Substituted oximes and hydrazones as neurokinin antagonists

Details Substituted oximes and hydrazones as neurokinin antagonists Substituted oximes and hydrazones as neurokinin antagonists

2001-01-12

2002-06-11

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C546S273700, C544S123000, C544S003000, C544S318000, C514S322000, C514S274000

Reexamination Certificate

active

06403582

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to a genus of substituted oximes and hydrazones useful as antagonists of tachykinin receptors, in particular as antagonists of the neuropeptides neurokinin-1 receptor (NK
1
) and/or neurokinin-2 receptor (NK
2
) and/or neurokinin-3 receptor (NK
3
).
Neurokinin receptors are found in the nervous system and the circulatory system and peripheral tissues of mammals, and therefore are involved in a variety of biological processes. Neurokinin receptor antagonists are consequently expected to be useful in the treatment or prevention of various mammalian disease states, for example asthma, cough, bronchospasm, inflammatory diseases such as arthritis, central nervous system conditions such as migraine and epilepsy, nociception, depression, and various gastrointestinal disorders such as Crohn's disease.
In particular, NK
1
receptors have been reported to be involved in microvascular leakage and mucus secretion, and NK
2
receptors have been associated with smooth muscle contraction, making NK
1
and NK
2
receptor antagonists especially useful in the treatment and prevention of asthma.
Substituted oxime and hydrazone NK
1
and NK
2
receptor antagonists have previously been disclosed in U.S. Pat. Nos. 5,696,267, 5,688,960, and 5,789,422.
SUMMARY OF THE INVENTION
Compounds of the present invention are represented by the formula I
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, C
1-6
alkyl, —OR
6
or —F;
A is ═N—OR
1
or ═N—N(R
2
)(R
3
);
when d is not 0, X is a bond, —C(O)—, —O—, —NR
9
—, —S(O)
e
—, —N(R
6
)C(O)—, —C(O)N(R
6
)—, —OC(O)NR
6
—, —OC(═S)NR
6
—, —N(R
6
)C(═S)O—, —S(O)
2
N(R
6
)—, —N(R
6
)S(O)
2
—, —N(R
6
)C(O)O—, —OC(O)— or —N(R
6
)C(O)NR
7
; and
when d is 0, X is a bond or —NR
6
—;
T is H, R
4
-aryl, R
4
-heterocycloalkyl or R
4
-heteroaryl;
Q is R
5
-phenyl, R
5
-naphthyl or R
5
-heteroaryl;
R
1
is H, C
1-6
alkyl, —(C(R
6
)(R
7
))
n
—G, —G
2
, —(C(R
6
)(R
7
))
p
—M—(C(R
13
)(R
14
))
n
—G or —(C(R
6
)(R
7
))
p
—M—(R
4
-heteroaryl);
R
2
and R
3
are independently selected from the group consisting of H, C
1-6
alkyl, —(C(R
6
)(R
7
))
n
—G, —G
2
and —S(O)
e
R
13
; or R
2
and R
3
, 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(R
19
)—;
R
4
and R
5
are independently 1-3 substituents independently selected from the group consisting of H, halogeno, —OR
6
, —OC(O)R
6
, —OC(O)N(R
6
)(R
7
), —N(R
6
)(R
7
), C
1-6
alkyl, —CF
3
, —C
2
F
5
, —COR
6
, —CO
2
R
6
, —CON(R
6
)(R
7
), —S(O)
e
R
13
, —CN, —OCF
3
, —OCHF
2
, —NR
6
CO
2
R
16
, —NR
6
COR
7
, —NR
8
CON(R
6
)(R
7
), NO
2
, —N(R
6
)S(O)
2
R
13
or —S(O)
2
N(R
6
)(R
7
); or adjacent R
4
substituents or adjacent R
5
substituents can form a —O—CH
2
—O— group;
R
6
, R
7
, R
8
, R
13
and R
14
are independently selected from the group consisting of H, C
1-6
alkyl, C
2
-C
6
hydroxyalkyl, C
1
-C
6
alkoxy-C
1
-C
6
alkyl, R
15
-phenyl, and R
15
-benzyl;
R
9
is independently selected from the group consisting of R
6
and —OR
6
;
or R
6
and R
7
, or R
7
and R
9
, 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(R
19
)—;
R
6a
, R
7a
, R
8a
, R
9a
, R
10
and R
10a
are independently selected from the group consisting of H and C
1-6
alkyl;
R
15
is 1 to 3 substituents independently selected from the group consisting of H, —OH, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
1
-C
6
alkylthio, halogeno, —CF
3
, —C
2
F
5
, —COR
10
, —CO
2
R
10
, —C(O)N(R
10
)
2
, —S(O)
e
R
10a
, —CN, —N(R
10
)COR
10
, —N(R
10
)CON(R
10
)
2
and —NO
2
;
R
16
is C
1-6
alkyl, R
15
-phenyl or R
15
-benzyl;
R
19
is H, C
1
-C
6
alkyl, —C(O)N(R
10
)
2
or —CO
2
R
10
;
n and p are independently 1-6;
