Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-08
2002-02-26
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C546S171000, C546S167000, C548S503000, C548S360100, C548S241000, 59, 59, 59, C544S235000, C514S311000, C514S314000, C514S415000, C514S405000, C514S379000, C514S469000, C514S443000
Reexamination Certificate
active
06350749
ABSTRACT:
This application is the National Stage of International Application No. PCT/JP99/00703, filed Feb. 18, 1999.
TECHNICAL FIELD
The present invention relates to aminoguanidinehydrazone derivatives which are useful as a medicine, their production and use.
Sodium-proton (Na—H) exchange inhibitor comprising the aminoguanidinehydrazone derivative of the present invention is effective for the prevention and treatment of myocardial infarction and insufficiency accompanying therewith, arrhythmia, unstable angina, cardiac hypertrophy, restenosis after PTCA (percutaneous transluminal coronary angioplasty), hypertension and tissue injury accompanying therewith, etc.
BACKGROUND ART
On the other hand, Na—H exchange inhibitors, assumed to exhibit ameliorating and cell-protecting action in cell disorders under ischemic conditions, especially on the myocardium, are drawing attention in the field of therapeutic drugs for ischemic diseases.
Amiloride, an acylguanidine derivative and potassium-retaining diuretic, possesses weak activities for inhibiting Na—H exchange and potent activities for inhibiting sodium channel opening.
As Na—H exchange inhibitors, various kinds of acylguanidine derivatives are disclosed in Japanese Patent Unexamined Publication No. 228082/1994, WO 96/04241, EP 708091 and EP 708088, etc.
On the other hand, in EP456133, it is disclosed that a compound of the formula:
wherein A is a chemical bond or —CH
2
—, X is a group of the formula: —C(═Y)—NR
6
R
7
, Y and Z are NH, R
1
is hydrogen, lower alkyl, hydroxy group, lower alkoxy or halogen atom, R
2
is hydrogen or lower alkyl, R
3
, R
4
and R
6
are hydrogen, and R
5
and R
7
are independently hydrogen, lower alkyl or hydroxy group; is useful as anti-cancer agent or agent for treating protozoiasis.
In addition, in Japanese Patent Publication No. 239454/1985, it is disclosed that a compound of the formula:
wherein R is hydrogen, halogen atom, etc., A is a chemical bond, CR
4
R
5
, CR
6
R
7
—CR
8
R
9
, CR
10
R
11
—CR
12
R
13
—CR
14
R
15
, etc., X is CR
1
R
2
, O, S(O)n (n=0,1,2), NR
3
, etc., and R
1
to R
15
are independently hydrogen, an optionally substituted aromatic or hetero-aromatic group, etc.; shows digitalis agonistic or antagonistic activity.
Amiloride causes hypotension and salt excretion, which activities are undesirable for the treatment of heart rate disorder, by its potent activities for inhibiting sodium channel opening.
DISCLOSURE OF INVENTION
The present invention is to provide a Na—H exchange inhibitor which is effective for the prevention and treatment of myocardial infarction and insufficiency accompanying therewith, arrhythmia, unstable angina, cardiac hypertrophy, restenosis after PTCA, hypertension and tissue injury accompanying therewith, etc.
The present inventors studied various compounds having activities for inhibiting Na—H exchange, and as a result, for the first time synthesized a novel compound of the formula (I):
wherein the ring A is an optionally substituted 5- to 6-membered aromatic heterocyclic ring, the ring B an optionally substituted 5- to 6-membered aromatic homocyclic ring or an optionally substituted 5- to 6-membered aromatic heterocyclic ring, R
1
is a hydrogen atom, a hydroxy group or a lower alkyl group, and n is 0 or 1, or a salt thereof [hereinafter referred to as Compound (I)], and found that said Compound (I) unexpectedly exhibits excellent activities for inhibiting Na—H exchange. The present inventors accomplished the present invention based on this finding.
