Compounds having [2.2.1] bicyclo skeleton

Details Compounds having [2.2.1] bicyclo skeleton Compounds having [2.2.1] bicyclo skeleton

2000-02-14

2001-05-01

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...

C514S445000, C514S448000, C548S492000, C549S051000, C549S055000, C549S057000, C549S064000, C549S072000, C549S471000

Reexamination Certificate

active

06225336

ABSTRACT:

TECHNICAL FIELD
This invention relates to compounds having a [2.2.1] bicyclo skeleton, and pharmaceutical compositions containing them antagonistic to both of thromboxane A
2
and prostagrandin D
2
.
BACKGROUND ART
Some compounds having a [2.2.1] bicyclo skeleton similar to the compounds of the present invention have been described in the Japanese Patent Publication (Kokoku) No. 53295/1991. In this publication, it is described that the compounds are useful as thromboxane A
2
(TXA
2
) antagonists. TXA
2
has been known to have various activities such as platelet aggregation, thrombogenesis, etc. The TXA
2
antagonists which antagonize TXA
2
have, therefore, been considered to be useful as anti-thrombotic agents as well as medicines for treating myocardinal infarction or asthma.
Further, the other compounds having a [2.2.] bicyclo skeleton similar to the compounds of the present invention have been described in WO97/00853. In this publication, it is described that the compounds are useful as prostagrandin D
2
(PGD
2
) antagonists. PGD
2
is a major prostanoid released from mast cells in which it is produced through PGG
2
and PGH
2
from arachidonic acid by the action of cyclooxygenase activated by immunological or unimmunological stimulation. PGD
2
has various potent physiological and pathological activities. For example, PGD
2
can cause strong contraction of smooth muscle of bronchus to lead to bronchial asthma, and in a systemic allergic state, it dilates the peripheral vessels to cause an anaphylactic shook. Accordingly, PGD
2
antagonists are useful for the improvement of conditions caused by excessive production of PGD
2
, particularly as drugs for treating diseases involved with mast cell dysfunction, for example, systemic mastocytosis and disorder of systemic mast cell activation as well as tracheal contraction. asthma, allergic rhinitis, allergic conjunctivitis, urticaria, atopic dermatitis, alimentary allergy, cerebrovascular disorder, ischemic reperfusion injury, and inflammation.
As shown above, PGD
2
antagonists have quite a different character from that of TXA
2
antagonists in the site of action, mechanism of action, and indication thereof.
On the other hand, TXA
2
and PGD
2
dual antagonistic compounds could be useful as therapeutic agents treating various diseases caused by TXA
2
or PGD2. For example, it is known that TXA
2
has a strong activity for tracheal contraction and respiratory anaphilaxia, and recently known that PGD
2
has an activity for infiltration of eosionophils. From these comprehension, TXA
2
and PGD
2
are thought to be one of causative substances of the pathopoiesis and advance of asthma, thus the dual antagonistic compounds are expected to be possible more useful agents for treating asthma than each of the known antagonists. Further, in case of allergic rhinitis, it is recognized that TXA
2
and PGD
2
cause the swelling of nasal mucosa through the aggravation of vascular permeability, and PGD
2
induces the nasal blockage through the enlargement of vascular volume. It is therefore expected to develop drugs having a dual antagonistic activity.
As shown above, the compounds having a dual antagonistic activity are expected to be used for many indications and to exhibit new excellent therapeutic effects which have not yet been.
DISCLOSURE OF INVENTION
The present inventors have studied intensively to develop PGD
2
receptor antagonists (blockers) specific to the PGD
2
receptor, and found out a new series of compounds which are useful not only as PGD
2
receptor antagonists but also as TXA
2
receptor antagonists and are of high safety, whereby accomplished the present invention.
Accordingly, the present invention provides a compound of the formula (I):
