Non-imidazole compounds

Details Non-imidazole compounds Non-imidazole compounds

2001-10-15

2004-04-13

Berch, Mark L (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S187000, C514S318000, C514S321000, C544S331000, C544S353000

Reexamination Certificate

active

06720328

ABSTRACT:

BACKGROUND OF THE INVENTION
WO 95/14007 published May 26, 1995 discloses H
3
receptor antagonists of the imidazole type.
WO99/24405 published May 20, 1999 discloses H
3
receptor ligands of the imidazole type.
U.S. Pat. No. 5,869,479 issued Feb. 9, 1999 discloses compositions for the treatment of the symptoms of allergic rhinitis using a combination of at least one histamine H
1
receptor antagonist and at least one histamine H
3
receptor antagonist.
In view of the art's interest in compounds which affect H
3
receptors, novel compounds that are antagonists of H
3
receptors would be a welcome contribution to the art. This invention provides just such a contribution.
SUMMARY OF THE INVENTION
The present invention provides novel compounds of structure I.
or a pharmaceutically acceptable salt or solvate thereof, wherein:
(1) R
1
is is selected from:
(a) aryl;
(b) heteroaryl;
(c) heterocycloalkyl
(d) alkyl;
(e) cycloalkyl; or
(f) alkylaryl;
wherein said R
1
groups are optionally substituted with 1 to 4 substituents independently selected from:
(1) halogen (e.g., Br, F, or Cl, preferably F or Cl);
(2) hydroxyl (i.e., —OH);
(3) lower alkoxy (e.g., C
1
to C
6
alkoxy, preferably C
1
to C
4
alkoxy, most preferably C
1
to C
2
alkoxy, more preferably methoxy);
(4) —CF
3
;
(5) CF
3
O—;
(6) —NR
4
R
5
;
(7) phenyl;
(8) —NO
2
,
(9) —CO
2
R
4
;
(10) —CON(R
4
)
2
wherein each R
4
is the same or different;
(11) —S(O)
m
N(R
20
)
2
wherein each R
20
is the same or different H or alkyl group, preferably C
1
to C
4
alkyl, most preferably C
1
-C
2
alkyl, and more preferably methyl;
(12) —CN; or
(13) alkyl; or
(2) R
1
and X taken together form a group selected from:
(3) X is selected from: ═C(O), ═C(NOR
3
), ═C(NNR
4
R
5
),
(4) M
1
is carbon;
(5) M
2
is selected from C or N;
(6) M
3
and M
4
are independently selected from C or N;
(7) Y is selected from: is —CH
2
—, ═C(O), ═C(NOR
20
) (wherein R
20
is as defined above), or ═C(S);
(8) Z is a C
1
-C
6
alkyl group;
(9) R
2
is a five or six-membered heteroaryl ring, said six-membered heteroaryl ring comprising 1 or 2 nitrogen atoms with the remaining ring atoms being carbon, and said five-membered heteroaryl ring containing 1 or 2 heteroatoms selected from: nitrogen, oxygen, or sulfur with the remaining ring atoms being carbon; said five or six membered heteroaryl rings being optionally substituted with 1 to 3 substituents independently selected from: halogen, hydroxyl, lower alkyl, lower alkoxy, —CF
3
, CF
3
O—, —NR
4
R
5
, phenyl, —NO
2
, —CO
2
R
4
, —CON(R
4
)
2
wherein each R
4
is the same or different, —CH
2
NR
4
R
5
, —(N)C(NR
4
R
5
)
2
, or —CN;
(10) R
3
is selected from:
(a) hydrogen;
(b) C
1
-C
6
alkyl;
(c) aryl;
(d) heteroaryl;
(e) heterocycloalkyl;
(f) arylalkyl (e.g., aryl(C
1
to C
4
)alkyl, e.g., —(CH
2
)
w
aryl wherein w is 1 to 4, preferably 1 or 2, and most preferably 1, such as, for example —CH
2
phenyl or —CH
2
substituted phenyl);
(g) —(CH
2
)
e
—C(O)N(R
4
)
2
wherein each R
4
is the same or different,
(h) —(CH
2
)
e
—C(O)OR
4
;
(i) —(CH
2
)
e
—C(O)R
30
wherein R
30
is a heterocycloalkyl group, such as, for example, morpholinyl, piperidinyl, piperazinyl or pyrrolidinyl, including
(j) —CF
3
; or
(k) —CH
2
CF
3
;
wherein said aryl, heteroaryl, heterocycloalkyl, and the aryl portion of said arylalkyl are optionally substituted with 1 to 3 (preferably 1) substituents selected from: halogen (e.g., F or Cl), —OH, —OCF
3
, —CF
3
, —CN, —N(R
45
)
2
, —CO
2
R
45
, or —C(O)N (R
45
)
2
, wherein each R
45
