Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-09-20
2003-09-23
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S300000, C544S127000, C546S121000
Reexamination Certificate
active
06624162
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel imidazopyridine compounds. These compounds have 5-HT
4
receptor binding activity (e.g., agonist or antagonist activities), and thus are useful for the treatment of or prevention of gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, Functional dyspepsia, irritable bowel syndrome, constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, alzheimers disease, cognitive disorder, emesis, migraine, neurological disease, pain, ischaemic stroke, anxiety, cardiovascular disorder or the like, in mammalian, especially human. The present invention also relates to a pharmaceutical composition comprising the above compounds.
BACKGROUND ART
Serotonin (5-HT) receptors are known to have a plurality of subtypes such as 5-HT
1
, 5-HT
2
, 5-HT
3
and 5-HT
4
. These 5-HT
4
receptors are disclosed in, for example, European Journal of Pharmacology 146 (1988), 187-188, and Naunyn-Schmiedeberg's Arch. Pharmacol. (1989) 340:403-410.
5-HT
4
receptor modulators (e.g., agonists and antagonists) are found to be useful for the treatment of a variety of diseases such as gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, Functional dyspepsia, irritable bowel syndrome, constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, alzheimers disease, cognitive disorder, emesis, migraine, neurological disease, pain, and cardiovascular disorders such as cardiac failure and heart arryhthmia (See TiPs, 1992, 13, 141; Ford A. P. D. W. et al.,
Med. Res. Rev
., 1993, 13, 633; Gullikson G. W. et al.,
Drug Dev. Res
., 1992, 26, 405; Richard M. Eglen et al, TiPS, 1995, 16, 391; Bockaert J. et al.,
CNS Drugs
, 1, 6; Romanelli M. N. et al.,
Arzheim Forsch./Drug Res
., 1993, 43, 30 913; Kaumann A. et al.,
Naunyn
-
Schmiedeberg's
. 1991, 344, 150; and Romanelli M. N. et al.,
Arzheim Forsch./Drug Res
., 1993, 43, 913).
A variety of imidazopyridine compounds have been known as 5HT receptor antagonists or agonists. For example, Japanese Patent Publication Laid-Open No. H01-258,674 and H02-643,274 disclose imidazopyridine compounds as 5HT receptor antagonists. WO 96/05166 discloses imidazopyridine compounds as 5HT
4
agonists. WO92/15593; U.S. Pat. No. 5,260,303; U.S. Pat. No. 5,604,239; U.S. Pat. No. 5,591,749; U.S. Pat. No. 5,219,850; U.S. Pat. No. 5,434,161; U.S. Pat. No. 5,137,893; U.S. Pat. No. 5,196,547; and EP 504679 describe a variety of imidazopyridine compounds as 5HT
3
receptor antagonists. WO94/08998 discloses imidazopyridine compounds as 5HT
4
receptor antagonists.
Also, imidazopyridine compounds synthesized for different uses are described in JP2001/6877; WO01/5763; WO 99/50247; WO 97/27852, WO 9738665 and EP 274867.
It would be desirable if there were provided 5HT
4
receptor modulators (e.g., agonists and antagonists) which have more 5HT
4
receptor modulating activities (e.g., angonist or antagonist activities).
BRIEF DISCLOSURE OF THE INVENTION
The present invention provides a compound of the following formula (I):
or the pharmaceutically acceptable salts thereof wherein
R
1
is hydrogen, halo or C
1-6
alkyl;
R
2
and R
3
are independently hydrogen, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, mono- or di-(C
1-5
)alkyl amino, amino(C
1-5
)alkyl or hydroxy(C
1-5
)alkyl; or R
2
and R
3
taken together with the nitrogen atom to which they are attached may form substituted or non-substituted nitrogen-containing hetrocyclic;
R
4
is hydrogen, halo, C
1-8
acyl, amino, amido, substituted or non-substituted aryl, substituted or non-substituted aryl(C
1-6
)alkyl, or substituted or non-substituted heterocyclic;
R
5
is hydrogen, halo, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
1-8
acyl, amino, amido, substituted or non-substituted aryl, substituted or non-substituted aryl(C
1-6
)alkyl, or substituted or non-substituted heterocyclic;
R
6
is hydrogen, C
1-6
alkyl or C
1-6
alkoxy (C
1-6
)alkyl;
X is NR
9
wherein R
9
is hydrogen or C
1-6
alkyl; and
Y is (CR
7
R
8
)
n
wherein R
7
and R
8
are independently hydrogen or C
1-6
alkyl, and n is an integer from 0 to 5.
