Butadiene derivatives and process for preparing thereof

Details Butadiene derivatives and process for preparing thereof Butadiene derivatives and process for preparing thereof

1998-08-28

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...

C514S343000, C514S352000, C514S425000, C544S382000, C546S309000, C546S278100, C548S547000

Reexamination Certificate

active

06248743

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel butadiene derivative and a novel pyrrolidine derivative, both having excellent activity for inhibiting the activity or production of type 1 plasminogen activator inhibitor (PAI-1) in living body and being useful as an antithrombotic agent, and processes for preparing the same.
BACKGROUND ART
Thrombus means the blood coagulation condition in the heart and the blood vessels of the living body, and by which the blood vessels are narrowed or occlused, and then, the circulation disorder is led in the tissues being dominated by said blood vessel, and the onset of necrosis or edema occurs in these tissues. As a result, various arterial and thrombotic diseases are caused such as myocardial infarction, intra-atrial thrombus in atrial fibrillation, arterial sclerosis, angina pectoris, stroke, pulmonary infarction, deep venous thrombus (DVT), disseminated intravascular coagulation syndrome (DIC), diabetic complications, restenosis after percutanous transluminal coronary angioplasty (PTCA), etc.
Various factors are considered to participate in the formation of thrombus, for example, the change in the conditions of the blood vessel wall, the change in the blood flow speed, and the change in the components of the plasma. The components of thrombus are, for example, platelets, erythrocytes, leukocytes, fibrin, etc.
In many cases, the fibrinolysis (fibrinolytic system) is secondarily activated in the living body in order to lyse microthrombus being formed in the living body. For instance, plasminogen, inactive precursor, is converted into active plasmin (a protease existing mainly in the plasma) by a plasminogen activator being specific to the active site thereof (PA; tissue plasminogen activator (t-PA), urokinase plasminogen activator (u-PA), etc.), and activated plasmin can interrupt the lysine-bond of polypeptide chain of fibrin, by which thrombus is lysed. On the other hand, the activity of PA is controlled by its specific inhibitor, Type 1 plasminogen activator inhibitor (PAI-1).
Therefore, the activity of the fibrinolysis is determined by the valance between the amount of PA, and the PAI-1, both secreted from the vascular endothelial cells, and the increase or decrease in the PAI-1 production in cells, or the change in the activity of PAI-1 molecule per se immediately affect the fibrinolysis in the blood.
In another word, it may be possible to prevent or treat various thrombotic diseases represented by the above-mentioned diseases by acting directly on the vascular endothelial cells and inhibiting PAI-1 activity or the production thereof, and by increasing PA activity.
Under the above circumstances, there have widely been used enzyme preparations such as tissue plasminogen activator, urokinase, streptokinase, etc. for lysis and prevention of thrombus. These drugs have, however, some deficits, for example, they are rapidly inactivated in the blood and as a result they lose their pharmacological activities in a very short time, or they can be administered only by parenteral route but not by oral route.
On the other hand, EP-A-563798 discloses as an antithrombotic agent 3-[(E)-benzylidene]-4-[(E)-3,4,5-trimethoxybenzylidene]-2,5-pyrrolidinedione and (E)-2-[(E)-3,4,5-trimethoxybenzylidene]-3-carboxy-4-phenyl-3-butenoic acid methyl ester, but these compounds also have some deficits such as less bio-availability, less safety as a medicament, and stability thereof, for example, (1) low solubility in water, (2) easily metabolized in the liver, (3) toxicity against in the liver and chromosome, etc.
Besides, Nouveau Journal De Chimie, vol. 1, No. 5, p 413-418 (1977) discloses benzylidenesuccinic acid as a product of reduction of electrolytes, but the pharmacological activities thereof have never been disclosed hitherto.
DISCLOSURE INVENTION
An object of the present invention is to provide novel butadiene derivatives and novel pyrrolidine derivatives having no drawback of the above-mentioned conventional antithrombotic agents, which can be administered either orally or parenterally and show an excellent antithrombotic activity. Another object of the present invention is to provide a process for preparing these compounds.
The present inventors have intensively studied and have found a novel butadiene derivative and a novel pyrrolidine derivative showing excellent antithrombotic activities by inhibiting the production of PAI-1, and finally have accomplished the present invention.
That is, the present invention relates to a butadiene derivative of the formula (1-a):
wherein
Ring A is a substituted or unsubstituted heterocyclic group, or a benzene ring which may optionally be substituted by a group selected from a lower alkyl group, an alkoxy group, a nitro group, a hydroxy group, a substituted or unsubstituted amino group and a halogen atom,
Ring B is a substituted or unsubstituted heterocyclic group, or a benzene ring which may optionally be substituted by a group selected from a lower alkoxy group, a lower alkylenedioxy group and a di-lower alkylamino group,
R
1
and R
2
are the same or different, and each are a hydrogen atom or a lower alkyl group,
one of a group: —COR
32
and a group: —COR
42
is a carboxyl group, and the other is a carboxyl group which may optionally be esterified,
provided that both Ring A and Ring B are not simultaneously an unsubstituted benzene ring, and when Ring A is a tri-lower alkoxybenzene ring, then Ring B is a substituted or unsubstituted heterocyclic group, or at least one of R
1
and R
2
is a lower alkyl group, or a pharmaceutically acceptable salt thereof.
The present invention also provides an amidobutadiene derivative of the formula (1-b):
wherein
Ring A is a substituted or unsubstituted heterocyclic group, or a benzene ring which may optionally be substituted by a group selected from a lower alkyl group, an alkoxy group, a nitro group, a hydroxy group, a substituted or unsubstituted amino group and a halogen atom,
Ring B is a substituted or unsubstituted heterocyclic group, or a benzene ring which may optionally be substituted by a group selected from a lower alkoxy group, a lower alkylenedioxy group and a di-lower alkylamino group,
R
1
and R
2
are the same or different, and each are a hydrogen atom or a lower alkyl group,
one of a group: —COR
33
and a group: —COR
43
is an amidated carboxyl group, and the other is a carboxyl group which may optionally be esterified, or an amidated carboxyl group,
provided that both Ring A and Ring B are not simultaneously an unsubstituted benzene ring, and when Ring A is a tri-lower alkoxybenzene ring, then Ring B is a substituted or unsubstituted heterocyclic group, or at least one of R
1
and R
2
is a lower alkyl group, or a pharmaceutically acceptable salt thereof.
The present invention further provides a pyrrolidine derivative of the formula (2):
wherein
Ring A is a substituted or unsubstituted heterocyclic group, or a benzene ring which may optionally be substituted by a group selected from a lower alkyl group, an alkoxy group, a nitro group, a hydroxy group, a substituted or unsubstituted amino group and a halogen atom,
Ring B is a substituted or unsubstituted heterocyclic group, or a benzene ring which may optionally be substituted by a group selected from a lower alkoxy group, a lower alkylenedioxy group and a di-lower alkylamino group,
R
1
and R
2
are the same or different, and each are a hydrogen atom or a lower alkyl group,
R
5
is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted amino group, or a substituted or unsubstituted nitrogen-containing heterocyclic group,
provided that both Ring A and Ring B are not simultaneously an unsubstituted benzene ring, and when Ring A is a tri-lower alkoxybenzene ring, then Ring B is a substituted or unsubstituted heterocyclic group, or at least one of R
1
and R
2
is a lower alkyl group, or a pharmaceutically acceptable salt thereof.
The heterocyclic group for Ring A and Ring B of the butadiene derivative (1-a), the amidobutadiene derivativ

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