US2019084949A1PendingUtilityA1
New class of mu-opioid receptor agonists
Individually held — no corporate assignee on recordPriority: Mar 12, 2014Filed: Nov 16, 2018Published: Mar 21, 2019
Est. expiryMar 12, 2034(~7.6 yrs left)· nominal 20-yr term from priority
Inventors:Andrew Carry KruegelAdam HenkeMadalee M. WulfMarie-Laure RivesJonathan A. JavitchDalibor Sames
A61P 25/24A61K 31/554C07D 513/04C07D 417/12A61K 45/06C07D 281/02A61K 2300/00
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Claims
Abstract
or a pharmaceutically acceptable salt or ester thereof.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound having the structure:
wherein
A is an aryl or heteroaryl, with or without substitution;
R 1 is —H or -(alkyl);
R 2 is -(alkyl), -(alkenyl), -(alkynyl), -(alkyl)-OH, -(alkyl)-CO 2 H, -(alkyl)-CO 2 -(alkyl), -(alkyl)-C(O)—NH 2 , -(alkyl)-C(O)—NH(alkyl), -(alkyl)-C(O)—NH-(hydroxyalkyl), -(alkyl)-C(O)—N(alkyl) 2 , -(alkyl)-C(O)—N(hydroxyalkyl) 2 , -(alkyl)-O-(alkyl), -(alkyl)-S-(alkyl), -(alkyl)-CF 3 , -(alkyl)-O-(hydroxyalkyl), -(alkyl)-O-(alkyl)-O-(alkyl), -(alkyl)-(CH)—(O-(alkyl)) 2 , -(alkyl)-(heterocyclyl), -(alkyl)-OAc, -(alkyl)-tetrahydrofuran, -(alkyl)-pyrrolidine, -(alkyl)-N-methylpyrrolidine, -(alkyl)-(1,3-dioxane) or -(alkyl)-(4,5-dihydrooxazole);
R 3 is —H or -(alkyl);
R 4 , R 5 , R 6 and R 7 are each absent or present, and when present, are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl)-NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —O—C(O) (alkyl), —O-(alkyl), —O-(alkylaryl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl), or —SO 2 -(heteroaryl); and
Y 1 , Y 2 , Y 3 and Y 4 are each independently N or C,
wherein when Y 1 is N, then R 4 is absent, and when Y 1 is C, then R 4 is present; when Y 2 is N, then R 5 is absent, and when Y 2 is C, then R 5 is present; when Y 3 is N, then R 6 is absent, and when Y 3 is C, then R 6 is present; when Y 4 is N, then R, is absent, and when Y 4 is C, then R 7 is present,
wherein when A is phenyl, R 1 is —CH 3 , R 3 , R 4 , R 6 , and R 7 are each —H, and R 5 is Cl, then R 2 is other than —(CH 2 ) 4 C(O)NH 2 , —(CH 2 ) 4 CO 2 H, —(CH 2 ) 5 CO 2 H, —(CH 2 ) 6 CO 2 H, —(CH 2 ) 7 CO 2 H, —(CH 2 ) 10 CO 2 H, —(CH 2 ) 6 CO 2 CH 2 CH 3 , —(CH 2 ) 6 CH 3 , —(CH 2 ) 20 H, —(CH 2 ) 40 H, —(CH 2 ) 7 OH,
wherein when A is phenyl, R 1 is —CH 3 , R 3 , R 4 , R 5 , R 6 , and R 7 are each —H, then R 2 is other than —(CH 2 ) CO 2 CH 2 CH 3 , —(CH 2 ) CO 2 CH 2 CH 3 , (CH 2 )CO 2 H, —(CH 2 ) 3 CO 2 H, —(CH 2 ) 4 CO 2 H or —(CH 2 ) 6 CO 2 H,
wherein when R 1 is —CH 3 , R 2 is —(CH 2 ) 5 CO 2 H, R 3 is —H, R 4 and R 7 are each H, R 5 is —Cl and R 6 is —H or R 5 and R 6 are each —H, then A is other than 2-chlorophenyl or 3-chlorophenyl,
wherein when R 1 is —CH 3 , R 2 is —(CH 2 ) 5 CO 2 H, R 3 is —H or —CH 3 , R 4 and R, are each —H, R 5 is Cl and R F is —H or R 6 is —Cl and R 5 is —H, then A is other than phenyl,
wherein when R 1 is —CH 3 , R 2 is —(CH 2 ) 3 CO 2 H, R 3 is —CH 3 , and R 4 , R 5 , R 6 and R 7 are each —H, then A is other than phenyl,
wherein when A is phenyl, R 1 is —CH 3 , R 3 , R 4 , R 6 , and R 7 are each —H, and R 5 is —SO 2 CH 3 , then R 2 is other than —(CH 2 ) 3 OCH 3 ,
wherein when A is phenyl, R 1 is —CH 3 , R 3 , R 4 , R 5 , and R 7 are each —H, and R 5 is —F, then R 2 is other than —(CH 2 ) 6 CO 2 H,
or a pharmaceutically acceptable salt or ester thereof.
