Substituted guanidine derivatives and process for producing...

Details Substituted guanidine derivatives and process for producing... Substituted guanidine derivatives and process for producing...

2000-11-27

2002-04-09

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C564S180000, C564S237000, C514S618000, C514S619000, C514S620000, C514S621000, C514S622000

Reexamination Certificate

active

06369110

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel substituted guanidine derivatives, prodrugs thereof or pharmaceutically acceptable salts of the derivatives or prodrugs, and a process for production of the derivatives, prodrugs or salts. The compounds of the present invention inhibit the sodium/proton (Na
+
/H
+
) exchange transport system and hence are useful as a therapeutic or prophylactic agent for diseases caused by the acceleration of the sodium/proton (Na
+
/H
+
) exchange transport system, for example, hypertension, arrhythmia, angina pectoris, cardiac hypertrophy, diabetes mellitus, organ disorders associated with ischemia or ischemic reperfusion [e.g. cardiac ischemic reperfusion-injury, acute renal failure, or disorders induced by surgical treatment such as organ transplantation or percutaneous transluminal coronary angioplasty (PTCA)], cerebro-ischemic injury [e.g. injury associated with cerebral infarction, injury caused as sequelae of stroke, or brain edema], diseases caused by hyperplasia such as hyperplasia of fibroblast, hyperplasia of smooth muscle cells or hyperplasia of mesangium cells, which diseases are, for example, atherosclerosis, pulmonary fibrosis, hepatic fibrosis, renal fibrosis, glomerular nephrosclerosis, organ hypertrophy, prostatic hypertrophy, diabetic complications or restenosis after PTCA, or diseases caused by endotherial cell injury.
BACKGROUND ART
As substituted guanidine derivatives having inhibitory effect on the sodium/proton (Na
+
/H
+
) exchange transport system, there are known, for example, pyrazinoylguanidine derivatives represented by amiloride (for instance, J. Membrane Biol., Vol. 105, 1(1988); Circulation, Vol. 79, 1257(1989)). It has been reported that benzoylguanidine derivatives inhibit the sodium/proton (Na
+
/H
+
) exchange transport system and hence have antiarrhythmic effect (for instance, J. Mol. Cell. Cardiol., Vol. 24, Suppl. I, S.92(1992); J. Mol. Cell. Cardiol., Vol. 24, Suppl. I, S.117(1992); Japanese Patent Unexamined Publication Nos. 5-339228, 6-9545, 6-345715 and 7-109251). It has also been reported that polycyclic aroylguanidine derivatives inhibit the sodium/proton (Na
+
/H
+
) exchange transport system (for instance, Japanese Patent Unexamined Publication Nos. 7-10839, 7-145149, 7-206823, 8-41028, 8-225513, 8-277269, 9-77753 and 9-291076). In addition, it has been reported that indenoylguanidine derivatives inhibit the sodium/proton (Na
+
/H
+
) exchange transport system (for instance, Japanese Patent Unexamined Publication Nos. 8-291131 and 9-268172). Furthermore, it has been reported that acryloylguanidine derivatives inhibit the sodium/proton (Na
+
/H
+
) exchange transport system (for instance, Japanese Patent Unexamined Publication Nos. 8-319266, 9-52823, 9-59245, 9-67332, 9-67340 and 9-249660).
DISCLOSURE OF THE INVENTION
The present invention is intended to provide novel substituted guanidine derivatives, prodrugs thereof or pharmaceutically acceptable salts of the derivatives or prodrugs, which inhibit the sodium/proton (Na
+
/H
+
) exchange transport system and hence are useful as a therapeutic or prophylactic agent for diseases caused by the acceleration of the sodium/proton (Na
+
/H
+
