Substituted oximes, hydrazones and olefins as neurokinin antagonists
First Claim
1. A compound represented by the structural formula ##STR384## or a pharmaceutically acceptable salt thereof, wherein:
- a is 0, 1, 2 or 3;
b and d are independently 0, 1 or 2;
R is H, C1-6 alkyl, --OR6 or C2 -C6 hydroxyalkyl;
A is ═
N--OR1, ═
N--N(R2)(R3), ═
C(R11)(R12) or ═
NR25 ;
X is a bond, --C(O)--, --O--, --NR6 --, --S(O)e --, --N(R6)C(O)--, --C(O)N(R6)----OC(O)NR6 --, --OC(═
S)NR6, --N(R6)C(═
S)O--, --C(═
NOR1), --S(O)2 N(R6)--, --N(R6)S(O)2 --, --N(R6)C(O)O-- or --OC(O)--, provided that when d is 0, X is a bond, --C(O)--, --NR6 --, C(O)N(R6)--, --N(R6)C(O)--, --OC(O)NR6 --, --C(═
NOR1)--, --N(R6)C(═
S)O--, --OC(═
S)NR6 --, --N(R6)S(O)2 -- or --N(R6)C(O)O--;
provided that when A is ═
C(R11)(R12) and d is 0, X is not --NR6 -- or --N(R6)C(O)--; and
provided that when A is ═
NR25, d is 0 and X is --NR6 -- or --N(R6)C(O)--;
T is H, R4 -aryl, R4 -heterocycloalkyl, R4 -heteroaryl, phthalimidyl, R4 -cycloalkyl or R10 -bridged cycloalkyl;
Q is R5 -phenyl, R5 -naphthyl, --SR6, --N(R6)(R7), --OR6, provided that when Q is --SR6, --N(R6)(R7) or --OR6, R is not --OR6 ;
R1 is H, C1-6 alkyl, --(C(R6)(R7))n --G, --G2, --(C(R6)(R7))p --M--(C(R13)(R14))n --(C(R8)(R9))u --G, --C(O)N(R6)--(C(R13)(R14)n -(C(R8)(R9))u --G or --(C(R6)(R7))p --M--(R4 -heteroaryl);
R2 and R3 are independently selected from the group consisting of H, C1-6 alkyl, --CN, --(C(R6)(R7))n --G, --G2, --C(O)--(C(R8)(R9))n --G and --S(O)e R13 ;
or R2 and R3, together with the nitrogen to which they are attached, form a ring of 5 to 6 members, wherein 0, 1 or 2 ring members are selected from the group consisting of --O--, --S-- and --N(R19)--;
R4 and R5 are independently 1-3 substituents independently selected from the group consisting of H, halogeno, --OR6, --OC(O)R6, --OC(O)N(R6)(R7), --N(R6)(R7), C1-6 alkyl, --CF3, --C2 F5, --COR6, --CO2 R6, --CON (R6)(R7), --S(O)e R13, --CN, --OCF3, --NR6 CO2 R16, --NR6 COR7, --NR8 CON(R6)(R7), R15 -phenyl, R15 -benzyl, NO2, --N(R6)S(O)2 R13 or --S(O)2 N(R6)(R7);
or adjacent R4 substituents or adjacent R5 substituents can form a --O--CH2 --O-- group; and
R4 can also be R15 -heteroaryl;
R6, R7, R8, R6a, R7a, R8a, R13 and R14 are independently selected from the group consisting of H, C1-6 alkyl, C2 -C6 hydroxyalkyl, C1 -C6 alkoxy-C1 -C6 alkyl, R15 -phenyl, and R15 -benzyl;
or R6 and R7, together with the nitrogen to which they are attached, form a ring of 5 to 6 members, wherein 0, 1 or 2 ring members are selected from the group consisting of --O--, --S-- and --N(R19)--;
R9 and R9a are independently selected from the group consisting of R6 and --OR6R10 and R10a are independently selected from the group consisting of H and C1-6 alkyl;
R11 and R12 are independently selected from the group consisting of H, C1 -C6 alkyl, --CO2 R6, --OR6, --C(O)N(R6)(R7), C1 -C6 hydroxyalkyl, --(CH2)r --OC(O)R6, --(CH2)r --OC(O)CH═