2 . The compound of claim 1 wherein
R 2 is -(alkyl), -(alkenyl), -(alkynyl), -(alkyl)-CO 2 H, -(alkyl)-CO 2 -(alkyl), -(alkyl)-C(O)—NH 2 , -(alkyl)-C(O)—NH(alkyl), -(alkyl)-C(O)—NH-(hydroxyalkyl), -(alkyl)-C(O)—N(alkyl) 2 , -(alkyl)-C(O)—N(hydroxyalkyl) 2 , -(alkyl)-O-(alkyl), -(alkyl)-S-(alkyl), -(alkyl)-CF 3 , -(alkyl)-O-(hydroxyalkyl), -(alkyl)-O-(alkyl)-OCH 3 , -(alkyl)-(CH)—(O-(alkyl)) 2 , -(alkyl)-(heterocyclyl), -(alkyl)-OAc, -(alkyl)-tetrahydrofuran, -(alkyl)-pyrrolidine, -(alkyl)-N-methylpyrrolidine, -(alkyl)-(1,3-dioxane) or -(alkyl)-(4,5-dihydrooxazole).
3 . The compound of claim 1 wherein
R 2 is -(alkyl), -(alkenyl), -(alkynyl), -(alkyl)-OH, -(alkyl)-CO 2 -(alkyl), -(alkyl)-C(O)—NH 2 , -(alkyl)-C(O)—NH(alkyl), -(alkyl)-C(O)—NH-(hydroxyalkyl), -(alkyl)-C(O)—N(alkyl) 2 , -(alkyl)-C(O)—N(hydroxyalkyl) 2 , -(alkyl)-O-(alkyl), -(alkyl)-S-(alkyl), -(alkyl)-CF 3 , -(alkyl)-O-(hydroxyalkyl), -(alkyl)-O-(alkyl)-OCH 3 , -(alkyl)-(CH)—(O-(alkyl)) 2 , -(alkyl)-(heterocyclyl), -(alkyl)-OAc, -(alkyl)-tetrahydrofuran, -(alkyl)-pyrrolidine, -(alkyl)-N-methylpyrrolidine, -(alkyl)-(1,3-dioxane) or -(alkyl)-(4,5-dihydrooxazole).
4 . The compound of claim 1 wherein
R 2 is -(alkyl), -(alkenyl), -(alkynyl), -(alkyl)-CO 2 -(alkyl), -(alkyl)-C(O)—NH 2 , -(alkyl)-C(O)—NH(alkyl), -(alkyl)-C(O)—NH-(hydroxyalkyl), -(alkyl)-C(O)—N(alkyl) 2 , -(alkyl)-C(O)—N(hydroxyalkyl), -(alkyl)-O-(alkyl), -(alkyl)-S-(alkyl), -(alkyl)-CF 3 , -(alkyl)-O-(hydroxyalkyl), -(alkyl)-O-(alkyl)-OCH 3 , -(alkyl)-(CH)—(O-(alkyl)) 2 , -(alkyl)-(heterocyclyl), -(alkyl)-OAc, -(alkyl)-tetrahydrofuran, -(alkyl)-pyrrolidine, -(alkyl)-N-methylpyrrolidine, -(alkyl)-(1,3-dioxane) or -(alkyl)-(4,5-dihydrooxazole).
5 . A compound having the structure:
wherein
A is an aryl or heteroaryl, with or without substitution;
R 1 is —H or -(alkyl);
R 2 is -(alkyl), -(alkenyl), -(alkynyl)-(alkyl)-OH, -(alkyl)-CO 2 H, -(alkyl)-CO 2 -(alkyl), -(alkyl)-C(O)—NH 2 , -(alkyl)-C(O)—NH(alkyl), -(alkyl)-C(O)—NH-(hydroxyalkyl), -(alkyl)-C(O)—N(alkyl) 2 , -(alkyl)-C(O)—N(hydroxyalkyl) 2 , -(alkyl)-O-(alkyl), -(alkyl)-S-(alkyl), -(alkyl)-CF 3 , -(alkyl)-O-(hydroxyalkyl), -(alkyl)-O-(alkyl)-OCH 3 , -(alkyl)-(CH)—(O-(alkyl)) 2 , -(alkyl)-(heterocyclyl), -(alkyl)-OAc, -(alkyl)-tetrahydrofuran, -(alkyl)-pyrrolidine, -(alkyl)-N-methylpyrrolidine, -(alkyl)-(1,3-dioxane) or -(alkyl)-(4,5-dihydrooxazole);
R 3 is —H or -(alkyl);
R 4 , R 5 , R 6 and R 7 are each absent or present, and when present, are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl)-NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —O—C(O)(alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl), or —SO 2 -(heteroaryl); and
Y 1 , Y 2 , Y 3 and Y 4 are each independently N or C,
wherein when Y 1 is N, then R 4 is absent, and when Y 1 is C, then R 4 is present; when Y 2 is N, then R 5 is absent, and when Y 2 is C, then R 5 is present; when Y 3 is N, then R 6 is absent,
Y 8 is N, then R 11 is absent, and when Y 8 is C, then R 11 is present.
