Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-08-04
2004-09-21
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S345100
Reexamination Certificate
active
06794405
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to alicyclic imidazoles which interact with the histamine H
3
receptor as agonists, antagonists or inverse agonists; pharmaceutically active compositions containing such compounds; and the use of such compounds in formulations for the control or prevention of disease states in which histamine H
3
receptors are involved, such as allergy, inflammation, hypotension, glaucoma, sleeping disorders, states of hyper- and hypo-motility of the gastro-intestinal tract, cardiovascular disease, hypo- and hyper-activity of the central nervous system, Alzheimer's, schizophrenia, obesity and migraines.
BACKGROUND OF THE INVENTION
Histamine plays a role in regulating attentiveness and cognition in the central nervous system (CNS), and histamine levels in the brain are controlled by the histamine H
3
receptor. Moreover, serotonin, norepinephrine, dopamine and acetylcholine all have been demonstrated to be regulated by the histamine H
3
receptor. These neurotransmitters are known to play a role in many CNS psychiatric disorders involving higher cognitive function and/or emotion, Consequently, compounds affecting H
3
receptor function (as agonists, antagonists or inverse agonists) could have utility in the treatment of a variety of CNS maladies, including but not limited to dementias, attention deficit hyperactivity disorder, depression, anxiety and schizophrenia.
Histamine is also involved in the control of sleep/wake states and appetite. Accordingly, histamine H
3
receptor ligands might be expected to be useful in treating insomnia, narcolepsy, age-related sleep disorders, obesity and anorexia. Although they exist in low density outside of the brain, histamine H
3
receptors are found on the sympathetic and parasympathetic nerve terminals in the periphery, including the vasculature and heart. Thus, compounds that alter histamine H
3
receptor activity might also have clinical utility in treating conditions such as migraine and cardiac dysfunction.
Various imidazole-containing compounds are disclosed in WO 92/15567, WO 93/12107, and U.S. Pat. Nos. 5,217,986 and 5,559,113. 2-(4-imidazolyl)cyclopropylamine is disclosed in U.S. Pat. No. 4,767,778. 1H-4(5)-substituted imidazole derivatives are disclosed in WO 96/38142 and U.S. Pat. No. 6,072,057. 2-(1H-4(5)-imidazoyl)cyclopropyl derivatives are disclosed in U.S. Pat. Nos. 6,008,240; 5,990,317 and 5,652,258. However, there is still a need for novel, histamine H, receptor-active imidazoyl cyclopropyl derivatives.
BRIEF SUMMARY OF THE INVENTION
The present invention is directed to alicyclic imidazoles which interact with the histamine H
3
receptor as agonists, antagonists or inverse agonists; pharmaceutically active compositions containing such compounds; and the use of such compounds in formulations for the control or prevention of disease states in which histamine H
3
receptors are involved, such as allergy, inflammation, hypotension, glaucoma, sleeping disorders, states of hyper- and hypo-motility of the gastro-intestinal tract, cardiovascular disease, hypo- and hyper-activity of the central nervous system, Alzheimer's, schizophrenia, obesity and migraines.
The invention is directed to novel compounds of Formula I as follows:
wherein n is an integer of zero to six;
p is an integer of zero to two;
q is an integer of zero to four;
T is selected from the group consisting of —NR
6
R
7
, —N(R
8
)C(NR
9
)R
10
, —CN, —OH, —H, —OR
11
, —OC(O)R
12
, —C(O)R
13
, —C(O)NH
2
, —C(N—OH)H, —SC(S)R
14
, —NR
15
C(S)R
16
, —NR
17
C(O)R
18
, —SC(NR
