Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2002-10-07
2004-05-18
Powers, Flona T. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S090000, C514S099000, C514S119000, C544S157000, C546S022000, C549S218000, C558S170000, C562S010000, C562S015000
Reexamination Certificate
active
06737416
ABSTRACT:
TECHNICAL FIELD
The present invention relates to phosphonic acid derivatives having inhibitory activity against carboxypeptidase B, and to pharmaceutical compositions which comprise at least one of said derivative as an active ingredient and are useful for therapeutic and preventive treatment of various thrombosis, diseases caused by a vascular disorder, and organ disorders resulting from reduction of fibrinolysis.
BACKGROUND ART
Numbers of patients suffering from circulatory diseases have been increasing due to growth of aged population and changes in social circumstances. Among the aforementioned diseases, those caused by thrombus such as cerebral infarction and myocardial infarction show an increasing tendency. For these diseases, various antithrombotic treatments have been clinically applied.
The antithrombotic treatments are classified basically into anticoagulant, antiplatelet, and thrombolytic treatments. Among them, the thrombolytic treatments involve the lysis of formed thrombus, per se. In that sense, they are considered as more reasonable remedies for therapeutic treatment of thrombosis than the anticoagulant treatments, which prevent generation and development of secondary thrombus. At present, enzymatic agents such as urokinase and plasminogen activator have been clinically used as thrombolytic agents, and their clinical effectiveness has been recognized as one of therapeutic treatments for patients suffering from thrombosis.
Detailed mechanisms as to fibrinolysis have been being revealed with the progress of biochemical researches. A factor, which was reported as a fibrinogenolysis-inhibitory factor TAFI (thrombin activatable fibrinolysis inhibitor factor) activated by stimulation of coagulation, was revealed to be identical to plasma carboxypeptidase B (J. Biol. Chem. 14477(1995)). It was elucidated that plasma carboxypeptidase B inhibits fibrinolysis by interrupting plasminogen, which is a fibrinolytic enzyme mainly acting in the lysis of thrombus (fibrin), from binding to thrombi (J. Clin. Invest., 2534(1995)., J. Biol. Chem., 16603(1996), Thromb. Haemost., 829(1998), Circulation, 1328(1996)). Accordingly, plasma carboxypeptidase B inhibitors are expected to be used as agents for therapeutic and preventive treatments of various thromboses, which are antithrombotic agents based on enhancement of the lysis of thrombi.
As substances inhibiting pancreatic carboxypeptidase B, GEMSA (Biochemistry, 401(1978)., Arch. Biochem. Biophys., 487(1979)), SQ24798 (Biochemistry, 1427(1979)) and the like have been known so far.
Plasminogen activators and the like, which have been clinically used as thrombolytic agents at present, are not fully satisfactory from a clinical therapeutic viewpoint as their low safety such as hemorrhagic adverse effects and poor pharmacokinetics such as a short half-life, although their thrombolytic activities in an acute stage after thrombus formation are reliable.
DISCLOSURE OF THE INVENTION
In order to provide a thrombolytic agent having higher safety, the inventors of the present invention conducted researches to find a compound having inhibitory activity against plasma carboxypeptidase B. As a result, they found that phosphonic acid derivatives have potent inhibitory activity against carboxypeptidase B.
The present invention thus provide a compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof:
wherein R
1
represents hydrogen atom, an alkyl group, a substituted alkyl group, an alkoxyl group, a substituted alkoxyl group, amino group, a substituted amino group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, or a substituted heterocyclic group;
R
2
and R
3
may be the same or different and independently represent hydrogen atom, an alkyl group, a substituted alkyl group, an alkoxyl group, a substituted alkoxyl group, amino group, a substituted amino group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, or a substituted heterocyclic group, or R
2
and R
3
may form a 5 to 7 membered carbon-ring together with the carbon atom to which they bind;
X represents —CH
2
—, —O—, or —NH—;
A represents a group of the following formula (II):
[in which R
7
and R
8
may be the same or different and independently represent hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, carbamoyl group, a substituted carbamoyl group, or amidino group;
R
9
and R
10
may be the same or different and independently represent hydrogen atom, a halogen atom, hydroxyl group, phenyl group, an alkyl group, an alkoxyl group, an aryloxy group, an acyl group, carboxyl group, an alkoxycarbonyl group, carbamoyl group, a substituted carbamoyl group, amino group, a substituted amino group, nitro group, —SR
11
group (R
11
represents an alkyl group, phenyl group, or a substituted phenyl group), —SOR
12
group (R
12
represents an alkyl group, phenyl group, a substituted phenyl group, an alkoxyl group, an aryloxy group, amino group, or a substituted amino group), or —SO
2
R
13
group (R
13
represents an alkyl group, phenyl group, a substituted phenyl group, an alkoxyl group, an aryloxy group, amino group, or a substituted amino group);
m represents an integer of from 1 to 8; and
—(C)
m
— represents a saturated or unsaturated carbon chain], or
A represents a group of the following formula (III):
[in which R
7
and R
8
may be the same or different and independently represent hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, carbamoyl group, a substituted carbamoyl group, or amidino group;
R
24
, R
25
, R
26
and R
27
may be the same or different and independently represent hydrogen atom, a halogen atom, hydroxyl group, an alkyl group, amino group, or a substituted amino group;
p and q independently represent an integer of from 0 to 2;
—(C)
p
— and —(C)
q
— independently represent single bond, or a saturated or unsaturated carbon chain; and
B represents a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, or a substituted heterocyclic group], or
A represents a group of the following formula (TV):
[in which R
20
represents hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group, carbamoyl group, an alkylcarbamoyl group, or amidino group;
R
28
and R
29
may be the same or different and independently represent hydrogen atom, a halogen atom, hydroxyl group, an alkyl group, amino group, or an alkylamino group;
n and o independently represent an integer of from 0 to 5;
r represents an integer of from 0 to 4;
—(C)
r
— independently represents single bond, or a saturated or unsaturated carbon chain; and
Y represents CH or nitrogen atom], or
A represents a group of the following formula (XIV):
[in which R
7
and R
8
may be the same or different and independently represent hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, carbamoyl group, a substituted carbamoyl group, or amidino group;
R
30
, R
31
, R
32
and R
33
may be the same or different and independently represent hydrogen atom, a halogen atom, hydroxyl group, an alkyl group, oxo group, amino group, or an alkylamino group;
s represents an integer of from 0 to 3;
t represents an integer of from 1 to 3;
—(C)
s
— and —(C)
t
— independently represent single bond, or a saturated or unsaturated carbon chain; and
V represents —O— or —NH—]; and,
E represents hydrogen atom, or —CH
2
CH
2
— to form together with A a piperidine ring group or a N-substituted piperidine ring group.
The present invention also provides a medicament which comprises as an active ingredient a substance selected from the group consisting of the compound represented by the aforementioned general formula (I) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof. According to a preferred embodiment, there is provided the aforementioned medicament in the form of a pharmaceut
Fushihara Kenichi
Kanemoto Kenichi
Kikuchi Chika
Matsushima Tetsuya
Satoh Eriko
Greenblum & Bernstein P.L.C.
Meiji Seika Kaisha Ltd.
Powers Flona T.
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