Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-01
2001-06-19
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S405000
Reexamination Certificate
active
06248777
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to therapeutic agents for peripheral vascular disease, comprising a benzopyran or benzoxazine derivative having a therapeutic effect for peripheral vascular disease as an active ingredient.
BACKGROUND ART
Peripheral vascular diseases are broadly classified into Buerger's disease and arterioscleorosis obliterans (ASO). In Japan, the former had previously prevailed, but the latter rapidly increased with an increase of arteriosclerotic diseases and the proportion between both was reversed about 20 years ago. Recent reports say that ASO occupies 80% or more of peripheral vascular disease. ASO is a disease which induces atherosclerotic lesion mainly in extremital aortae, resulting in stenosis or occlusion with ischemic condition. Arteriosclerosis often occurs in leg-governing arteries extending from subrenal aorta to femoral arteries among systemic vessels, so that ASO is one of the most frequent diseases in advancing society.
Most of ASO patients basically have arteriosclerosis. Therefore, ASO therapy involves not only improvement of peripheral vascular disease but also correction of risk factors of arteriosclerosis. Important risk factors of ASO are similar to those of other arterioscleroses, such as male, aging, smoking, hypertension, hyperlipemia, diabetes, etc. particularly smoking, hyperlipemia (especially, low HDL and high neutral fats) and diabetes. In-cases complicated with diabetes, peripheral vessels are more likely to occlude to invite more severe condition leading to leg amputation.
Subjective symptoms of leg circulatory disorders vary with the severity of disorders in the leg. Early mild cases show little symptoms only with occasional “cold feeling or numbness”, but-advanced cases (medium illness) show “intermittent claudication” with pain in leg muscles during walking, and more advanced circulatory disorders (severe illness) hamper bloodstream in legs even at rest to invite “pain at rest, gangrene or ulceration”. Many cases showing pain-at rest, gangrene or ulceration have too complex arterial lesions to treat so that it is not unusual to resort to leg amputation. If such diseases could be diagnosed earlier and appropriately treated at earlier stages, the improvement of QOL (quality of life) of patients would be promoted.
Therapeutic guidelines for ASO have proposed correction of risk factors of arteriosclerosis (quitting the habit of smoking, diet therapy, exercise, and therapy with hypolipemic agents, antihypertensive agents or hypoglycemic agents) and therapy with internal medicines for mild illness; injection, catherterization (PTA) and surgical therapy in addition to said therapies for medium illness; and surgical therapy for severe illness (when it is inadaptable, intravenous injection or arterial injection).
The primary object of pharmacotherapy for ASO is to ensure bloodstream to affected limbs. In order to increase local bloodstream, it is important to enlarge vessels at that site and to enhance the rheology of blood at the same time. Currently commercialized or developed drugs are classified into two major groups according to these purposes. Namely, they are peripheral vasodilators and blood rheology promoters (including platelet aggregation inhibitors and anticoagulants), that are used alone or in combination. They are administered orally or via injection (intravenous injection or arterial injection), particularly via injection in medium or more severe cases with strong subjective symptoms.
Currently used oral drugs include cilostazol having a vasodilative effect as well as an antiplatelet effect (commercial name: Pletaal), prostaglandin (PG) preparations (commercial names: Dorner, Opalmon, etc.), ticlopidine mainly having an antiplatelet effect (commercial name: Panaldine), sarpogrelate (commercial name: Anplag) and ethyl icosapentate (commercial name: Epadel) which is also adaptable to hyperlipemia. They have different action mechanisms, so that it may be required to use two or three preparations in combination depending on pathology. Particularly in medium illness, multiple drugs are more likely to be applied. Injectable preparations include prostaglandin E
1
preparations, antithrombin preparations (commercial name: Argatroban), etc. They are in principle used for medium or more severe illness requiring hospitalization.
The efficacy of the existing drugs is not wholly satisfactory. Particularly, antiplatelets such as ticlopidine or ethyl icosapentate are less effective, probably because it is unclear to which extent platelets are involved in each pathology, or whether the vasodilative effect is sufficient even if a drug has such an effect, or whether bloodstream at ischemic sites can be selectively enough ensured. As to bloodstream at ischemic sites, steal phenomenon has been reported with PG preparations, i.e. bloodstream at ischemic sites rather decreased in about 20% of patients particularly treated via injection. This means that pharmacotherapy with PG injection may rather deteriorate pathology.
DISCLOSURE OF THE INVENTION
It is an object of the present invention to provide novel therapeutic agents for peripheral vascular disease.
As a result of careful studies of therapeutic agents for peripheral vascular disease, we accomplished the present invention on the basis of the finding that compounds of the following general formula (1) have excellent effects of improving peripheral vascular disease.
Accordingly, the present invention provides pharmaceutical compositions comprising a benzopyran or benzoxazine derivative of the general formula (1):
wherein:
R
1
represents a hydrogen atom, a lower alkyl group or an aryl group, or R
1
directly couples with Q or R
11
to form a single bond;
R
2
represents a substituted or unsubstituted amino group, a saturated or unsaturated heterocyclic group, A—O—wherein A represents a saturated or unsaturated carbocyclic group or a saturated or unsaturated heterocyclic group, or —C(═X)Y wherein X represents O, S, N—Z or CHNO2 with Z denoting a hydrogen atom, a lower alkyl group, an aryl group, a hydroxyl group, a lower alkoxy group, a cyano group, a carbamoyl group or a sulfamoyl group, and Y represents —NR
7
R
8
, —OR
9
or —SR
10
wherein R
7
and R
8
are identical or different and each represent a hydrogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted and saturated or unsaturated aliphatic hydrocarbon group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, or R
7
and R
8
are joined together to form an optionally substituted heterocycle with a nitrogen atom, and R
9
and R
10
each represent a hydrogen atom, a lower alkyl group or an aryl group;
Q represents ═N—, N
+
—O
−
or C(R
11
)R
12
wherein R
11
and R
12
are identical or different and each represent a hydrogen atom, a hydroxyl group or a lower acyloxy group, or R
11
directly couples with R
1
to form a single bond, or R
11
and R
12
are joined together to form ═O;
R
3
and R
4
are identical or different and each represent a hydrogen atom, a lower alkyl group or a substituted lower alkyl group having a halogen atom or a lower alkoxy group as a substituent, or R
3
and R
4
are joined together to represent a polymethylene group, or R
3
and R
4
are joined together to represent a heterocycle having an oxygen atom or a sulfur atom as a heteroatom; and
R
5
and R
6
are identical or different and each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower haloalkyl group, a lower alkoxy group, a lower haloalkoxy group, an amino group, an acylamino group, a nitro group, a cyano group, an ester group, a lower alkylsulfonyl group or an arylsulfonyl group, or R
5
and R
6
are joined together to represent ═N—O—N═; and a pharmaceutically acceptable carrier.
Preferably, the present invention provides pharmaceutical compositions comprising a benzopyran derivative of the general formula (2):
wherein:
R
3
and R
4
are id
Koga Hiroshi
Kumagai Eiji
Takanashi Hisanori
Browdy and Neimark
Chugai Seiyaku Kabushiki Kaisha
Lambkin Deborah C.
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