CH2, --(CH2)r --O(CH2)s --CO2 R6, --(CH2)r --O--(CH2)s --C(O)N(R6)(R7) and --(CH2)r --N(R6)(R7);
R15 is 1 to 3 substituents independently selected from the group consisting of H, C1 -C6 alkyl, C1 -C6 alkoxy, C1 -C6 alkylthio, halogeno, --CF3, --C2 F5, --COR10, --CO2 R10, --C(O)N(R10)2, --S(O)e R10a, --CN, --N(R10)COR10, --N(R10)CON(R10)2 and --NO2 ;
R16 is C1-6 alkyl, R15 -phenyl or R15 -benzyl;
R19 is H, C1-6 alkyl, --C(O)N(R10)2, --CO2 R10, --(C(R8)(R9))f --CO2 R10 or --(C(R8)(R9))u --C(O)N(R10)2 ;
f, n, p, r and s are independently 1-6;
u is 0-6;
G is selected from the group consisting of H, R4 -aryl, R4 -heterocycloalkyl, R4 -heteroaryl, R4 -cycloalkyl, --OR6, --N(R6)(R7), --COR6, --CO2 R6, --CON(R7)(R9), --S(O)e R13, --NR6 CO2 R16, --NR6 COR7, --NR8 CON(R6)(R7), --N(R6)S(O)2 R13, --S(O)2 N(R6)(R7), --OC(O)R6, --OC(O)N(R6)(R7), --C(═
NOR8)N(R6)(R7), --C(═
NR25)N(R6)(R7), --N(R8)C(═
NR25)N(R6)(R7), --CN, --C(O)N(R6)OR7, and --C(O)N(R9)--(R4 -heteroaryl), provided that when n is 1 and u is 0, or when R9 is --OR6, G is not --OH or --N(R6)(R7);
M is selected from the group consisting of a double bond, --O--, --N(R6)--, --C(O)--, --C(R6)(OR7)--, --C(R8)(N(R6)(R7))--, --C(═
NOR6)N(R7)--, --C(N(R6)(R7))═
NO--, --C(═
NR25)N(R6)--, --C(O)N(R9)--, --N(R9)C(O)--, --C(═
S)N(R9)--, --N(R9)C(═
S)-- and --N(R6)C(O)N(R7)--, provided that when n is 1, G is not OH or --NH(R6); and
when p is 2-6, M can also be --N(R6)C(═
NR25)N(R7)-- or --OC(O)N(R6)--;
G2 is R4 -aryl, R4 -heterocycloalkyl, R4 -heteroaryl, R4 -cycloalkyl, --COR6, --CO2 R16, --S(O)2 N(R6)(R7) or --CON(R6)(R7);
e is 0, 1 or 2, provided that when e is 1 or 2, R13 and R10a are not H;
R25 is H, C1 -C6 alkyl, --CN, R15 -phenyl or R15 -benzyl;
Z is ##STR385## g and j are independently 0-3;
h and k are independently 1-4, provided the sum of h and g is 1-7;
J is two hydrogen atoms, ═
O, ═
S, ═
NR9 or ═
NOR1 ;
L and L1 are independently selected from the group consisting of H, C1 -C6 alkyl, C1 -C6 alkenyl, --CH2 -cycloalkyl, R15 -benzyl, R15 -heteroaryl, C(O)R6, --(CH2)m --OR6, --(CH2)m --N(R6)(R7), --(CH2)m --C(O)--OR6 and --(CH2)m --C(O)N(R6)(R7);
m is 0 to 4, provided that when j is 0, m is 1-4;
R26 and R27 are independently selected from the group consisting of H, C1 -C6 alkyl, R4 -aryl and R4 -heteroaryl;
or R26 is H, C1 -C6 alkyl, R4 -aryl or R4 -heteroaryl, and R27 is --C(O)R6, --C(O)--N(R6)(R7), --C(O)(R4 -aryl), --C(O)(R4 -heteroaryl), --SO2 R13 or --SO2 --(R4 -aryl);
R28 is H, --(C(R6)(R19))t --G, --(C(R6)(R7))v --G2 or --NO2 ;
t and v are 0, 1, 2 or 3, provided that when j is 0, t is 1, 2 or 3;
R29 is H, C1 -C6 alkyl, --C(R10)2 S(O)e R6, R4 -phenyl or R4 -heteroaryl;
R30 is H, C1 -C6 alkyl, R4 -cycloalkyl, --(C(R10)2)w --(R4 -phenyl), --(C(R10)2)w --(R4 -heteroaryl), --C(O)R6, --C(O)OR6, --C(O)N(R6)(R7), ##STR386## w is 0, 1,2, or 3;
V is ═
O, ═
S or ═
NR6 ; and
q is 0-4.