6 . The compound of anyone of claims 1 - 5 , wherein
A is
wherein R 8 , R 9 , R 10 and R 11 are each absent or present, and when present, are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(aryl), -(heteroaryl)-(alkenyl), -(alkynyl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl)-NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —O—C(O)(alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl), or —SO 2 -(heteroaryl);
Y 5 , Y 6 , Y 7 and Y 8 are each independently N or C,
wherein when Y 5 is N, then R 8 is absent, and when Y 5 is C, then R 8 is present; when Y 6 is N, then R 9 is absent, and when Y 6 is C, then R 9 is present; when Y 7 is N, then R 10 is absent, and when Y, is C, then R 10 is present; when (heteroaryl), —OH, —OAc, —O—C(O)(alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl), or —SO 2 -(heteroaryl); and
Y 1 , Y 2 , Y 3 and Y 4 are each independently N or C,
wherein when Y 1 is N, then R 4 is absent, and when Y 1 is C, then R 4 is present; when Y 2 is N, then R 5 is absent, and when Y 2 is C, then R 5 is present; when Y 3 is N, then R 6 is absent, and when Y 3 is C, then R 6 is present; when Y 4 is N, then R 7 is absent, and when Y 4 is C, then R, is present.
7 . A compound having the structure:
wherein
R 1 is —H or -(alkyl);
R 2 is -(alkyl), -(alkenyl), -(alkynyl), -(alkyl)-OH, -(alkyl)-CO 2 H, -(alkyl)-CO 2 -(alkyl), -(alkyl)-C(O)—NH 2 , -(alkyl)-C(O)—NH(alkyl), -(alkyl)-C(O)—NH-(hydroxyalkyl), -(alkyl)-C(O)—N(alkyl) 2 , -(alkyl)-C(O)—N(hydroxyalkyl) 2 , -(alkyl)-O-(alkyl), -(alkyl)-S-(alkyl), -(alkyl)-CF 3 , -(alkyl)-O-(hydroxyalkyl), -(alkyl)-O-(alkyl)-OCH 3 , -(alkyl)-(CH)—(O-(alkyl)) 2 , -(alkyl)-(heterocyclyl), -(alkyl)-OAc, -(alkyl)-tetrahydrofuran, -(alkyl)-pyrrolidine, -(alkyl)-N-methylpyrrolidine, -(alkyl)-(1,3-dioxane) or -(alkyl)-(4,5-dihydrooxazole);
R 3 is —H or -(alkyl);
R 4 , R 5 , R 6 and R, are each absent or present, and when present, are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl)-NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —O—C(O)(alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl), or —SO 2 -(heteroaryl); R 12 and R 13 are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(aryl), -(heteroaryl)-(alkenyl), -(alkynyl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl)-NH-(aryl), —NH—
and when Y 3 is C, then R 6 is present; when Y 4 is N, then R 7 is absent, and when Y 4 is C, then R, is present,
wherein when A is phenyl, R 1 is —CH 3 , R 3 , R 4 , R 6 , and R 7 , are each —H, and R 5 is Cl, then R 2 is other than —(CH 2 ) 4 CO 2 H, —(CH 2 ) 6 CO 2 H, —(CH 2 ) 6 CO 2 CH 2 CH 3 , or —(CH 2 ) 6 CH 3 ,
wherein when A is phenyl, R 1 is —CH 3 , R 3 , R 4 , R 6 , and R 7 , are each —H, and R 5 is —SO 2 CH 3 , then R 2 is other than —(CH 2 ) 3 OCH 3 ,
or a pharmaceutically acceptable salt thereof.
8 . A compound having the structure:
wherein
R 2 is -(alkyl), -(alkenyl), -(alkynyl), -(alkyl)-OH, -(alkyl)-CO 2 H, -(alkyl)-CO 2 -(alkyl), -(alkyl)-C(O)—NH 2 , -(alkyl)-C(O)—NH(alkyl), -(alkyl)-C(O)—NH-(hydroxyalkyl), -(alkyl)-C(O)—N(alkyl) 2 , -(alkyl)-C(O)—N(hydroxyalkyl) 2 , -(alkyl)-O-(alkyl), -(alkyl)-S-(alkyl), -(alkyl)-CF 3 , -(alkyl)-O-(hydroxyalkyl), -(alkyl)-O-(alkyl)-O-(alkyl), -(alkyl)-(CH)—(O-(alkyl)) 2 , -(alkyl)-(heterocyclyl), -(alkyl)-OAc, -(alkyl)-tetrahydrofuran, -(alkyl)-pyrrolidine, -(alkyl)-N-methylpyrrolidine, -(alkyl)-(1,3-dioxane) or -(alkyl)-(4,5-dihydrooxazole);
R 5 is —Br, or —I;
R 4 , R 6 and R 7 are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl)-NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —O—C(O)(alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl) or —SO 2 -(heteroaryl).
