is selected from the group consisting of H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C 4 -C 7  cycloalkylalkyl and C 1 -C 6  haloalkyl; 
         R 3  is selected from the group consisting of 14, halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl and C 3 -C 6  cycloalkyl, wherein C 1 -C 6  alkyl, C 1 -C 6  haloalkyl and C 3 -C 6  cycloalkyl are optionally substituted with 1 to 3 substituents selected independently at each occurrence from OR 8  and NR 8 R 9 ; 
         R 4 , R 5  and R 6  are each independently selected at each occurrence thereof from the group consisting of H, halogen, —OR 10 , —NO 2 , NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 C(O)NR 11 R 12 , —S(O) n R 11 , —CN, —C(O)R 11 , —C(O) 2 R 11 , —C(O)NR 11 R 12 , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl and C 4 -C 7  cycloalkylalkyl, wherein each of C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl and C 4 -C 7  cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C 1 -C 3  alkyl, halogen, ═O, —CN, —OR 8 , —NR 8 R 9  and phenyl, and wherein phenyl is optionally substituted with 1-3 substituents selected independently at each occurrence from halogen, —CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, —OR 8  and —NR 8 R 9 ; alternatively R 5  and R 6  are —O—C(R 11 ) 2 —O—; 
         R 7  is selected from the group consisting of H, halogen and OR 10 ; 
         R 8  and R 9  are each independently selected from the group consisting of H, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 1 -C 4  alkoxyalkyl, C 1 -C 4  alkoxyalkylalkyl, C 3 -C 6  cycloalkyl, C 4 -C 7  cycloalkylalkyl, —C(O)R 2 , phenyl and benzyl, wherein phenyl and benzyl are optionally substituted with 1 to 3 substituents selected independently at each occurrence from halogen, cyano, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 1 -C 4  alkoxy and C 1 -C 4  haloalkoxy; 
         R 10  is selected from the group consisting of H, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 1 -C 4  alkoxyalkyl, C 3 -C 6  cycloalkyl, C 4 -C 7  cycloalkylalkyl, —C(O)R 12 , phenyl and benzyl, wherein phenyl and benzyl are optionally substituted with 1 to 3 substituents selected independently at each occurrence from halogen, —NH 2 , —OH, cyano, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 1 -C 4  alkoxy and C 1 -C 4  haloalkoxy; 
         R 11  is selected from the group consisting of H, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 1 -C 4  alkoxyalkyl, C 3 -C 6  cycloalkyl, C 4 -C 7  cycloalkylalkyl, phenyl and benzyl, where phenyl and benzyl are optionally substituted with 1 to 3 substituents selected independently at each occurrence from halogen, —NH 2 , —OH, cyano, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 1 -C 4  alkoxy and C 1 -C 4  haloalkoxy; 
         R 12  is selected from the group consisting of C 1 -C 4  alkyl, C 1 -C 4  haloalkyl and phenyl; 
         X is selected from the group consisting of O, NR 13  and S, with the proviso that X is not NR 13  when a compound is of Formula (IA); 
         n is 0, 1, or 2; and, 
         R 13  is selected from the group consisting of H, C 1 -C 6  alkyl, benzyl and phenyl, wherein C 1 -C 6  alkyl, benzyl and phenyl are optionally substituted with 1-3 substituents selected independently at each occurrence from halogen, —NH 2 , —OH, cyano, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 1 -C 4  alkoxy and C 1 -C 4  haloalkoxy, 
       
       or a pharmaceutically acceptable salt thereof under conditions effective to treat the subject for the neurological or psychological disorder. 
     
     
         2 . The method of  claim 1 , wherein the neurological or psychological disorder is attention deficit-hyperactivity disorder. 
     
     
         3 . The method according to  claim 1 , wherein the subject is a human. 
     
     
         4 . The method according to  claim 1 , wherein R 1  is C 1 -C 6  alkyl. 
     
     
         5 . The method according to  claim 4 , wherein R 1  is CH 3 . 
     
