Indoloylguanidine derivatives

Details Indoloylguanidine derivatives Indoloylguanidine derivatives

2000-06-27

2001-06-19

Stocton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S414000, C514S415000, C548S492000, C548S503000

Reexamination Certificate

active

06248772

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel indoloylguanidine derivatives. The present invention also relates to sodium/proton (Na
+
/H
+
) exchanger inhibitors comprising the indoloylguanidine derivatives as the active component which are useful for the treatment and prevention of diseases caused by increased sodium/proton (Na
+
/H
+
) exchanger activity.
2. Related Art Statement
Certain polycyclic aroylguanidine derivatives are known as those having polycondensed rings, for example, a naphthalene, 9,10-dihydroanthracene, benzofuran, 2,3-dihydrobenzofuran, benzothiophene, benzothiazole, methylenedioxybenzene, pyridothiophene, pyrimidothiophene, quinoline, 1,6-naphthylidine, 1,8-naphthylidine, 3,4-dihydrobenzopyran, 3,4-dihydro-quinazolin-4-one, 1,2,3,4-tetrahydroquinazolin-2-one, quinoxaline, 5,6,7,8-tetrahydroquinoxaline, benzoazepine, benzotriazepine, benzimidazolothiazine, benzopyranopyran or benzocarbazole ring. As one of the aroylguanidine derivatives having indole rings there is known 1-guanidino-carbonyltryptophane but this compound is merely registered in Chemical Abstracts under Registered No. 18322-34-4, without any reference to its source.
Turning to some monocyclic aroylguanidine derivatives, pyrazinoylguanidine derivatives represented by, e.g., Amiloride, are known to exhibit the sodium/proton (Na
+
/H
+
) exchanger inhibition activity and anti-arrhythmic activity, cf., J. Membrane Biol., Vol. 105, 1 (1988); and Circulation, Vol. 79, 1257 (1989). Recent reports also reveal that benzoylguanidine derivatives possess the sodium/proton (Na
+
/H
+
) exchanger inhibition and anti-arrhythmic activities, cf., J. Mol. Cell. Cardiol., Vol. 24, Supple. I, S. 92 (1992); ibid., Vol. 24, Suppl. I, S. 117 (1992); and Japanese Patent KOKAI Nos. 3-106858 and 5-339228.
SUMMARY OF THE INVENTION
An object of the present invention is to provide novel indoloylguanidine derivatives which inhibit the sodium/proton (Na
+
/H
+
) exchanger activity and are therefore useful for the treatment and prevention of diseases caused by increased sodium/proton (Na
+
/H
+
) exchanger activity, for example, hypertension, arrhythmia, angina pectoris, cardiac hypertrophy, diabetes mellitus, organ disorders associated with ischemia or ischemic reperfusion such as cardiac ischemic reperfusion injury (e.g., heart muscle ischemic reperfusion-associated disorders, acute renal failure, disorders induced by surgical treatment such as organ transplantation or percutaneous transluminal coronary angioplasty (PTCA), cerebro-ischemic disorders such as disorders associated with cerebral infarction, disorders caused after cerebral apoplexy as sequelae, or cerebral edema; or diseases caused by excessive cell proliferation such as proliferation of fibroblast, proliferation of smooth muscle cells or proliferation of mesangium cells, which diseases are, e.g., atherosclerosis, pulmonary fibrosis, hepatic fibrosis, renal fibrosis, glomerular nephrosclerosis, organ hypertrophy, prostatic hypertrophy, diabetic complications or recurrent stricture after PTCA, or diseases caused by endothelial cell injury.
Another object of the present invention is to provide compositions comprising the indoloylguanidine derivatives as the active component which inhibit the sodium/proton (Na
+
/H
+
) exchanger activity and are useful for the prevention and treatment of diseases caused by abnormal sodium/proton (Na
+
/H
+
) exchanger activity.
The present invention relates to indoloylguanidine derivatives represented by the following formula (1):
wherein:
R
1
represents one or more, the same or different substituent(s) which is selected from the group consisting of a hydrogen atom, a C
1
-C
8
alkyl group, a substituted C
1
-C
8
alkyl group, a C
2
-C
6
alkenyl group, a C
2
-C
6
alkynyl group, a C
3
-C
7
cycloalkyl group, a halogen atom, nitro, a C
2
-C
8
alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, carboxyl, a C
2
-C
6
alkoxycarbonyl group, an aromatic group, a group shown by formula: —OR
3
, —NR
6
R
7
, —SO
2
NR
6
R
7
or —S(O)
n
R
40
, and a group shown by formula:
 wherein A represents an oxygen atom or a group shown by formula: —S(O)
n
— or —N(R
50
)— (in which R
50
is a hydrogen atom or a C
1
-C
8
alkyl group; R′ represents a hydrogen atom, a C
1
-C
8
alkyl group or a substituted C
1
-C
8
alkyl group); and the ring represents a saturated 3 to 8-membered hetero ring containing one nitrogen atom;
R
2
represents a hydrogen atom, a C
1
-C
8
alkyl group, a substituted C
1
-C
8
alkyl group, a C
3
-C
7
cycloalkyl group, hydroxy, a C
1
-C
6
alkoxy group, an aromatic group or a group shown by formula: —CH
2
R
20
;
R
3
represents a hydrogen atom, a C
1
-C
8
alkyl group, a substituted C
1
-C
8
alkyl group, a C
3
-C
7
cycloalkyl group, an aromatic group or a group shown by formula: —CH
2
R
30
, in which R
30
represents an alkenyl group or an alkynyl group;
each of R
6
and R
7
independently represents a hydrogen atom, a C
1
-C
8
alkyl group, a substituted C
1
-C
8
alkyl group, a C
3
-C
7
cycloalkyl group, a C
2
-C
8
alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, an aromatic group or a group shown by formula: —CH
2
R
60
(in which R
60
represents a C
2
-C
6
alkenyl group or a C
2
-C
6
alkynyl group); or R
6
and R
7
are combined together to form a saturated 5- to 7-membered cyclic amino group which may contain other hetero atom(s) in the ring thereof;
R
40
represents a C
1
-C
8
alkyl group, a substituted C
1
-C
8
alkyl group or an aromatic group;
n represents 0, 1 or 2; and,
R
20
represents a C
2
-C
6
alkenyl group or a C
2
-C
6
alkynyl group;
in which:
the substituent(s) of the substituted C
l
-C
8
alkyl group means a halogen atom, hydroxy, a C
1
-C
6
alkoxy group, cyano, carboxyl, a C
2
-C
6
alkoxycarbonyl group, a C
2
-C
8
alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, an aromatic group, —CONR
4
R
5
in which each of R
4
and R
5
independently represents a hydrogen atom or a C
1
-C
8
alkyl group or R
4
and R
5
are combined together to form a saturated 5- to 7-membered cyclic amino group which may contain other hetero atom(s) in the ring; —NR
6
R
7
; or a group shown by:
in which:
E represents a nitrogen atom or a CH group and
R″ represents a hydrogen atom, a C
1
-C
8
alkyl group or a substituted C
1
-C
8
alkyl group substituted with hydroxy, a C
1
-C
6
alkoxy group, cyano, carboxyl, a C
2
-C
6
alkoxycarbonyl group, a C
2
-C
8
alkanoyl group, an arylalkanoyl group having carbon atoms up to 10, an aroyl group having carbon atoms up to 11, an aromatic group, a group shown by —NR
6
R
7
, or a group shown by —CONR
4
R
5
, in which each of R
4
and R
5
independently represents a hydrogen atom or a C
1
-C
8
alkyl group or R
4
and R
5
are combined together to form a saturated 5- to 7-membered cyclic amino group which may contain other hetero atom(s) therein; and the ring of
 is a 3- to 8-membered saturated aliphatic ring or saturated hetero ring containing one nitrogen atom;
all of the aromatic groups hereinabove means an aryl group having carbon atoms up to 10, a 5- or 6-membered hetero-aryl group containing 1 to 4 nitrogen atom(s), a 5- or 6-membered hetero-aryl group containing 1 to 2 nitrogen atom(s) and one oxygen atom or one sulfur atom, or furyl; and,
all of the aromatic groups hereinabove may be substituted with a substituent selected from the group consisting of a C
1
-C
8
alkyl group, a substituted C
1
-C
8
alkyl group, a halogen atom, nitro, a C
2
-C
6
alkoxy-carbonyl group, carboxyl and a group selected from the group shown by formulae: —OR
3
, —NR
6
R
7
, —CONR
6
R
7
, —SO
2
NR
6
R
7
and —S(O)
n
R
40
;
provided that R
1
and the guanidinocarbonyl group may be substituted at any one of the 5- and 6-membered rings of the indole nucleus; or,

Affiliated with

Also associated with

Rating

Indoloylguanidine derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Indoloylguanidine derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Indoloylguanidine derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2532887