Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-01
2003-04-29
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S372000, C514S378000, C514S382000, C514S383000, C514S444000, C514S460000, C546S284100, C548S134000, C548S214000, C548S247000, C548S252000, C548S253000, C548S266400, C054S069000, C054S050000, C054S050000
Reexamination Certificate
active
06555559
ABSTRACT:
This application is a 371 of PCT/JP99/05854, with an international filing date of Oct. 22, 1999, and claims priority of JP 10-320014, filed Oct. 23, 1998.
TECHNICAL FIELD
The present invention relates to novel prostaglandin I
2
(abbreviated to “PGI
2
” hereinafter) derivatives and application of the derivatives. Particularly, the present invention relates to novel 5,6,7-trinor-4,8-inter-m-phenylene PGI
2
derivatives useful for medicines, and medical application thereof.
BACKGROUND ART
PGI
2
(prostacyclin) is a compound found by J. R. Vane et al in 1976, which is a substance biosynthesized in the arterial wall from arachidonic acid through endoperoxide (PGH
2
or PGG
2
) and which has a strong platelet aggregation inhibiting effect, gastric acid secretion inhibiting effect, and dilation of the peripheral vascular system. However, PGI
2
which has an unstable exo-enol structure is extremely unstable even in neutral aqueous solution and is subjected to conversion to 6-oxo PGF
1&agr;
which has little physiological effect. The unstableness of PGI
2
causes a great fault in an attempt to use this compound for medicines. PGI
2
is also unstable in vivo, and has the fault that the physiological effects are nonpersistent.
On the other hand, the inventors have achieved a series of inventions relating to stable PGI
2
derivatives having a skeleton in which the structure of an exo-enol ether moiety which causes the unstableness of PGI
2
, is changed to inter-m-phenylene (refer to Ohno et at., Japanese Examined Patent Publication Nos. 59-31510, 1-53672, 2-12226, 2-57548, 3-69909, 6-62599, and 7-5582).
Prostaglandin derivatives are used as therapy of ulcers or the like in the digestive area because they are defensive factor potentiators for increasing mucosal blood flow and mucous secretion. However, it is unknown that the PGI
2
derivatives have an antibacterial effect on Helicobacter bacteria such as
Helicobacter pylori
, which attract attention as a pathogenic factor of upper gastric diseases such as chronic gastritis, gastroduodenal ulcer, gastric cancer, lymphoma, etc.
Diseases exhibiting a bleeding tendency due to platelet hypofunction in spite of the normal platelet count are generically named platelet functional disorders. The platelet functional disorders are divided into congenital disorders and acquired disorders. The congenital platelet functional disorders are divided into disorders of platelet adhesion, aggregation and releasing dysfunction.
On the other hand, the acquired platelet functional disorders occur with greater frequency than the congenital disorders, and, for example, the acquired disorders are accompanied with various diseases such as chronic renal failure, liver diseases, blood diseases, and the like, and are caused by extracorporeal circulation or medicines. Furthermore, administration of such medicines for diseases exhibiting the bleeding tendency is dangerous because the bleeding tendency is prolonged. Therefore, it is necessary to prevent the bleeding tendency caused by these diseases and the use of medicines.
Although DDAVP (1-deamino-8-arginine vasopressin) or the like is used for the congenital disorders of platelet releasing dysfunction and the acquired platelet functional disorders, in some cases, arterial thrombosis or hyponatremia occurs as a side effect. Although, in case of emergency, platelet transfusion is conducted, a serious side effect occurs due to the production of antibodies against platelets and lymphocytes.
On the other hand, the inventors have reported that PGI
2
derivatives have the effect to potentiate the platelet function without through thromboxane A
2
(abbreviated to “TXA
2
” hereinafter) receptors (Miyamdto et al., WO98/11899).
Also the prostaglandin derivatives are known to be useful as medicines for accelerating cervical ripening in the gynecological area.
During pregnancy, the cervical canal is strongly closed for pregnancy continuation up to late pregnancy, for preventing abortion and premature delivery. on the other hand, at the 36th week or later in pregnancy, softening of the cervical canal proceeds for facilitating fetus expulsion, accompanied by dilation of the cervical opening and shortening of the cervical canal length (effacement). This is a phenomenon referred to as “cervical ripening”. The cervical ripening is an important factor which controls the process of fatal delivery. Therefore, in order to safely and normally extract a fetus, it is necessary to sufficiently ripen the cervical canal as a preparatory step for delivery before the start of contraction (pains) of the myometrium.