     
         6 . The method according to  claim 1 , wherein R 2  is H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, or C 1 -C 6  haloalkyl. 
     
     
         7 . The method according to  claim 6 , wherein R 2  is H or C 1 -C 6  alkyl. 
     
     
         8 . The method according to  claim 7 , wherein R 2  is H. 
     
     
         9 . The method according to  claim 1 , wherein R 1  is at each occurrence thereof independently H, halogen, C 1 -C 6  alkyl, or C 1 -C 6  alkyl substituted with from 1 to 3 of OR 8  or NR 8 R 9 . 
     
     
         10 . The method according to  claim 9 , wherein R 3  is H or C 1 -C 6  alkyl. 
     
     
         11 . The method according to  claim 10 , wherein R 3  is H. 
     
     
         12 . The method according to  claim 1 , wherein R 1  is CH 3 , R 2  is H and R 3  is H. 
     
     
         13 . The method according to  claim 1 , wherein R 4 , R 5  and R 6  are each independently H, halogen, C 1 -C 6  alkyl or —OR 10 . 
     
     
         14 . The method according to  claim 13 , wherein at least one of R 4 , R 5  and R 6  is H. 
     
     
         15 . The method according to  claim 14 , wherein each of R 4 , R 5  and 16 are H. 
     
     
         16 . The method according to  claim 13 , wherein one of R 4 , R 5  and R 6  is halogen. 
     
     
         17 . The method according to  claim 1 , wherein R 1  is CH 3 , R 2  and R 3  are each H, and at least one of R 4 , R 5  and R 6  is H. 
     
     
         18 . The method according to  claim 1 , wherein the compound is a compound of Formula (10): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt form thereof selected from the group consisting of:
 a compound of Formula (10) wherein R 4  is H, R 5  is H and R 6  is H; 
 a compound of Formula (10) wherein R 4  is H, R 5  is Me and R 6  is H; 
 a compound of Formula (10) wherein R 4  is Cl, R 5  is H and R 6  is H; and 
 a compound of Formula (10) wherein R 4  is H, R 5  is F and R 6  is II. 
 
     
     
         19 . The method according to  claim 1 , wherein the compound is a compound of Formula (20): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt form thereof selected from the group consisting of:
 a compound of Formula (20) wherein R 4  is H, R 5  is H and R 6  is H; 
 a compound of Formula (20) wherein R 4  is H, R 5  is Me and R 6  is H; 
 a compound of Formula (20) wherein R 4  is H, R 5  is Cl and R 6  is H; 
 a compound of Formula (20) wherein R 4  is H, R 5  is F and R 6  is H; and 
 a compound of Formula (20) wherein R 4  is F, R 5  is H and R 6  is F. 
 
     
     
         20 . The method according to  claim 1 , wherein the compound is a compound of Formula (30): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt form thereof selected from the group consisting of:
 a compound of Formula (30) wherein R 3  is H, R 4  is H, R 5  is H and R 6  is H; 
 a compound of Formula (30) wherein R 3  is H, R 4  is H, R 5  is H and R 6  is H; 
 a compound of Formula (30) wherein R 3  is H, R 4  is H, R 5  is H and R 6  is F; 
 a compound of Formula (30) wherein R 3  is H, R 4  is F, R 5  is F and R 6  is H; 
 a compound of Formula (30) wherein R 3  is H, R 4  is Cl, R 5  is H and R 6  is H; 
 a compound of Formula (30) wherein R 3  is H, R 4  is H, R 5  is Cl and R 6  is H; 
 a compound of Formula (30) wherein R 3  is H, R 4  is H, R 5  is Cl and R 6  is F; 
 a compound of Formula (30) wherein R 3  is H, R 4  is H, R 5  is F and R 6  is Cl; 
 a compound of Formula (30) wherein R 3  is H, R 4  is F, R 5  is H and R 6  is Cl; 
 a compound of Formula (30) wherein R 3  is H, R 4  is H, R 5  is OMe and R 6  is H; and 
 a compound of Formula (30) wherein R 3  is H, R 4  is F, R 5  is H and R 6  is H. 
 
