N-type calcium channel antagonists for the treatment of pain
Compounds useful for the treatment of pain in accord with the following structural diagram, wherein A, R 1 , b, R 3 , d, R 4 , R 5 , R 6 and R 7 are any of a number of groups as defined in the specification, and pharmaceutical compositions and methods of treatment utilizing such compounds.
1. A compound of formula I:
wherein:
A is phenyl or morpholine;
R 1 at each occurrence is independently selected from halogen, (C 1 –C 6 )alkyl, heterocyclyl, OH, (C 1 –C 6 ) alkoxy or NR 2 2 ;
b is an integer selected from 0, 1, 2 or 3;
R 2 at each occurrence is independently selected from H or (C 1 –C 4 )alkyl;
R 3 at each occurrence is independently selected from halogen or (C 1 –C 4 )alkyl;
d is an integer selected from 0, 1, 2 or 3;
R 4 is selected from H or (C 1 –C 4 )alkyl;
R 5 is selected from the group consisting of H, halogen, (C 1 –C 3 )alkyl, (C 1 –C 3 )perfluoroalkyl, (C 1 –C 3 )alkoxy, hydroxy, NH 2 or NHR 2 ;
R 6 is selected from H, halogen, (C 1 –C 6 )alkyl, (C 1 –C 4 ) perfluoroalkyl, (C 1 –C 6 )alkoxy, hydroxy, (C 1 –C 6 )alkanoyl, C(═O)NR 2 2 or —NR 2 2 ; and
R 7 selected from H or methyl.
2. A compound of claim 1 wherein:
R 4 and R 7 are H; and
R 5 is selected from H, halogen, (C 1 –C 3 )alkyl, (C 1 –C 3 )perfluoroalkyl or (C 1 –C 3 )alkoxy.
3. A method for the treatment of pain in a subject suffering therefrom, comprising administering to said subject a pain-ameliorating effective amount of a compound according to claim 1 .
4. A pharmaceutical composition comprising a therapeutically-effective amount of a compound according to claim 1 together with at least one pharmaceutically-acceptable excipient or diluent.
5. A method for preparing a compound according to claim 1 , said method comprising:
a) reacting a substituted 2,4-quinolinediol (formula II) with three equivalents of an aryl amine in N-methylpyrrolidinone and 6N HCl in 2-propanol, in a sealed tube at a temperature of about 180° C.;
wherein R 3 , R 4 , R 5 , R 6 and d are as defined as in claim 1 ;
b) chlorinating the 2-hydroxy-4-aminoquinoline compound according to formula III by refluxing with POCl 3 to form a compound according to formula IV;
wherein R 3 , R 4 , R 5 , R 6 and d are as defined as in claim 1 ; and
c) reacting the 2-chloro-4-aminoquinoline compound with a compound having the formula R 7 —NH—A—(R 1 )b in N-methylpyrrolidinone at a temperature of 100–180° C.;
wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , A, b, and d are as defined as in claim 1 .
6. The method according to claim 5 , wherein step c) is performed in a parallel fashion using robotic instrumentality.
7. A method for preparing a compound according to claim 1 , said method comprising:
a) reacting a substituted 2,4-quinolinediol in accord with formula II with two equivalents of an aryl amine in N-methylpyrrolidinone and 4 M HCl in dioxane, in a sealed tube using microwave irradiation at a 400 W upper set point to maintain a 200° C. temperature for 30 minutes;
wherein R 3 , R 4 , R 5 , R 6 and d are as defined as in claim 1 ;
b) chlorinating the 2-hydroxy-4-aminoquinoline compound according to formula III by refluxing with POCl 3 to form a compound according to formula IV;
wherein R 3 , R 4 , R 5 , R 6 and d are as defined as in claim 1 ; and
c) reacting the 2-chloro-4-aminoquinoline compound with a compound having the formula R 7 —NH—A—(R 1 ) b in N-methylpyrrolidinone at a temperature of 100–180° C.;
wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , A, b, and d are as defined as in claim 1 .
8. The method according to claim 7 , wherein step c) is performed in a parallel fashion using robotic instrumentality.