9 . A compound having the structure:
wherein
R 2 is -(alkyl)-O-(alkyl) or -(alkyl)-O-(alkyl)-O-(alkyl);
R 5 is —Cl, —Br, —F, or —I;
R 4 , R 6 and R 7 are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl)-NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —O—C(O) (alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl) or —SO 2 -(heteroaryl);
R 8 , R 9 , R 10 and R 11 are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(aryl), -(heteroaryl)-(alkenyl), -(alkynyl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl)-NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —O—C(O)(alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl), or —SO 2 -(heteroaryl).
10 . The compound of claim 7 having the structure:
wherein
R 2 is -(alkyl), -(alkenyl), -(alkynyl), -(alkyl)-OH, -(alkyl)-CO 2 H, -(alkyl)-CO 2 -(alkyl), -(alkyl)-C(O)—NH 2 , -(alkyl)-C(O)—NH(alkyl), -(alkyl)-C(O)—NH-(hydroxyalkyl), -(alkyl)-C(O)—N(alkyl) 2 , -(alkyl)-C(O)—N(hydroxyalkyl) 2 , -(alkyl)-O-(alkyl), -(alkyl)-S-(alkyl), -(alkyl)-CF 3 , -(alkyl)-O-(hydroxyalkyl), -(alkyl)-O-(alkyl)-O-(alkyl), -(alkyl)-(CH)—(O-(alkyl)) 2 , -(alkyl)-(heterocyclyl), -(alkyl)-OAc, -(alkyl)-tetrahydrofuran, -(alkyl)-pyrrolidine, -(alkyl)-N-methylpyrrolidine, -(alkyl)-(1,3-dioxane) or -(alkyl)-(4,5-dihydrooxazole);
R 5 is —Cl, —Br, —F, or —I;
R 4 , R 6 and R 7 are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl)-NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —O—C(O)(alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl) or —SO-(heteroaryl).
11 . The compound of claim 7 having the structure:
wherein
R 2 is -(alkyl)-CO 2 -(alkyl), -(alkyl)-O-(alkyl) or -(alkyl)-O-(alkyl)-O-(alkyl);
R 5 is —Cl, —Br, —F, or —I;
R 4 , R 6 and R 7 are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl)-NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —O—C(O)(alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl) or —SO 2 -(heteroaryl);
R 8 , R 9 , R 10 and R 11 are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(aryl), -(heteroaryl)-(alkenyl), -(alkynyl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl)-NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —O—C(O)(alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl), or —SO 2 -(heteroaryl).
12 . The compound of claim 1 having the structure:
or a pharmaceutically acceptable salt thereof.
13 . The compound of claim 1 having the structure:
or a pharmaceutically acceptable salt thereof.
14 . The compound of claim 1 having the structure:
or a pharmaceutically acceptable salt thereof.
15 . The compound of claim 7 having the structure:
or a pharmaceutically acceptable salt thereof.
16 . The compound of claim 7 having the structure:
or a pharmaceutically acceptable salt thereof.
17 . The compound of claim 1 having the structure:
wherein
Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y, and Y 8 are each C;
R 1 is —CH 3 or —CH 2 CH 3 ;
R 2 is —(C 1 -C 8 alkyl), —(C 1 -C 6 alkyl)-OH, —(C 1 -C 6 alkyl)-CO 2 H, —(C 1 -C 6 alkyl)-CO 2 CH 2 CH 3 , —(C 1 -C 6 alkyl)-OCH 3 , —(C 1 -C 6 alkyl)-C(O)NH 2 , —(C 1 -C 6 alkyl)-CF 3 , —(C 1 -C 6 alkyl)-SCH 3 , —(C 1 -C 6 alkyl)-OAc, —(C 1 -C 6 alkyl)-CH(CH 2 CH 3 ) 2 , —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-(1,3-dioxane), —(C 1 -C 6 alkyl)-(1,3-dioxane), —(C 1 -C 6 alkyl)-(4,5-dihydrooxazole), —(C 1 -C 2 alkyl)-O—(C 1 -C 2 alkyl)-OCH 3 , —(C 1 -C 2 alkyl)-O—(C 1 -C 2 alkyl)-OH, —(C 1 -C 6 alkyl)-C(O)—NH—(C 1 -C 2 hydroxyalkyl), —(C 1 -C 2 alkyl)-tetrahydrofuran, or —(C 1 -C 2 alkyl)-pyrrolidine;
R 3 is —H;
R 4 , R 5 , R 10 and R 11 are each independently —H, —OCH 3 , or —Br; and
R 4 , R 5 , R 6 , and R 7 are each independently —H, —Cl, —Br, —F, —I, —CH 3 , —OCH 3 , —OH, —OAc, —SCH 3 , —SCH 2 CH 3 , S-iPr, —SO 2 CH 3 , —S(O)CH 3 , -(phenyl), —O—CH 2 (phenyl) or —O-(phenyl),
or a pharmaceutically acceptable salt thereof.
18 . The compound of claim 7 having the structure:
Y 1 , Y 2 , Y 3 , and Y 4 are each C;
R 1 is —CH 3 ;
R 2 is —(C 1 -C 6 alkyl)-OCH 3 , —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-CO 2 CH 2 CH 3 or —(C 1 -C 6 alkyl)-OCH 3 ;
R 3 , R 4 , R 5 , R 6 and R 12 are each —H, —Cl, —Br, —F, —I; and
R 13 is —H or —Br,
or a pharmaceutically acceptable salt thereof.