     
     
         21 . The method according to  claim 1 , wherein the compound is a compound of Formula (40): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt form thereof selected from the group consisting of:
 a compound of Formula (40) wherein R 3  is H, R 4  is H, R 5  is H and R 6  is H; 
 a compound of Formula (40) wherein R 3  is H, R 4  is F, R 5  is F and R 6  is H; 
 a compound of Formula (40) wherein R 3  is H, R 4  is F, R 5  is H and R 6  is F; 
 a compound of Formula (40) wherein R 3  is H, R 4  is F, R 5  is H and R 6  is H; 
 a compound of Formula (40) wherein R 3  is H, R 4  is H, R 5  is F and R 6  is H; 
 a compound of Formula (40) wherein R 3  is 1H, R 4  is C, R 5  is H and R 6  is H; 
 a compound of Formula (40) wherein R 3  is H, R 4  is Cl, R 5  is Cl and R 6  is H; 
 a compound of Formula (40) wherein R 3  is H, R 4  is H, R 5  is Cl and R 6  is F; 
 a compound of Formula (40) wherein R 3  is H, R 4  is 1, R 5  is F and R 6  is Cl; 
 a compound of Formula (40) wherein R 3  is H, R 4  is F, R 5  is H and R 6  is Cl; 
 a compound of Formula (40) wherein R 3  is H, R 4  is F, R 5  is H and R 6  is H; 
 a compound of Formula (40) wherein R 3  is Me, R 4  is H, R 5  is H and R 6  is H; 
 a compound of Formula (40) wherein R 3  is Et, R 4  is H, R 5  is H and R 6  is H; and 
 a compound of Formula (40) wherein R 3  is CH 2 OH, R 4  is H, R 5  is H and R 6  is H. 
 
     
     
         22 . The method according to  claim 1 , wherein the compound is a compound of Formula (50): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt form thereof selected from the group consisting of:
 a compound of Formula (50) wherein R 3  is H, R 4  is H, R 5  is H and R 6  is H. 
 
     
     
         23 . The method according to  claim 1 , wherein the compound is a compound of Formula (60): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt form thereof selected from the group consisting of:
 a compound of Formula (60) wherein R 3  is H, R 4  is H, R 5  is H, R 6  is H and R 13  is H; 
 a compound of Formula (60) wherein R 3  is H, R 4  is H, R 5  is H, R 6  is H and R 13  is Me; 
 a compound of Formula (60) wherein R 3  is H, R 4  is H, R 5  is H, R 6  is H and R 13  is Et; 
 a compound of Formula (60) wherein R 3  is H, R 4  is H, R 5  is F, R 6  is F and R 13  is H; 
 a compound of Formula (60) wherein R 3  is H, R 4  is H, R 5  is F, R 6  is F and R 13  is Me; 
 a compound of Formula (60) wherein R 3  is H, R 4  is F, R 5  is H, R 6  is F and R 13  is H; 
 a compound of Formula (60) wherein R 3  is H, R 4  is F, R 5  is H, R 6  is F and R 13  is Me; 
 a compound of Formula (60) wherein R 3  is H, R 4  is Cl, R 5  is H, R 6  is H and R 13  is H; 
 a compound of Formula (60) wherein R 3  is H, R 4  is Cl, R 5  is H, R 6  is H and R 13  is Me; 
 a compound of Formula (60) wherein R 3  is H, R 4  is F, R 5  is H, R 6  is H and R 13  is H; 
 a compound of Formula (60) wherein R 3  is H, R 4  is H, R 5  is F, R 6  is H and R 13  is H; 
 a compound of Formula (60) wherein R 3  is H, R 4  is F, R 5  is Cl, R 6  is H and R 13  is H; 
 a compound of Formula (60) wherein R 3  is H, R 4  is F, R 5  is Cl, R 6  is H and R 13  is Me; 
 a compound of Formula (60) wherein R 3  is H, R 4  is Cl, R 5  is F, R 6  is H and R 13  is H; and 
 a compound of Formula (60) wherein R 3  is H, R 4  is Cl, R 5  is F, R 6  is Hi and R 13  is Me. 
 
