Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-29
2003-04-29
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S400000
Reexamination Certificate
active
06555574
ABSTRACT:
DESCRIPTION
1. Technical Field
The present invention relates to 4-oxybenzopyran derivatives having a prolongation effect on the functional refractory period, which are used for treatments of arrhythmia in mammal including human beings.
2. 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 the treatment of hypertension or asthma, but there has not been any mention as to the treatment for arrhythmia based on the prolongation effect on the functional refractory period.
Now, conventional antiarrhythmic agents having the prolongation effect on the functional 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) having 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 functional refractory period, which become the therapeutic problems. Thus, agents having less side effects are desired.
The inventors of the present invention have made an intensive study of compounds having the prolongation effect on the functional refractory period more selective for atrium muscle than for ventricular muscle, and found that the compound of the general formula (I) has a prolongation effect on the functional refractory period selective for atrium muscle without any influence on the refractory period of ventricular muscle and action potential parameters.
DISCLOSURE OF INVENTION
The inventors of the present invention have studied eagerly 4-oxybenzopyran derivatives, and found that the compound of the formula (I) has the strong prolongation effect on the functional refractory period, and it is useful as an antiarrhythmic agent. The present invention has been made based on this finding.
The present invention relates to a 4-oxybenzopyran derivative of the formula (I)
wherein, R
1
and R
2
represent each independently a hydrogen atom; a C
1-6
alkyl group in which said alkyl group may be optionally substituted with a halogen atom, a C
1-6
alkoxy group or a hydroxyl group; or a phenyl group in which said phenyl group may be optionally substituted with a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C
1-6
alkyl group or a C
1-6
alkoxy group;
R
3
represents a hydroxyl group or a C
1-6
alkylcarbonyloxy group;
R
4
represents a hydrogen atom, a C
3-6
cycloalkyl group, a C
1-6
alkyl group, a C
1-6
alkylcarbonyl group, a C
1-6
alkylaminocarbonyl group or a di-C
1-6
alkylaminocarbonyl group in which said C
1-6
alkyl group, said C
1-6
alkylcarbonyl groups, said C
1-6
alkylaminocarbonyl group and said di-C
1-6
alkylaminocarbonyl group may be each optionally substituted with a halogen atom, a C
1-6
alkoxy group, a C
1-6
alkoxy group substituted by a halogen atom; a carboxyl group, a C
1-6
alkoxycarbonyl group, a hydroxyl group, or an aryl group or a heteroaryl group; in which said aryl group and said heteroaryl group may be optionally substituted with (R
9
)
4
, in which R
9
represents a halogen atom, a hydroxyl group, a C
1-6
alkyl group, a C
1-6
alkyl group substituted by a halogen atom or a C
1-6
alkoxy group; a C
1-6
alkoxy group, A C
1-6
alkoxy group substituted by a halogen atom; or R
9
represents a nitro group, a cyano group, a formyl group, a formamide group, an amino 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, an aminosulfonyl group, a C
1-6
alkylsulfonyl group, a carboxyl group or an arylcarbonyl group if r represents 2 r 3; or R
4
represents an aryl group or a heteroaryl group in which said aryl group and said heteroaryl group may be optionally substituted with (R
10
)
q
in which R
10
has the same meaning as R
9
, q represents an integer of 1-3, and each R
10
may be same or different if q represents 2 or 3;
n represents an integer of 0-4;
X represents —C(═O)NR
7
—, —NR
8
—, —NHC(═O)NH— or —S(O)
2
NH— (in which R
7
and R
8
represent each independently a hydrogen atom or a C
1-6
alkyl group);
R
5
represents a hydrogen atom; or a group of the formula:
in which R
12
represents a hydrogen atom; a halogen atom; a C
1-6
alkyl group in which the alkyl group may be optionally substituted with a halogen atom or a C
1-6
alkoxy group; a C
1-6
alkoxy group in which said alkoxy group may be optionally substituted with a halogen atom; a phenyl group in which said phenyl group may be optionally substituted with a halogen atom, a hydroxyl group, a C
1-6
alkyl group or a C
1-6
alkoxy group; or R
12
represents a hydroxyl group, a nitro group, a cyano group, a formyl group, a formamide group, an amino 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, an aminosulfonyl group, a C
1-6
alkylsulfonyl group, a carboxyl group or an arylcarbonyl group, m represents an integer of 1-3, and each R
12
may be same or different if m represents 2 or 3, and R
13
represents a hydrogen atom or a C
1-6
alkyl group; and
R
6
represents a hydrogen atom, a halogen atom, a nitro group or a cyano group;
or a pharmaceutically acceptable salt thereof.
The compound according to the present invention has the strong prolongation effect on the functional 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 specifically as follows.
Herein, “n” means normal, “i” means iso, “s” means secondary, “t” means tertiary, “c” means cyclo, “o” means ortho, “m” means meta, and “p” means para.
As C
1-6
alkyl groups, there may be mentioned methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, 1-pentyl, 2-pentyl, 3-pentyl, i-pentyl, neopentyl, 2,2-dimethylpropyl, 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, trifluoromethyl, trifluoroethyl, pentafluoroethyl, cyanomethyl and hydroxymethyl, 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, trifluoromethoxy, 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
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
Ohrai Kazuhiko
Shigeta Yukihiro
Tanikawa Keizo
Tsukagoshi Toru
Yamashita Toru
Nissan Chemical Industries Ltd.
Owens Amelia
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