G is selected from the group consisting of H, R
4
-aryl, R
4
-hetero-cycloalkyl, R
4
-heteroaryl, R
4
-cycloalkyl, —CH
2
F, —CHF
2
, —CF
3
, —OR
6
, —N(R
6
)(R
7
), —COR
6
, —CO
2
R
6
, —CON(R
7
)(R
9
), —S(O)
e
R
13
, —NR
6
CO
2
R
16
, —NR
6
COR
7
, —NR
8
CON(R
6
)(R
7
), —N(R
6
)S(O)
2
R
13
, —N(R
6
)S(O)
2
N(R
33
)(R
34
), —S(O)
2
N(R
6
)(R
7
), —OC(O)R
6
, —OC(O)N(R
6
)(R
7
), —C(═NOR
8
)N(R
6
)(R
7
), —C(═NR
25
)N(R
6
)(R
7
), —N(R
8
)C(═NR
25
)N(R
6
)(R
7
), —CN, —C(O)N(R
6
)OR
7
, and —C(O)N(R
9
)—(R
4
-heteroaryl), provided that when n is 1, G is not —OH or —N(R
6
)(R
7
);
M is selected from the group consisting of a double bond, —O—, —N(R
6
)—, —C(O)—, —C(R
6
)(OR
7
)—, —C(R
8
)(N(R
6
)(R
7
))—, —C(═NOR
6
) N(R
7
)—, —C(N(R
6
)(R
7
))═NO—, —C(═NR
25
)N(R
6
)—, —C(O)N(R
9
)—, —N(R
9
)C(O)—, —C(═S)N(R
9
)—, —N(R
9
)C(═S)— and —N(R
6
)C(O)N(R
7
)—, provided that when n is 1, G is not OH or —NH(R
6
); and when p is 2-6, M can also be —N(R
6
)C(═NR
25
)N(R
7
)— or —OC(O)N(R
6
)—;
G
2
is R
4
-aryl, R
4
-heterocycloalkyl, R
4
-heteroaryl, R
4
-cycloalkyl, —COR
6
, —CO
2
R
16
, —S(O)
2
N(R
6
)(R
7
) or —CON(R
6
)(R
7
);
e is 0, 1 or 2, provided that when e is 1 or 2, R
13
and R
10a
are not H;
R
25
is H, C
1
-C
6
alkyl, —CN, R
15
-phenyl or R
15
-benzyl;
Z is
g, h and j are independently 0-2;
k is1-4;
X
1
is —O—, —S— or —NR
9
—;
J is ═O, ═S, ═NR
9
, ═NCN or ═NOR
1
;
J
1
and J
2
are independently selected from the group consisting of two hydrogen atoms, ═O, ═S, ═NR
9
and ═NOR
1
;
R
26
, R
27
and R
29
are independently selected from the group consisting of H, C
1-6
alkyl, —(C(R
6
)(R
7
))
n
—G, —G
2
, —C(O)—(C(R
8
)(R
9
))
n
—G and —S(O)
e
R
13
;
R
28
is H, —(C(R
6
)(R
7
))
t
—G or —CON(R
6
)(R
7
);
t is 0, 1, 2 or 3, provided that when j is 0, t is 1, 2 or 3;
R
30
is 1-3 substituents independently selected from the group consisting of H, halogeno, —OR
6
, —OC(O)R
6
, —OC(O)N(R
6
)(R
7
), —N(R
6
)(R
7
), C
1-6
alkyl, —CF
3
, —C
2
F
5
, —COR
6
, —CO
2
R
6
, —CON(R
6
)(R
7
), —S(O)
e
R
13
, —CN, —OCF
3
, —NR
6
CO
2
R
16
, —NR
6
COR
7
, —NR
8
CON(R
6
)(R
7
), NO
2
, —N(R
6
)S(O)
2
R
13
or —S(O)
2
N(R
6
)(R
7
); or adjacent R
30
substituents can form a —O—CH
2
—O— group;
R
31
is independently selected from the group consisting of H and C
1
-C
6
alkyl;
R
32
is independently selected from the group consisting of H, —OH and C
1
-C
6
alkoxy; and
R
33
and R
34
are independently selected from the group consisting of H, C
1
-C
6
alkyl, R
15
-phenyl and R
15
-benzyl.
Preferred are compounds of formula I wherein X is —O—, —C(O)—, a bond, —NR
6
—, —S(O)
e
—, —N(R
6
)C(O)—, —OC(O)NR
6
or —C(═NOR
1
)—. More preferred are compounds of formula I wherein X is —O—, —NR
6
—, —N(R
6
)C(O)— or —OC(O)NR
6
. Additional preferred definitions are: b is 1 or 2 when X is —O— or —N(R
6
)—; b is 0 when X is —N(R
6
)C(O)—; and d is 1 or 2. T is preferably R
4
-aryl, with R
4
-phenyl being more preferred. Also preferred are compounds wherein R
6a
, R
7a
, R
8a
and R
9a
are independently hydrogen, hydroxyalkyl or alkoxyalkyl, with hydrogen being more preferred. Especially preferred are compounds wherein R
8a
and R
9a
are each hydrogen, d and b are each 1, X is —O—, —NR
6
—, —N(R
6
)C(O)— or —OC(O)NR
6
, T is R
4
-aryl and R
4
is two substituents selected from C
1
-C
6
alkyl, halogeno, —CF
3
and C
1
-C
6
alkoxy.
Also preferred are compounds of formula I wherein R is hydrogen. Q is preferably R
5
-phenyl; an especially preferred definition for Q is R
5
-phenyl, wherein R
5
is two halogeno substituents.
Preferred are compounds of formula I wherein A is ═N—OR
1
. R
1
is preferably H, alkyl, —(CH
2
)
n
—G, —(CH
2
)
p
—M—(CH
2
)
n
—G or —C(O)N(R
6
)(R
7
), wherein M is —O— or —C(O)N(R
9
)— and G is —CO
2
R
6
, —OR
6
, —C(O)N(R
7
)(R
9
),—C(═NOR
8
)N(R
6
)(R
7
), —C(O)N(R
9
)(R
4
-heteroaryl) or R
4
-heteroaryl. When A is ═N—N(R
2
)(R
3
), R
2
and R
3
are independently preferably H, C
1
-C
6
alkyl, —(C(R
6
)(R
7
))
n
—G or G
2
.
Preferred definitions of

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