Ethylamine derivatives

Details Ethylamine derivatives Ethylamine derivatives

2001-03-21

2003-07-01

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C514S616000, C514S461000, C514S443000, C548S491000, C549S479000

Reexamination Certificate

active

06586630

ABSTRACT:

TECHNICAL FIELD
This invention relates to ethylamine derivatives that function as a motilin receptor antagonist and that are useful as medicines.
BACKGROUND ART
Motilin, which is one of the gastrointestinal hormones, is a straight-chained peptide consisting of 22 amino acids and is well known to be responsible for regulating the motility of the gastrointestinal tract in animals including human. It has been reported that exogenously administered motilin causes contractions in humans and dogs that are similar to interdigestive migrating contractions, thus promoting gastric emptying (Itoh et al., Scand. J. Gastroenterol., 11, 93-110 (1976); Peeters et al., Gastroenterology 102, 97-101 (1992)). Hence, erythromycin derivatives which are an agonist of motilin are under development as an gastrointestinal tract motor activity enhancer (Satoh et al., J. Pharmacol. Exp. Therap., 271, 574-579 (1994); Lartey et al., J. Med. Chem., 38, 1793-1798 (1995); Drug of the Future, 19, 910-912 (1994)).
Peptide and polypeptide derivatives have been reported as antagonists of motilin receptors (Depoortere et al., Eur. J. Pharmacol., 286, 241-247 (1995); Poitras et al., Biochem. Biophys. Res. Commun., 205, 449-454 (1994); Takanashi et al., J. Pharmacol. Exp. Ther., 273, 624-628 (1995)). These derivatives are used as a pharmacological tool in the study of the action of motilin on the motility of the gastrointestinal tract and in the research and development of medicines in the field of the art contemplated by the invention.
Motilin receptors had been known to occur principally in the duodenum but recently it has been shown that they also occur in the large intestine, or the lower part of the gastrointestinal tract (William et al., Am. J. Physiol., 262, G50-G55 (1992)), and this indicates the possibility that motilin is involved not only in the motility of the upper part of the gastrointestinal tract but also in the motility of its lower part.
Reports have also been made of the cases of hypermotilinemia in patients with irritable bowel syndrome who were manifesting diarrhea and in patients with irritable bowel syndrome who were under stress (Preston et al., Gut, 26, 1059-1064 (1985); Fukudo et al., Tohoku J. Exp. Med., 151, 373-385 (1987)) and this suggests the possibility that increased blood motilin levels are involved in the disease. Other diseases that have been reported to involve hypermotilinemia include crohn's disease, ulcerative colitis, pancreatitis, diabetes mellitus, obesity, malabsorption syndrome, bacterial diarrhea, atrophic gastritis and postgastroenterectomy syndrome. The antagonists of motilin receptors have the potential to ameliorate irritable bowel syndrome and other diseased states accompanied by increased blood motilin levels.
DISCLOSURE OF INVENTION
An object of the present invention is to provide ethylamine derivatives that function as an antagonist of motilin receptors and which are useful as medicines.
The present inventors conducted repeated intensive studies in an attempt to develop compounds having an outstanding motilin receptor antagonistic action. As a result, they found that ethylamine derivatives represented by the general formula (1) were an excellent antagonist of motilin receptors. The present invention has been accomplished on the basis of this finding.
Thus, the present invention provides compounds represented by the general formula (1):
wherein
R
1
is an optionally substituted phenyl group, an optionally substituted heterocyclic ring, a straight-chained or branched alkenyl group having 2-6 carbon atoms or a straight-chained or branched alkynyl group having 2-6 carbon atoms;
R
2
is a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-3 carbon atoms, an amino group or a hydroxy group;
R
3
is a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-3 carbon atoms, an optionally substituted amino group or a hydroxy group;
R
4
is a hydrogen atom, a methyl group or an ethyl group;
R
5
is an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, a cycloalkyl group having 3-7 carbon atoms or an optionally substituted phenyl group;
R
6
is a hydrogen atom, a methyl group or an ethyl group;
R
7
is a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-3 carbon atoms or —CO—N(R
9
)R
10
;
R
8
is an optionally substituted heterocyclic ring having 3-9 carbon atoms or the general formula (2)
 R
9
and R
10
, which may be the same or different, each represent a hydrogen atom or an optionally substituted straight-chained or branched alkyl group having 1-3 carbon atoms;
R
11
is a hydroxy group or a halogen atom;
R
12
, in the case where R
11
is a hydroxy group, represents a substituted straight-chained or branched alkyl group having 1-6 carbon atoms, a substituted straight-chained or branched alkenyl group having 2-6 carbon atoms, a substituted straight-chained or branched alkynyl group having 2-6 carbon atoms, a straight-chained or branched acyl group having 2-6 carbon atoms, a straight-chained or branched alkylsulfonyl group having 1-5 carbon atoms or an amino group mono- or di-substituted with straight-chained or branched alkyl groups having 1-5 carbon atoms, and R
12
, when R
11
is a halogen atom, represents an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, an optionally substituted straight-chained or branched alkenyl group having 2-6 carbon atoms, an optionally substituted straight-chained or branched alkynyl group having 2-6 carbon atoms, a straight-chained or branched acyl group having 2-6 carbon atoms, a straight-chained or branched alkylsulfonyl group having 1-5 carbon atoms or an amino group mono- or di-substituted with straight-chained or branched alkyl groups having 1-5 carbon atoms;
X is a carbonyl group or a methylene group; and
Y is a carbonyl group or a methylene group;
or hydrates or pharmaceutically acceptable salts thereof.
The present invention also provides a medicine containing a compound of the general formula (1) as an active ingredient. Further, the present invention provides a motilin receptor antagonist composition containing the compound. The present invention also provides a gastrointestinal motility suppressor agent containing the compound as an active ingredient. Further, the present invention provides a therapeutic of hypermotilinemia containing the compound as an active ingredient.
In the definition of the compounds represented by the general formula (1), exemplary substituents for the optionally substituted phenyl group as R
1
include a halogen atom, a hydroxy group, an amino group, a carboxyl group and a methyl group, with a halogen atom and a hydroxy group, particularly a fluorine atom, being preferred.
The optionally substituted phenyl group as R
1
is exemplified by a phenyl group optionally substituted with one or more of the above substituents, which may be the same or different; examples include a phenyl group, a para-fluorophenyl group and a para-hydroxyphenyl group, with a phenyl group and a para-fluorophenyl group being particularly preferred.
The heterocyclic ring of the optionally substituted heterocyclic ring as R
1
is exemplified by aliphatic or aromatic 5- to 10-membered monocyclic or fused rings containing at least one hetero atom selected from among O, N and S; specific examples include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 2-oxazolyl and 3-indolyl groups.
Exemplary substituents for the optionally substituted heterocyclic ring as R
1
include a halogen atom, a hydroxy group, an amino group, a carboxyl group and a straight-chained or branched alkyl group having 1-3 carbon atoms.
Examples of the optionally substituted heterocyclic ring as R
1
are 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 2-oxazolyl and 3-indolyl groups and the like.
Preferred examples of the straight-chained or branched alkenyl group having 2-6 carbon atoms as R
1
are straight-chained or branched alkenyl groups having 4-6 carbon atoms.
Pref

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