1 Assignment
0 Petitions
Accused Products
Abstract
Compound represented by the structural formula ##STR1## or a pharmaceutically acceptable salt thereof, wherein: a is 0, 1, 2 or 3;
b, d and e are independently 0, 1 or 2;
R is H, C1-6 alkyl, --OH or C2 -C6 hydroxyalkyl;
A is an optionally substituted oxime, hydrazone or olefin;
X is a bond, --C(O)--, --O--, --NR6 --, --S(O)e --, --N(R6)C(O)--, --C(O)N(R6)--OC(O)NR6 --, --OC(═S)NR6 --, --N(R6)C(═S)O--, --C(═NOR1)--, --S(O)2 N(R6)--, --N(R6)S(O)2 --,--N(R6)C(O)O-- or --OC(O)--;
T is H, phthalimidyl, aryl, heterocycloalkyl, heteroaryl, cycloalkyl or bridged cycloalkyl;
Q is --SR6, --N(R6)(R7), --OR6, phenyl, naphthyl or heteroaryl;
R6a, R7a, R8a, R9a, R6 and R7 are H, C1-6 alkyl, C2 -C6 hydroxyalkyl, C1 -C6 alkoxy-C1 -C6 alkyl, phenyl or benzyl; or R6 and R7, together with the nitrogen to which they are attached, form a ring;
R9a is R6 or --OR6 ;
Z is morpholinyl, optionally N-substituted piperazinyl, optionally
substituted ##STR2## or substituted ##STR3## g is 0-3 and h is 1-4, provided the sum of h and g is 1-7; wherein aryl, heterocycloalkyl, heteroaryl, cycloalkyl and bridged cycloalkyl groups are optionally substituted; methods of treating asthma, cough, bronchospasm, imflammatory diseases, and gastrointestinal disorders with said compounds, and pharmaceutical compositions comprising said compounds are disclosed.
