Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-27
2001-09-25
Aulakh, C. S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S187000, C546S188000, C546S189000, C546S190000
Reexamination Certificate
active
06294555
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel 1-[(1-substituted-4-piperidinyl)methyl]-4-piperidine derivative exhibiting a potent agonistic activity on serotonin 4 receptors (hereinafter, occasionally referred to as 5-HT
4
receptors).
More particularly, the present invention relates to a 1-[(1-substituted-4-piperidinyl)methyl]-4-piperidine derivative forming an amide with a 4-amino-5-halogenobenzoic acid or a 4-amino-5-halogeno-2,3-dihydrobenzo[b]furan-7-carboxylic acid, a process for the preparation thereof, a pharmaceutical composition containing the same, and an intermediate therefor.
BACKGROUND ART
WO-95-26953 Publication discloses that the compounds of the following formula (P-1), etc. have selective antagonistic effects on 5-HT
4
receptors, and are useful for the prophylaxis or treatment of various gastrointestinal diseases, etc.
wherein R
1
is a halogen atom, R
2
is a lower alkoxy group, etc., m is 1 or 2, p is an integer of 1 to 6, B is a group of the formula:
—N(R
4
)—X
1
—R
5
,
—N(R
4
)—X
2
—N(R
6
)(R
7
),
—X
1
—N(R
8
)(R
9
),
or
—Het
(X
1
is CO, CS or SO
2
, X
2
is CO or CS, R
4
is a hydrogen atom, a lower alkyl group, etc., R
6
and R
7
are a lower alkyl group, etc., or R
6
and R
7
may combine together with the adjacent nitrogen atom to form a ring, R
8
and R
9
are a lower alkyl group, etc., or R
8
and R
9
may combine together with the adjacent nitrogen atom to form a ring, Het is a 5- or 6-membered, mono- or bicyclic heterocycle group having an amide or urea in the ring and having 1-5 heteroatom(s) selected from oxygen atom, sulfur atom and nitrogen atom, and the definitions for some substituents are omitted)
The compounds of the present invention of the formula (I) as mentioned below are distinguished from the compounds of the formula (P-1) having an amide-bond and a piperidine moiety bonded each other via an alkylene, and further having different substituents at the 1-position of the piperidine ring.
In addition, EP-A-445862 (=JP-A-04-211685) Publication discloses that N-(4-piperidinyl)(dihydrobenzofuran or dihydro-2H-benzopyran)carboxamide derivatives of the following formula (P-2) exhibit gastrointestinal motility stimulation properties.
wherein A is a group of the following formula:
—CH
2
—CH
2
— (a-1);
—CH
2
—CH
2
—CH
2
— (a-2);
or
—CH
2
—CH
2
—CH
2
—CH
2
— (a-3);
R
1
is a hydrogen atom or a halogen atom, R
2
is a hydrogen atom, an amino group, etc., R
3
is a hydrogen atom, a C
1-6
alkyl group, etc., L is a C
3-6
cycloalkyl group, etc., L is a group of the formula:
—Alk—R
4
(b-1);
—Alk—X—R
5
(b-2);
—Alk—Y(C═O)—R
7
(b-3);
or
—Alk—Y(C═O)—NR
9
R
10
(b-4);
(each Alk is a C
1-6
alkanediyl group, R
4
is a hydrogen atom, a cyano group, a C
1-6
alkysulfonylamino group, a C
3-6
cycloalkyl group, a C
5-6
cycloalkanone group, an aryl group, a di(aryl)-methyl group, or Het (Het is a 5- or 6-membered heterocyclic group having 1, 2, 3 or 4 heteroatom(s) selected from oxygen, sulfur and nitrogen, etc.), R
5
is a hydrogen atom, a C
1-6
alkyl group, etc., X is O, S, SO
2
or NR
6
(R
6
is a hydrogen atom, a C
1-6
alkyl group or an aryl group), R
7
is a hydrogen atom, a C
1-6
alkyl group, etc., Y is NR
8
or a direct bond (R
8
is a hydrogen atom, a C
1-6
alkyl group or an aryl group), R
9
and R
10
are independently a hydrogen atom, a C
1-6
alkyl group, etc., or R
9
and R
10
may combine together with the nitrogen atom to which R
9
and R
10
bond to form a pyrrolidinyl or piperidinyl ring being optionally substituted with a C
1-6
alkyl group, an amino group, etc., or R
9
and R
10
may combine together with the nitrogen atom to which R
9
and R
10
bond to form a piperazinyl or 4-morpholinyl ring being optionally substituted with a C
1-6
alkyl group, and the definitions for some substituents are omitted).
