Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-11-28
2004-03-16
Desai, Rita (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S171000
Reexamination Certificate
active
06706732
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a nasal preparation which contains a novel aminoguanidine hydrazone derivative and the like. A nasal preparation according to the present invention has a prophylactic and therapeutic effect on myocardial infarction and accompanying dysfunctions, arrhythmia, unstable angina, cardiac hypertrophy, restenosis after PTCA (percutaneous transluminal coronary angioplasty), hypertension and accompanying tissue failures and the like, since its active ingredient, i.e., amino guanidine hydrazone derivative, has a sodium-proton (Na—H) exchange inhibiting activity.
BACKGROUND OF THE INVENTION
While various pharmaceuticals were developed and employed in clinical practice widely, most of them are employed as oral or injectable preparations. An injectable preparation is employed instead of an oral preparation, when an active ingredient is poorly absorbed orally due to an instability in a digestive tract, a poor migration through the wall of a digestive tract and a disadvantageous first pass effect, or when an active ingredient has a digestive tract tissue damaging effect, or when a pharmacological effect should be exerted instantaneously. However, administration via an injection poses a substantial pain to a patient and a substantial inconvenience due to the impossibility of being performed by a patient himself, and becomes problematic especially when the treatment is prolonged.
A nasal administration is an attractive non-injection method for administering an agent conveniently. A nasal administration is advantageous because it can be performed by a patient himself and also because it is scarcely subjected to a metabolism in a liver (first-pass effect) due to a direct introduction of an agent into a systemic blood circulation, and also advantageous because it may exhibit a rapid pharmacological effect due to a generally rapid absorption of an agent once given nasally.
On the other hand, an Na—H exchange inhibitor which is considered to have an improving effect or a cell protecting effect on a cytopathy under an ischemic condition (especially on a myocardial cell) is an attractive agent in the field of the treatment of ischemic diseases.
Various acylguanidine derivatives are disclosed as Na—H exchange inhibitors in JP-A-6-228082, WO96/04241, EP708091 and EP708088.
JP-A-6-509798 discloses a pyrazine derivative represented by the formula:
wherein R
1
is H or a C
1-6
alkyl, R
2
is 1-morpholinyl, an optionally substituted C
1-6
alkyl and the like, R
3
, R
4
, R
5
and R
4
are same or different and each denotes hydrogen, a C
1-6
alkyl or benzyl as an agent which has an Na—H exchange inhibiting effect and which may be administered as a nasal preparation.
JP-A-9-504535 discloses a benzoylguanidine derivative represented by the formula:
wherein A is —C
m
H
2m
—NR
4
— and the like, R
1
is F, Cl, CF
3
, R
1
—SO
2
— or R
1
—NH—SO
2
— (in which R
1
is a C
1-5
alkyl, halogen- or phenyl-substituted C
1-5
alkyl and the like), R
2
is a group represented by the formula:
and R
3
, R
4
and R
5
are same or different and each denotes hydrogen or a C
1-4
alkyl and the like as an agent which has an Na—H exchange inhibiting effect and which may be administered as nose drops if possible.
JP-A-9-505035 discloses a pyrazine carboxyamide derivative represented by the formula:
wherein A is —C
m
H
2m
—NR
4
— and the like which is bound via a nitrogen atom to a pyrazine carboxyamide system, R
1
is hydrogen, fluorine, chlorine, a C
1-4
alkyl and the like, R
2
is a group represented by the formula:
and R
3
, R
4
and R
4
′ are same or different and each denotes hydrogen or a C
1-4
alkyl and the like as an agent which has an Na—H exchange inhibiting effect and which may be administered as nose drops if possible.
WO98/19682 discloses an aminosterol compound represented by the formula:
as an agent which has an Na—H exchange inhibiting effect and which can be administered to a nasal cavity.
SUMMARY OF THE INVENTION
An objective of the present invention is to provide a nasal preparation which exerts an excellent effect as a prophylactic and therapeutic agent for myocardial infarction and accompanying dysfunctions, arrhythmia, unstable angina, cardiac hypertrophy, restenosis after PTCA, hypertension and accompanying tissue failures and the like and is a sufficiently satisfactory pharmaceutical composition when compared with an oral preparation or an injectable preparation.
The present inventors have studied nasal preparations intensively for obtaining a prophylactic and therapeutic agent described above. As a result, it has been found that a novel aminoguanidine hydrazone compound represented by the formula (I):
wherein Ring A is an optionally substituted 5- or 6-membered aromatic heterocyclic ring, Ring B is an optionally substituted 5- or 6-membered aromatic homocyclic or heterocyclic ring, R
1
is a hydrogen atom, a hydroxyl group or a lower alkyl group, and n is 0 or 1, or a salt thereof (hereinafter abbreviated as Compound (I)) exhibits an excellent Na—H exchange inhibiting activity (especially NHE-1 selective Na—H exchange inhibiting activity) as well as an excellent in vivo absorption via a nasal mucosa and an excellent migration into a heart, and exerts an unexpectedly excellent pharmacological activity, when used in a nasal preparation, which is comparable with an oral or injectable preparation and is satisfactory characteristically as a medicine, whereby establishing the present invention.
Thus, the present invention relates to:
(1) a nasal preparation comprising a compound represented by the formula (I) or a prodrug thereof;
(2) the nasal preparation as described in the above (1), wherein Ring A is a 5- or 6-membered nitrogen-containing aromatic heterocyclic ring containing 1 or 2 nitrogen atoms optionally substituted by an optionally halogenated C
1-6
alkyl or an optionally halogenated C
1-6
alkoxy, Ring B is a 5- or 6-membered aromatic homocyclic or heterocyclic ring optionally containing one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen atoms which is optionally substituted by a halogen atom, an optionally halogenated C
1-6
alkyl, a hydroxyl group or an optionally halogenated C
1-6
alkoxy, R
1
is a hydrogen atom or a hydroxyl group, and n is 1;
(3) the nasal preparation as described in the above (1) comprising (±)-7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a prodrug or a salt thereof; (±)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a prodrug or a salt thereof; or (±)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a prodrug or a salt thereof;
(4) the nasal preparation as described in the above (1) comprising (S)-(−)-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a prodrug or a salt thereof; (S)-(−)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a prodrug or a salt thereof; or (S)-(−)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a prodrug or a salt thereof;
(5) the nasal preparation as described in the above (1) which is a prophylactic and therapeutic agent for an ischemic heart disease;
(6) the nasal preparation as described in the above (1), wherein said ischemic heart disease is myocardial infarction, unstable angina or arrhythmia;
(7) the nasal preparation as described in the above (1) which is a prophylactic and therapeutic agent for cardiac insufficiency;
(8) (S)-(−)-7-(5-Fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a prodrug or a salt thereof;
(9) (S)-(−)-7-(2-Chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a prodrug or a salt thereof;
(10) a pharmaceutical composition comprising (S)-(−)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a prodrug or a salt thereof; or (S)-(−)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimi
Fukumoto Shoji
Misaki Masafumi
Shiraishi Mitsuru
Takada Shigeyuki
Chao Mark
Desai Rita
Ramesh Elaine M.
Takeda Chemical Industries Ltd.
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