Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1989-01-11
1990-10-02
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514220, 540564, A61K 3155, C07D24324
Patent
active
049607707
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to pharmaceutically useful and novel thieno(triazolo)diazepine compounds which have coronary vasodilating activity, vertebral blood flow increasing activity, calmodulin inhibitory activity, calcium/calmodulin dependent phosphodiesterase inhibitory activity, red cell deformability improving activity and/or antagonistic activity on platelet activating factor (hereinunder referred to as PAF), and pharmaceutically acceptable acid addition salts thereof, and pharmaceutical uses thereof.
BACKGROUND ART
Japanese Patent Application Publication (Kokoku) Nos. 49-40000 and 49-40238 disclose that certain thieno[2,3-e]1,4-diazepine derivatives possess activities against the central nervous system such as antianxiety or anticonvulsant activities, and Japanese Patent Application Publication (Kokai) No. 61-87623 discloses that the similar compounds exhibit antagonistic activity on PAF.
Furthermore, certain thienotriazolodiazepine compounds are known to exhibit activities against the central nervous system such as antianxiety or anticonvulsant activities as disclosed in, for example, Arzneim. Forsch. (Drug Res.) Vol. 28(II), p. 1165 (1978). Japanese Patent Application Publication (Kokai) No. 61-87684 and so on also disclose that the similar kinds of compounds possess antagonistic activity on PAF.
However, the several kinds of compounds explicitly disclosed in the column of pharmacological experiments of the above Japanese Patent Application Publication (Kokai) No. 61-87684 are not desirable as drugs for treatment of various PAF-induced diseases because they have excellent antianxiety activities and their activities against the central nervous system are very potent. Therefore, it has been desired to provide more useful compounds in view of the separation from the effect on the central nervous system, the reinforcement of antagonistic activity on PAF, the manifestation of activity by oral administration or the duration of activity.
It is also recognized that research and development of effective drugs against various circulatory diseases are matter of urgent necessity because of the recent increase of mortality caused by such diseases However, these preceding thienotriazolodiazepine compounds are not known to exhibit useful direct activity on circulatory systems except antagonistic activity on PAF-induced action.
DISCLOSURE OF INVENTION
The present inventors have made intensive investigations in order to develop compounds which exhibit less activity against the central nervous system, but which possess potent antagonistic activity on PAF show also effectiveness by oral administration and long-lasting, and furthermore other useful activities. As a result of such investigations, the present inventors have surprisingly found that certain thienotriazolodiazepine compounds and thienodiazepine compounds, starting materials thereof, which are not definitely disclosed in the above Japanese Patent Application Publication (Kokai) No. 61-87684 possess potent coronary vasodilating activity, vertebral blood flow increasing activity, calmodulin inhibitory activity, calcium/calmodulin dependent phosphodiesterase inhibitory activity and red cell deformability improving activity and are useful for the treatment of heart failure, ischemic heart disease, cerebral circulatory disturbance or various diseases induced by them. Furthermore, the present inventors have found that the compounds exhibit excellent antagonistic activity on PAF compared to those preceeding compounds and substantially have no activity against the central nervous system and are also effective by oral administration and long-lasting, and completed the present invention.
The present invention relates to ##STR3## wherein Ar is phenyl, pyridyl, substituted phenyl or substituted pyridyl; R.sup.1 and R.sup.3 are the same or different and each is hydrogen, alkyl having 1 to 4 carbon atoms; R.sup.2 is hydrogen, alkyl having 1 to 4 carbon atoms or trifluoromethyl; R.sup.4 is straight or branched chain alkyl, alkenyl or alkynyl ha
REFERENCES:
Merck Index, 11th Ed., (Merck and Co., Rahway, N.J., 1989), Manologe No. 3830, p. 608.
Abe Masao
Mikashima Hiroshi
Moriwaki Minoru
Tahara Tetsuya
Shah Mukund J.
Ward E. C.
Yoshitomi Pharmaceutical Industries Ltd.
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