Benzene fused heterocyclic derivatives having thromboxane A2...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C514S227500, C514S231200

Reexamination Certificate

active

06407096

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel benzene fused ring derivatives, and a thromboxane A
2
(referred to as “TXA
2
” hereinafter) receptor antagonist comprising one of the compounds as an active component.
BACKGROUND ART
TXA
2
discovered by Samuelsson et al in 1975 has strong platelet aggregating action, vascular smooth muscle contracting action and bronchial smooth muscle contracting action (Proc. Natl. Acad. Sci. U.S.A., 72, 2994 (1975)). On the other hand, as a compound having reverse actions, i.e., strong platelet aggregation inhibiting action and vascular relaxing action, prostaglandin I
2
(PGI
2
) is known (Nature, 263, 663 (1976)). Both compounds are synthesized from arachidonic acid in vivo, and it is said that a balance between TXA
2
and PGI
2
greatly concerns maintenance of the homeostasis of the circulatory system because of the strong actions thereof. Therefore, with the balance shifted to the TXA
2
side, phenomena such as activation of the platelets and subsequent thrombogenesis and vascular contraction occur. This is possibly a factor that causes ischemic heart diseases such as angina pectoris, myocardial infarction, etc., and circulatory diseases such as celebrovascular disorder, nephropathy, etc. It is also thought that TXA
2
concerns bronchial asthma because of its strong bronchial smooth muscle contracting action. Therefore, in order to treat ischemic heart diseases such as angina pectoris, myocardial infarction, etc., circulatory diseases such as celebrovascular disorder, nephropathy, etc., or bronchial asthma or the like, it is thought to be important to return the off-balance state of TXA
2
and PGI
2
to the normal state, and a medicine for inhibiting the action of TXA
2
or a medicine having the action as a PGI
2
receptor agonist is thought to be effective to treat these diseases. As medicines for inhibiting the actions of TXA
2
concerning the occurrence of the above-described diseases, TXA
2
receptor antagonists have been reported so far (Circulation, 81, Suppl I, I-69 (1990), Medicinal Research Reviews, 11, 503 (1991)). However, conventional TXA
2
receptor antagonists exhibit unsatisfactory clinical effects.
An object of the present invention is to provide an excellent TXA
2
receptor antagonist having the action as a PGI
2
receptor agonist.
DISCLOSURE OF INVENTION
The present invention provides benzene fused heterocyclic derivatives represented by the following formula (I):
wherein
A
1
is —CH
2
—, —O—, —S—, or —NR
4
—, wherein R
4
is hydrogen or alkyl having 1 to 5 carbon atoms;
A
2
is —(N—)—CH
2
, —(N—)—CO—, —(CH—)—, or —(C—)═CH—;
A
3
is alkylene having 1 to 4 carbon atoms, alkenylene having 2 to 4 carbon atoms, or alkynylene having 2 to 4 carbon atoms;
A
4
is —S(O)
p
—, —O—, —CH
2
—, —NR
5
—, —NR
5
CO—, or —CONR
5
—, wherein R
5
is hydrogen, alkyl having 1 to 5 carbon atoms, or phenyl (which may be substituted by a group or groups selected from alkyl having 1 to 5 carbon atoms, phenyl, hydroxyl, alkoxy having 1 to 5 carbon atoms, phenoxy, halogen, trifluoromethyl, cyano, nitro, amino, and alkylamino having 1 to 5 carbon atoms), and p is an integer of 0 to 2;
m is an integer of 1 to 3;
R
1
is —X—(CH
2
)
n
COOR
6
wherein X is —O—, —S—, or —CH
2
—, R
6
is hydrogen, alkyl having 1 to 5 carbon atoms, or an atom or group which gives a pharmacologically acceptable salt, and n is an integer of 1 to 3;
R
2
is the following:
(1) —Ar (wherein Ar is phenyl, naphthyl, furyl, or thienyl (wherein phenyl, naphthyl, furyl, or thienyl may be substituted by a group or groups selected from alkyl having 1 to 5 carbon atoms, phenyl, hydroxyl, alkoxy having 1 to 5 carbon atoms, phenoxy, halogen, trifluoromethyl, cyano, nitro, amino, and alkylamino having 1 to 5 carbon atoms); or