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Citations
23 Claims
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1. A compound represented by the structural formula ##STR384## or a pharmaceutically acceptable salt thereof, wherein:
- a is 0, 1, 2 or 3;
b and d are independently 0, 1 or 2; R is H, C1-6 alkyl, --OR6 or C2 -C6 hydroxyalkyl; A is ═
N--OR1, ═
N--N(R2)(R3), ═
C(R11)(R12) or ═
NR25 ;X is a bond, --C(O)--, --O--, --NR6 --, --S(O)e --, --N(R6)C(O)--, --C(O)N(R6)----OC(O)NR6 --, --OC(═
S)NR6, --N(R6)C(═
S)O--, --C(═
NOR1), --S(O)2 N(R6)--, --N(R6)S(O)2 --, --N(R6)C(O)O-- or --OC(O)--, provided that when d is 0, X is a bond, --C(O)--, --NR6 --, C(O)N(R6)--, --N(R6)C(O)--, --OC(O)NR6 --, --C(═
NOR1)--, --N(R6)C(═
S)O--, --OC(═
S)NR6 --, --N(R6)S(O)2 -- or --N(R6)C(O)O--;
provided that when A is ═
C(R11)(R12) and d is 0, X is not --NR6 -- or --N(R6)C(O)--; and
provided that when A is ═
NR25, d is 0 and X is --NR6 -- or --N(R6)C(O)--;T is H, R4 -aryl, R4 -heterocycloalkyl, R4 -heteroaryl, phthalimidyl, R4 -cycloalkyl or R10 -bridged cycloalkyl; Q is R5 -phenyl, R5 -naphthyl, --SR6, --N(R6)(R7), --OR6, provided that when Q is --SR6, --N(R6)(R7) or --OR6, R is not --OR6 ; R1 is H, C1-6 alkyl, --(C(R6)(R7))n --G, --G2, --(C(R6)(R7))p --M--(C(R13)(R14))n --(C(R8)(R9))u --G, --C(O)N(R6)--(C(R13)(R14)n -(C(R8)(R9))u --G or --(C(R6)(R7))p --M--(R4 -heteroaryl); R2 and R3 are independently selected from the group consisting of H, C1-6 alkyl, --CN, --(C(R6)(R7))n --G, --G2, --C(O)--(C(R8)(R9))n --G and --S(O)e R13 ;
or R2 and R3, together with the nitrogen to which they are attached, form a ring of 5 to 6 members, wherein 0, 1 or 2 ring members are selected from the group consisting of --O--, --S-- and --N(R19)--;R4 and R5 are independently 1-3 substituents independently selected from the group consisting of H, halogeno, --OR6, --OC(O)R6, --OC(O)N(R6)(R7), --N(R6)(R7), C1-6 alkyl, --CF3, --C2 F5, --COR6, --CO2 R6, --CON (R6)(R7), --S(O)e R13, --CN, --OCF3, --NR6 CO2 R16, --NR6 COR7, --NR8 CON(R6)(R7), R15 -phenyl, R15 -benzyl, NO2, --N(R6)S(O)2 R13 or --S(O)2 N(R6)(R7);
or adjacent R4 substituents or adjacent R5 substituents can form a --O--CH2 --O-- group; and
R4 can also be R15 -heteroaryl;R6, R7, R8, R6a, R7a, R8a, R13 and R14 are independently selected from the group consisting of H, C1-6 alkyl, C2 -C6 hydroxyalkyl, C1 -C6 alkoxy-C1 -C6 alkyl, R15 -phenyl, and R15 -benzyl;
or R6 and R7, together with the nitrogen to which they are attached, form a ring of 5 to 6 members, wherein 0, 1 or 2 ring members are selected from the group consisting of --O--, --S-- and --N(R19)--;R9 and R9a are independently selected from the group consisting of R6 and --OR6 R10 and R10a are independently selected from the group consisting of H and C1-6 alkyl; R11 and R12 are independently selected from the group consisting of H, C1 -C6 alkyl, --CO2 R6, --OR6, --C(O)N(R6)(R7), C1 -C6 hydroxyalkyl, --(CH2)r --OC(O)R6, --(CH2)r --OC(O)CH═
