Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-03
2001-07-10
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S112000, C546S113000, C546S183000
Reexamination Certificate
active
06258829
ABSTRACT:
TECHNICAL FIELD
This invention relates to a novel cycloalka[b]pyridine-3-carbonylguanidine derivative or a salt thereof, a process for producing the same, and a drug containing the same.
BACKGROUND ART
It has been reported that a pyrazine derivative having an acylguanidine, namely amiloride represented by the following formula, has a Na
+
/H
+
exchange transport inhibitory action and shows anti-arrhythmic action [
Circulation
, 79, 1257 (1989)]. However, anti-arrhythmic action of amiloride is weak and it accompanies hypotensive action and salt excretion action, so that this compound is not desirable for the treatment of arrhythmia.
Recently, benzoylguanidine derivatives have been disclosed in
J. Mol. Cell. Cardiol
., 24, Suppl. I, S. 92 (1992), JP-A-5-33922 (the term “JP-A” as used herein means an “unexamined published Japanese patent application”) and JP-A-8-73427, and also an indoloylguanidine derivative in JP-A-8-208602, all as derivatives which have Na
+
/H
+
exchange transport inhibitory action and show anti-arrhythmic action.
The object of the present invention is to find a novel cycloalka[b]pyridine-3-carbonylguanidine derivative which has Na
+
/H
+
exchange transport inhibitory action and is useful as a therapeutic or preventive drug for diseases caused by the acceleration of Na
+
/H
+
exchange transport system, such as hypertension, arrhythmia, angina pectoris, cardiac hypertrophy, diabetes, organ disorders due to ischemia or ischemia reperfusion, cerebral ischemic disorders, diseases due to excess proliferation of cells and diseases due to endothelial cell damage.
DISCLOSURE OF THE INVENTION
As a result of extensive investigation to achieve the just described object, the inventors of the present invention have found that a novel cycloalka[b]pyridine-3-carbonylguanidine derivative has excellent Na
+
/H
+
exchange transport inhibitory action. Accordingly, the present invention relates to a cycloalka[b]pyridine-3-carbonylguanidine derivative represented by the following general formula (1):
[wherein R
1
represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, an amino lower alkyl group, a lower alkoxyalkyl group, an aryl group, a heterocyclic group, an aralkyl group, a phenoxy lower alkyl group or an aralkyloxy lower alkyl group; R
2
represents a hydrogen atom, a halogen atom, a lower alkoxy group or a nitro group; A represents a single bond or a vinylene group; B represents a vinylene group or
(wherein R
3
represents a hydrogen atom, a halogen atom, a hydroxy group, a lower alkyl group, a lower alkylidene group, a lower alkoxy group, a hydroxyower alkyl group, an aralkyl group, an aralkylidene group, a phenoxy lower alkyl group, a hydroxyimino group, a lower alkoxyimino group, an oxo group or a (CH
2
)
n
ONO
2
group (n is 0 or an integer of 1), and P represents a methine group or a carbon atom); D represents a single bond, a methylene group or an ethylene group; and E represents a vinylene group,
(wherein R
4
represents a hydrogen atom, a halogen atom, a hydroxy group which may be protected or an oxo group, R
5
represents unsubstitution, a hydrogen atom or a lower alkyl group, P represents a methine group or a carbon atom, and Q represents a methine group or an oxygen atom), provided that when A and D are a single bond, B and E are not a vinylene group at the same time]or a salt thereof, a process for the production thereof, and its use as a Na
+
/H
+
exchange transport inhibitor.