) exchange transport system, for example, hypertension, arrhythmia, angina pectoris, cardiac hypertrophy, diabetes mellitus, organ disorders associated with ischemia or ischemic reperfusion [e.g. heart muscle ischemic reperfusion-associated disorders, acute renal failure, or disorders induced by surgical treatment such as organ transplantation or percutaneous transluminal coronary angioplasty (PTCA)], cerebro-ischemic disorders [e.g. disorders associated with cerebral infarction, disorders caused after cerebral apoplexy as sequelae, or cerebral edema], diseases caused by excessive cell proliferation such as proliferation of fibroblast, proliferation of smooth muscle cells or proliferation of mesangium cells, which diseases are, for example, atherosclerosis, pulmonary fibrosis, hepatic fibrosis, renal fibrosis, glomerular nephrosclerosis, organ hypertrophy, prostatic hypertrophy, diabetic complications or recurrent stricture after PTCA, or diseases caused by endotherial cell injury; and
a process for production of said derivatives, prodrugs thereof, or salts of the derivatives or prodrugs.
The present invention includes the aspects described in the following items [1] to [23].
[1]
A compound represented by the general formula (1):
wherein R
1
is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a saturated heterocyclic group, an aromatic group, an acyl group, a halogen atom, —OR
6
, —S(O)
n
R
7
, —Q—Ra or
wherein A is an oxygen atom or —S(O)
n
—, R
10
is a hydrogen atom, an alkyl group, a substituted alkyl group, an acyl group, —S(O)
n
R
7
or —Q—Ra, and the ring is a 3- to 8-membered saturated heterocyclic group composed of a nitrogen atom and carbon atoms;
R
2
, R
3
, R
4
and R
5
are independently a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a saturated heterocyclic group, an aromatic group, an acyl group, a carboxyl group, an alkoxycarbonyl group, a halogen atom, a nitro group, —OR
6
, —N(R
8
)R
9
, —CON(R
8
)R
9
, —SO
2
N(R
8
)R
9
, —S(O)
n
R
7
, —Q—Ra or
 wherein A′ is an oxygen atom, —S(O)
n
— or —N(R
51
)—, and R
10
and the ring are as defined above;
Y
1
, Y
2
, Y
3
and Y
4
, which may be the same or different, are independently a single bond, —CH
2
—, —O—, —CO—, —C(═C(R
12
)R
13
)— or —N(R
11
)—, provided that at least two of Y
1
through Y
4
are independently a group other than a single bond;
Z may be absent, or one or more Zs may be present and are, the same or different, independently the following substituent for a hydrogen atom bonded to any of the carbon atoms constituting the ring formed by Y
1
through Y
4
: an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a saturated heterocyclic group, a halogen atom, a carboxyl group, an alkoxycarbonyl group, an aromatic group, an acyl group, —OR
6
, —N(R
8
)R
9
, —S(O)
n
R
7
, —C(O)N(R
8
)R
9
, —SO
2
N(R
8
)R
9
, or —Q—Ra;
Q is a substituted or unsubstituted lower alkylene group;
Ra is a substituted or unsubstituted vinyl group, or a substituted or unsubstituted ethynyl group;
R
6
is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a cycloalkenyl group, a saturated heterocyclic group or an aromatic group;
R
7
is an alkyl group, a substituted alkyl group or an aromatic group;
n is an integer of 0, 1 or 2;
R
8
and R
9
are independently a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a cycloalkenyl group, a saturated heterocyclic group, an aromatic group, an acyl group, —S(O)
2
R
7
or —Q—Ra, or R
8
and R
9
, when taken together with the nitrogen atom to which they are bonded, form a 5- to 7-membered saturated cyclic amino group which may contain other heteroatom(s) in the ring and may be substituted by one or more alkyl groups, substituted alkyl groups, hydroxyl groups or —OR
6
groups;
R
11
is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a saturated heterocyclic group, an aromatic group, an acyl group, —S(O)
2
R
7
or —Q—Ra;
R
51
is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a saturated heterocyclic group, an aromatic group, an acyl group, —S(O)
2
R
7
or —Q—Ra; and
R
12
and R
13
are independently a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a saturated heterocyclic group, a halogen atom, a carboxyl group, an alkoxycarbonyl group, an aromatic group, an acyl group, —OR
6
, —CON(R
8
)R
9
, —S(O)
n

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