Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-07-19
2004-08-31
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S312000, C546S153000, C546S193000, C546S194000
Reexamination Certificate
active
06784192
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel piperidine compound, a salt thereof or a hydrate of them, a production process thereof, and a pharmaceutical composition comprising these compounds and the like and a preparation thereof.
PRIOR ART
The atrial fibrillation, which is one type of arrhythmia, is a condition in which the atrium does not carry out regular excitation and contraction in accordance with stimulation from the sinoatrial node, and frequently repeats the excitation at random, and is classified in paroxysmal atrial fibrillation and chronic atrial fibrillation. In many cases, crisis occurs as the complication of organic heart diseases, such as mitral valve disease, coronary artery disease, hypertensive heart disease, thyrotoxicosis (which are four major basic diseases), increases, and lone atrial fibrillation only causing atrial fibrillation is also reported. Further, a condition in heart failure is often exhibited in addition to palpitation and chest discomfort, and thrombus is formed in the left atrium, which can provoke thromboembolism in various organs of system. Although the treatment of atrial fibrillation (the termination of paroxysm, the prevention of recurrence, and the like) differs in the cases of paroxysmal atrial fibrillation and chronic atrial fibrillation, the effectiveness of non-medication is insufficient in both cases, and the administration of an antiarrhythmic drug is designated as the first choice at present. There are known antiarrhythmics, such as Class I drugs of Vaughan Williams classification (Class I: a drug suppressing the conduction in atrial muscle by selective blocking of Na
+
channel and inhibiting the reentry circuit), Class II drugs (Class II: &bgr;-adrenergic receptor blocker), Class III drugs (Class III: a drug of selectively blocking K
+
channel and prolonging the action potential duration), Class IV drugs (Class IV: Ca+ channel blocker), and the like. However, a drug of inhibiting the reentry circuit of potential in atrial muscle is effective for termination of atrial fibrillation, and it is considered that the class I antiarrhythmic drug and the class III antiarrhythmic drug are effective. Concerning this kind of antiarrhythmics, many reports have been hitherto disclosed, and, for example, the inventions relating to piperidine compounds as antiarrhythmics are disclosed in Japanese patent Application No. 62-281858, JP-A 6-501242, JP-A 7-502273, JP-A 8-511014 etc., in addition to the inventions relating to the antiarrhythmics disclosed in JP-A 9-505597, JP-A 8-511014, WO96/13479, etc.
However, since the class I antiarrhythmic drug has a negative inotropic effect (the reduction of the pumping function of heart) based on the Na
+
channel inhibitory action, it has been a problem in that it causes the deterioration or exasperation of heart failure. To the contrary, the class III antiarrhythmic drug does not exhibit such an effect and is superior in only extending the refractory period, but a conventional class III antiarrhythmic drug is not always effective in the termination rate of atrial fibrillation, extends also the refractory period of atrial muscle, and often extends the refractory period of atrial muscle at a normal time than at tachycardia (reverse use-dependency), and therefore it has been a problem to induce ventricular arrhythmia at a dose of showing a medicinal effect.
On the other hand, it is also known that the compound having the Na
+
channel inhibitory action is useful for remedy of various neuralgia (for example, postherpetic neuralgia, diabetic neuralgia, HIV neuralgia etc.). For example, Lidoderm in remedy for postherpetic neuralgia, Carbamazepine in trigeminal neuralgia, Na
+
channel inhibitor as antiarrhythmic (for example, Mexiletin), Na
+
channel inhibitors as antidepressant and anticonvulsant (for example, Amitriptyline, Carbamazepine) and the like are used as various antineuralgic remedies. In addition to these, there are several reports (Pain. 83 (1999) 389-400: European Journal of Pain 2 (1998) 3-14; Pain. 73 (1997) 123-139) concerning the fact that arrhythmia drug (Mexiletine, Lidocaine) is effective as analgesic.
However, since a conventional N
+
channel inhibitor has an equal effect to the heart and nerves in the remedy of a conventional neuralgia, the dose of a Na
+
channel inhibiting compound cannot be increased, and a distinct analgesic effect could not be exhibited.
