Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-17
2001-09-11
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06288056
ABSTRACT:
This is a 371 of PCT/JP00/00883 filed Feb. 17, 2000.
TECHNICAL FIELD
This invention relates to intermittent claudication therapeutic drugs which comprise pyrroloazepine derivatives as active ingredients. More specifically, this invention is concerned with intermittent claudication therapeutic drugs which comprise as active ingredients pyrrolo[3,2-c]azepine derivatives or pharmacologically acceptable salts thereof and which further prevent or improve chronic arterial occlusive diseases, arteriosclerosis obliterans and thromboangiitis obliterans.
BACKGROUND ART
Chronic arterial occlusive diseases indicate diseases characterized by peripheral blood flow disturbances and are represented by arteriosclerosis obliterans and thromboangiitis obliterans. For symptoms of blood flow disturbances, the Fontaine's classification is applied to determine their severity of the diseases and treatment methods. According to this classification, they are divided into stage I: rhigosis or numbness at legs, stage II: intermittent claudication, stage III: rest pain, and stage IV: ulceration. At present, many patients complain of intermittent claudication, and the number of patients is increasing year after year.
Intermittent claudication is a symptom common to chronic arterial occlusive diseases, especially to arteriosclerosis obliterans or thromboangiitis obliterans, all of which are associated primarily with chronic obstructions of large arteries of legs, and means a state in which upon muscle work, ischemia of leg muscles occurs and continuation of walking becomes difficult due to a dull pain, numbness or the like caused by the muscle ischemia, but a rest makes it possible to resume walking. It is considered to be a main cause that at a hypertrophic part of a tunica intima resulted from arteriosclerosis of a large artery in a leg, a thrombus is formed with expulsion of the tunica intima, hemorrhage, ulceration of the tunica intima or the like as an impetus, leading to obstruction of a lumen, and an ischemic disturbance occurs at a periphery of the large artery [Itoh, M., et al., Geriatric Medicine, 33, 857-880 (1995)].
In a patient with intermittent claudication, vascular endothelial cells have been damaged by arteriosclerosis, or often by his additional diseases such as hypertension, hyperlipidemia or diabetes. Adhering and aggregating ability for platelets has therefore been potentiated at the damaged site, and as a result of platelet aggregation, various vasoconstrictors containing serotonin are released, leading to further potentiation of vasoconstriction. There is hence an outstanding demand for drug capable of inhibiting both platelet aggregation and vasoconstriction at the same time and moreover, of acting specifically to the site of a lesion, especially having a potency profile particularly suited for the improvement of intermittent claudication.
In recent years, some compounds have been disclosed as potent therapeutic drugs for intermittent claudication. However, none of them are satisfactory in potency, effective duration, toxicity and side effects, or such potency profile as mentioned above.
As is appreciated from the foregoing, it is the current circumstance that practically no suitable drug is available for the treatment or improvement of intermittent claudication, and development of drug having high effectiveness is desired [William, R. H., Vascular Medicine, 2. 257-262 (1997)].
Accordingly, an object of the present invention is to provide a drug for treating or improving intermittent claudication, which can satisfy characters in potency, effect duration, toxicity and side effects, and potency profile. Another object of the present invention is to provide a preventive or therapeutic drug for chronic arterial occlusive diseases, arteriosclerosis obliterans or thromboangiitis obliterans.
DISCLOSURE OF THE INVENTION
With the foregoing circumstances in view, the present inventors have proceeded with extensive research, seeking for compounds which have strong action and long effect duration, exhibit stable action for a long time, have low toxicity and side effects, and possess a potency profile best suited for the treatment and improvement of intermittent claudication. As a result of evaluation of drug efficacy and toxicity and evaluation of side effects by various in vivo evaluation models, the present invention has been completed based on finding that strong serotonin (5-HT
2
) receptor blocking action and mild adrenargic (&agr;
1
) receptor blocking action—which pyrroloazepine derivatives represented by the following formula (I):
wherein the dotted line indicates existence or non-existence of a bond; when the bond of the dotted line exists, X does not exist, and, when the bond of the dotted line does not exist, X represents a hydrogen atom, a hydroxy group or a group OR
1
in which R
1
represents a substituted or unsubstituted alkyl group; Y represents a linear or branched, substituted or unsubstituted alkyl group; Z
1
and Z
2
are the same or different and each independently represent a hydrogen atom, a hydroxy group or a halogen atom; and W represents a hydrogen atom or a methyl group—surprisingly provide well-balanced inhibitory actions against platelet aggregation and lesion-specific vasoconstriction and have a potency profile optimal as long-awaited intermittent claudication therapeutic drugs.
Therefore, the present invention provides a therapeutic drug for intermittent claudication, which comprises as an active ingredient a pyrroloazepine derivative represented by the formula (I) or a pharmacologically acceptable salt thereof, and hence provides a preventive or therapeutic for chronic arterial occlusive diseases, a preventive or therapeutic for arteriosclerosis obliterans, and a preventive or therapeutic for thromboangiitis obliterans, all of which comprise as an active ingredient a pyrroloazepine derivative represented by the formula (I) or a pharmacologically acceptable salt thereof. The active ingredient has excellent properties as a medicament, including extremely strong action, long effect duration and superb oral absorption, and moreover specifically inhibits vasoconstriction at the site of a lesion. These preventing and therapeutic drugs, therefore, have marked characteristics that they advantageously act for the enhancement of blood flow not only at peripheral area but also at proximal area without developing hypotension or a headache which would otherwise occur due to nonspecific vasodilating action. In addition, concerning action on blood vessels themselves, they effectively act mainly at the area, where a damage was received and a lesion has advanced, not only on arteries but also on veins and thus inhibit platelet aggregation.
The present invention also provide a method of treating or improving intermittent claudication, which comprises administering to a patient with intermittent claudication a pyrroloazepine derivative represented by the formula (I) or a pharmacologically acceptable salt thereof; and also use of a pyrroloazepine derivative represented by the formula (I) or a pharmacologically acceptable salt thereof for the production of an intermittent claudication therapeutic drug.
BEST MODES FOR CARRYING OUT THE INVENTION
The pyrroloazepine derivative (I) as the active ingredient in the intermittent claudication therapeutic drug according to the present invention is an already known compound or a compound producible in accordance with a known process.
Specifically, such pyrroloazepine derivatives are disclosed in PCT International Publication No. WO97/20845 filed by the present Applicant, and can be produced following the description of the PCT international publication.
As preferred examples of the group X in the pyrroloazepine derivative (I), the group X may not exist when the bond of the dotted line exists, and the group X may be a hydroxy group, a hydrogen atom or a group OR
1
when the bond of the dotted line does not exist. Among such pyrroloazepine derivatives, those without the optional double bond of the dotted line
Inomata Norio
Mizuno Akira
Ogata Atsuto
Henley III Raymond
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Suntory Limited
LandOfFree
Intermittent claudication therapeutic drugs comprising... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Intermittent claudication therapeutic drugs comprising..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Intermittent claudication therapeutic drugs comprising... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2455424