19 . A pharmaceutical composition comprising the compound of any one of claims 1 - 18 and a pharmaceutically acceptable carrier.
20 . A method of activating a mu-opioid receptor or delta-opioid receptor comprising contacting the mu-opioid receptor or delta-opioid receptor with the compound of any one of claims 1 - 18 .
21 . A method of treating a subject afflicted with pain, a depressive disorder or a mood disorder comprising administering an effective amount of the compound of any one of claims 1 - 18 to the subject so as to treat the pain, depressive disorder or mood disorder.
22 . A method of activating mu-opioid receptor or delta-opioid receptor comprising contacting the mu-opioid receptor or delta-opioid receptor with a compound having the structure:
wherein
A is an aryl or heteroaryl, with or without substitution;
R 1 is —H or -(alkyl);
R 2 is -(alkyl), -(alkenyl), -(alkynyl), -(alkyl)-OH, -(alkyl)-CO 2 H, -(alkyl)-CO 2 -(alkyl), -(alkyl)-C(O)—NH 2 , -(alkyl)-C(O)—NH(alkyl), -(alkyl)-C(O)—NH-(hydroxyalkyl), -(alkyl)-C(O)—N(alkyl) 2 , -(alkyl)-C(O)—N(hydroxyalkyl) 2 , -(alkyl)-O-(alkyl), -(alkyl)-S-(alkyl), -(alkyl)-CF 3 , -(alkyl)-O-(hydroxyalkyl), -(alkyl)-O-(alkyl)-O-(alkyl), -(alkyl)-(CH)—(O-(alkyl)) 2 , -(alkyl)-(heterocyclyl), -(alkyl)-OAc, -(alkyl)-tetrahydrofuran, -(alkyl)-pyrrolidine, -(alkyl)-N-methylpyrrolidine, -(alkyl)-(l, 3-dioxane) or -(alkyl)-(4,5-dihydrooxazole);
R 3 is —H or -(alkyl);
R 4 , R 5 , R 6 and R, are each absent or present, and when present, are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl)-NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —O—C(O) (alkyl), —O-(alkyl), —O-(alkylaryl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl), or —SO 2 -(heteroaryl); and
Y 1 , Y 2 , Y 3 and Y 4 are each independently N or C,
wherein when Y 1 is N, then R 4 is absent, and when Y 1 is C, then R 4 is present; when Y 2 is N, then R 5 is absent, and when Y 2 is C, then R 5 is present; when Y 3 is N, then R 6 is absent, and when Y 3 is C, then R 6 is present; when Y 4 is N, then R, is absent, and when Y 4 is C, then R 7 is present,
or a pharmaceutically acceptable salt or ester thereof, so as to thereby activate the mu-opioid receptor or delta-opioid receptor.
23 . A method of treating a subject afflicted with with pain, a depressive disorder or a mood disorder comprising administering an effective amount of the compound having the structure:
wherein
A is an aryl or heteroaryl, with or without substitution;
R 1 is —H or -(alkyl);
R 2 is -(alkyl), -(alkenyl), -(alkynyl), -(alkyl)-OH, -(alkyl)-CO 2 H, -(alkyl)-CO 2 -(alkyl), -(alkyl)-C(O)—NH 2 , -(alkyl)-C(O)—NH(alkyl), -(alkyl)-C(O)—NH-(hydroxyalkyl), -(alkyl)-C(O)—N(alkyl) 2 , -(alkyl)-C(O)—N(hydroxyalkyl) 2 , -(alkyl)-O-(alkyl), -(alkyl)-S-(alkyl), -(alkyl)-CF 3 , -(alkyl)-O-(hydroxyalkyl), -(alkyl)-O-(alkyl)-O-(alkyl), -(alkyl)-(CH)—(O-(alkyl)) 2 , -(alkyl)-(heterocyclyl), -(alkyl)-OAc, -(alkyl)-tetrahydrofuran, -(alkyl)-pyrrolidine, -(alkyl)-N-methylpyrrolidine, -(alkyl)-(1,3-dioxane) or -(alkyl)-(4,5-dihydrooxazole);
R 3 is —H or -(alkyl);
R 4 , R 5 , R 6 and R, are each absent or present, and when present, are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl)-NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —O—C(O) (alkyl), —O-(alkyl), —O-(alkylaryl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl), or —SO 2 -(heteroaryl); and
Y 1 , Y 2 , Y 3 and Y 4 are each independently N or C,
wherein when Y 1 is N, then R 1 is absent, and when Y 1 is C, then R 4 is present; when Y 2 is N, then R 5 is absent, and when Y 2 is C, then R 5 is present; when Y 3 is N, then R 6 is absent, and when Y 3 is C, then R 6 is present; when Y 4 is N, then R 7 is absent, and when Y 4 is C, then R 7 is present,
or a pharmaceutically acceptable salt thereof, to the subject so as to thereby treat the pain, depressive disorder or mood disorder.