CH2, --(CH2)r --O(CH2)s --CO2 R6, --(CH2)r --O--(CH2)s --C(O)N(R6)(R7) and --(CH2)r --N(R6)(R7);R15 is 1 to 3 substituents independently selected from the group consisting of H, C1 -C6 alkyl, C1 -C6 alkoxy, C1 -C6 alkylthio, halogeno, --CF3, --C2 F5, --COR10, --CO2 R10, --C(O)N(R10)2, --S(O)e R10a, --CN, --N(R10)COR10, --N(R10)CON(R10)2 and --NO2 ; R16 is C1-6 alkyl, R15 -phenyl or R15 -benzyl; R19 is H, C1-6 alkyl, --C(O)N(R10)2, --CO2 R10, --(C(R8)(R9))f --CO2 R10 or --(C(R8)(R9))u --C(O)N(R10)2 ; f, n, p, r and s are independently 1-6; u is 0-6; G is selected from the group consisting of H, R4 -aryl, R4 -heterocycloalkyl, R4 -heteroaryl, R4 -cycloalkyl, --OR6, --N(R6)(R7), --COR6, --CO2 R6, --CON(R7)(R9), --S(O)e R13, --NR6 CO2 R16, --NR6 COR7, --NR8 CON(R6)(R7), --N(R6)S(O)2 R13, --S(O)2 N(R6)(R7), --OC(O)R6, --OC(O)N(R6)(R7), --C(═
NOR8)N(R6)(R7), --C(═
NR25)N(R6)(R7), --N(R8)C(═
NR25)N(R6)(R7), --CN, --C(O)N(R6)OR7, and --C(O)N(R9)--(R4 -heteroaryl), provided that when n is 1 and u is 0, or when R9 is --OR6, G is not --OH or --N(R6)(R7);M is selected from the group consisting of a double bond, --O--, --N(R6)--, --C(O)--, --C(R6)(OR7)--, --C(R8)(N(R6)(R7))--, --C(═
NOR6)N(R7)--, --C(N(R6)(R7))═
NO--, --C(═
NR25)N(R6)--, --C(O)N(R9)--, --N(R9)C(O)--, --C(═
S)N(R9)--, --N(R9)C(═
S)-- and --N(R6)C(O)N(R7)--, provided that when n is 1, G is not OH or --NH(R6); and
when p is 2-6, M can also be --N(R6)C(═
NR25)N(R7)-- or --OC(O)N(R6)--;G2 is R4 -aryl, R4 -heterocycloalkyl, R4 -heteroaryl, R4 -cycloalkyl, --COR6, --CO2 R16, --S(O)2 N(R6)(R7) or --CON(R6)(R7); e is 0, 1 or 2, provided that when e is 1 or 2, R13 and R10a are not H; R25 is H, C1 -C6 alkyl, --CN, R15 -phenyl or R15 -benzyl; Z is ##STR385## g and j are independently 0-3;
h and k are independently 1-4, provided the sum of h and g is 1-7;J is two hydrogen atoms, ═
O, ═
S, ═
NR9 or ═
NOR1 ;L and L1 are independently selected from the group consisting of H, C1 -C6 alkyl, C1 -C6 alkenyl, --CH2 -cycloalkyl, R15 -benzyl, R15 -heteroaryl, C(O)R6, --(CH2)m --OR6, --(CH2)m --N(R6)(R7), --(CH2)m --C(O)--OR6 and --(CH2)m --C(O)N(R6)(R7); m is 0 to 4, provided that when j is 0, m is 1-4; R26 and R27 are independently selected from the group consisting of H, C1 -C6 alkyl, R4 -aryl and R4 -heteroaryl;
or R26 is H, C1 -C6 alkyl, R4 -aryl or R4 -heteroaryl, and R27 is --C(O)R6, --C(O)--N(R6)(R7), --C(O)(R4 -aryl), --C(O)(R4 -heteroaryl), --SO2 R13 or --SO2 --(R4 -aryl);R28 is H, --(C(R6)(R19))t --G, --(C(R6)(R7))v --G2 or --NO2 ; t and v are 0, 1, 2 or 3, provided that when j is 0, t is 1, 2 or 3; R29 is H, C1 -C6 alkyl, --C(R10)2 S(O)e R6, R4 -phenyl or R4 -heteroaryl; R30 is H, C1 -C6 alkyl, R4 -cycloalkyl, --(C(R10)2)w --(R4 -phenyl), --(C(R10)2)w --(R4 -heteroaryl), --C(O)R6, --C(O)OR6, --C(O)N(R6)(R7), ##STR386## w is 0, 1,2, or 3;
V is ═
O, ═
S or ═
NR6 ; andq is 0-4. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23)
- a is 0, 1, 2 or 3;
Specification