Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-12-18
2004-02-24
Morris, Patricia L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S182000
Reexamination Certificate
active
06696468
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel (S)-4-amino-5-chloro-2-methoxy-N-[1-[1-(2-tetrahydrofurylcarbonyl)-4-piperidinylmethyl]-4-piperidinyl]benzamide exhibiting a potent gastrointestinal motility enhancing effect based on its agonistic activity on serotonin 4 receptor (hereinafter, occasionally referred to as 5-HT
4
receptor) and having few effects on the heart. Said compound is an amide compound of 4-amino-5-chloro-2-methoxybenzoic acid.
The present invention also relates to a process for the preparation of said compound, a pharmaceutical composition containing said compound, and an intermediate therefor.
BACKGROUND ART
JP-A-2000-80081 discloses that 1-(1-substituted-4-piperidinyl-methyl)-4-piperidinylbenzamide and an ester derivative thereof of the following formula (P-1), which is formed by binding a 1-(1-substituted-4-piperidinylmethyl)-4-amino(or hydroxy)-piperidine derivative with a 4-amino-5-halogeno-2-alkoxybenzoic acid via an amide or ester bond, have selective agonistic effects on 5-HT
4
receptor, and are useful as a medicament in the prophylaxis or treatment of various gastrointestinal diseases, etc.
wherein R′ is a halogen atom;
R
2
is a hydrogen atom or a lower alkyl group;
R
3
is a hydrogen atom, a lower alkyl group, etc.;
R
4
is a hydrogen atom or a lower alkyl group;
X is —NH— or —O—;
A is a group of the following formula (A-1), (A-2) or (A-3):
—(CH
2
)
p
—C(R
7
)(R
8
)—COR
9
(A-1)
(in which p is 0, 1, 2, 3, 4 or 5,
R
7
is a hydrogen atom, a lower alkyl group, etc.,
R
8
is a hydrogen atom or a lower alkyl group,
R
9
is a lower alkoxy group, etc.),
—CO—R
10
(A-2)
(in which R
10
is a substituted or unsubstituted phenyl-lower alkyl group, a substituted or unsubstituted heteroaryl group, a saturated monocyclic or bicyclic hetero ring, a cycloalkyl group, a lower alkenyl group, a trifluoromethyl group, a lower alkyl group being substituted by a heteroaryl group, etc.),
—(CH
2
)
q
—Z—R
11
(A-3)
(in which q is 0, 1, 2, 3 or 4,
Z is —CH
2
— or —O—,
R
11
is a hydrogen atom, a lower alkyl group, a cycloalkyl group, etc., provided that (1) when q is 0, then Z is —CH
2
—, etc.).
The above patent publication also discloses the compound of Example 5 of the following formula (Compound A) as a compound of the formula (P-1) wherein R
10
in the above formula (A-2) is a saturated monocyclic hetero ring containing an oxygen atom.
In addition, the above patent publication discloses the compound of Example 19 of the following formula (Compound B) as a compound of the formula (P-1) wherein R
10
in the formula (A-2) is a heteroaryl group containing an oxygen atom.
However, the above patent publication never concretely discloses the compound of the present invention of the formula (I) as disclosed below in the form of an (S)-optical isomer, which corresponds to compounds of the formula (P-1) wherein R′″ in the above formula (A-2) is a 2-tetrahydrofuryl group.
In the 1990s, 5-HT
4
receptor was found during the studies on 5-HT receptor subtypes being participated in gastrointestinal motility enhancing effect by metoclopramide and cisapride, and it was confirmed that said benzamide derivatives enhance the gastrointestinal motility by activating 5-HT
4
receptor being widely distributed throughout the gastrointestinal organs (cf., J. Pharmacol. Exp. Ther., 252, 1378-1386 (1990); J. Pharmacol. Exp. Ther., 257, 781-787 (1991)). Thus, a compound activating 5-HT
4
receptor may be expected to enhance the gastrointestinal motility, but metoclopramide as mentioned above shows the central nervous system depression based on the antagonistic activity on dopamine D
2
receptor, and cisapride was observed to show disadvantageous effects on the heart, and hence, it is difficult to use these medicaments in the clinical field [cf., J. Pharmacol. Exp. Ther., 282, 220-227 (1997); The Journal of Pediatrics, January. 164 (1997)].
