US2015191494A1PendingUtilityA1

Tetrahydroisoquinolines and intermediates therefor

Assignee: BRISTOL MYERS SQUIBB COPriority: Jun 4, 2008Filed: Mar 18, 2015Published: Jul 9, 2015
Est. expiryJun 4, 2028(~1.9 yrs left)· nominal 20-yr term from priority
A61P 5/24A61P 43/00A61P 3/00A61P 25/04A61P 25/34A61P 25/22A61P 25/28A61P 25/30A61P 25/32A61P 3/04A61P 29/00A61P 25/16A61P 25/14A61P 25/24A61P 25/00A61P 25/06A61P 15/10A61P 21/00A61P 15/08A61P 13/02A61P 13/10C07D 401/04C07F 5/025C07D 217/04C07D 237/20C07D 413/10C07C 215/20C07F 5/04C07C 217/58C07C 223/02C07F 5/022
49
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Claims

Abstract

Disclosed are processes for preparing tetrahydroisoquinolines, intermediates useful in the preparation of tetrahydroisoquinolines, processes for preparing such intermediates, and a crystalline form of 6-[(4S)-2-methyl-4-(naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine. Also disclosed are pharmaceutical compositions comprising tetrahydroisoquinolines, methods of using tetrahydroisoquinolines in the treatment of depression and other conditions and methods for obtaining the crystalline form.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A compound having the following formula: 
       
         
           
           
               
               
           
         
         where R 1  is selected from the group consisting of Br and H 3 CO. 
       
     
     
         2 . A compound of  claim 1  having the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound having the following formula: 
       
         
           
           
               
               
           
         
         where R 1  is selected from the group consisting of Br and H 3 CO. 
       
     
     
         4 . A compound of  claim 3  having the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         5 . A compound having the following formula: 
       
         
           
           
               
               
           
         
         where R 2  is selected from the group consisting of Br, H 3 CO and HO. 
       
     
     
         6 . A compound of  claim 5  having the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         7 . A compound having the following formula: 
       
         
           
           
               
               
           
         
         where R 3  is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         where R 4  is C 1 -C 4  alky, aryl or phenyl, and n is 1 or 2. 
       
     
     
         8 . A compound of  claim 7  having the following formula 
       
         
           
           
               
               
           
         
       
     
     
         9 . A compound having the following formula: 
       
         
           
           
               
               
           
         
         Where each R 5  is independently selected from the group consisting of hydrogen t-butoxycarbonyl, carboxybenzyl, para-methoxybenzylcarbonyl, para-methoxybenzyl, 2,4-dimethoxybenzyl, benzyl, 9-fluorenylmethyloxycarbonyl, N-phthalimide, COCH 3  and COCF 3 . 
       
     
     
         10 . A compound of  claim 9  having the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         11 . A compound having the following formula: 
       
         
           
           
               
               
           
         
         Where each R 5  is selected from the group consisting of hydrogen, t-butoxycarbonyl, carboxybenzyl, para-methoxybenzylcarbonyl, para-methoxybenzyl, 2,4-dimethoxybenzyl, benzyl, 9-fluorenylmethyloxycarbonyl, N-phthalimide, COCH 3  and COCF 3 . 
       
     
     
         12 . A compound of  claim 11  having the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         13 . A compound having the following formula: 
       
         
           
           
               
               
           
         
         where each R 5  is selected from the group consisting of hydrogen, t-butoxycarbonyl, carboxybenzyl, para-methoxybenzylcarbonyl, para-methoxybenzyl, 2,4-dimethoxybenzyl, benzyl, 9-fluorenylmethyloxycarbonyl, N-phthalimide, COCH 3  and COCF 3 . 
       
     
     
         14 . A compound of  claim 13  having the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         15 . A compound having the following formula: 
       
         
           
           
               
               
           
         
         Where each R 5  is selected from the group consisting of hydrogen, t-butoxycarbonyl, carboxybenzyl, para-methoxybenzylcarbonyl, para-methoxybenzyl, 2,4-dimethoxybenzyl, benzyl, 9-fluorenylmethyloxycarbonyl, N-phthalimide, COCH 3  and COCF 3 , and X is selected from the group consisting of Cl, Br, I and trifluoromethanesulfonyloxy. 
       
     
     
         16 . A compound of  claim 15  having the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         17 . A process of making a compound having the formula: 
       
         
           
           
               
               
           
         
         where R 2  is selected from the group consisting of Br, H 3 CO and HO, comprising reacting a compound having the formula: 
       
       
         
           
           
               
               
           
         
         where R 1  is selected from Br or H 3 CO, under conditions effective to promote the formation of Compound 17R. 
       
     
     
         18 . A process of making a compound having the formula: 
       
         
           
           
               
               
           
         
         comprising reacting a compound having the formula: 
       
       
         
           
           
               
               
           
         
         under conditions effective to promote the formation of compound 6. 
       
