Therapeutic method for thrombocytopathy treatment

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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Reexamination Certificate

active

06201015

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a platelet function increment agent and a therapeutic method for treating thrombocytopathy with a prostaglandin I
2
derivative.
BACKGROUND ART
Diseases which exhibit hemorrhagic diathesis due to platelet function incline even when the platelet count is within a normal range, are generically called thrombocytopathy. Such thrombocytopathy is classified into congenital thrombocytopathy and acquired thrombocytopathy. Congenital thrombocytopathy is further classified into abnormalities in adhesion, aggregation and releasing based upon the species of the abnormalities.
Acquired thrombocytopathy has a higher frequency than that of congenital thrombocytopathy and, for example, occurs with a variety of diseases such as chronic renal failure, liver diseases and blood disorders, or is attributed to extracorporeal circulation or use of drugs. Further, administration of any of the aforementioned drugs to such a disease exhibiting hemorrhagic diathesis enhances hemorrhagic diathesis and hence is dangerous. Therefore, prevention of such diseases, and of hemorrhagic diathesis due to the use of a drug, is required.
To these congenital platelet abnormalities in release and acquired thrombocytopathy, DDAVP (1-diamino 8-D-arginine vasopressin) and other agents are applied, but these drugs may induce arterial thrombosis and/or hyponatremia as adverse drug reactions. In an emergency, platelet transfusion may be conducted, but this treatment may invite a serious adverse reaction or side effect due to production of antibodies to platelets or lymphocytes.
Meanwhile, prostaglandin I
2
(PGI
2
, prostacyclin, referred to in Nature, 1976;268:688) is known as a substance having strong antiplatelet activity and telangiectatic activity. Since this substance has an unstable exo-enol structure, it is extremely unstable even in a neutral aqueous solution and is converted into 6-oxo-PGF
1a
which has almost no physiological activity (bioactivity). The instability of PGI
2
is markedly disadvantageous when this compound is intended to be used as a drug. Further disadvantageously, PGI
2
is unstable in vivo and its activity is not long-lasting. As a compound in which these defects are markedly improved, a PGI
2
derivative having a skeleton obtained by converting an exo-enol moiety which characterizes PGI
2
to an inter-m-phenylene structure, i.e., a 4,8-inter-m-phenylene-prostaglandin I
2
derivative is described in the specifications of Japanese Examined Patent Publication No. 6-62599 and the like. This PGI
2
derivative has already been known to have antiplatelet activity, vasodilating activity, gastric acid inhibitory activity, bronchial muscle relaxant activity, uterine contraction activity and other activities. Its platelet function increment activity has, however, not been known, and its usefulness as a platelet function increment agent has been first found by us.
In addition, there are chemically stable PGI
2
derivatives having modified skeletons obtained by converting the structure to a carbacyclin structure or an isocarbacyclin structure. These PGI
2
derivatives, however, have not yet been reported to intensify or enhance platelet function in the presence of a thromboxane A
2
agonist (hereinafter referred to as a “TXA
2
”) antagonist, though they have antiplatelet activities. Hence, it has not been known that these derivatives exhibit platelet function increasing or enhancing activity without the intermediation of TXA
2
receptors.
It is an object of the present invention to provide a platelet function increment agent which by itself does not induce platelet aggregation but enhances the function of platelets sufficiently, and a therapeutic method for treatment of thrombocytopathy.
SUMMARY OF THE INVENTION
The present invention relates to a platelet function increment agent comprising a prostaglandin I
2
