Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1997-10-29
2001-02-27
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S575000, C540S553000, C540S596000, C540S597000, C540S602000
Reexamination Certificate
active
06194406
ABSTRACT:
The present invention relates to novel substituted 4-(1H-benzimidazol-2-yl)[1,4]diazepane derivatives (herein referred to as a compound or compounds of formula (1)) and their use as histamine receptor antagonists and tachykinin receptor antagonists. Such antagonists are useful in the treatment of asthma; bronchitis; inflammatory bowel diseases, including Crohn's disease and ulcerative colitis; allergic rhinitis, including seasonal rhinitis and sinusitis; allergies; and emesis.
The compounds of the present invention are useful in their pharmacological activities, such as histamine receptor antagonism and tachykinin receptor antagonism. Antagonism of histamine responses can be elicited through blocking of histamine receptors. Antagonism of tachykinin responses can be elicited through blocking of tachykinin receptors. One object of the present invention is to provide new and useful antagonists of histamine. A further object of the present invention is to provide new and useful antagonists of tachykinins. A particular object of the present invention are those compounds that exhibit both histamine and tachykinin receptor antagonism.
SUMMARY OF THE INVENTION
The present invention provides novel substituted 4-(1H-benzimidazol-2-yl)[1,4]diazepane derivatives of the formula:
wherein
m is 2 or 3;
n is 0 or 1;
q is 1 or 2;
r is 0 or 1;
G
1
is —CH
2
— or —C(O)—;
G
2
is —CH
2
—, —CH(CH
3
)— or —C(O)—;
G
3
is —CH
2
— or —C(O)—;
Ar
1
is a radical chosen from the group consisting of:
wherein
R
1
is from 1 to 3 substituents each independently chosen from the group consisting of hydrogen, halogen, hydroxy, —CF
3
, C
1
-C
6
alkyl, and C
1
-C
6
alkoxy;
R
2
is from 1 to 2 substituents each independently chosen from the group consisting of hydrogen, halogen, C
1
-C
6
alkyl, and C
1
-C
6
alkoxy;
Ar
2
is a radical selected from the group consisting of:
wherein
z is 1 or 2;
R
20
is from 1 to 2 substituents each independently chosen from the group consisting of hydrogen, hydroxy, halogen, C
1
-C
6
alkyl, and C
1
-C
6
alkoxy;
R
3
is from 1 to 3 substituents each independently chosen from the group consisting of hydrogen, hydroxy, halogen, —OCF
3
, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, —(CH
2
)
d
S(O)
b
R
22
, —(CH
2
)
e
CN, —O(CH
2
)
c
CO
2
R
23
, —NH
2
, —NHC(O)CH
3
, —NHSO
2
CH
3
wherein c is an integer from 1 to 5; b is 0, 1, or 2; d is 0 or 1; e is 0 or 1; R
22
is C
1
-C
4
alkyl; and R
23
is hydrogen or C
1
-C
4
alkyl;
R
21
is hydrogen or a radical chosen from the group consisting of:
wherein
f is 0 or 1;
R
25
is hydrogen or —CH
3
;
R
24
is selected from the group consisting of hydrogen, C
1
-C
4
alkyl, —CF
3
, phenyl, S(O)
x
R
26
, and CH
2
N(CH
3
)
2
wherein x is 0, 1, or 2; R
26
is C
1
-C
4
alkyl;
R
4
is from 1 to 2 substituents each independently chosen from the group consisting of hydrogen halogen, —CF
3
, C
1
-C
6
alkyl, and C
1
-C
6
alkoxy;
R
5
is chosen from the group consisting of hydrogen, C
1
-C
4
alkyl, —(CH
2
)
w
—O—(CH
2
)
t
CO
2
R
8
, —(CH
2
)
j
CN, —(CH
2
)
u
CO
2
R
6
, —(CH
2
)
u
C(O)NR
16
R
17
, —(CH
2
)
u
C(O)CH
3
, —(CH
2
)
p
Ar
3
, —(CH
2
)
w
—O—R
7
, —CH
2
CH═CHCF
3
, —(CH
2
)
2
CH═CH
2
, —CH
2
CH═CH
2
, —CH
2
CH═CHCH
3
, —CH
2
CH═CHCH
2
CH
3
, —CH
2
CH═C(CH
3
)
2
, and —(CH
2
)
g
S(O)
k
R
19
,
wherein
w is an integer from 2 to 5;
t is an integer from 1 to 3;
j is an integer from 1 to 5;
u is an integer from 1 to 5;
p is an integer from 1 to 4;
g is 2 or 3;
k is 0, 1, or 2;
R
8
is hydrogen or C
1
-C
4
alkyl;
R
6
is hydrogen or C
1
-C
4
alkyl;
R
16
is hydrogen or C
1
-C
4
alkyl;
R
17
is hydrogen or C
1
-C
4
alkyl;
R
19
is C
1
-C
4
alkyl or a radical of the formula:
Ar
3
is a radical chosen from the group consisting of:
wherein
R
9
is from 1 to 3 substituents each independently chosen from the group consisting of hydrogen, halogen, —CF
3
, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, and —CO
2
R
13
wherein R
13
is chosen from the group consisting of hydrogen and C