     
     
         24 . The method according to  claim 1 , wherein the compound is a compound of Formula (70); 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt form thereof selected from the group consisting of:
 a compound of Formula (70) wherein R 3  is H, R 4  is H, R 5  is H, R 6  is H and R 13  is H; 
 a compound of Formula (70) wherein R 3  is H, R 4  is H, R 5  is H, R 6  is H and R 13  is Me; 
 a compound of Formula (70) wherein R 3  is H, R 4  is H, R 5  is H, R 5  is H and R 13  is Et; 
 a compound of Formula (70) wherein R 3  is H, R 4  is H, R 5  is H, R 6  is H and R 13  is Bn; 
 a compound of Formula (70) wherein R 3  is H, R 4  is H, R 5  is F, R 6  is F and R 13  is H; 
 a compound of Formula (70) wherein R 3  is H, R 4  is H, R 5  is F, K is F and R 13  is Me; 
 a compound of Formula (70) wherein R 3  is H, R 4  is F, R 5  is H, R 6  is F and R 13  is Me; 
 a compound of Formula (70) wherein R 3  is H, R 4  is Cl, R 5  is H, R 6  is H and R 13  is H; 
 a compound of Formula (70) wherein R 3  is H, R 4  is Cl, R 5  is H, R 6  is H and R 13  is Me; 
 a compound of Formula (70) wherein R 3  is H, R 4  is F, R 5  is H, R 6  is H and R 13  is H; 
 a compound of Formula (70) wherein R 3  is H, R 4  is F, R 5  is H, R 6  is H and R 13  is Me; 
 a compound of Formula (70) wherein R 3  is H, R 4  is H, R 5  is F, R 6  is H and R 13  is H; 
 a compound of Formula (70) wherein R 3  is H, R 4  is F, R 5  is Cl, R 6  is H and R 13  is H; 
 a compound of Formula (70) wherein R 3  is H, R 4  is F, R 5  is Cl, R 6  is H and R 13  is Me; 
 a compound of Formula (70) wherein R 3  is H, R 4  is Cl, R 5  is F, R 6  is H and R 13  is H; and 
 a compound of Formula (70) wherein R 3  is H, R 4  is Cl, R 5  is F, R 6  is H and R 13  is Me. 
 
     
     
         25 . The method according to  claim 1 , wherein the compound is a compound of Formula (80); 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt form thereof selected from the group consisting of:
 a compound of Formula (80) wherein R 4  is H, R 5  is 14 and R 6  is H; 
 a compound of Formula (80) wherein R 4  is H, R 5  is F and R 6  is H; and 
 a compound of Formula (80) wherein R 4  is H, R 5  is F and R 6  is F. 
 
     
     
         26 . The method according to  claim 1 , wherein the compound is a compound of Formula (90): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt form thereof selected from the group consisting of:
 a compound of Formula (90) wherein R 4  is H, R 5  is H and R 6  is H. 
 a compound of Formula (90) wherein R 4  is H, R 5  is F and R 6  is F; and 
 a compound of Formula (90) wherein R 4  is H, R 5  is F and R 6  is H. 
 
     
     
         27 . The method according to  claim 1 , wherein the compound is a compound of Formula (100): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt form thereof selected from the group consisting of:
 a compound of Formula (100) wherein R 4  is H, R 5  is H, R 6  is H and R 13  is H. 
 
     
     
         28 . The method according to  claim 1 , wherein the compound is a compound of Formula (110): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt form thereof selected from the group consisting of:
 a compound of Formula (10) wherein R 4  is H, R 5  is H and R 6  is H; 
 a compound of Formula (110) wherein R 4  is H, R 5  is F and R 6  is F; 
 a compound of Formula (10) wherein R 4  is H, R 5  is F and R 6  is H; 
 a compound of Formula (110) wherein R 4  is H, R 5  is H and R 6  is Cl; 
 a compound of Formula (110) wherein R 4  is H, R 5  is Cl and R 6  is F; 
 a compound of Formula (110) wherein R 4  is H, R 5  is F and R 6  is Cl; and 
 a compound of Formula (110) wherein R 4  is H, R 5  is OMe and R 6  is H. 
 
