Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-07-14
2004-10-26
Owens, Amelia A. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S399000, C549S404000
Reexamination Certificate
active
06809114
ABSTRACT:
TECHNICAL FIELD
The present invention relates to benzopyran derivatives having a prolongation effect on the refractory period, which are used for treatments of arrhythmia in mammals including human being.
BACKGROUND ART
As benzopyran derivatives, there have been known 4-acylaminobenzopyran derivatives exemplified by Cromakalim (Japanese Patent Application Laid-Open No. Sho 58-67683). These 4-acylaminobenzopyran derivatives exemplified by Cromakalim are known to open an ATP sensitive K
+
channel and to be effective for treatments of hypertension and asthma, but there has not been any mention as to the treatment of arrhythmia based on a prolongation effect on the refractory period.
Now, conventional antiarrhythmic agents having a prolongation effect on the refractory period as a main function (such as Class I drugs of antiarrhythmic agent classification according to Vaughan Williams, or d-sotalol belonging to Class III) have highly dangerous arrhythmic inducing actions that can result in sudden death such as torsades de pointes based on extension of ventricular muscle action potential relating to the prolongation effect on the refractory period, which become the therapeutic problems. Thus, agents having less side effects are desired.
DISCLOSURE OF INVENTION
The inventors of the present invention have made an intensive search and study of compounds having a prolongation effect on the refractory period more selective for atrium muscle than for ventricular muscle, and found that the compound of the formula (I) has a prolongation effect on the refractory period selective for atrium muscle without any influence on the refractory period and action potential of ventricular muscle.
The inventors of the present invention have studied eagerly benzopyran derivatives, and surprisingly found that the compound of the formula (I) has a strong prolongation effect on the refractory period, and that it is useful as an antiarrhythmic agent. The present invention has been made based on this finding.
The present invention relates to a benzopyran derivative of the formula (I)
wherein,
R
1
and R
2
represent each independently a hydrogen atom or a C
1-6
alkyl group in which said alkyl group may be optionally substituted with a halogen atom, a hydroxyl group or a C
1-6
alkoxy group in which said alkoxy group may be optionally substituted with a fluorine atom,
R
3
represents a hydroxyl group or a C
1-6
alkylcarbonyloxy group,
R
4
represents a hydrogen atom, or R
3
and R
4
together form a bond,
R
6
represents a hydrogen atom,
R
7
represents a hydrogen atom or a C
1-6
alkyl group,
X is absent, or represents C═O or SO
2
,
R
8
represents a hydrogen atom or a C
1-6
alkyl group in which said alkyl group may be optionally substituted with a hydroxyl group or a C
1-6
alkoxy group,
R
9
represents a hydrogen atom or a nitro group,
when R
9
represents a hydrogen atom,
Y represents a C
3-8
alkylene group or —(CH
2
)
m
—CR
11
R
12
—(CH
2
)
n
— in which m and n represent each independently 0, 1, 2, 3 or 4, and m+n is equal to or more than 2; when m represents 0, R
11
and R1
2
represent each independently a C
1-6
alkyl group, and when m represents those other than 0, R
11
and R
12
represent each independently a C
1-3
alkyl group or a hydroxyl group, or R
11
and R
12
together form a oxygen atom,
R
5
represents a fluorine atom, a trifluoromethyl group, an amino group, a C
1-6
alkylthio group, a C
1-6
alkylamino group, a di-C
1-6
alkylamino group, a C
1-6
alkylcarbonylamino group, a C
1-6
alkylsulfonylamino group, an aminocarbonyl group, a C
1-6
alkylaminocarbonyl group, a di-C
1-16
alkylaminocarbonyl group, a C
1-6
alkylcarbonyl group, a C
1-6
alkoxycarbonyl group, a C
1-6
alkoxycarbonylamino group, an aminosulfonyl group, a C
1-6
alkylsulfonyl group, a carboxyl group or a benzoyl group in which said benzoyl group may be optionally substituted with a C
1-6
alkyl group, a C
1-6
alkoxy group, a halogen atom, a nitro group or a cyano group, and
when R
9
represents a nitro group,
Y represents a C
4-8
alkylene group, —(CH
2
)
m
—CR
11
R
12
—(CH
2
)
n
— in which m, n, R
11
and R
12
are same as the above or —(CH
2
)
o
—O—(CH
2
)
p
— in which o and p represent each independently 2, 3 or 4,
R
5
represents a hydrogen atom, a fluorine atom, a trifluoromethyl group, a hydroxyl group, a formamide group, an amino group, a C
1-6
alkoxy group, a C
3-8
cycloalkyl group, a C
1-6
alkylthio group, a C
1-6
alkylamino group, a di-C
1-6
alkylamino group, a C
1-6
alkylcarbonylamino group, a C
1-6
alkylsulfonylamino group, an aminocarbonyl group, a C
1-6
alkylaminocarbonyl group, a di-C
1-6
alkylaminocarbonyl group, a C
1-6
alkylcarbonyl group, a C
1-6
alkoxycarbonyl group, a C
1-6
alkoxycarbonylamino group, an aminosulfonyl group, a C
1-6
alkylsulfonyl group, a carboxyl group or a benzoyl group in which said benzoyl group may be optionally substituted with a C
1-6
alkyl group, a C
1-6
alkoxy group, a halogen atom, a nitro group or a cyano group;
or a pharmaceutically acceptable salt thereof.
