Potassium channel activators

Details Potassium channel activators Potassium channel activators

2000-06-29

2002-03-05

Powers, Fiona T. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S426000, C514S427000

Reexamination Certificate

active

06353016

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a potassium channel (K
+
-channel) activator comprising a pyrrole derivative or its pharmaceutically acceptable salt as an active ingredient. A potassium channel activator is useful for the prophylaxis or therapy of K
+
-channel-associated physiologic disorders.
BACKGROUND ART
The potassium channel exists in a variety of cells such as nerve cells and smooth muscle cells and is involved in various physiological processes and control the homeostasis of normal cell ions. Generally potassium ions regulate the resting membrane potential of cells, and an efflux of potassium ions following depolarization of the cell membrane results in repolarization of the membrane. The potassium channel activator causes hyperpolarization of cells. Thereby, in nerve cells, suppress cellular activity to reduce the transmitters release from the nerve endings and, in smooth muscle cells, suppress the contractility.
Therefore, a potassium channel activator is considered to be of value in the therapy of nervous system disorders inducing spasmodic or ischemic responses through its action on nerve cells. Furthermore, through its action on smooth muscle cells, a potassium channel activator is expected to be useful in the therapy of various diseases such as hypertension, angina pectoris, asthma and irritable bowel syndrome.
Already known as compounds having potassium channel activating activity are benzopyran derivatives (Japanese Laid-Open S58-67683, Japanese Laid-Open H6-25233, WO 94/13297, etc.), thienopyran derivatives (WO 94/13297 etc.), benzoxazine derivatives (Japanese Laid-Open H5-70464, WO 94/13297, etc.), benzoxepine derivatives (WO 94/13297 etc.), quinoline derivatives (WO 94/13297 etc.), indole derivatives (WO 94/13297 etc.), benzocycloheptane derivatives (WO 94/13297 etc.) and pyridine derivatives (The Merck Index, 11th edition, 7407), among others.
The compound according to the present invention (hereinafter referred to as the compound of the invention) is a pyrrole derivative which is structurally different from any of the above-mentioned compounds having potassium channel activating activity. It has not heretofore been known that a pyrrole derivative ever has potassium channel activating activity.
DISCLOSURE OF INVENTION
The object of the present invention is to provide a novel potassium channel activator.
Exploring into various compounds with enthusiasm, the inventors of the present invention found surprisingly that a pyrrole derivative of the following general formula [1] has potassium channel activating activity and have completed this invention.
The present invention, therefore, is directed to a potassium channel activator composition comprising a pyrrole derivative of the following general formula [1] or a pharmaceutically acceptable salt thereof as an active ingredient.
wherein R
1
represents hydrogen or alkoxycarbonylamino;
R
2
represents (i) alkyl, (ii) aryl which may be substituted, (iii) aromatic heterocyclyl which may be substituted, (iv) a group of the following formula [2]
[wherein R
6
and R
7
may be the same or different and each represents (1) hydrogen or (2) alkyl (said alkyl may be substituted by (1) aryl which may be substituted by alkoxy, (2) aromatic heterocyclyl, or (3) hydroxy)], or (v) a group of the following formula [3]
Z
1
and Z
2
may be the same or different and each represents —CH
2
— or >C═O; provided that Z
1
and Z
2
do not concurrently represent >C═O;
Y represents —CH
2
—, —O—, —S—, or >NR
9
;
R
9
represents hydrogen, alkyl, acyl, aryl, or aromatic heterocyclyl;
m represents an integer of 1-3; n represents an integer of 0-2; p represents 0 or 1;
in case R
2
