Selective neurokinin antagonists

Details Selective neurokinin antagonists Selective neurokinin antagonists

2000-12-14

2002-08-20

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S396000, C514S399000, C514S400000, C548S316100, C548S323500

Reexamination Certificate

active

06436928

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to a genus of substituted cyclic ureas and derivatives thereof useful as antagonists of tachykinin receptors, in particular as antagonists of the neuropeptides neurokinin-1 receptor (NK
1
).
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 respiratory diseases such as chronic lung disease, bronchitis, pneumonia, asthma, allergy, cough, bronchospasm; inflammatory diseases such as arthritis and psoriasis; skin disorders such as atopic dermatitis and contact dermatitis; ophthalmalogical disorders such as retinitis, ocular hypertension and cataracts; addictions such as alcohol dependence and psychoactive substance abuse; stress related disorders such as post tramautic stress disorder; obsessive/compulsive disorders; eating disorders such as bulemia, anorexia nervosa and binge eating disorders; mania; premenstrual syndrome; central nervous system conditions such as anxiety, general anxiety disorder, panic disorder, phobias, bipolar disorders, migraine, epilepsy, nociception, emesis, depression, psychosis, schizophrenia, Alzheimer's disease, AIDs related dementia and Towne's disease; gastrointestinal disorders such as Crohn's disease and colitis; nausea; bladder disorders; atherosclerosis; fibrosing disorders; obesity; Type II diabetes; pain related disorders such as neuropathic pain, post-operative pain, headache and chronic pain syndromes; and genitourinary disorders such as interstitial cystitis and urinary incontinence.
In particular, NK
1
receptors have been reported to be involved in microvascular leakage and mucus secretion, making NK
1
receptor antagonists especially useful in the treatment and prevention of asthma, emesis, nausea, depression, anxiety, cough, pain and migraine.
SUMMARY OF THE INVENTION
Compounds of the present invention are represented by the formula I
or a pharmaceutically acceptable salt thereof, wherein
Ar
1
and Ar
2
are independently selected from the group consisting of R
17
-heteroaryl and
X
1
is —O—, —S—, —SO—, —SO
2
—, —NR
12
—, —N(COR
12
)— or is N(SO
2
R
15
)—;
R
1
, R
2
, R
3
and R
7
are each independently selected from the group consisting of H, C
1
-C
6
alkyl, hydroxy(C
1
-C
3
)alkyl, C
3
-C
8
cycloalkyl, —CH
2
F, —CHF
2
and —CF
3
; or R
1
and R
2
, together with the carbon to which they are attached, form a C
3
-C
6
alkylene ring; or, when X
1
is —O—, —S— or —NR
12
—, R
1
and R
2
together are ═O;
each R
6
is independently selected from H, C
1
-C
6
alkyl, —OR
13
or —SR
12
;
n is 1-4, if n is greater than 1, then R
6
and R
7
can be the same or different on each carbon;
 is selected from the group consisting of
X
2
is —O—, —S— or —NR
5
—;
Y is ═O, ═S or ═NR
11
;
Y
1
is H, C
1
-C
6
alkyl, —NR
17
R
13
, —SCH
3
, R
19
-aryl(CH
2
)
n6
—, R
19
-heteroaryl-(CH
2
)
n6
—, —(CH
2
)
n6
-heterocycloalkyl, —(C
1
-C
3
)alkyl-NH—C(O)O(C
1
-C
6
)alkyl or —NHC(O)R
15
;
R
5
is H or —(CH
2
)
n1
—G, wherein n
1
is 0-5, G is H, —CF
3
, —CHF
2
, —CH
2
F, —OH, —O—(C
1
-C
6
alkyl), —SO
2
R
13
, —O—(C
3
-C
8
cycloalkyl), —NR
13
R
14
, —SO
2
NR
13
R
14
, —NR
13
SO
2
R
15
, —NR
13
COR
12
, —NR
12
(CONR
13
R
14
), —CONR
13
R
14
, —COOR
12
, C
3
-C
8
cycloalkyl, R
19
-aryl, R
19
-heteroaryl.
 or when n
1
is 0, R
5
can also be —C(O)R
13
; or —C(S)R
13
; provided that G is not H when n1=0;
X is —NR
20
—, —N(CONR
13
R
14
)—, —N(CO
2
R
13
)—, —N(SO
2
R
15
)—, —N(COR
12
)—, N(SO
2
NHR
13
)—, —O—, —S—, —SO—, —SO
2
—, —CF
2
—, —CH
2
— or —CR
12
F—;
R
8
, R
9
and R
10
are independently selected from the group consisting of H, C
1
-C
6
alkyl, C
3
-C
8
cycloalkyl, —OR
12
, halogen, —CN, —NO
2
, —CF
3
, —CHF
2
, —CH
2
F, —OCF
3
, —OCHF
2
, —OCH
2
F, —COOR
12
, —CONR
21
R
22
, —NR
21