The compound according to the present invention has a strong prolongation effect on the refractory period and it can be used as a drug for treating arrhythmia.
Respective substituents for the compound (I) according to the present invention are illustrated concretely specifically as follows.
Herein, “n” means normal, “i” means iso, “s” means secondary, “t” means tertiary, “c” means cyclo, and “p” means para.
As C
1-3
alkyl groups, there may be mentioned methyl, ethyl, n-propyl, i-propyl and c-propyl, etc.
As C
1-6
alkyl groups, there may be mentioned methyl, ethyl, n-propyl, i-propyl, c-propyl, n-butyl, i-butyl, s-butyl, t-butyl, c-butyl, 1-pentyl, 2-pentyl, 3-pentyl, i-pentyl, neopentyl, 2,2-dimethylpropyl, c-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-methyl-n-pentyl, 1,1,2-trimethyl-n-propyl, 1,2,2-trimethyl-n-propyl, 3,3-dimethyl-n-butyl and c-hexyl, etc. Preferably, there may be mentioned methyl, ethyl, n-propyl, i-propyl and n-butyl.
As halogen atoms, there may be mentioned a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Preferably, there may be mentioned a fluorine atom, a chlorine atom and a bromine atom.
As C
1-6
alkoxy groups, there may be mentioned methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, i-pentyloxy, neopentyloxy, 2,2-dimethylpropoxy, 1-hexyloxy, 2-hexyloxy, 3-hexyloxy, 1-methyl-n-pentyloxy, 1,1,2-trimethyl-n-propoxy, 1,2,2-trimethyl-n-propoxy and 3,3-dimethyl-n-butoxy, etc. Preferably, there may be mentioned methoxy, ethoxy, n-propoxy and i-propoxy.
As C
4-8
alkylene groups, there may be mentioned butylene, pentylene, hexylene, heptylene and octylene, etc. Preferably, there may be mentioned pentylene.
As C
3-8
alkylene groups, there may be mentioned propylene in addition to the aforementioned C
4-8
alkylene groups. Preferably, there may be mentioned pentylene.
As C
1-6
alkylcarbonyloxy groups, there may be mentioned methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, i-propylcarbonyloxy, n-butylcarbonyloxy, i-butylcarbonyloxy, s-butylcarbonyloxy, t-butylcarbonyloxy, 1-pentylcarbonyloxy, 2-pentylcarbonyloxy, 3-pentylcarbonyloxy, i-pentylcarbonyloxy, neopentylcarbonyloxy, t-pentylcarbonyloxy, 1-hexylcarbonyloxy, 2-hexylcarbonyloxy, 3-hexylcarbonyloxy, 1-methyl-n-pentylcarbonyloxy, 1,1,2-trimethyl-n-propylcarbonyloxy, 1,2,2-trimethyl-n-propylcarbonyloxy and 3,3-dimethyl-n-butylcarbonyloxy, etc. Preferably, there may be mentioned methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, i-propylcarbonyloxy, n-butylcarbonyloxy and t-butylcarbonyloxy.
As C
3-8
cycloalkyl groups, there may be mentioned c-propyl, c-butyl, c-pentyl, c-hexyl, c-heptyl and c-octyl, etc. Preferably, there may be mentioned c-propyl, c-butyl and c-hexyl.
As C
1-6
alkylthio groups, there may be mentioned metylthio, ethylthio, n-propylthio, i-propylthio, c-propylthio, n-butylthio, i-butylthio, s-butylthio, t-butylthio, c-butylthio, 1-pentylthio, 2-pentylthio, 3-pentylthio, i-pentylthio, neopentylthio, t-pentylthio, c-pentylthio, 1-hexylthio, 2
Ohara Yoshio
Ohrai Kazuhiko
Shigeta Yukihiro
Tsukagoshi Toru
Yamashita Toru
Nissan Chemical Industries Ltd.
Oliff & Berridg,e PLC
Owens Amelia A.
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