Cyclic and bicyclic diamino histamine-3 receptor antagonists

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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Details

C544S372000, C544S360000, C514S254010, C514S253120, C540S200000

Reexamination Certificate

active

06559140

ABSTRACT:

TECHNICAL FIELD
This invention relates to compounds which may be useful for treating diseases caused or exacerbated by H
3
receptor activity, pharmaceutical compositions containing the compounds, preparation of the compounds, and methods of treatment using the compounds.
BACKGROUND OF THE INVENTION
Histamine is a well-known mediator in hypersensitive reactions (e.g. allergies, hay fever, and asthma) which are commonly treated with antagonists of histamine or “antihistamines.” It has also been established that histamine receptors exist in at least two distinct types, referred to as H
1
and H
2
receptors.
A third histamine receptor (the H
3
receptor) is believed to play a role as a neurotransmitter in the central nervous system, where it is thought to be disposed presynaptically on histaminergic nerve endings (
Nature,
302, 832-837 (1983)). The existence of the H
3
receptor has been confirmed by the development of selective H
3
agonists and antagonists (
Nature,
327, 117-123 (1987)) and has subsequently been shown to regulate the release of other neurotransmitters in both the central nervous system and peripheral organs, particularly the lungs and gastrointestinal tract.
Thus, it is anticipated that H
3
receptor antagonists may have therapeutic utility for a number of indications such as asthma, ardiovasular disorders, gastrointestinal disorders, inflammation, sedatives, sleep regulators, anticonvulsants, and antidepressants.
SUMMARY OF THE INVENTION
In its principle embodiment, this invention discloses a compound selected from the group consisting of a compound of formula (I)
a compound of formula (II)
a compound of formula (III)
and
a compound of formula (IV)
or pharmaceutically acceptable salts thereof wherein,
L
1
is absent or optionally substituted cycloalkyl or optionally substituted cycloalkylalkylene;
L
2
is absent or alkylene, optionally substituted with aryl;
with the proviso that at least one of L
1
or L
2
is not absent;
n is one or two;
Q
1
is absent or selected from the group consisting of —C(═O)—, —C(═S)—, —SO
2
—, and —C(═N—R
9
)—;
Q
2
is selected from the group consisting of —O—, —S—, —S(═O)—, —SO
2
—, and acetylene;
R
1
, R
2
, and R
3
are independently hydrogen or alkyl;
R
4
is selected from the group consisting of alkoxy, amino, optionally substituted aryl, aryloxy, optionally substituted cycloalkyl, cycloalkoxy, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, and —W
1
—C(R
11
)(R
11a
)—NR
12
R
12a
;
R
5
is hydrogen or R
4
;
with the proviso that Q
1
is not absent in compounds of formula (I) and when Q
1
is carbonyl in formula (I), then R
4
is not alkyl; and
with the proviso that when R
5
is hydrogen, Q
1
is absent or —C(═O)—;
R
6
and R
7
are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amino, azido, carboxaldehyde, carboxyl, cyano, halo, hydroxyl, nitro, perfluoroalkyl, and perfluoroalkoxy; or
R
6
and R
7
are on adjacent carbon atoms and taken together are —OCH
2
C(O)—;
R
8
is selected from the group consisting of alkyl, alkanoyl, alkoxy, alkoxycarbonyl, amino, optionally substituted aryl, arylalkyl, aryloyl, arylsulfonyl, carboxamido, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloyl, halo, optionally substituted heteroaryl, heteroarylalkyl, heteroaryloyl, heteroarylsulfonyl, perfluoroalkyl, —C(H)(R
3
)—OR, and —C(R
13
)═N—OR
14
;
R
9
is selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, and hydroxyl;
R
10
is selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, and a nitrogen protecting group;
R
11
and R
11a
are independently selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, amino, aminoalkyl, arylalkyl, arylalkoxyalkyl, heteroarylalkyl, hydroxyalkyl, and ureidoalkyl;
W
1
is absent or is optionally substituted alkylene;
R
12
and R
12a
are independently selected from the group consisting of hydrogen, alkyl, alkanoyl, alkylsulfonyl, a nitrogen protecting group, aminosulfonyl, optionally substituted aryl, arylalkyl, aryloyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkyloyl, cycloalkylsulfonyl, optionally substituted heteroaryl, heteroarylalkyl, heteroaryloyl, heteroarylsulfonyl, optionally substituted heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloyl, heterocycloalkyloyl, and heterocycloalkylsulfonyl; or
R
12
and R
12a
, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycloalkyl ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfone, dihydropyrimidinyl, tetrahydropyrimidinyl, and hexahydropyrimidinyl; or
W
1
is an optionally substituted alkylene, and R
11
and R
12
together with the carbon and nitrogen atom to which they are respectively attached, form an optionally substituted heterocycloalkyl ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and azepanyl;
R
13
is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl; and
R
14
is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, and an hydroxyl protecting group.
In another embodiment, this invention discloses a compound of formula (I)
or a pharmaceutically acceptable salt thereof, wherein L
1
, L
2
, n, Q
1
, Q
2
, R
1
, R
2
, R
3
, R
4
, R
6
, R
7
, and R
8
are defined above.
In another embodiment, this invention discloses a compound of formula (I), wherein L
1
is absent and L
2
is alkylene optionally substituted with aryl.
In another embodiment, this invention discloses a compound of formula (I), wherein n is one.
In another embodiment, this invention discloses a compound of formula (I), wherein n is two.
In another embodiment, this invention discloses a compound of formula (I), wherein Q
1
is —C(═O)—.
In another embodiment, this invention discloses a compound of formula (I), wherein Q
2
is —O—.
In another embodiment, this invention discloses a compound of formula (I), wherein R
1
, R
2
, and R
3
are hydrogen.
In another embodiment, this invention discloses a compound of formula (I), wherein R
4
is
wherein
one of R
11
and R
11a
is hydrogen or alkyl, and the other is selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, amino, aminoalkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, and ureidoalkyl; and
R
12
and R
12a
are independently selected from the group consisting of hydrogen, alkyl, alkanoyl, alkylsulfonyl, a nitrogen protecting group, aminosulfonyl, optionally substituted aryl, arylalkyl, aryloyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkyloyl, cycloalkylsulfonyl, optionally substituted heteroaryl, heteroarylalkyl, heteroaryloyl, heteroarylsulfonyl, optionally substituted heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloyl, heterocycloalkyloyl, and heterocycloalkylsulfonyl.
In another embodiment, this invention discloses a compound of formula (I), wherein the relative stereochemistry of R
4
is depicted by the formula
wherein
R
11
is hydrogen; and
R
11a
, R
12
and R
12a
are defined in the embodiment immediately above.
In another embodiment, this invention discloses a compound of formula (I), wherein the relative stereochemistry of R
4
is depicted by the formula
wherein
R
11
is hydrogen; and
R
11a
, R
12
and R
12a
are defined in the embodiment proximally above.
In another embodiment, this invention discloses a compound of formula (I), wherein R
4
is
wherein
R
E
, and R
F
, and R
G
are independently selected from the group consisting of hydrogen, alkyl, amino, alkoxy, alkoxycarbonyl, carboxaldehyde, carboxyl, halo, hydroxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, and ureido; or
R
E
and R
F
are taken together on the same carbon and are oxo or thioxo, and R
G
is selected

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