     
     
         19 . A process of making a compound having the formula: 
       
         
           
           
               
               
           
         
         comprising reacting a compound having the formula; 
       
       
         
           
           
               
               
           
         
         where R 2  is selected from the group consisting of Br, H 3 CO and HO, 
         under conditions effective to promote the formation of a compound having the formula; 
       
       
         
           
           
               
               
           
         
         where R 3  is selected from 
       
       
         
           
           
               
               
           
         
         where R 4  is C 1 -C 4  alky, aryl or phenyl, and n is 1 or 2, and reacting Compound 18R under conditions effective to promote the formation of compound rac-1. 
       
     
     
         20 . A process of making a compound having the formula: 
       
         
           
           
               
               
           
         
         comprising reacting a compound having the formula; 
       
       
         
           
           
               
               
           
         
         under conditions effective to promote the formation of a compound having the formula 
       
       
         
           
           
               
               
           
         
         and reacting compound 8 under conditions effective to promote the formation of Compound 2. 
       
     
     
         21 . A process of making a compound having the formula: 
       
         
           
           
               
               
           
         
         comprising reacting a compound having the formula; 
       
       
         
           
           
               
               
           
         
         under conditions effective to promote the formation of Compound 28. 
       
     
     
         22 . A process of making a compound having the formula: 
       
         
           
           
               
               
           
         
         comprising reacting a compound having the formula; 
       
       
         
           
           
               
               
           
         
         under conditions effective to promote the formation of compound rac-1. 
       
     
     
         23 . A process of making a compound having the formula: 
       
         
           
           
               
               
           
         
         comprising reacting a compound having the formula; 
       
       
         
           
           
               
               
           
         
         under conditions effective to promote the formation of Compound 29. 
       
     
     
         24 . A process of making a compound having the formula: 
       
         
           
           
               
               
           
         
         comprising reacting a compound having the formula; 
       
       
         
           
           
               
               
           
         
         under conditions effective to promote the formation of compound rac-1. 
       
     
     
         25 . A process of making a compound having the formula: 
       
         
           
           
               
               
           
         
         comprising reacting a compound having the formula 
       
       
         
           
           
               
               
           
         
         where each R 5  is selected from the group consisting of hydrogen, t-butoxycarbonyl, carboxybenzyl, para-methoxybenzylcarbonyl, para-methoxybenzyl, 2,4-dimethoxybenzyl, benzyl, 9-fluorenylmethyloxycarbonyl, N-phthalimide, COCH 3  and COCF 3 , under conditions effective to promote the formation of Compound 2. 
       
     
     
         26 . A process of making a compound having the formula: 
       
         
           
           
               
               
           
         
         comprising reacting a compound having the formula 
       
       
         
           
           
               
               
           
         
         
           where R 3  is selected from the group consisting of 
         
       
       
         
           
           
               
               
           
         
         where R 4  is C 1 -C 4  alky, aryl or phenyl, and n is 1 or 2, under conditions effective to promote the formation of compound rac-1. 
       
     
     
         27 . A process of making a compound having the formula: 
       
         
           
           
               
               
           
         
         where R 6  is selected from the group consisting of C 1 -C 4  alkyl, benzyl, para-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and triisopropylsilyl,
 comprising reacting a compound of formula 
 
       
       
         
           
           
               
               
           
         
         under conditions effective to promote the formation of compound 7R. 
       
     
     
         28 . A process of making a compound having the formula: 
       
         
           
           
               
               
           
         
         where R 6  is selected from the group consisting of C 1 -C 4  alkyl, benzyl, para-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and triisopropylsilyl,
 comprising reacting a compound of formula 
 
       
       
         
           
           
               
               
           
         
         
           under conditions effective to promote the formation of compound 7R. 
         
       
     
     
         29 . A compound having the following formula: 
       
         
           
           
               
               
           
         
         where R 6  is selected from the group consisting of C 1 -C 4  alkyl, benzyl, para-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and triisopropylsilyl. 
       
     
     
         30 . A compound according to  claim 5 , wherein R 6  is CH 3 . 
     
     
         31 . A process of making a compound having the formula: 
       
         
           
           
               
               
           
         
         where R 6  is selected from the group consisting of C 1 -C 4  alkyl, benzyl, para-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and triisopropylsilyl,
 comprising reacting a compound of formula 
 
       
       
         
           
           
               
               
           
         
         
           under conditions effective to promote the formation of Compound 22R. 
         
       
     
     
         32 . A compound having the following formula: 
       
         
           
           
               
               
           
         
         where each R 5  is independently selected from the group consisting of hydrogen, t-butoxycarbonyl, carboxybenzyl, para-methoxybenzylcarbonyl, para-methoxybenzyl, 2,4-dimethoxybenzyl, benzyl, 9-fluorenylmethyloxycarbonyl, N-phthalimide, COCH 3  and COCF 3 . 
       
     
     
         33 . A compound of  claim 32  having the following formula:

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