derivative as an active ingredient, and to a therapeutic method for thrombocytopathy using the same.
BEST MODE FOR CARRYING OUT THE INVENTION
The prostaglandin I
2
derivative used in the present invention includes, but is not limited to, carbacyclin, isocarbacyclin, meta-phenylene-form prostaglandin I
2
derivatives and the like. Preferably, a meta-phenylene-form prostaglandin I
2
derivative is used, and particularly preferably, a 4,8-inter-m-phenylene-prostaglandin derivative having the following general formula (I) (hereinafter referred to as “the present prostaglandin I
2
derivative”) or its pharmacologically acceptable salt.
[wherein R
1
is,
(A) COOR
2
wherein R
2
is,
1) a hydrogen or a pharmacologically acceptable cation,
2) a straight-chain alkyl having 1 to 12 carbon atoms or a branched alkyl having 3 to 14 carbon atoms,
3) —Z—R
3
wherein Z is a balance bond, or a straight-chain or branched alkylene shown by C
t
H
2t
, t represents an integer from 1 to 6, R
3
is a cycloalkyl having 3 to 12 carbon atoms or a substituted cycloalkyl having 3 to 12 carbon atoms which is substituted with 1 to 3 substituents R
4
, where R
4
is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms,
4) —(CH
2
CH
2
O)
n
CH
3
wherein n is an integer from 1 to 5,
5) —Z—Ar
1
wherein Z has the same meaning as defined above, Ar
1
is phenyl, &agr;-naphthyl, &bgr;-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, &agr;-furyl, &bgr;-furyl, &agr;-thienyl, &bgr;-thienyl or a substituted phenyl (wherein the substituent is at least one chlorine, bromine, fluorine, iodine, trifluoromethyl, an alkyl having 1 to 4 carbon atoms, nitro, cyano, methoxy, phenyl, phenoxy, p-acetamidebezamide, —CH═N—NH—C(═O)—NH
2
, —NH—C(═O)—Ph, —NH—C(═O)—CH
3
or —NH—C(═O)—NH
2
),
6) —C
t
H
2t
COOR
4
wherein C
t
H
2t
and R
4
have the same meanings as defined above,
7) —C
t
H
2t
N(R
4
)
2
wherein C
t
H
2t
and R
4
have the same meanings as defined above,
8) —CH(R
5
)—C(═O)—R
6
wherein R
5
is a hydrogen or benzoyl, R
6
is phenyl, p-bromophenyl, p-chlorophenyl, p-biphenyl, p-nitrophenyl, p-benzamidephenyl or 2-naphthyl,
9) C
p
H
2p
—W—R
7
wherein W is —CH═CH—, —CH═CR
7
— or —C≡C—, R
7
is a hydrogen, or a straight-chain or branched alkyl or aralkyl each having 1 to 30 carbon atoms, p is an integer from 1 to 5, or,
10) —CH(CH
2
OR
8
)
2
wherein R
8
is an alkyl or acyl each having 1 to 30 carbon atoms,
(B) —CH
2
OH
(C) —C(═O)N(R
9
)
2
wherein R
9
is a hydrogen, a straight-chain alkyl having 1 to 12 carbon atoms, a branched alkyl having 3 to 12 carbon atoms, a cycloalkyl having 3 to 12 carbon atoms, a cycloalkylalkylene having 4 to 13 carbon atoms, phenyl, a substituted phenyl (wherein the substituent has the same meaning as defined in the above item (A) 5)), an aralkyl having 7 to 12 carbon atoms or —SO
2
R
10
, where R
10
is an alkyl having 1 to 10 carbon atoms, a cycloalkyl having 3 to 12 carbon atoms, phenyl, a substituted phenyl (wherein the substituent has the same meaning as defined in the above item (A) 5)) or an aralkyl having 7 to 12 carbon atoms, and two of the substituents R
9
may be the same or different provided that when one is —SO
2
R
10
, the other is not —SO
2
R
10
, or,
(D) —CH
2
OTHP (where THP is a tetrahydropyranyl group);
A is,
1) —(CH
2
)
m

2) —CH═CH—CH
2

3) —CH
2
—CH═CH—
4) —CH
2
—O—CH
2

5) —CH═CH—
6) —O—CH
2
— or
7) —C≡C—
wherein m is an integer of 1 or 2, Y is a hydrogen, an alkyl having 1 to 4 carbon atoms, chlorine, bromine, fluorine, formyl, methoxy or nitro;
B is,
—X—C(R
11
)(R
12
)OR
13
 wherein R
11
is a hydrogen or an alkyl having 1 to 4 carbon atoms, R
13
is a hydrogen, an acyl having 1 to 14 carbon atoms, an aroyl having 6 to 15 carbon atoms, tetrahydropyranyl, tetrahydrofuranyl, 1-ethoxyethyl or t-butyl;
X is,
1) —CH
2
—CH
2

2) —CH═CH—
3) —C≡C—,
R
12
is,
1) a straight-chain alkyl having 1 to 12 carbon atoms, a branched alkyl having 3 to 14 carbon atoms or,
2) —Z—Ar
2
wherein Z has the same meaning as defined above, Ar
2
is phenyl, &agr;-naphthyl, &bgr;-naphthyl, or a phenyl substituted with at least one chlorine, bromine, fluorine, iodine, tri

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