Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-02-15
2001-07-03
Russel, Jeffrey E. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S019300, C514S020800, C514S616000, C514S620000, C514S626000, C530S331000, C562S443000, C562S444000, C562S445000, C562S448000, C562S450000, C564S153000, C564S155000, C564S158000, C564S164000, C564S165000, C564S196000
Reexamination Certificate
active
06255285
ABSTRACT:
CROSS REFERENCE TO RELATED APPLICATION
The present application is the national stage under 35 U.S.C. 371 of PCT/JP98/03627, filed Aug. 14, 1998.
1. Technical Field
This invention relates to phenethylamine derivatives that typically function as a motilin receptor antagonist and which are useful as medicines.
2. 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 exist principally in the duodenum but recently it has been shown that they also exist 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 invention is to provide phenethylamine 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 phenethylamine 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), hydrates thereof or pharmaceutically acceptable salts thereof:
(wherein A is an amino acid residue or an N&agr;-substituted amino acid residue, provided that A binds with —NR
2
— to form an amide;
R
1
is R
6
—CO—, an optionally substituted straight-chained or branched alkyl group having 2-7 carbon atoms, an optionally substituted straight-chained or branched alkenyl group having 3-8 carbon atoms, or an optionally substituted straight-chained or branched alkynyl group having 3-8 carbon atoms;
R
2
is a hydrogen atom or an optionally substituted straight-chained or branched alkyl group having 1-3 carbon atoms;
R
3
is —CO—R
7
, an optionally substituted straight-chained or branched alkyl group having 1-5 carbon atoms, an optionally substituted straight-chained or branched alkenyl group having 2-5 carbon atoms or an optionally substituted straight-chained or branched alkynyl group having 2-5 carbon atoms;
R
4
is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, a straight-chained or branched alkenyl group having 2-6 carbon atoms, a straight-chained or branched alkynyl group having 2-6 carbon atoms, or the general formula (2):
R
5
is a hydrogen atom or —OR
8
;
R
6
is an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, an optionally substituted straight-chained or branched alkenyl group having 2-7 carbon atoms, an optionally substituted alkynyl group having 2-7 carbon atoms, a cycloalkyl group having 3-7 carbon atoms that may be fused to a benzene ring or a heterocyclic ring, an optionally substituted aromatic ring having 6-12 carbon atoms, an optionally substituted saturated or unsaturated heterocyclic ring having 3-12 carbon atoms, —N(R
9
)R
10
or —OR
11
;
R
7
is a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-5 carbon atoms, a cycloalkyl group having 3-7 carbon atoms, —N(R
12
)R
13
or —OR
14
;
R
8
is a hydrogen atom or a straight-chained alkyl group having 1-4 carbon atoms;
R
9
and R
10
, which may be the same or different, each represent a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-5 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 cycloalkyl group having 3-6 carbon atoms that may be fused to a benzene ring or a heterocyclic ring, or an optionally substituted aromatic ring having 6-12 carbon atoms;
R
11
is an optionally substituted straight-chained or branched alkyl group having 1-5 carbon atoms, an optionally substituted straight-chained branched alkenyl group having 2-6 carbon atoms, an optionally substituted straight-chained or branched alkynyl group having 2-6 carbon atoms, a cycloalkyl group having 3-6 carbon atoms that may be fused to a benzene ring or a heterocyclic ring, or an optionally substituted aromatic ring having 6-12 carbon atoms;
R
12
and R
13
, which may be the same or different, each represent a hydrogen atom, a straight-chained or branched alkyl group having 1-4 carbon atoms or a cycloalkyl group having 3-7 carbon atoms;
R
14
is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, or a cycloalkyl group having 3-7 carbon atoms;
R
15
is a hydrogen atom or a methyl group;
R
16
and R
17
, are taken together and represent a cycloalkyl or cycloalkenyl group having 3-7 carbon atoms).
The present invention also provides a medicine containing a compound of the general formula (1) as an active ingredient. Further, the invention provides a motilin receptor antagonist containing said compound. The invention also provides a gastrointestinal motility suppressor containing said compound as an active ingredient. Further, the invention provides a therapeutic of hypermotilinemia containing said compound as an active ingredient.
In the definition of the compounds represented by the general formula (1), the amino acid residue as A may be of any types commonly known in the art, as exemplified by &agr;-, &bgr;- and &ggr;-amino acid residues. Specific examples include glycine (Gly), alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), phenylalanine (Phe), tyrosine (Tyr), tryptophan (trp), histidine (His), asparagine (Asn), glutamine (Gln), aspartic acid (Asp), glutamic acid (Glu), lysine (Lys), serine (Ser), threonine (Thr), methionine (Met), proline (Pro), &bgr;-alanine (&bgr;-Ala), hydroxypr
Kotake Ken-ichiro
Kozono Toshiro
Sato Tsutomu
Takanashi Hisanori
Browdy and Neimark
Chugai Seiyaku Kabushiki Kaisha
Russel Jeffrey E.
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