Besides, recently, there has been a growing tendency of increase in the number of patients being suffering from symptoms associated with gastrointestinal motility disorders due to the complicated society and aging society, and under these circumstances, it has been strongly desired to develop an excellent gastrointestinal motility enhancer (gastrointestinal prokinetic agent) with less adverse effects.
DISCLOSURE OF INVENTION
Under these circumstances, the present inventors have intensively studied on 1-(1-substituted-4-piperidinylmethyl)-4-piperidine derivatives activating 5-HT
4
receptor, and have found that 1-(1-substituted-4-piperidinylmethyl)-4-piperidinylamide or a corresponding ester derivative thereof, which is bound with a 4-amino-5-halogeno-2-alkoxybenzoic acid or a 4-amino-5-halogeno-2,3-dihydro-benzo[b]furan-7-carboxylic acid respectively via an amide or ester bond, shows a potent agonistic activity on 5-HT
4
receptor, and is useful as an excellent gastrointestinal motility enhancer, and they filed a patent application as to the compounds of the above-mentioned formula (P-1) (i.e., the above patent publication JP-A-2000-80081).
Although it is apparent that medicaments belonging to this kind of category exhibit sufficient gastrointestinal motility enhancing activity, but it has strongly been desired to develop medicaments having no disadvantageous effects on the heart, particularly, no action of prolonging QT interval of electrocardiogram, which is a serious clinical problem of a gastrointestinal motility enhancer, cisapride as mentioned above, and having no central nervous system depression based on the dopamine D
2
receptor antagonistic activity as observed in metoclopramide, and it has become a new big issue to solve these problems.
Under these circumstances, in order to find out a safer benzoic acid derivative, which exhibits an excellent enhancing activity on the digestive tract with few effects on the heart, etc. as few as possible and further show no antagonistic effects on dopamine D
2
receptor, the present inventors synthesized various derivatives and studied on the pharmacological activities thereof.
Aiming at the compounds of the formula (P-1) wherein a saturated monocyclic hetero ring bonds to the carbonyl group as a substituent A, the present inventors have tried to convert the substituents into various ones wherein a hetero atom does not directly bond to the carbonyl group, they have finally found that only a compound of the formula (P-1) wherein the substituent A is a specific substituent binding to the carbonyl group at the 2-position of the tetrahydrofuran ring, i.e., 4-amino-5-chloro-2-methoxy-N-[1-[1-(2-tetrahydrofurylcarbonyl) -4-piperidinylmethyl]-4-piperidinyl]benzamide, maintains a potent agonistic activity on 5-HT
4
receptor and a potent inducing activity of defecation by oral administration thereof, and further said compound has high safety with extremely weak effects on the heart. 4-Amino-5-chloro-2-methoxy-N-[1-[1-(2-tetrahydrofuryl-carbonyl)-4-piperidinylmethyl]-4-piperidinyl]benzamide thus newly found has an asymmetric carbon atom at the 2-position of the tetrahydrofuryl ring. Then, the present inventors separated said compound to an (S)-isomer and an (R)-isomer, and tried various pharmacological tests thereon. As a result, they have found that these optical isomers showed pharmacological activities such as a 5-HT
4
receptor agonistic activity and an inducing activity of defecation as almost equal to the racemic compound thereof, and further that these optical isomers showed few effects on the heart. In addition, the present inventors tested on these optical isomers with respect to their binding activities to various receptors, and they have unexpectedly found that only one of these optional isomers, (S)-4-amino-5-chloro-2-methoxy-N-[1-[1-(2-tetrahydrofurylcarbonyl)-4-piperidinylmethyl]-4-piperidinyl]benzamide, is a selective 5-HT
4
receptor agonist having no inhibitory activity of dopamine D
2
, which can be a cause for side effects on the central n
Hirokawa Yoshimi
Kan Yoko
Kato Shiro
Morikage Kazuo
Morikage Yukiko
Dainippon Pharmaceutical Co., Ltd.
Morris Patricia L.
Wenderoth , Lind & Ponack, L.L.P.
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