Novel compounds and a novel process for their preparation

Abstract

The present invention is directed to a procedure for making an enantidimerically enriched compound containing a hydronaphthalene ring structure. The process involves reacting oxabenzonorbornadienes with nuclophiles using rhodium as a catalyst and in the presence of a phosphine ligand. The compounds synthesized may be used in pharmaceutical preparations for the treatment of a variety of diseases and conditions.

1 - 68 . (canceled) 
   
   
       69 . A compound according to formula I: 
     
       
         
         
             
             
         
       
       wherein R is selected from the group consisting of: 
       (a) H; 
       (b) a C 1 -C 6  straight or branched alkyl; 
       (c) a straight or branched C 2 -C 6  alkenyl; 
       (d) —(CH 2 ) n R 1 , wherein R 1  is a C 3 -C 6  aryl, optionally substituted at one or more positions with a group selected from: Cl; F; NO 2 ; I; Br; a C 1 -C 3  alkyl; and a C 1 -C 3  alkoxy wherein n=0-3; 
       (e) —C(O)R 2 , wherein R 2  is selected from the group consisting of: H;
 —(CH 2 ) n R 1 , wherein R 1  is as described above and n=0-3; and 
 —(CH 2 ) n C(O)R 3 , wherein R 3  is a C 1 -C 6  straight or branched alkyl and n=0-3; 
 
       (f) —C(O)(CH 2 ) p —C(O)—O—R 4 , wherein R 4  is a straight or branched C 1 -C 6  alkyl and wherein p=0-3; 
       (g) —R d (CF 3 ) j , wherein R d  is a straight or branched C 1 -C 6  alkyl and j=1-3, and 
       (h) (CH 2 ) j -TMS, wherein TMS is trimethylsilyl and j=1-3 
       wherein X and Y are independently selected from the group consisting of H; NH 2 ; F; Cl; Br; a C 1 -C 3  alkyl; and a C 1 -C 3  alkoxy; 
       or wherein the combination XY or YY together form a C 3 -C 6  carbocyclic ring or a C 3 -C 6  heterocyclic ring containing one or more heteroatoms selected from the group consisting of: 0; N; and S; and 
       wherein Z is NR a , wherein R a  is selected from: 
       (i) phenyl; 
       (j) (O)—C—OR b , wherein R b  is a straight or branched C 1 -C 6  alkyl; 
       (k) —SO 2 —R c , wherein (1) R c  is selected from the group of:
 i) C 1 -C 6  straight or branched alkyl, 
 ii) (CH 2 ) q R e , wherein q=0-3 and R e  is a C 3 -C 6  aryl, optionally substituted at one or more positions with a group selected from: Cl, F, NO 2 , CN, I, Br, a straight or branched C 1 -C 3  alkyl, a C 1 -C 3  alkoxy, and C(O)R f , wherein R f  is a C 1 -C 3  alkyl or (CH 2 ) r CF 3 , wherein r=1-3, 
 iii) —R g (CF 3 ) r, wherein R g  is a C 1 -C 3  straight or branched alkyl and r=1-3, 
 iv) (CH 2 ) s -TMS, wherein TMS is trimethylsilyl and s=1-3; 
 
       (l) —SO 2 —(CH 2 ) q —Si(CH 3 ) 3 , wherein q is 1-3. 
     
   
   
       70 . A compound according to  claim 69 , wherein R is —(CH 2 ) n R 1 , and R 1  is a C 3 -C 6  aryl optionally substituted at one or more positions with a group selected from: Cl; F; NO 2 ; I; Br; a C 1 -C 3  alkyl; and a C 1 -C 3  alkoxy and wherein n=0-3. 
   
   
       71 . A compound according to formula II: 
     
       
         
         
             
             
         
       
       wherein R is selected from the group consisting of: 
       (a) a C 1 -C 6  straight or branched alkyl; 
       (b) —(CH 2 ) q R 5 , wherein q=0-3 and R 5  is a C 3 -C 6  aryl, optionally substituted at one or more positions with a group selected from: a straight or branched C 1 -C 3  alkyl; a C 1 -C 3  alkoxy; Br; I; Cl; CN; F; NO 2 ; —(CH 2 ) r CF 3 , wherein r=0-3; and —C(O)R 6 , wherein R 6  is a C 1 -C 3  alkyl; 
       (c) —R 7 (CF 3 ) s , wherein R 7  is a C 1 -C 3  straight or branched alkyl and s=1-3; 
       (d) —(CH 2 ) s -TMS, wherein TMS=trimethylsilyl and s=1-3; 
       wherein X and Y are independently selected from the group consisting of H; NH 2 ; F; Cl; Br; a C 1 -C 3  alkyl; and a C 1 -C 3  alkoxy; 
       or wherein the combination XY or YY together form a C 3 -C 6  carbocyclic ring or a C 3 -C 6  heterocyclic ring containing one or more heteroatoms selected from the group consisting of: 0; N; and S, and 
       wherein Z is NR a , wherein R a  is selected from: 
       (i) phenyl; 
       (j) (O)—C—OR b , wherein R b  is a straight or branched C 1 -C 6  alkyl; 
       (k) —SO 2 —R c , wherein (1) R c  is selected from the group of:
 i) C 1 -C 6  straight or branched alkyl, 
 ii) (CH 2 ) q R e , wherein q=0-3 and R e  is a C 3 -C 6  aryl, optionally substituted at one or more positions with a group selected from: Cl, F, NO 2 , CN, I, Br, a straight or branched C 1 -C 3  alkyl, a C 1 -C 3  alkoxy, and C(O)R f , wherein R f  is a C 1 -C 3  alkyl or (CH 2 ) r CF 3 , wherein r=1-3, 
 iii) —R g (CF 3 ) r, wherein R g  is a C 1 -C 3  straight or branched alkyl and r=1-3, 
 iv) (CH 2 ) s -TMS, wherein TMS is trimethylsilyl and s=1-3; 
 
