Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1989-02-03
1991-07-02
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540560, C07D49512, A61K 3155
Patent
active
050286030
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel and pharmaceutically useful ester substituted thienotriazolodiazepine compounds and pharmaceutically acceptable salts thereof, and pharmaceutical uses thereof.
BACKGROUND ART
Certain s-triazolo[3,4-c]thieno[2,3-e][1,4]diazepine compounds are known to exhibit useful pharmacological activities against the central nervous system such as antianxiety or anticonvulsant activities as disclosed in U.S. Pat. No. 3,904,641.
Japan. J. Pharmacol., vol. 44, p. 381-391 (1987) discloses that the similar type of the compounds exhibits antagonistic activity on platelet-activating factor (hereinunder also referred to as PAF), and further EP-A 194416 discloses that another type of the compounds having a carboxylic acid amide derivatives as the side chain exhibit antagonistic activity on PAF.
According to the elucidation of the structure of platelet-activating factor, its physiological roles have been investigated, and various PAF-induced inflammatory diseases such as allergic diseases, anaphylactic shocks, vascular diseases as DIC (disseminated intravascular coagulation syndrome), myocardial diseases, asthma, pulmonary edema and adult respiratory diseases have been known. The PAF-antagonistic compounds are considered to be very useful for the prevention and treatment of above-mentioned diseases. It is known that certain thienotriazolodiazepine compounds exhibit PAF-antagonist activity as mentioned above. However, such compounds are not sufficient in view of the separation from the effect on the central nervous system, the potency, the effectiveness by the oral administration or the duration of activity.
DISCLOSURE OF THE INVENTION
The present inventors have made intensive invenstigations in order to develop the compounds which have PAF-antagonistic activity and possess less central depressing effect such as sedative activity or muscle relaxation activity, and are effective by oral administration and long-lasting, and to provide useful compounds and medicines.
As a result, the present invetors have found that the thienotriazolodiazepine compounds substituted by an acyloxyalkyl group as a side chain at the 2-position exhibit potent PAF-antagonistic activity and accord with the target of the development as mentioned above, and completed the present invention.
Moreover, it is expected that the compounds, especially, wherein the acyl residue is carboxyl residue of the carboxylic acid compounds having a cyclooxygenase-inhibitory acid antiinflammatory activity produce metabolically the acid antiinflammatory compounds in vivo and are also effective against non-PAF-induced inflammatory models which are not sufficient in the potencies of the treatment based on only PAF-antagonistic activity.
Namely, the first present invention relates to provide ester-substituted thienotriazolodiazepine compounds of the formula: ##STR1## wherein Ar is pyridyl, phenyl or substituted phenyl by one to three substituents (wherein the substituents are the same or different and each is halogen, alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms), R.sup.1 and R.sup.3 are the same or different and each is hydrogen or alkyl having 1 to 4 carbon atoms, R.sup.2 is hydrogen, alkyl having 1 to 4 carbon atoms or trifluoromethyl, R is straight or branched chain alkyl having 1 to 18 carbon atoms, straight or branched chain alkenyl having 2 to 18 carbon atoms, aryl, substituted aryl by one to three substituents which are the same or different (wherein substituents are halogen, hydroxy, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 8 carbon atoms or aralkyloxy), aralkyl, substituted aralkyl by at least one substituent which is the same or different on aromatic ring or alkyl chain [wherein the substituent on the aromatic ring is halogen, hydroxy, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 8 carbon atoms, aralkyloxy, cycloalkyl, alkenyloxy having 2 to 4 carbon atoms, acyl, phenyl, pyridyl, phenoxy, phenylamino which may be substituted by one to three substituents (wherein th
REFERENCES:
patent: 4900729 (1990-02-01), Stransky et al.
Abe Masao
Moriwaki Minoru
Tahara Tetsuya
Terasawa Michio
Datlow Philip I.
Shah Mukund J.
Yoshitomi Pharmaceutical Industries Ltd.
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