is independently selected from: H, alkyl, alkylaryl, or alkylaryl wherein said aryl moiety is substituted with 1 to 3 substituents independently selected from —CF
3
, —OH, halogen, alkyl, —NO
2
, or —CN;
(11) R
4
is selected from: hydrogen, C
1
-C
6
alkyl, aryl, alkylaryl, said aryl and alkylaryl groups being optionally substituted with 1 to 3 substituents selected from: halogen, —CF
3
, —OCF
3
, —OH, —N(R
45
)
2
, —CO
2
R
45
, —C(O)N(R
45
)
2
, or —CN; wherein R
45
is as defined above;
(12) R
5
is selected from: hydrogen, C
1
-C
6
alkyl, —C(O)R
4
, —C(O)
2
R
4
, or —C(O)N(R
4
)
2
wherein each R
4
is independently selected, and R
4
is as defined above;
(13) or R
4
and R
5
taken together with the nitrogen atom to which they are bound forms a five or six membered heterocycloalkyl ring (e.g., morpholine);
(14) R
6
is selected from: alkyl, aryl, alkylaryl, halogen, hydroxyl, lower alkoxy, —CF
3
, CF
3
O—, —NR
4
R
5
, phenyl, —NO
2
, —CO
2
R
4
, —CON(R
4
)
2
wherein each R
4
is the same or different, or —CN;
(15) R
12
is selected from: alkyl, hydroxyl, alkoxy, or fluoro;
(16) R
13
is selected from: alkyl, hydroxyl, alkoxy, or fluoro;
(17) a (subscript for R
12
) is 0 to 2;
(18) b (subscript for R
13
) is 0 to 2;
(19) c (subscript for R
6
) is 0 to 2;
(20) e is 0 to 5;
(21) m is 1 or 2;
(22) n is 1, 2 or 3; and
(23) p is 1, 2 or 3, with the proviso that when M
3
and M
4
are both nitrogen, then p is 2 or 3 (i.e., p is not 1 when M
3
and M
2
are both nitrogen).
This invention also provides a pharmaceutical composition comprising an effective amount of compound of Formula I, and a pharmaceutically acceptable carrier.
This invention further provides a method of treating: allergy, allergy-induced airway (e.g., upper airway) responses, congestion (e.g., nasal congestion), hypotension, cardiovascular disease, diseases of the GI tract, hyper and hypo motility and acidic secretion of the gastrointestinal tract, obesity, sleeping disorders (e.g., hypersomnia, somnolence, and narcolepsy), disturbances of the central nervous system, attention deficit hyperactivity disorder ADHD), hypo and hyperactivity of the central nervous system (for example, agitation and depression), and other CNS disorders (such as Alzheimer's, schizophrenia, and migraine) comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I.
This invention further provides a method of treating: allergy comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I.
This invention further provides a method of treating: allergy-induced airway (e.g., upper airway) responses comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I.
This invention further provides a method of treating: congestion (e.g., nasal congestion) comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I.
This invention further provides a pharmaceutical composition comprising an effective amount of a compound of Formula I, and an effective amount of a H
1
receptor antagonist in combination with a pharmaceutically acceptable carrier.
This invention further provides a method of treating: allergy, allergy-induced airway (e.g., upper airway) responses, and congestion (e.g., nasal congestion) comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I in combination with an effective amount of an H
1
receptor antagonist.
This invention further provides a method of treating: allergy comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I in combination with an effective amount of an H
1
receptor antagonist.
This invention further provides a method of treating: allergy-induced airway (e.g., upper airway) responses comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I in combination with an effective amount of an H
1
receptor antagonist.
This invention further provides a method of treating: congestion (e.g., nasal congestion) comprising administering to a patient in need of such treatment (e.g., a ma

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