24 . A method of treating a subject afflicted with a depressive disorder or a mood disorder comprising administering to the subject an effective amount of a NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist, a neurokinin 2 receptor antagonist or a neurokinin 3 receptor antagonist and an effective amount of a compound having the structure:
wherein
R 1 is —H or -(alkyl);
R 2 is -(alkyl), -(alkenyl), -(alkynyl), -(alkyl)-OH, -(alkyl)-CO 2 H, -(alkyl)-CO 2 -(alkyl), -(alkyl)-C(O)—NH 2 , -(alkyl)-C(O)—NH(alkyl), -(alkyl)-C(O)—NH-(hydroxyalkyl), -(alkyl)-C(O)—N(alkyl) 2 , -(alkyl)-C(O)—N(hydroxyalkyl) 2 , -(alkyl)-O-(alkyl), -(alkyl)-S-(alkyl), -(alkyl)-CF 3 , -(alkyl)-O-(hydroxyalkyl), -(alkyl)-O-(alkyl)-O-(alkyl), -(alkyl)-(CH)—(O-(alkyl)) 2 , -(alkyl)-(heterocyclyl), -(alkyl)-OAc, -(alkyl)-tetrahydrofuran, -(alkyl)-pyrrolidine, -(alkyl)-N-methylpyrrolidine, -(alkyl)-(1,3-dioxane) or -(alkyl)-(4,5-dihydrooxazole);
R 3 is —H or -(alkyl);
R 4 , R 5 , R 6 and R, are each absent or present, and when present, are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl)-NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —O—C(O)(alkyl), —O-(alkyl), —O-(alkylaryl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl), or —SO 2 -(heteroaryl); and
Y 1 , Y 2 , Y 3 and Y 4 are each independently N or C,
wherein when Y 1 is N, then R 4 is absent, and when Y 1 is C, then R 4 is present; when Y 2 is N, then R 5 is absent, and when Y 2 is C, then R 5 is present; when Y 3 is N, then R 6 is absent, and when Y 3 is C, then R 6 is present; when Y 4 is N, then R 7 is absent, and when Y 4 is C, then R, is present,
or a pharmaceutically acceptable salt thereof, so as to thereby treat the subject.
25 . A method of treating a subject afflicted with pain comprising administering to the subject an effective amount of a NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist, a neurokinin 2 receptor antagonist or a neurokinin 3 receptor antagonist and an effective amount of a compound having the structure:
wherein
A is an aryl or heteroaryl, with or without substitution;
R 1 is —H or -(alkyl);
R 1 is -(alkyl), -(alkenyl), -(alkynyl), -(alkyl)-OH, -(alkyl)-CO_H, -(alkyl)-CO 2 -(alkyl), -(alkyl)-C(O)—NH 2 , -(alkyl)-C(O)—NH(alkyl), -(alkyl)-C(O)—NH-(hydroxyalkyl), -(alkyl)-C(O)—N(alkyl) 2 , -(alkyl)-C(O)—N(hydroxyalkyl) 2 , -(alkyl)-O-(alkyl), -(alkyl)-S-(alkyl), -(alkyl)-CF 3 , -(alkyl)-O-(hydroxyalkyl), -(alkyl)-O-(alkyl)-O-(alkyl), -(alkyl)-(CH)—(O-(alkyl)) 2 , -(alkyl)-(heterocyclyl), -(alkyl)-OAc, -(alkyl)-tetrahydrofuran, -(alkyl)-pyrrolidine, -(alkyl)-N-methylpyrrolidine, -(alkyl)-(l, 3-dioxane) or -(alkyl)-(4,5-dihydrooxazole);
R 3 is —H or -(alkyl);
R 4 , R 5 , R 6 and R, are each absent or present, and when present, are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl)-NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —O—C(O) (alkyl), —O-(alkyl), —O-(alkylaryl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl), or —SO 2 -(heteroaryl); and
Y 1 , Y 2 , Y 3 and Y 4 are each independently N or C,
wherein when Y 1 is N, then R 4 is absent, and when Y 1 is C, then R 4 is present; when Y 2 is N, then R 5 is absent, and when Y 2 is C, then R 5 is present; when Y 3 is N, then R 6 is absent, and when Y 3 is C, then R 6 is present; when Y 4 is N, then R 7 is absent, and when Y 4 is C, then R, is present,
or a pharmaceutically acceptable salt thereof, so as to thereby treat the subject.