COR
12
, —NR
21
CO
2
R
15
, —NR
21
CONR
21
R
22
, —NR
21
SO
2
R
15
, —NR
21
R
22
, —SO
2
NR
21
R
22
, —S(O)
n5
R
15
, R
16
-aryl and R
19
-heteroaryl;
R
11
is H, C
1
-C
6
alkyl, C
3
-C
8
cycloalkyl, —NO
2
, —CN, OH, —OR
12
, —O(CH
2
)
n6
R
12
, —(C
1
-C
3
)alkyl-C(O)NHR
12
, R
19
-aryl(CH
2
)
n6
— or R
19
-heteroaryl(CH
2
)
n6
—;
R
4
and R
12
are each independently selected from the group consisting of H, C
1
-C
6
alkyl and C
3
-C
8
cycloalkyl;
R
13
and R
14
are independently selected from the group consisting of H, C
1
-C
6
alkyl, C
3
-C
8
cycloalkyl, R
19
-aryl(CH
2
)
n6
— or R
19
-heteroaryl(CH
2
)
n6
—; or R
13
and R
14
together are C
3
-C
6
alkylene and with the nitrogen to which they are attached form a 4-7 membered ring, or one of the carbon atoms in the alklyene chain formed by R
13
and R
14
is replaced by a heteroatom selected from the group consisting of —O—, —S— and —NR
12
—;
R
15
is C
1
-C
6
alkyl, C
3
-C
8
cycloalkyl or —CF
3
;
R
16
is 1 to 3 substituents independently selected from the group consisting of H, C
1
-C
6
alkyl, C
3
-C
8
cycloalkyl, C
1
-C
6
alkoxy, halogen and —CF
3
;
R
17
is H, C
1
-C
6
alkyl, C
3
-C
8
cycloalkyl, —COOR
12
, —CONR
21
R
22
, —NR
21
R
22
, —NR
21
COR
12
, —NR
21
CO
2
R
12
, —NR
21
CONR
21
R
22
, —NR
21
SO
2
R
15
or —S(O)
n5
R
15
;
R
18
is H, C
1
-C
6
alkyl or —P(O)(OH)
2
;
R
19
is 1 to 3 substituents independently selected from the group consisting of H, C
1
-C
6
alkyl, C
3
-C
8
cycloalkyl, —OH, halogen, —CN, —NO
2
, —CF
3
, —CHF
2
, —CH
2
F, —OCF
3
, —OCHF
2
, —OCH
2
F, —O—(C
1
-C
6
alkyl), —O—(C
3
-C
8
cycloalkyl), —COOR
12
, —CONR
21
R
22
, —NR
21
R
22
, —NR
21
COR
12
, —NR
21
CO
2
R
12
, —NR
21
CONR
21
R
22
, —NR
21
SO
2
R
15
and —S(O)
n5
R
15
;
R
20
is H, C
1
-C
6
alkyl, C
3
-C
8
cycloalkyl or —(CH
2
)
n6
-heterocycloalkyl;
R
21
and R
22
are independently selected from the group consisting of H, C
1
-C
6
alkyl, C
3
-C
8
cycloalkyl and benzyl; or R
21
and R
22
together are C
3
-C
6
alkylene and with the nitrogen to which they are attached form a 4-7 membered ring, or one of the carbon atoms in the alklyene chain formed by R
21
and R
22
is replaced by a heteroatom selected from the group consisting of —O—, —S— and —NR
12
—;
R
23
, R
24
, R
25
and R
26
are H, C
1
-C
6
alkyl and can be together as ═O; when n
5
=0, and R
25
and R
26
=H, X is not O, N, S;
n
3
and n
4
are independently 1-5, provided that the sum of n
3
and n
4
is 2-6;
n
5
is independently 0-2;
n
6
is independently 0-3; and
q and r are independently 1 or 2.
Preferred are compounds of formula I wherein R
4
and R
7
are each H. Also preferred are compounds of formula I wherein R
1
and R
3
are each H. Also preferred are compounds of formula I wherein R
1
, R
3
, R
4
and R
7
are each H. R
6
is preferably H or —OH. Preferably, X
1
is —O— or —NR
12
—. Ar
1
and Ar
2
are each preferably R
8
, R
9
, R
10
-phenyl, wherein R
8
, R
9
and R
10
are independently selected. Y is preferably ═O, and n is preferably 1 or 2. When Y is ═O, X
2
is preferably —NR
5
—. More preferred are compounds of formula I wherein Q is —X
2
—C(═Y)—NR
4
— (i.e., the first structure shown in the definition of Q), R
1
, R
3
, R
4
and R
7
are each H; R
6
is H or —OH; X
1
is —O— or —NR
12
—; Ar
1
and Ar
2
are each R
8
,R
9
,R
10
-phenyl; Y is ═O and X
2
is —NR
5
—; n is 1 or 2; R
5
is H or —(CH
2
)
n1
—G, G is not H when n
1
=0; R
19
-aryl or R
19
-heteroaryl. Most preferred are compounds of formula I wherein R
5
is H.
This invention also relates to the use of a compound of formula I in the treatment of, for example, respiratory diseases such as chronic lung disease, bronchitis, pneumonia, asthma, allergy, cough, bronchospasm; inflammatory diseases such as arthritis and psoriasis; skin disorders such as atopic dermatitis and contact dermatitis; ophthalmalogical disorders such as retinitis, ocular hypertension and cataracts; addictions such as alcohol dependence and psychoactive substance abuse; stre

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