1
-C
4
alkyl;
R
10
is from 1 to 2 substituents each independently chosen from the group consisting of hydrogen, halogen, C
1
-C
6
alkyl, and C
1
-C
6
alkoxy;
R
11
is chosen from the group consisting of hydrogen, —CH
3
, and —CH
2
OH;
R
12
is chosen from the group consisting of hydrogen, C
1
-C
4
alkyl, and benzyl;
R
18
is chosen from the group consisting of hydrogen, halogen, —CH
3
, and —CH
2
OH;
R
7
is hydrogen, C
1
-C
4
alkyl, —(CH
2
)
y
—CF
3
, —CH
2
CN or a radical chosen from the group consisting of:
wherein
v is an integer from 1 to 3;
y is an integer from 0 to 2;
R
14
is chosen from the group consisting of hydrogen, halogen, C
1
-C
4
alkyl, and —CO
2
R
15
wherein R
15
is hydrogen or C
1
-C
4
alkyl;
provided that when G
1
is —C(O)— then G
2
is either —CH
2
— or —CH(CH
3
)— and G
3
is —CH
2
—;
further provided that when G
2
is —C(O)— then G
1
is —CH
2
— and G
3
is —CH
2
—;
still further provided that when G
3
is —C(O)— then G
1
is —CH
2
— and G
2
is either —CH
2
— or —CH(CH
3
)—;
or stereoisomers, or pharmaceutically acceptable salts thereof.
As is appreciated by one of ordinary skill in the art the compounds of the formula (1) may exist as stereoisomers depending on the nature of the substituents present. Any reference in this application to one of the compounds of the formula (1) is meant to encompass either specific stereoisomers or a mixture of stereoisomers. Where indicated, the compounds follow the designation of (+)- and (−)- or (R)- and (S)- or (E)- and (Z)- for the stereochemistry of compounds represented by formula (1). It is specifically recognized that in the substituted 3-aryl-3-((1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)alkyl)pyrrolidines, substituted 3-arylmethyl-3-((1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)alkyl)pyrrolidines, substituted 3-aryl-3-((1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)alkyl)piperidines, and substituted 3-arylmethyl-3-((1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)alkyl)piperidines; the 3-position of the pyrrolidine or piperidine is asymmetric, and may be in the (R)- or (S)-configuration, or may be a mixture thereof. It is specifically recognized that compounds of formula (1) in which G
2
is —CH(CH
3
)— are asymetric at the methyl bearing carbon and may be in the (R)- or (S)-configuration, or may be a mixture thereof. It is specifically recognized that compounds of formula (1) in which R
5
is —CH
2
CH═CHCF
3
, —CH
2
CH═CHCH
3
, and —CH
2
CH═CHCH
2
CH
3
may exist as stereoisomers and may be in the (E)- or (Z)-configuration, or may be a mixture thereof.
The specific stereoisomers can be prepared by stereospecific synthesis using enantiomerically or geometrically pure or enantiomerically or geometrically enriched starting materials. The specific stereoisomers of either starting materials or products can be resolved and recovered by techniques known in the art, such as chromatography on chiral stationary phases, enzymatic resolution, or fractional recrystallization of addition salts formed by reagents used for that purpose. Useful methods of resolving and recovering specific stereoisomers are know in the art and described in
Stereochemistry of Organic Compounds,
E. L. Eliel and S. H. Wilen, Wiley (1994) and
Enantiomers, Racemates, and Resolutions,
J. Jacques, A. Collet, and S. H. Wilen, Wiley (1981).
As is appreciated by one of ordinary skill in the art some of the compounds of the formula (1) may exist as tautomers. Any reference in this application to one of the tautomers of compounds of the formula (1) is meant to encompass every tautomeric form and mixtures thereof.
As used in this application:
a) the term “halogen” refers to a fluorine atom, chlorine atom, bromine atom, or iodine atom;
b) the term “C
1
-C
6
alkyl” refers to a branched or straight chained alkyl radical containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, etc;
c) the term “C
1
-C
6
alkoxy” refers to a straight or branched al
Bratton Larry D.
Burkholder Timothy P.
Dalton Christopher R.
Kane John M.
Kudlacz Elizabeth M.
Aulakh Charanjit S.
Aventis Pharmaceuticals Inc.
Gupta Balaram
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