As a medicine for accelerating ripening of the cervical canal, i.e., a cervical ripening agent, prostaglandin E
2
(abbreviated to “PGE
2
” hereinafter) is clinically used. However, PGE
2
also has an oxytocic action, and thus has the problem of the possibility of causing excessively contraction of the myometrium. On the other hand, the inventors have reported that PGI
2
derivatives are useful as cervical ripening agents without causing the oxytocic action (Ochi et al., WO99/13881).
However, conventional PGI
2
derivatives cannot be said to sufficiently remove side effects such as reduction of the blood pressure, etc., and thus the invention of a new PGI
2
derivative is in demand.
An object of the present invention is to provide novel PGI
2
derivatives having excellent stability in vivo, a strong medical effect, and a little side effect, and medicines each comprising any of the PGI
2
derivatives as an active ingredient.
DISCLOSURE OF INVENTION
As a result of intensive research, the inventors succeeded in obtaining novel PGI
2
derivatives, and found that these PGI
2
derivatives have an excellent anti Helicobacter action, platelet function potentiating effect or cervical ripening effect, and the little action to reduce blood pressure as a side effect, resulting in the achievement of the present invention.
Namely, the present invention provides 5,6,7-trinor-4,8-inter-m-phenylene PGI
2
derivatives represented by the following formula (I):
[wherein R
1
represents the following:
wherein R
2
is hydrogen, straight chain alkyl having 1 to 4 carbon atoms, branched alkyl having 3 or 4 carbon atoms, trifluoromethyl, —C(═O)—R
4
or —C(═O)—O—R
4
wherein R
4
is straight chain alkyl having 1 to 12 carbon atoms, branched alkyl having 3 to 14 carbon atoms, cycloalkyl having 3 to 12 carbon atoms, aralkyl having 7 to 12 carbon atoms, phenyl, or substituted phenyl (wherein a substituent is at least one of fluorine, chlorine, bromine, iodine, trifluoromethyl, alkyl having 1 to 4 carbon atoms, nitro, cyano, methoxy, phenyl, phenoxy, p-acetamidebenzamide, —CH═N—NH—C(═O)—NH
2
, —NH—C(═O)—Ph, —NH—C(═O)—CH
3
, or —NH—C(═O)—NH
2
), two R
2
groups may be the same or different, and R
3
is hydrogen, alkyl having 1 to 4 carbon atoms, acyl having 1 to 4 carbon atoms, aroyl having 7 to 16 carbon atoms, aralkyl having 7 to 16 carbon atoms, tetrahydropyranyl, tetrahydrofuranyl, 1-ethoxyethyl, allyl, tert-butyl, or tert-butyldimethylsilyl;
(B) —COOR
5
wherein R
5
is:
1) hydrogen or a pharmacologically acceptable cation;
2) straight chain alkyl having 1 to 12 carbon atoms, or branched alkyl having 3 to 14 carbon atoms;
3) —Z—R
6
wherein Z is a valence bond or straight chain or branched alkylene represented by C
t
H
2t
wherein t represents an integer of 1 to 6, and R
6
is cycloalkyl having 3 to 12 carbon atoms or substituted cycloalkyl having 3 to 12 carbon atoms substituted by 1 to 3 R
7
, R
7
is hydrogen or alkyl having 1 to 4 carbon atoms;
4) —(CH
2
CH
2
O)
n
CH
3
wherein n is an integer of 1 to 5;
5) —Z—Ar
1
wherein Z is defined as the same as the above, and Ar
1
is phenyl, &agr;-naphthyl, &bgr;-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, &agr;-furyl, &bgr;-furyl, &agr;-thienyl, &bgr;-thienyl or substituted phenyl (wherein a substituent is the same as the substituent defined for the substituted phenyl);
6) —C
t
H
2t
COOR
7
wherein t and R
7
are defined as the same as the above;
7) —C
t
H
2t
N(R
7
)
Hatakeyama Hitoshi
Hirano Noriyuki
Ishigaki Takeshi
Mori Takeshi
Wakita Hisanori
Dentz Bernard
Schnader Harrison Segal & Lewis LLP
Toray Industries Inc.
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