19
)R
20
, —OC(NR
21
)R
22
, R
23
, —N(R
24
)C(O)N(R
25
), —N(R
26
)C(O), and —O(O)NR
27
R
28
;
R
1
is selected from the group consisting of hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, —CF
3
, —N(C
1
-C
3
alkyl)—C(O)(C
1
-C
3
alkyl), —NHC(O)NH(C
1
-C
3
alkyl), —NHC(O)N(C
1
-C
3
alkyl)C(O)NH(C
1
-C
3
alkyl), —C
1
-C
3
alkylamino, alkenylamino, alkynylamino, di(C
1
-C
3
alkyl)amino, —C(O)O—(C
1
-C
3
alkyl), —C(O)NH—(C
1
-C
3
alkyl), —CH═NOH, —PO
3
H
2
, —OPO
3
H
2
, —C(O)N(C
1
—C
3
alkyl)
2
, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, —SO
2
—(C
1
-C
3
alkyl), —SO
3
—(C
1
-C
3
alkyl), sulfonamido, aryloxyalkyl, carboxyl, carbamate and —C(O)NH(benzyl); and
R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
15
, R
16
, R
17
, R
18
, R
19
, R
20
, R
21
, R
22
, R
23
, R
24
, R
25
, R
26
, R
27
and R
28
are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, —CF
3
, —NO
2
, amino, —CN, carboxy, —N(C
1
-C
3
alkyl)—C(O)(C
1
-C
3
alkyl), —NHC(O)NH(C
1
-C
3
alkyl), —NHC(O)N(C
1
-C
3
alkyl)C(O)NH(C
1
-C
3
alkyl), —C
1
-C
3
alkylamino, alkenylamino, alkynylamino, di(C
1
-C
3
alkyl)amino, —C(O)O—(C
1
-C
3
alkyl), —C(O)NH—(C
1
-C
3
alkyl), —CH═NOH, —PO
3
H
2
, —OPO
3
H
2
, —C(O)N(C
1
-C
3
alkyl)
2
, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, —SO
2
—(C
1
-C
3
alkyl), —SO
3
—(C
1
-C
3
alkyl), sulfonamido, aryloxyalkyl, carboxyl, carbamate and —C(O)NH(benzyl);
wherein R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
15
, R
16
, R
17
, R
18
, R
19
, R
20
, R
21
, R
22
, R
23
, R
24
, R
25
, R
26
, R
27
and R
28
are unsubstituted or substituted with at least one electron donating or electron withdrawing group; and pharmaceutically acceptable salts thereof;
with the proviso that when T is —NR
6
R
7
, R
1
is hydrogen and n is zero, R
6
and R
7
are not both hydrogen;
and the proviso that when T is —OH, n is one, R
4
and R
5
are each hydrogen, and p and q are zero, R
1
is not triphenylmethyl;
and the proviso that when T is —C(O)R
13
and n is zero, R
13
is not hydrogen or a chiral moiety.
For compounds of Formula I, n may be an integer of zero to three; R
1
may be hydrogen, R
2
, R
3
, R
4
and R
5
may each independently be hydrogen, halogen, hydroxyl, lower alkyl, alkenyl, alkynyl or aryl; and R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
15
, R
16
, R
17
, R
18
, R
19
, R
20
, R
21
, R
22
and R
23
may each be hydrogen, lower alkyl, alkenyl, alkynyl, aryl and heterocyclyl. Presently preferred compounds of Formula I have T as —N(R
8
)C(NR
9
)R
10
, —OC(O)R
12
, —C(O)R
13
, —C(O)NH
2
, —C(N—OH)H, —SC(S)R
14
, —NR
15
C(S)R
16
, —NR
17
C(O)R
18
, —SC(NR
19
)R
20
or —OC(NR
21
)R
22
when n is zero or T as —NR
6
R
7
, —CN, —OH, —H, —OR
11
or R
23
when n is one.
More specifically, the compounds of this invention may be described by Formula II below
wherein n is an integer of zero to three;
T is selected from the group consisting of —NR
6
R
7
, —N(R
8
)C(NR
9
)R
10
, —CN, —OH, —H, —OR
11
, —OC(O)R
12
, —C(O)R
13
, —C(O)NH
2
, —C(N—OH)H, —SC(S)R
14
, —NR
15
C(S)R
16
, —NR
17
C(O)R
18
, —SC(NR
19
)R
20
, —OC(NR
21
)R
22
and R
23
;
R
1
is selected from the group consisting of hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, —CF
3
, —N(C
1
-C
3
alkyl)—C(O)(C
1
-C
3
alkyl), —NHC(O)NH(C
1
-C
3
alkyl), —NHC(O)N(C
1
-C
3
alkyl)C(O)NH(C
1
-C
3
alkyl), —C
1
-C
3
alkylamino, alkenylamino, alkynylamino, di(C
1
-C
3
alkyl)amino, —C(O)O—(C
1
-C
3
alkyl), —C(O)NH—(C
1
-C
3
alkyl), —CH═NOH, —PO
3
H
2
, —OPO
3
H
2
, —C(O)N(C
1
-C
3
alkyl)
2
, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkyla
Ali Syed M.
Jiang Jack B.
Rong Yajing
Merck & Co. , Inc.
Stockton Laura L.
Thies I. Eric
Winokur Melvin
LandOfFree
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