represents aryl which is substituted or aromatic heterocyclyl which is substituted, the particular aryl or aromatic heterocyclyl may be substituted by 1-3 same or different members selected from the group consisting of (1) halogen, (2) alkyl which may be substituted by halogen, (3) cyano, (4) nitro, (5) alkoxycarbonyl, (6) hydroxy, (7) alkoxy (said alkoxy may be substituted by (1) halogen, (2) aryl which may be substituted by alkoxy, or (3) alkoxy), (8) —NHSO
2
R
82
, and (9) —NR
83
R
84
; or two adjacent substituent groups may jointly represent —O—(CH
2
)
t
—O— (t represents 1 or 2);
R
82
represents (1) alkyl or (2) aryl which may be substituted by alkyl;
R
83
and R
84
may be the same or different and each represents (1) hydrogen, (2) alkyl, or (3) acyl; or R
83
and R
84
jointly and taken together with the adjacent N atom represent 5- through 7-membered cyclic amino;
R
3
represents cyano or carbamoyl;
R
4
represents hydrogen or alkyl;
E represents alkylene; q represents 0 or 1;
A represents (1) methyl, (2) aryl which may be substituted, or (3) aromatic heterocyclyl which may be substituted;
in case A represents aryl which is substituted or aromatic heterocyclyl which is substituted, the particular aryl or aromatic heterocyclyl may be substituted by 1-3 same or different members selected from the group consisting of (1) halogen, (2) alkyl which may be substituted by halogen, (3) cyano, (4) nitro, (5) alkoxycarbonyl, (6) hydroxy, (7) alkoxy (said alkoxy may be substituted by (1) halogen, (2) aryl which may be substituted by alkoxy, or (3) alkoxy), (8) —NHSO
2
R
92
, and (9) —NR
93
R
94
; or two adjacent substituent groups may jointly represent —O—(CH
2
)
u
—O— (u represents 1 or 2);
R
92
represents (1) alkyl or (2) aryl which may be substituted by alkyl;
R
93
and R
94
may be the same or different and each represents (1) hydrogen, (2) alkyl, or (3) acyl; or R
93
and R
94
jointly and taken together with the adjacent N atom represent 5- through 7-membered cyclic amino;
A—(E)q, R
4
, and the double bond of the pyrrole ring may jointly, i.e.
X represents —O—, —S—, or >NR
90
where R
90
represents alkyl;
R
95
, R
96
and R
97
may be the same or different and each is selected from the group consisting of (1) hydrogen, (2) halogen, (3) alkyl which may be substituted by halogen, (4) cyano, (5) nitro, (6) alkoxycarbonyl, (7) hydroxy, (8) alkoxy (said alkoxy may be substituted by halogen or alkoxy), (9) —NHSO
2
R
92
(R
92
is as defined above), and (10) —NR
93
R
94
(R
93
and R
94
are as defined above); any two adjacent substituent groups among R
95
, R
96
, and R
97
may jointly represent —O—(CH
2
)
u
—O— (u is as defined above).
In the context of the present invention, the “alkyl” includes straight-chain or branched-chain alkyl groups containing 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
The “aryl” includes aryl groups of 6-12 carbon atoms, such as phenyl, 1-naphthyl, 2-naphthyl, 3-biphenyl and 4-biphenyl.
The “aromatic heterocyclyl” includes groups of aromatic 5- or 6-membered rings containing 1-4 nitrogen, oxygen or sulfur atoms as ring members and the corresponding benzene-fused ring systems (however, 2-pyrrolyl and 3-pyrrolyl are excluded), thus including 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 1-indolyl, 2-indolyl, 3-indolyl, 1-tetrazolyl, 2-furyl, 3-furyl, 2-benzofuranyl, 3-benzofuranyl, 2-thienyl, and 3-thienyl, among others.
The “alkylene” includes straight-chain or branched groups of 1-4 carbon atoms, such as the following.
The alkyl moiety of said “alkoxy”, “alkoxycarbonyl” or “alkoxycarbonylamino” includes the alkyl groups mentioned above.
The “halogen” includes fluoro, chloro, bromo and iodo.
The “acyl” includes groups of 1-7 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, isohexanoyl and benzoyl.
The 5-7-membered cyclic amino represented by NR
83
R
84
or NR
93
R
94
includes but is not limited to 1-pyrrolidinyl, 1-piperidinyl and 1-hexamethyleneimino.
The preferred species of the compound [1] of the invention includes the compound in which R
1
is hydrogen, R
2
is NH
2
, pyrrolidino or methyl, R
3
is cyano, R
4
is hydrogen or methyl, q is 0, and A is aryl which may be substituted or a a

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