Substituted guanidine derivatives

Details Substituted guanidine derivatives Substituted guanidine derivatives

2002-06-17

2004-05-11

Pamsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C548S414000, C548S492000

Reexamination Certificate

active

06734205

ABSTRACT:

This application is a 371 of PCT/JP00/08669 filed Dec. 7, 2000.
TECHNICAL FIELD
The present invention relates to novel substituted guanidine derivatives, prodrugs thereof or pharmaceutically acceptable salts of the derivatives or prodrugs, pharmaceutical uses of the derivatives, prodrugs or salts, 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, cardiac insufficiency, diabetes mellitus, organ disorders associated with ischemia or ischemic reperfusion [e.g. cardiac ischemic reperfusion-injury, acute renal failure, or disorder induced by surgical treatment such as organ transplantation or percutaneous transluminal coronary angioplasty (PTCA)], 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 may be exemplified the compounds disclosed in Japanese Patent Unexamined Publication Nos. 7-10839, 8-208602, 10-237073 and 9-291076 and International Publication No. WO 9961414.
In recent years, there has been reported the degeneration of nerve cells in mice which have underwent gene mutation relating to the sodium/proton (Na
+
/H
+
) exchange transport system (for instance, Cell, 91, 139-148 (1997)). It has been revealed that among known substituted guanidine derivatives having inhibitory effect on the sodium/proton (Na
+
/H
+
) exchange transport system, such as those exemplified above, there are substituted guanidine derivatives having an undesirable effect on nerve cells, i.e., substituted guanidine derivatives capable of degenerating nerve cells. It is suggested that such degeneration of nerve cells is likely to cause various neuropathies. Therefore, there is desired the development of a Na
+
/H
+
exchange transport system inhibitor reduced in such an effect on nerve cells.
DISCLOSURE OF THE INVENTION
The present inventors earnestly investigated in order to achieve the above object, and consequently found that a compound represented by the general formula (1), a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug (if necessary, the compound, prodrug or salt is hereinafter abbreviated as the present inventive compound in some cases) has an excellent inhibitory effect on the sodium/proton (Na
+
/H
+
) exchange transport system and exhibits only markedly lessened side effects on the nervous system, in particular, the central nervous system. That is, the present invention relates to the following.
[1]
A compound represented by the formula (1):
wherein R is a substituted or unsubstituted benzene ring, a fused polycyclic hydrocarbon ring which is substituted or unsubstituted, a monocyclic heterocyclic ring which is substituted or unsubstituted, or a polycyclic heterocyclic ring which is substituted or unsubstituted;
A and E are independently a single bond or a substituted or unsubstituted lower alkylene group (one or more of the —CH
2
— groups of said lower alkylene group may be replaced by one or more groups, which may be the same or different and are selected from the groups consisting of a group represented by the formula: —O—, —S—, —N(R
1
)— or —C(═O)—, a benzene ring and a cycloalkane ring (one or more of the —CH
2
— groups in said cycloalkane ring may be replaced by one or more groups, which may be the same or different and are represented by the formula: —O—, —S—, —N(R
2
)— or —C(═O)—) and any two adjacent atoms of said lower alkylene group may form a double bond or a triple bond);
G is a single bond or a group represented by the formula: —O— or —N(R
11
)—;
Y is a group represented by the formula: —SO
3
H, —PO
3
H
2
, —CO
2
H or
 provided that G is a single bond when Y is a group represented by the formula: —PO
3
H
2
or —CO
2
H;
R
1
, R
11
and R
2
are independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted acyl group, or a group represented by the formula: —C(═O)N(R
5
)R
6
,
 or —S(O)
n
R
3
.
R
3
and R
3a
are independently a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, or a substituted or unsubstituted heterocyclic group;
R
5
, R
6
, R
7
and R
8
are independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted acyl group, or R
5
and R
6
, or R
7
and R
8
may bind to each other to form, together with the nitrogen atom to which they are bonded, 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 substituted or unsubstituted alkyl groups, hydroxyl groups or —OR
4b
groups;
R
4
, R
4a
and R
4b
are independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted heterocyclic group or —SO
3
H; and
n is an integer of 0, 1 or 2, or
a prodrug of said compound, or a pharmaceutically acceptable salt of said compound or prodrug.
[2]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to the above item [1], wherein E is a single bond.
[3]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to the above item [1] or [2], wherein A is a single bond, and G is a group represented by the formula: —O—.
[4]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to the above item [1], [2] or [3], wherein Y is a group represented by the formula: —SO
3
H.
[5]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to the above item [1] or [2], wherein Y is a group represented by the formula: —PO
3
H
2
.
[6]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to the above item [1], [4] or [5], wherein each of E and G is a single bond.
[7]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to the above item [1] or [4], wherein each of E, A and G is a single bond.
[8]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the

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