     
     
         29 . The method according to  claim 1 , wherein the compound is a compound of Formula (120): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt form thereof selected from the group consisting of:
 a compound of Formula (120) wherein R 4  is H, R 5  is H and R 6  is H; 
 a compound of Formula (120) wherein R 4  is H, R 5  is F and R 6  is F; 
 a compound of Formula (120) wherein R 4  is H, R 5  is F and R 6  is H; 
 a compound of Formula (120) wherein R 4  is H-E, R 5  is H and R 6  is Cl; 
 a compound of Formula (120) wherein R 4  is H, R 5  is Cl and R 6  is F; 
 a compound of Formula (120) wherein R 4  is H, R 5  is OMe and R 6  is H; and 
 a compound of Formula (120) wherein R 4  is H, R 5  is F and R 6  is Cl. 
 
     
     
         30 . The method according to  claim 1 , wherein the compound is a compound of Formula (130): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt form thereof selected from the group consisting of:
 a compound of Formula (130) wherein R 4  is H, R 5  is H and R 6  is H; and 
 a compound of Formula (130) wherein R 4  is H, R 5  is Bn and R 6  is H. 
 
     
     
         31 . The method according to  claim 1 , wherein the compound is a compound of Formula (140): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt form thereof selected from the group consisting of:
 a compound of Formula (140) wherein R 4  is H, R 5  is H and R 6  is 1-H; 
 a compound of Formula (140) wherein R 4  is H, R 5  is F and R 6  is H; 
 a compound of Formula (140) wherein R 4  is H, R 5  is F and R 6  is Cl; 
 a compound of Formula (140) wherein R 4  is H, R 5  is Cl and R 6  is F; 
 a compound of Formula (140) wherein R 4  is H, R 5  is H and R 6  is Cl; 
 a compound of Formula (140) wherein R 4  is H, R 5  is OMe and R 16  is H; and 
 a compound of Formula (140) wherein R 4  is H, R 5  is F and R 6  is F. 
 
     
     
         32 . The method according to  claim 1 , wherein the compound is a compound of Formula (150): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt form thereof selected from the group consisting of:
 a compound of Formula (150) wherein R 4  is H, R 5  is H and R 6  is H; 
 a compound of Formula (150) wherein R 4  is H, R 5  is F and R 6  is H; 
 a compound of Formula (150) wherein R 4  is H, R 5  is F and R 1  is Cl; 
 a compound of Formula (150) wherein R 4  is H, R 5  is Cl and R 6  is F; 
 a compound of Formula (150) wherein R 4  is H, R 5  is H and R 6  is Cl; 
 a compound of Formula (150) wherein R 4  is H, R 5  is OMe and R 6  is H; and 
 a compound of Formula (150) wherein R 4  is H, R 5  is F and R 5  is F. 
 
     
     
         33 . The method according to  claim 1 , wherein the compound is a compound of Formula (I 60): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt form thereof selected from the group consisting of:
 a compound of Formula (160) wherein R 4  is H, R 5  is H and R 6  is H. 
 
     
     
         34 . The method according to  claim 1 , wherein the compound is a compound of Formula (170): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt form thereof selected from the group consisting of:
 a compound of Formula (170) wherein R 4  is H, R 5  is Ed and R 6  is H; 
 a compound of Formula (170) wherein R 4  is H, R 5  is F and R 6  is H; and 
 a compound of Formula (170) wherein R 4  is H, R 5  is F and R 6  is F. 
 