       (l) —SO 2 —(CH 2 ) q —Si(CH 3 ) 3 , wherein q is 1-3. 
     
   
   
       72 . A compound according to  claim 71 , wherein R is —(CH 2 ) q R 5  wherein q=0-3 and R 5  is a C 3 -C 6  aryl optionally substituted at one or more positions with a group selected from: a straight or branched C 1 -C 3  alkyl; a C 1 -C 3  alkoxy; I; Cl; CN; F; NO 2 ; —(CH 2 ) r CF 3 , wherein r=0-3; and —C(O)R 6 , wherein R 6  is a C 1 -C 3  alkyl. 
   
   
       73 . The compound of  claim 69 , wherein X═H and Y═H. 
   
   
       74 . A pharmaceutical composition comprising a compound according  claim 69  and a pharmaceutically acceptable carrier or excipient. 
   
   
       75 . A compound selected from the group consisting of: 
     4-methyl-N-[(1R,2S)-2-(1-piperidinyl)-1,2-dihydro-1-naphthalenyl]benzenesulfonamide; 
     N-[(1R,2S)-2-(3,4-dihydro-2(1H)-quinolinyl)-1,2-dihydro-1-naphthalenyl]-4-methylbenzenesulfonamide; 
     N,4-dimethyl-N-[(1R,2S)-2-(1-pyrrolidinyl)-1,2,3,4-tetrahydro-1-naphthalenyl]-benzenesulfonamide; 
     N,4-dimethyl-N-[(1R,2S)-2-(1-pyrrolidinyl)-1,2-dihydro-1-naphthalenyl]-benzenesulfonamide; 
     N-hydroxy-4-({methyl[(1R,2S)-2-(1-pyrrolidinyl)-1,2-dihydro-1-naphthalenyl]amino}sulfonyl)-N-oxobenzenamminium; 
     N-methyl-4-nitro-N-[(1R,2S)-2-(1-pyrrolidinyl)-1,2-dihydro-1-naphthalenyl]-benzenesulfonamide; and 
     4-nitro-N-[(1R,2S)-2-(1-pyrrolidinyl)-1,2-dihydro-1-naphthalenyl]-benzenesulfonamide. 
   
   
       76 . A pharmaceutical composition comprising a compound according to  claim 75  and a pharmaceutically acceptable carrier or excipient. 
   
   
       77 . A process for preparing a compound according to  claim 69 , comprising reacting a compound of formula ROH with a compound of formula V: 
     
       
         
         
             
             
         
       
     
     wherein R, X, and Y are as defined in  claim 69 ; 
     and wherein said reaction is catalyzed by [Rh(COD)Cl] 2  in the presence of a chiral phosphine ligand. 
   
   
       78 . The process of  claim 77 , wherein said chiral phosphine ligand is selected from the group consisting of: (R)-(S)-BPPFA; and (R)-(S)-PPF-P t Bu 2 . 
   
   
       79 . A process for preparing a compound according to  claim 71 , comprising reacting a compound of formula ROH with a compound of formula V: 
     
       
         
         
             
             
         
       
     
     wherein R, X, and Y are as defined in  claim 71 ; 
     and wherein said reaction is catalyzed by [Rh(COD)Cl] 2  in the presence of a chiral phosphine ligand. 
   
   
       80 . The process of  claim 79 , wherein said chiral phosphine ligand is (S)-(R)-PPF-P t Bu 2 . 
   
   
       81 . The compound of  claim 70 , wherein X═H and Y═H. 
   
   
       82 . The compound of  claim 71 , wherein X═H and Y═H. 
   
   
       83 . The compound of  claim 72 , wherein X═H and Y═H. 
   
   
       84 . A pharmaceutical composition comprising a compound according  claim 70  and a pharmaceutically acceptable carrier or excipient. 
   
   
       85 . A pharmaceutical composition comprising a compound according  claim 71  and a pharmaceutically acceptable carrier or excipient. 
   
   
       86 . A pharmaceutical composition comprising a compound according  claim 72  and a pharmaceutically acceptable carrier or excipient. 
   
   
       87 . A pharmaceutical composition comprising a compound according  claim 73  and a pharmaceutically acceptable carrier or excipient. 
   
   
       88 . A pharmaceutical composition comprising a compound according  claim 81  and a pharmaceutically acceptable carrier or excipient. 
   
   
       89 . A pharmaceutical composition comprising a compound according  claim 82  and a pharmaceutically acceptable carrier or excipient. 
   
   
       90 . A pharmaceutical composition comprising a compound according  claim 83  and a pharmaceutically acceptable carrier or excipient.