Substituted guanidine derivatives, process for production...

Details Substituted guanidine derivatives, process for production... Substituted guanidine derivatives, process for production...

1999-06-29

2001-08-07

Kifle, Bruck (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C540S471000

Reexamination Certificate

active

06271251

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel guanidine derivatives or salts thereof, a process for production thereof, and pharmaceutical uses thereof. The compounds of the present invention have inhibitory effect on 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, hyperpiesia, arrhythmia, angina pectoris, hypercardia, diabetes, organopathies due to ischemia or ischemia re-perfusion [for instance, troubles caused by myocardial ischemia re-perfusion, acute renal failute, and surgical treatments (e.g. organ transplantation and PTCA (percutaneous transluminal coronary angioplasty))], troubles due to cerebral ischemia (e.g. troubles accompanying cerebral infarction, troubles brought about as after-effects of cerebral apoplexy, and cerebral edema), diseases caused by cell over-proliferations (e.g. fibroblast proliferation, smooth muscle cell proliferation and mesangial cell proliferation) (e.g. atherosclerosis, fibroid lung, fibroid liver, fibroid kidney, renal glomerulosclerosis, organ hypertrophy, prostatomegaly, complications of diabetes, and re-constriction after PTCA), and diseases caused by trouble with endothelial cells.
2. Related Art Statement
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 have inhibitory effect on the sodium/proton (Na
+
/H
+
) exchange transport system and hence 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 have inhibitory effect on the sodium/proton (Na+/H+) exchange transport system (for instance, Japanese Patent Unexamined Publication Nos. 7-10839, 7-145149 and 7-206823).
SUMMARY OF THE INVENTION
The present invention is intended to provide novel guanidine derivatives or salts thereof, which have inhibitory effect on 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, hyperpiesia, arrhythmia, angina pectoris, hypercardia, diabetes, organopathies due to ischemia or ischemia re-perfusion [for instance, troubles caused by myocardial ischemia re-perfusion, acute renal failute, and surgical treatments (e.g. organ transplantation and PTCA (percutaneous transluminal coronary angioplasty))], troubles due to cerebral ischemia (e.g. troubles accompanying cerebral infarction, troubles brought about as after-effects of cerebral apoplexy, and cerebral edema), diseases caused by cell over-proliferations (e.g. fibroblast proliferation, smooth muscle cell proliferation and mesangial cell proliferation) (e.g. atherosclerosis, fibroid lung, fibroid liver, fibroid kidney, renal glomerulosclerosis, organ hypertrophy, prostatomegaly, complications of diabetes, and re-constriction after PTCA), and diseases caused by trouble with endothelial cells;
a process for production of said derivatives or salts thereof; and
pharmaceutical uses of the derivatives or salts.
The first aspect of the present invention is directed to a novel substituted guanidine derivative represented by the general formula (1):
wherein R
1
, R
2
, R
3
and R
4
are independently a hydrogen atom, an unsubstituted alkyl group, a substituted alkyl group, a cycloalkyl group, a cycloalkenyl group, a saturated heterocyclic group, a halogen atom, a nitro group, a carboxyl group, an alkoxycarbonyl group, an aromatic group, an acyl group, —OR
5
, —N(R
6
)R
7
, —CON(R
6
)R
7
, —SO
2
N(R
6
)R
7
, —S(O)
n
R
8
wherein R
8
is an unsubstituted alkyl group, a substituted alkyl group or an aromatic group, and n is an integer of 0, 1 or 2, —Q—Ra, or
wherein A is an oxygen atom, —S(O)
n
— wherein n is as defined above or —N(R
10
)—, R
9
is a hydrogen atom, an unsubstituted alkyl group, a substituted alkyl group, an acyl group or —Q—Ra, and the ring is a 3- to 8-membered saturated heterocyclic group composed of a nitrogen atom and carbon atoms;
Y
1
, Y
2
, Y
3
, Y
4
, Y
5
, Y
6
and Y
7
, which may be the same or different, are independently a single bond, —CH
2
—, —O—, —CO—, —C(═C(R
11
)R
12
)—, —S(O)
n
— or —N(R
10
)—, adjacent members of a group consisting of Y
1
through Y
7
being able to be taken together to represent —CH═CH—, and at least two of Y
1
through Y
7
being 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
7
: an unsubstituted 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
5
, —N(R
6
)R
7
, —S(O)
n
R
8
, —C(O)N(R
6
)R
7
, or —Q—Ra, provided that when Z is a substituent for the hydrogen atom of —CH═CH—, Z is not —N(R
6
)R
7
or —S(O)
n
R
8
;
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
5
is a hydrogen atom, an unsubstituted alkyl group, a substituted alkyl group, a cycloalkyl group, a cycloalkenyl group, a saturated heterocyclic group or an aromatic group;
R
6
and R
7
are independently a hydrogen atom, an unsubstituted alkyl group, a substituted alkyl group, a cycloalkyl group, a cycloalkenyl group, a saturated heterocyclic group, an aromatic group, an acyl group or —Q—Ra, or R
6
and R
7
, when taken together with the nitrogen atom to which they are bonded, form a saturated 5- to 7-membered cyclic amino group which may contain an oxygen atom or a sulfur atom in the ring and may be substituted by one or more unsubstituted alkyl groups, substituted alkyl groups, hydroxyl groups or —OR
5
groups;
R
8
is an unsubstituted alkyl group, a substituted alkyl group or an aromatic group;
R
10
is a hydrogen atom, an unsubstituted alkyl group, a substituted alkyl group, a cycloalkyl group, a saturated heterocyclic group, an aromatic group, an acyl group or —Q—Ra; and
R
11
and R
12
are independently a hydrogen atom, an unsubstituted 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
5
, —N(R
6
)R
7
, —CON(R
6
)R
7
, —S(O)
n
R
8
or —Q—Ra or a pharmaceutically acceptable acid addition salt thereof.
The second aspect of the present invention is directed to a process for producing a compound of the formula (1) or a pharmaceutically acceptable acid addition salt thereof which comprises reacting a compound represented by the formula (2):
wherein R
1
, R
2
, R
3
, R
4
, Y
1
, Y
2
, Y
3
, Y
4
, Y
5
, Y
6
, Y
7
and Z are as defined above, and J is a leaving group replaceable by a nucleophilic reagent, with guanidine.
The third aspect of the present invention is directed to a pharmaceutical composition comprising a substituted guanidine derivative of the formula (1) or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.
The fourth aspect of the present invention is directed to a pharmaceutical composition

Affiliated with

Also associated with

Rating

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

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

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2551650