     
     
         35 . The method according to  claim 1 , wherein the compound is a compound of Formula (180): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt form thereof selected from the group consisting of:
 a compound of Formula (180) wherein R 4  is H, R 5  is H and R 6  is H; 
 a compound of Formula (180) wherein R 4  is H, R 5  is F and R 6  is H; and 
 a compound of Formula (180) wherein R 4  is H, R 5  is F and R 6  is F. 
 
     
     
         36 . The method according to  claim 1 , wherein the compound is a compound of Formula (I 90): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt form thereof selected from the group consisting of:
 a compound of Formula (190) wherein R 4  is H, R 5  is H and R 6  is H. 
 
     
     
         37 . The method according to  claim 1 , wherein the compound is a compound of Formula (200): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt form thereof selected from the group consisting of:
 a compound of Formula (200) wherein R 4  is H, R 5  is H and R 6  is H and R 13  is H; and 
 a compound of Formula (200) wherein R 4  is H, R 5  is H and R 6  is H and R 13  is Me. 
 
     
     
         38 . The method according to  claim 1 , wherein the compound is selected from the group consisting of: 
       (R)-2-methyl-4-phenyl-1,2,3,4,8,9-hexahydro-furo[2,3-h]isoquinoline; 
       (S)-2-methyl-4-phenyl-1,2,3,4,8,9-hexahydro-furo[2,3-h]isoquinoline; 
       (R)-7-methyl-5-phenyl-5,6,7,8-tetrahydro-furo[3,2-g]isoquinoline; 
       (S)-7-methyl-5-phenyl-5,6,7,8-tetrahydro-furo[3,2-g]isoquinoline; 
       (R)-4-(4-fluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline: 
       (S)-4-(4-fluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline; 
       (R)-4-(3,4-difluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline; 
       (S)-4-(3,4-difluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline; 
       (R)-2-methyl-4-phenyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline; 
       (S)-2-methyl-4-phenyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline; 
       (R)-4-(4-chloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline; 
       (S)-4-(4-chloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline; 
       (R)-8-methyl-6-phenyl-2,3,6,7,8,9-hexahydro-furo[3,2-h]isoquinoline; 
       (S)-8-methyl-6-phenyl-2,3,6,7,8,9-hexahydro-furo[3,2-h]isoquinoline; 
       (R)-4-(4-fluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline; 
       (S)-4-(4-fluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline; 
       (R)-4-(3,5-difluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline; 
       (S)-4-(3,5-difluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline; 
       (R)-2-methyl-4-phenyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinoline; and 
       (S)-2-methyl-4-phenyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinoline. 
     
     
         39 . The method according to  claim 1 , wherein the compound is selected from the group consisting of:
 (+)-2-methyl-4-phenyl-1,2,3,4,8,9-hexahydro-furo[2,3-h]isoquinoline;   (−)-2-methyl-4-phenyl-1,2,3,4,8,9-hexahydro-furo[2,3-h]isoquinoline;   (+)-7-methyl-5-phenyl-5,6,7,8-tetrahydro-furo[3,2-g]isoquinoline;   (−)-7-methyl-5-phenyl-5,6,7,8-tetrahydro-furo[3,2-g]isoquinoline;   (+)-4-(4-fluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline;   (−)-4-(4-fluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline;   (+)-4-(3,4-difluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline;   (−)-4-(3,4-difluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline;   (+)-2-methyl-4-phenyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline;   (−)-2-methyl-4-phenyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline;   
       (+)-4-(4-chloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline;
 (−)-4-(4-chloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline; 
 (+)-8-methyl-6-phenyl-2,3,6,7,8,9-hexahydro-furo[3,2-h]isoquinoline; 
 (−)-8-methyl-6-phenyl-2,3,6,7,8,9-hexahydro-furo[3,2-h]isoquinoline; 
 (+)-4-(4-fluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline; 
 (−)-4-(4-fluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline; 
 (+)-4-(3,5-difluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline; 
 (−)-4-(3,5-difluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-furo[2,3-h]isoquinoline; 
 (+)-2-methyl-4-phenyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinoline; and 
 (−)-2-methyl-4-phenyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinoline.

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