Examples of the halogen atom of the substituent group R
1
, R
2
, R
3
or R
4
of the cycloalka[b]pyridine-3-carbonylguanidine derivative represented by the general formula (1) include fluorine atom, chlorine atom, bromine atom and iodine atom. Examples of the lower alkyl group of R
1
, R
3
or R
5
include straight, branched or halogen atom-substituted lower alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl and tert-butyl groups. Examples of the lower alkylidene group of R
3
include lower alkylidene groups having 1 to 4 carbon atoms, methylene, ethylidene and propylidene groups. Examples of the lower alkoxy group of R
1
, R
2
or R
3
include straight or branched lower alkoxy group having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy and sec-butoxy groups. The hydroxy group of R
4
may be protected with a protecting group such as trimethylsilyl group or tert-butyldimethylsilyl group. Examples of the amino lower alkyl group of R
1
include aminomethyl, methylaminomethyl, dimethylaminomethyl, ethylaminomethyl, diethylaminomethyl and benzylaminomethyl. Examples of the lower alkoxyalkyl group of R
1
include methoxymethyl, methoxyethyl, methoxypropyl and methoxybutyl. Examples of the hydroxyower alkyl group of R
3
include hydroxymethyl, 1-hydroxyethyl and 1-hydroxypropyl. Examples of the aryl group of R
1
include phenyl, biphenyl and naphthyl. Examples of the heterocyclic group of R
1
include pyridyl, pyrimidinyl and thienyl. Examples of the aralkyl group of R
1
or R
3
include those in which the cyclic moiety is not only an aromatic ring but also a heterocyclic ring, such as benzyl, 1-methylpyrrolinylmethyl and pyridinylmethyl. Examples of the aralkylidene group of R
3
include those in which the cyclic moiety is not only an aromatic ring but also a heterocyclic ring, such as benzylidene, pyridylmethylene and thienylmethylene. Examples of the phenoxy lower alkyl group of R
1
or R
3
include phenoxymethyl which may be substituted, and examples of the substituent group include N-[2-(dimethylamino)ethyl]aminocarbonyl and N-[2-(diethylamino)ethyl]aminocarbonyl. Examples of the aralkyloxy lower alkyl group of R
1
include 3-pyridylmethyloxymethyl and 1-imidazolylmethyloxymethyl. Examples of the lower alkoxyimino group of R
3
include methoxyimino, ethoxyimino and propoxyimino.
Stereoisomers such as geometrical isomers and enantiomers based on asymmetric carbon atoms are also included in the cycloalka[b]pyridine-3-carbonylguanidine derivative represented by the general formula (1).
In general, cycloalka[b]pyridine-3-carbonylguanidine derivative (1) is weak basic and therefore is bonded to an acid to form a salt. All of pharmacologically acceptable acid addition salts can be used, and their examples include acid addition salts with mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, acid addition salts with organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid and acid addition salts with organic carboxylic acids such as acetic acid, tartaric acid, maleic acid, fumaric acid, oxalic acid, lactic acid and citric acid.
EMBODIMENT OF THE INVENTION
The compound of the present invention represented by the aforementioned general formula (1) can be produced by a production method described by the following reaction formula.
(In the above formula, X is a hydroxy group or a leaving group which can be substituted easily by nucleophilic reaction, and R
1
, R
2
, A, B, D and E are as defined in the foregoing.)
Examples of the leaving group which can be substituted easily by nucleophilic reaction include a halogen atom, an alkoxy group, a p-nitrophenoxy group and a pentafluorophenoxy group.
When X is a hydroxy group, the compound (1) can be produced by allowing a cycloalka[b]pyridine-3-carboxylic acid represented by the general formula (2) to react with guanidine in an inert solvent in the presence of a condensing agent.
Examples of the condensing agent to be used in the reaction include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), benzotriazol-1-yltris(dimethylamino)phosphonium hexafluorophosphide salt (BOP), diphenylphosphonyl azide (DPPA) and N,N-carbonyldiimidazole (CDI).
Guanidine is used in an amount of from 1 to 50 equivalents, preferably from 3
Aihara Kazuyuki
Genkyou Kaoru
Kimura Tetsuo
Kogi Kentaro
Sasamori Jun
Arent Fox Plotkin & Kahn PLLC
Desai Rita
Rotman Alan L.
Toa Eiyo Ltd.
LandOfFree
Cycloalka[b]pyridine-3-carbonylguanidine... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Cycloalka[b]pyridine-3-carbonylguanidine..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Cycloalka[b]pyridine-3-carbonylguanidine... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2463505