Among the compounds of the above formula (P-2), when R
4
is Het and said Het is a piperidine, the compound of the formula (P-2) may theoretically be overlapped with some of the compounds of the formula (I) of the present invention, but said EP Publication exemplifies as such compounds only a compound of the formula (P-2′) (Compound 57):
The compound of the above formula (P-2′) has an unsubstituted piperidine bonded at the 1-position thereof, which is quite different from the compounds (I) of the present invention, because the present compound (I) has a piperidine ring having a specific substituent (i.e., A) at the 1-position of said piperidine ring, and said piperidine ring is bonded at the 4-position thereof, as described below.
At the present, cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)-propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide (general name; cisapride, cf., Merck Index, 12 ed., 2377 (1996)) has widely been used in the clinical field as a gastrointestinal motility enhancer or as a gastrointestinal prokinetic agent. Recently, 5-HT
4
receptors were found during the studies on serotonin receptors being participated in gastrointestinal motility stimulation by metoclopramide or cisapride, and it has been confirmed that these benzamide derivatives enhance the gastrointestinal motility by stimulating 5-HT
4
receptors (cf., J. Pharmacol. Exp. Ther., 1990, 252, 1378; J. Pharmacol. Exp. Ther., 1991, 257, 781). Thus, a compound stimulating 5-HT
4
receptors being widely distributed throughout the gastrointestinal organs may be expected to enhance the gastrointestinal motility, but cisapride as mentioned above shows disadvantageously inhibitory effects on the central nervous system based on the antagonistic activity against dopamine D
2
receptors, or side effects on the heart. Therefore, it is difficult to use cisapride in the clinical field. Besides, there is a growing tendency to increase patients being suffering from symptoms associated with gastrointestinal motor disorders due to the complicated society and aging society, and under these circumstances, it has been strongly desired to develop an excellent gastrointestinal prokinetic agent.
DISCLOSURE OF INVENTION
The present inventors have intensively studied on 1-[(1-substituted-4-piperidinyl)methyl]-4-piperidine derivative acting on 5-HT
4
receptors, and have found that a 1-[(1-substituted-4-piperidinyl)-methyl]-4-piperidine derivative forming an amide with a 4-amino-5-halogenobenzoic acid or a 4-amino-5-halogeno-2,3-dihydrobenzo[b]-furan-7-carboxylic acid shows a potent agonistic activity on 5-HT
4
receptors, and is useful as an excellent gastrointestinal motility enhancer or as an excellent gastrointestinal prokinetic agent, and finally have accomplished the present invention.
An object of the present invention is to provide a novel 1-[(1-substituted-4-piperidinyl)methyl]-4-piperidine derivative having a potent agonistic activity on 5-HT
4
receptors, more particularly, to provide a 1-[(1-substituted-4-piperidinyl)methyl]-4-piperidine derivative forming an amide with a 4-amino-5-halogenobenzoic acid or a 4-amino-5-halogeno-2,3-dihydrobenzo[b]furan-7-carboxylic acid. Especially, the present invention provides a compound being useful as a gastro-intestinal motility enhancer or as a gastrointestinal prokinetic agent. Another object of the present invention is to provide a process for preparing said compound. Still further object of the present invention is to provide a pharmaceutical composition containing said compound. Further object of the present invention is to provide an intermediate for preparing said compound. These and other objects and advantages of the present invention are obvious to any person skilled in the art from the following disclosure.
The present invention provides a 1-[(1-substituted-4-piperidinyl)methyl]-4-piperidine derivative of the following formula (I), a pharmaceutically acceptable acid addition salt thereof, a process for preparing the same, and a pharmaceutical composition containing the same:
wher
Harada Hiroshi
Kato Shiro
Morikage Kazuo
Morikage Yukiko
Tateishi Hirotake
Aulakh C. S.
Dainippon Pharmaceutical Co., Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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