(2) alkyl having 1 to 5 carbon atoms, alkenyl having 2 to 5 carbon atoms, or alkynyl having 2 to 5 carbon atoms, wherein alkyl, alkenyl, or alkynyl is substituted by one or two Ar (wherein Ar is defined as the same as the above), and may be further substituted by a group or groups selected from —OH, —CF
3
, and cycloallyl having 3 to 8 carbon atoms);
R
3
is hydrogen, halogen, alkyl having 1 to 5 carbon atoms, or alkoxy having 1 to 5 carbon atoms: and
either or both of A
1
and A
2
contain a hetero atom other than carbon. The present invention also provides a TXA
2
receptor antagonist containing one of the above compounds of the present invention as an active ingredient.
The compounds of the present invention have strong TXA
2
receptor antagonistic action and PGI
2
receptor agonistic action, and are effective as medicines for treating or preventing diseases concerning TXA
2
.
BEST MODE FOR CARRYING OUT THE INVENTION
Of the compounds represented by the above formula (I), compounds represented by the following formula (II) are preferred.
[wherein R
1
, R
2
, R
3
, A
1
, A
2
, A
3
, A
4
and m are defined as the same as the above].
Although R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, A
1
, A
2
, A
3
, A
4
, X, m, n, and Ar in formula (I) or (II) are defined as described above, these groups are described in further detail below.
R
1
is —X—(CH
2
)
n
—COOR
6
(wherein X is —O—, —S—, or —CH
2
—, R
6
is hydrogen, alkyl having 1 to 5 carbon atoms, or an atom or group which gives a pharmacologically acceptable salt, and n is an integer of 1 to 3). X is particularly preferably —O—, and n is preferably 1 or 2, more preferably 1.
Examples of alkyl R
6
having 1 to 5 carbon atoms include methyl, ethyl, propyl, butyl, pentyl, isopropyl, sec-butyl, t-butyl, isobutyl, 1-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, and the like.
Examples of pharmacologically acceptable cations of R
6
include metal cations, ammonium, amine cations, and quaternary ammonium cations. Preferred examples of metal cations include cations derived from alkali metals, for example, such as lithium, sodium, and potassium, alkali earth metals, for example, such as magnesium and calcium. Of course, the present invention include cations of other metals, for example, such as aluminum, zinc, and iron.
Pharmacologically acceptable amine cations are derived from primary, secondary or tertiary amines. Examples of suitable amines include methylamine, dimethylamine, triethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, &agr;-phenylethylamine, &bgr;-phenylethylamine, ethylenediamine, diethylenetriamine, similar aliphatic, alicyclic or heterocyclic amines having up to 18 carbon atoms, for example, such as 1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrolidine, 2-methylpyrolidine, 4-dimethylpiperazine, 2-methylpiperidine, and the like, amines containing water-soluble or hydrophilic groups, for example, such as mono-, di-, or tri-ethanolamine, N-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol, tris(hydroxymethyl)aminomethane, N-phenylethanolamine, N-(p-aminophenyl)diethanolamine, galactamine, N-methylglucamine, N-methylglucosamine, ephedrine, phenylephedrine, epinephrine, procaine, and the like, basic amino acids such as lysine, alginine, and the like.
R
2
is preferably alkyl having 1 to 5 carbon atoms, alkenyl having 2 to 5 carbon atoms, or alkynyl having 2 to 5 carbon atoms (alkyl, alkenyl, or alkynyl is substituted by an one or two Ar (Ar is phenyl, naphthyl, furyl, or thienyl (phenyl, naphthyl, furyl, or thienyl may be substituted by a group selected from alkyl having 1 to 5 carbon atoms, phenyl, hydroxyl, alkoxy having 1 to 5 carbon atoms, phenoxy, halogen, trifluoromethyl, cyano, nitro, amino, and alkylamino having 1 to 5 carbon atoms)), and may be further substituted by a group selected from —OH, —CF
3
, and cycloalkyl having 3 to 8 carbon atoms), more preferably alkyl having 1 to 5 carbon atoms, which is substituted by one or two Ar (Ar is defined as the same as the above). Particularly, alkyl having 1 to 5 carbon atoms, which is substituted by one or two phenyl groups (which may be substituted by a group selected from alky

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