Accordingly, the present invention relates to
(1) Compound (I);
(2) a pro-drug of Compound (I);
(3) a compound of the formula:
wherein each symbol is as defined in the above (1) or a salt thereof;
(4) a compound of the formula:
wherein each symbol is as defined in the above (1) or a salt thereof;
(5) Compound (I) as described in the above (1), wherein the aromatic heterocyclic ring is an aromatic heterocyclic ring containing 1 to 3 hetero-atoms selected from the class consisting of oxygen atom, sulfur atom and nitrogen atom;
(6) Compound (I) as described in the above (1), wherein the ring A is pyridine ring, pyridazine ring, pyrrole ring, pyrazole ring, furan ring, thiophene ring, isoxazole ring or pyrimidine ring, each of which may be substituted;
(7) Compound (I) as described in the above (1), wherein the ring B is pyridine ring, pyrrole ring, furan ring, thiophene ring or benzene ring, each of which may be substituted;
(8) Compound (I) as described in the above (1), wherein R
1
is a hydrogen atom;
(9) Compound (I) as described in the above (1), wherein n is 1;
(10) (S)-(−)-7-(2,5-dichlorothiophen-3-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a salt thereof;
(11) (±)-7-(2,5-dichlorothiophen-3-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a salt thereof;
(12) (S)-(−)-7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a salt thereof;
(13) (±)-7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a salt thereof;
(14) (±)-7-(2,5-dichlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline or a salt thereof;
(15) (±)-7-(5-chloro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a salt thereof;
(16) (±)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a salt thereof;
(17) (±)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a salt thereof;
(18) (±)-7-(5-chloro-2-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a salt thereof;
(19) (±)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline or a salt thereof;
(20) (±)-7-(5-chloro-2-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline or a salt thereof;
(21) a pharmaceutical composition comprising Compound (I) as described in the above (1) or a salt thereof;
(22) a composition of the above (21), which is for Na—H exchange inhibitor;
(23) a composition of the above (21), which is for the prevention or treatment of ischemic cardiac disease;
(24) a composition of the above (23), wherein the ischemic cardiac disease is myocardial infarction, unstable angina or arrhythmia;
(25) a composition of the above (21), which is for the prevention or treatment of cardiac insufficiency;
(26) use of Compound (I) as described in the above (1) or a salt thereof for manufacturing Na—H exchange inhibitor;
(27) use of Compound (I) as described in the above (1) or a salt thereof for manufacturing a pharmaceutical composition for the prevention or treatment of ischemic cardiac disease;
(28) use of Compound (I) as described in the above (1) or a salt thereof for manufacturing a pharmaceutical composition for the prevention or treatment of cardiac insufficiency;
(29) a method for inhibiting Na—H exchange in a mammal which comprises administering to said mammal an effective amount of Compound (I) as described in the above (1) or a salt thereof;
(30) a method for preventing or treating ischemic cardiac disease in a mammal which comprises administering to said mammal an effective amount of Compound (I) as described in the above (1) or a salt thereof;
(31) a method for preventing or treating cardiac insufficiency in a mammal which comprises administering to said mammal an effective amount of Compound (I) as described in the above (1) or a salt thereof; and
(32) a method for producing a compound of the formula (I):
wherein each symbol is as defined below, or a salt thereof, which comprises reacting a compound of the formula (II):
wherein the ring A is an optionally substituted 5- to 6-membered aromatic heterocyclic ring, the ring B an optionally substituted 5- to 6-membered aromatic homocyclic ring or an optionally substituted 5- to 6-membered aromatic heterocyclic ring, and n is 0 or 1, or a salt thereof with a compound of the formula (III):
H
2
N—N═C(NH
2
)(NHR
1
)
wherein R
1
is a hydrogen atom, a hydroxy group or a lower
Fukumoto Shoji
Kusumoto Keiji
Shiraishi Mitsuru
Chao Mark
Liu Hoang
Ramesh Elaine M.
Raymond Richard L.
Takeda Chemical Industries Ltd.
LandOfFree
Aminoguanidine hydrazone derivatives, process for producing... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Aminoguanidine hydrazone derivatives, process for producing..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Aminoguanidine hydrazone derivatives, process for producing... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2972251