The imidazopyridine compounds of this invention have 5-HT
4
receptor modulating activities (e.g., an antagonistic or agonistic function towards 5-HT
4
receptor), and are thus useful for the treatment or prevention of disease conditions mediated by 5-HT
4
receptor activities.
Thus, the present invention provides a pharmaceutical composition for the treatment of disease conditions mediated by 5-HT
4
receptor activities, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
Further, the present invention also provides a pharmaceutical composition for the treatment of gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, upper gut motility disorder, non-ulcer dyspepsia, Functional dyspepsia, irritable bowel syndrome, constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, alzheimers disease, cognitive disorder, emesis, migraine, neurological disease, pain, ischaemic stroke, anxiety, cardiovascular disorders such as cardiac failure and heart arryhthmia, or the like, which comprises a therapeutically effective amount of the imidazopyridine compound of formula (I) or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier.
Also, the present invention provides a method for the treatment of disease conditions mediated by 5-HT
4
receptor activities, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I). Further, the present invention provides a method for the treatment of the disease conditions as mentioned above. Furthermore, the present invention provides use of the compound of formula (I) in the manufacture of a medicament for the treatment or prevention of disease conditions mediated by 5-HT
4
receptor activity, in a mammalian subject. The conditions mediated by 5-HT
4
receptor activity are those diseases or disorders described as above.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term “halo” means fluoro, chloro, bromo and iodo, preferably fluoro or chloro.
As used herein, the term “alkyl” means straight or branched chain saturated radicals, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, secondary-butyl, tertiary-butyl.
As used herein, the term “alkenyl” means a hydrocarbon radical having at least one double bond including, but not limited to, ethenyl, propenyl, 1-butenyl, 2-butenyl and the like.
As used herein, the term “alkynyl” means a hydrocarbon radical having at least one triple bond including, but not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl and the like.
As used herein, the term “alkoxy” means alkyl-O—, including, but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, secondary-butoxy, tertiary-butoxy.
As used herein, the term “acyl” means a group having carbonyl such as R′″—C(O)— wherein R′″ is C
1-5
alkyl, phenyl or C
3-7
cycloalkyl, including, but not limited to formyl, acetyl, ethyl-C(O)—, n-propyl-C(O)—, isopropyl-C(O)—, n-butyl-C(O)—, iso-butyl-C(O)—, secondary-butyl-C(O)—, tertiary-butyl-C(O)—, cyclopropyl-C(O)—, cyclobutyl-C(O)—, cyclopentyl-C(O)—, cyclohexyl-C(O)—, cycloheptyl-C(O)—, and the like.
As used herein, the term “nitrogen-containing heterocyclic” means 5- to 10-membered monocyclic or bicyclic rings having at least one nitrogen ring atom, including, but not limited to, a heterocyclic ring selected from morpholino, piperazino, piperidino, pyrrolidino, azetidino, pyrazolidino, (1,2,3,4)-tetrahydroisoqunolino and perhydroisoquinolino, preferably morpholino, piperazino and piperidino.
As used herein, the term “aryl” means a monocyclic or bicyclic aromatic carbocyclic ring of 6
Fenwick David
Gymer Geoffrey
Noguchi Hirohide
Stobie Alan
Uchida Chikara
Benson Gregg C.
Munchhof Martha G.
Pfizer Inc.
Ramsuer Robert W.
Richardson Peter C.
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