wherein R is an optionally substituted monocyclic or condensed heterocycle, provided that R is not an optionally substituted dibenzofuryl, X is hydrogen or an alkyl, and the double bond has E configuration or Z configuration, pharmaceutically acceptable salt thereof, or hydrate thereof, and a TXA
2
and PGD
2
antagonistic pharmaceutical composition comprising them, preferably a pharmaceutical composition for treating asthma or nasal blockage comprising them.
Best Mode for Carrying Out the Invention
In the above formula, “optionally substituted monocyclic or condensed heterocycle” for R means a 5-7 membered ring containing one or more hetero atoms selected from the group consisting of oxygen, sulfur, and nitrogen atoms in the ring, or such a heterocycle as condensed with one or more carbocycle or other heterocycle and both rings may have a bond and substituent(s) at any substitutable position(s), provided that R does not include an optionally substituted dibenzofuryl.
The term “carbocycle or other heterocycle” means a 5-7 membered ring which may have one or more hetero atoms selected from the group consisting of oxygen, sulfur, and nitrogen atoms in the ring, or a condensed ring consisting of two or more of such rings.
Examples of “monocyclic or condensed heterocycle” include pyrrolidinyl (e.g., 2-pyrrolidinyl), pyrrolyl (e.g., 2-pyrrolyl, 3-pyrrolyl), piperidinyl (e.g., 3-piperidinyl, 4-piperidinyl), pyridyl (e.g., 3-pyridyl, 4-pyridyl), pyrazolyl (e.g., 3-pyrazolyl), imidazolyl (e.g., 2-imidazolyl, 3-imidazolyl), piperazinyl (e.g., 2-piperazinyl), pyrimidinyl (e.g., 4-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), indolyl (e.g., 2-indolyl, 3-indolyl), carbazolyl (e.g., 3-carbazolyl), benzoimidazolyl (e.g., 2-benzoimidazolyl), indazolyl (e.g., 3-indazolyl), quinolyl (e.g., 8-quinolyl), isoquinolyl (e.g., 3-isoquinolyl), tetrahydrofuryl (e.g., 3-tetrahydrofuryl), furyl (e.g., 2-furyl, 3-furyl), benzofuryl (e.g., 2-benzofuryl, 3-benzofuryl), tetrahydrothienyl (e.g., 2-tetrahydrothienyl, 3-tetrahydrothienyl), thienyl (e.g., 2-thienyl, 3-thienyl), benzothienyl (e.g., benzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl), dibenzothienyl (e.g., 2-dibenzothienyl, 3-dibenzothienyl), tetrahydrodibenzothienyl (e.g., 1,2,3,4-tetrahydrodibenzothienyl), naphthothienyl (e.g., naphtho[2,3-b]thienyl, naphtho[1,2-b]thienyl), oxazolyl (e.g., 2-oxazolyl), isoxazolyl (e.g., 4-isoxazolyl), thiazolyl e.g., 2-thiazolyl, 4-thiazolyl), isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl), and the like.
The preferable embodiment of “monocyclic or condensed heterocycle” is an aromatic monocyclic or condensed heterocycle such as pyrrolyl (e.g., 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 3-pyridyl, 4-pyridyl), pyrazolyl (e.g., 3-pyrazolyl), imidazolyl (e.g., 2-imidazolyl, 3-imidazolyl), pyrimidinyl (e.g., 4-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), indolyl (e.g., 2-indolyl, 3-indolyl), carbazolyl (e.g., 3-carbazolyl), benzoimidazolyl (e.g., 2-benzoimidazolyl), indazolyl (e.g., 3-indazolyl), quinolyl (e.g., 8-quinolyl), isoquinolyl (e.g., 3-isoquinolyl), furyl (e.g., 2-furyl, 3-furyl), benzofuryl (e.g., 2-benzofuryl, 3-benzofuryl), thienyl (e.g., 2-thienyl, 3-thienyl), benzothienyl (e.g., benzo [b]thiophen-2-yl, benzo[b]thiophen-3-yl), dibenzothienyl (e.g., 2-dibenzothienyl, 3-dibenzothienyl), tetrabydrodibenzothienyl (e.g., 1,2,3,4-tetrahydrodibenzothienyl), naphthothienyl (e.g., naphtho[2,3-b]thienyl, naphtho[1,2-b]thienyl), oxazolyl (e.g., 2-oxazolyl), isoxazolyl (e.g., 4-isoxazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl), isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl), and the like.
The present invention includes a compound of the formula (I) wherein R is an optionally substituted monocyclic or condensed heterocycle containing only a sulfur atom(s) as hetero atom.
“Optionally substituted monocyclic or condensed heterocycle containing only a sulfur atom(s) as hetero atom” includes the following groups which are optionally substituted:
The substituents of “optionally substituted monocyclic or condensed heterocycle” include a substituent selected from an alkyl an alkenyl, an acyl, an alkoxy, an alkylthio, an acyloxy, hydroxy, a halogen, nitro, and a substituted or unsubstituted amino. The substituent may

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