26 . A compound having the structure
wherein
A is an aryl or heteroaryl, with or without substitution;
R 1 is —H or -(alkyl);
R 2 is -(alkyl), -(alkenyl), -(alkynyl), -(alkyl)-OH, -(alkyl)-CO 2 H, -(alkyl)-CO 2 -(alkyl), -(alkyl)-C(O)—NH 2 , -(alkyl)-C(O)—NH(alkyl), -(alkyl)-C(O)—NH-(hydroxyalkyl), -(alkyl)-C(O)—N(alkyl) 2 , -(alkyl)-C(O)—N(hydroxyalkyl) 2 , -(alkyl)-O-(alkyl), -(alkyl)-S-(alkyl), -(alkyl)-CF 3 , -(alkyl)-O-(hydroxyalkyl), -(alkyl)-O-(alkyl)-O-(alkyl), -(alkyl)-(CH)—(O-(alkyl)) 2 , -(alkyl)-(heterocyclyl), -(alkyl)-OAc, -(alkyl)-tetrahydrofuran, -(alkyl)-pyrrolidine, -(alkyl)-N-methylpyrrolidine, -(alkyl)-(1,3-dioxane) or -(alkyl)-(4,5-dihydrooxazole);
R 3 is —H or -(alkyl);
R 4 , R 5 , R 6 and R 7 are each absent or present, and when present, are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl)-NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —O—C(O)(alkyl), —O-(alkyl), —O-(alkylaryl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl), or —SO 2 -(heteroaryl); and
Y 1 , Y 2 , Y 3 and Y 4 are each independently N or C,
wherein when Y 1 is N, then R 4 is absent, and when Y 1 is C, then R 4 is present; when Y 2 is N, then R 5 is absent, and when Y 2 is C, then R 5 is present; when Y 3 is N, then R 6 is absent, and when Y 3 is C, then R 6 is present; when Y 4 is N, then R 7 is absent, and when Y 4 is C, then R 7 is present,
or a salt or ester thereof, for use as an add-on therapy or in combination with a a NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist, a neurokinin 2 receptor antagonist or a neurokinin 3 receptor antagonist in treating a subject afflicted with a depressive disorder or a mood disorder.
27 . A compound having the structure
wherein
A is an aryl or heteroaryl, with or without substitution;
R 1 is —H or -(alkyl);
R 2 is -(alkyl), -(alkenyl), -(alkynyl), -(alkyl)-OH, -(alkyl)-CO 2 H, -(alkyl)-CO 2 -(alkyl), -(alkyl)-C(O)—NH 2 , -(alkyl)-C(O)—NH(alkyl), -(alkyl)-C(O)—NH-(hydroxyalkyl), -(alkyl)-C(O)—N(alkyl) 2 , -(alkyl)-C(O)—N(hydroxyalkyl) 2 , -(alkyl)-O-(alkyl), -(alkyl)-S-(alkyl), -(alkyl)-CF 3 , -(alkyl)-O-(hydroxyalkyl), -(alkyl)-O-(alkyl)-O-(alkyl), -(alkyl)-(CH)—(O-(alkyl)) 2 , -(alkyl)-(heterocyclyl), -(alkyl)-OAc, -(alkyl)-tetrahydrofuran, -(alkyl)-pyrrolidine, -(alkyl)-N-methylpyrrolidine, -(alkyl)-(1,3-dioxane) or -(alkyl)-(4,5-dihydrooxazole);
R 3 is —H or -(alkyl);
R 4 , R 5 , R 6 and R 7 are each absent or present, and when present, are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl)-NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —O—C(O) (alkyl), —O-(alkyl), —O-(alkylaryl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl), or —SO 2 -(heteroaryl); and
Y 1 , Y 2 , Y 3 and Y 4 are each independently N or C,
wherein when Y 1 is N, then R 4 is absent, and when Y 1 is C, then R 4 is present; when Y 2 is N, then R 5 is absent, and when Y 2 is C, then R 5 is present; when Y 3 is N, then R 6 is absent, and when Y 3 is C, then R 6 is present; when Y 4 is N, then R 7 is absent, and when Y 4 is C, then R 7 is present,
or a salt or ester thereof, for use as an add-on therapy or in combination with a a NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist, a neurokinin 2 receptor antagonist or a neurokinin 3 receptor antagonist in treating a subject afflicted with pain.
28 . A pharmaceutical composition comprising an amount of a compound having the structure
wherein
A is an aryl or heteroaryl, with or without substitution;
R 1 is —H or -(alkyl);
R 2 is -(alkyl), -(alkenyl), -(alkynyl), -(alkyl)-OH, -(alkyl)-CO 2 H, -(alkyl)-CO 2 -(alkyl), -(alkyl)-C(O)—NH 2 , -(alkyl)-C(O)—NH(alkyl), -(alkyl)-C(O)—NH-(hydroxyalkyl), -(alkyl)-C(O)—N(alkyl) 2 , -(alkyl)-C(O)—N(hydroxyalkyl) 2 , -(alkyl)-O-(alkyl), -(alkyl)-S-(alkyl), -(alkyl)-CF 3 , -(alkyl)-O-(hydroxyalkyl), -(alkyl)-O-(alkyl)-O-(alkyl), -(alkyl)-(CH)—(O-(alkyl)) 2 , -(alkyl)-(heterocyclyl), -(alkyl)-OAc, -(alkyl)-tetrahydrofuran, -(alkyl)-pyrrolidine, -(alkyl)-N-methylpyrrolidine, -(alkyl)-(1,3-dioxane) or -(alkyl)-(4,5-dihydrooxazole);
R 3 is —H or -(alkyl);
R 4 , R 5 , R 6 and R 7 are each absent or present, and when present, are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl)-NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —O—C(O) (alkyl), —O-(alkyl), —O-(alkylaryl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl), or —SO 2 -(heteroaryl); and
Y 1 , Y 2 , Y 3 and Y 4 are each independently N or C,
wherein when Y 1 is N, then R 4 is absent, and when Y 1 is C, then R 4 is present; when Y 2 is N, then R 5 is absent, and when Y 2 is C, then R 5 is present; when Y 3 is N, then R 6 is absent, and when Y 3 is C, then R 6 is present; when Y 1 is N, then R, is absent, and when Y 4 is C, then R, is present,
or a salt or ester thereof, and an amount of a NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist, a neurokinin 2 receptor antagonist or a neurokinin 3 receptor antagonist for use in treating a subject afflicted with a depressive disorder or a mood disorder.