A drug which exhibits a superior Na
+
channel inhibitory action, that satisfies the requirements of pharmacological activity, a dose, safety and the like, as pharmaceuticals, and effective in clinical use, has been not found. Namely, it is the object of the present invention to investigate and find a superior Na
+
channel inhibiting compound which solves the above-mentioned problems.
DISCLOSURE OF THE INVENTION
The present inventors have intensively studied in view of the above-mentioned circumstances, and as a result, have succeeded in synthesizing a compound which is a quite novel piperidine compound represented by the formula (I):
(wherein the ring A indicates a ring represented by the formula:
(wherein R
1
means (1) a hydrogen atom, (2) a halogen atom, (3) a cyano group, (4) an optionally substituted C
1-6
alkyl group, (5) an optionally substituted C
2-6
alkenyl group, (6) an optionally substituted C
2-6
alkynyl group, (7) an optionally substituted C
3-8
cycloalkyl group, (8) an optionally substituted C
3-8
cycloalkenyl group, (9) an optionally substituted C
1-6
alkoxy group, (10) an optionally substituted C
1-6
alkylthio group, (11) an optionally substituted C
1-6
alkylsulfinyl group, (12) an optionally substituted C
1-6
alkylsulfonyl group, (13) an optionally substituted C
6-14
aromatic hydrocarbon cyclic group or (14) an optionally substituted 5- to 14-membered aromatic heterocyclic group;
R
2
means (1) a hydrogen atom, (2) an optionally substituted C
1-6
alkyl group, (3) an optionally substituted C
2-6
alkenyl group, (4) an optionally substituted C
2-6
alkynyl group, (5) an optionally substituted C
3-8
cycloalkyl group, (6) an optionally substituted C
3-8
cycloalkenyl group, (7) an optionally substituted amino group, (8) an optionally substituted C
6-14
aromatic hydrocarbon cyclic group or (9) an optionally substituted 5- to 14-membered aromatic heterocyclic group; and
R
3
means (1) an optionally substituted C
1-6
alkoxy group, (2) an optionally substituted C
2-6
alkenyloxy group, (3) an optionally substituted C
3-7
cycloalkyloxy group or (4) an optionally substituted C
3-7
cycloalkenyloxy group);
W means (1) a single bond, (2) an optionally substituted C
1-6
alkylene group, (3) an optionally substituted C
2-6
alkenylene group, (4) an optionally substituted C
2-6
alkynylene group or (5) a group represented by the formula —U—V— (wherein U means (i) a single bond, (ii) an oxygen atom, (iii) a sulfur atom, (iv) a group represented by the formula —NH—, (v) an optionally substituted C
1-6
alkylene group, (vi) an optionally substituted C
2-6
alkenylene group or (vii) an optionally substituted C
2-6
alkynylene group; V means (i) a single bond, (ii) an optionally substituted C
1-6
alkylene group, (iii) an optionally substituted C
2-6
alkenylene group, (iv) an optionally substituted C
2-6
alkynylene group, (v) an oxygen atom, (vi) a sulfur atom, or (vii) a group represented by the formula —CO—, (viii) —SO— or (ix) —SO
2
—, provided that the case where U and V mean the same group in the above definition is excluded, and one of U and V means a single bond, an optionally substituted C
1-6
alkylene group, an optionally substituted C
2-6
alkenylene group or an optionally substituted C
2-6
alkynylene group);
Z means (1) an optionally substituted C
6-14
aromatic hydrocarbon cyclic group, (2) an optionally substituted 5- to 14-membered aromatic heterocyclic group or (3) a group represented by the formula —N(R
4
)R
5
(wherein R
4
and R
5
may be the same as or different from each other and each represents (i) a hydrogen atom, (ii
Ishihara Hiroki
Kamata Jun-ichi
Kaneko Toshihiko
Katoh Hiroshi
Kobayashi Kiyoaki
Birch & Stewart Kolasch & Birch, LLP
Chang Ceila
Eisai Co. Ltd.
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