29 . A pharmaceutical composition comprising an amount of a compound having the structure
wherein
A is an aryl or heteroaryl, with or without substitution;
R 1 is —H or -(alkyl);
R 2 is -(alkyl), -(alkenyl), -(alkynyl), -(alkyl)-OH, -(alkyl)-CO 2 H, -(alkyl)-CO 2 -(alkyl), -(alkyl)-C(O)—NH 2 , -(alkyl)-C(O)—NH(alkyl), -(alkyl)-C(O)—NH-(hydroxyalkyl), -(alkyl)-C(O)—N(alkyl) 2 , -(alkyl)-C(O)—N(hydroxyalkyl) 2 , -(alkyl)-O-(alkyl), -(alkyl)-S-(alkyl), -(alkyl)-CF 3 , -(alkyl)-O-(hydroxyalkyl), -(alkyl)-O-(alkyl)-O-(alkyl), -(alkyl)-(CH)—(O-(alkyl)) 2 , -(alkyl)-(heterocyclyl), -(alkyl)-OAc, -(alkyl)-tetrahydrofuran, -(alkyl)-pyrrolidine, -(alkyl)-N-methylpyrrolidine, -(alkyl)-(1,3-dioxane) or -(alkyl)-(4,5-dihydrooxazole);
R 3 is —H or -(alkyl);
R 4 , R 5 , R 6 and R 7 are each absent or present, and when present, are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl)-NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —O—C(O)(alkyl), —O-(alkyl), —O-(alkylaryl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl), or —SO 2 -(heteroaryl); and
Y 1 , Y 2 , Y 3 and Y 4 are each independently N or C,
wherein when Y 1 is N, then R 4 is absent, and when Y 1 is C, then R 4 is present; when Y 2 is N, then R 5 is absent, and when Y 2 is C, then R 5 is present; when Y 3 is N, then R 6 is absent, and when Y 3 is C, then R 6 is present; when Y 4 is N, then R 7 is absent, and when Y 4 is C, then R 7 is present,
or a salt or ester thereof, and an amount of a NMDA receptor antagonist, an NMDA receptor partial agonist, a neurokinin 1 receptor antagonist, a neurokinin 2 receptor antagonist or a neurokinin 3 receptor antagonist for use in treating a subject afflicted with pain.
30 . The method of any one of claims 22 - 25 , the compound of any one of claims 26 - 27 or the pharmaceutical composition of any one of claims 28 - 29 , wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof.
31 . The method of any one of claims 22 - 25 , the compound of any one of claims 26 - 27 or the pharmaceutical composition of any one of claims 28 - 29 , wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof.
32 . The method of any one of claims 22 - 25 , the compound of any one of claims 26 - 27 or the pharmaceutical composition of any one of claims 28 - 29 , wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof.
33 . The method of any one of claims 22 - 25 , the compound of any one of claims 26 - 27 or the pharmaceutical composition of any one of claims 28 - 29 , wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof.
34 . The method of any one of claims 22 - 25 , the compound of any one of claims 26 - 27 or the pharmaceutical composition of any one of claims 28 - 29 , wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof.
35 . A compound having the structure:
wherein
α is a bond, which may be present or absent;
X is O, OH, OTf, Cl, or Br,
wherein when a is present, then X is O, and when α is absent,
then X is OH, OTf, Cl, or Br;
A is an aryl or heteroaryl, with or without substitution;
R 1 is —H or -(alkyl);
R 4 , R 5 , R 6 and R 7 are each absent or present, and when present, are each independently —H, —Cl, —Br, —F, —I, —CN, —CF 3 , —OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), —NH 2 , —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl)-NH-(aryl), —NH-(heteroaryl), —OH, —OAc, —O—C(O)(alkyl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —S(O)-(alkyl), —S(O)-(aryl), —S(O)-(heteroaryl), —SO 2 -(alkyl), —SO 2 -(aryl), or —SO 2 -(heteroaryl); and
Y 1 , Y 2 , Y 3 and Y 4 are each independently N or C,
wherein when Y 1 is N, then R 4 is absent, and when Y 1 is C, then R 4 is present; when Y 2 is N, then R 5 is absent, and when Y 2 is C, then R 5 is present; when Y 3 is N, then R 6 is absent, and when Y 3 is C, then R 6 is present; when Y 4 is N, then R, is absent, and when Y 4 is C, then R, is present,
or a pharmaceutically acceptable salt thereof.Join the waitlist — get patent alerts
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