The present invention relates to novel tricyclic compounds which strongly antagonize an action of thromboxane A.sub.2 (hereafter referred to as TXA.sub.2).
It is hitherto known that TXA.sub.2 strongly aggregates platelets and is a potent vasoconstrictor [cf. Arachidonic Acid Cascade and Drugs, edited by Shozo Yamamoto, Gendai Iryo Publishing Co., Ltd. (1958)]. Further TXA.sub.2 is a powerful vasoconstrictor against bronchus and bronchial smooth muscle. Therefore, TXA.sub.2 is considered to take part in pathological conditions over a wide range. The following diseases can be exemplified.
(1) Ischemic disease
For example, myocardial infarction, angina pectoris, and thrombosis
(2) Cerebro-vascular disease
For example, transient ischemic attack, migraine, cerebral hemorrhage, and cerebral infarction,
(3) Peripheral vascular diseases and disease caused by unbalanced lipid.
For example, atherosclerosis, capillary convulsion, peripheral circulation disorders, hypertension, and pulmonary embolism
(4) Inflammatory and allergic diseases
For example, bronchial asthma, bronchitis, pneumonia, nephritis, and hepatitis
(5) Shock
(6) Cancer metastasis
Accordingly, compounds that antagonize the action of TXA.sub.2 are expected to have therapeutic effects in preventing or treating one or more of the diseases described above or other diseases involving TXA.sub.2. Further where in drugs used for medical purposes heretofore, application thereof is limited due to side effects mediated by TXA.sub.2 or assumed to be mediated by TXA.sub.2, it is expected to alleviate the side effects by the use of compounds which antagonize the action of TXA.sub.2.
As an antagonist of TXA.sub.2, representative compounds are exemplified in Thrombosis Research, 44, 377 (1986). Furthermore, an indole compound having the following structure: ##STR2## etc. is disclosed in Japanese Published Unexamined Patent Application No. 249960/1986 [West German Patent Application (DE) No. 3,514,696] and a compound having the following structure: ##STR3## is disclosed in Japanese Published Unexamined Patent Application No. 212552/1986 [West German Patent Application (DE) No. 3,508,692]. These compounds are derivatives having a phenylsulfonamide group and exhibit an activity of antagonizing TXA.sub.2.
On the other hand, among tricyclic compounds represented by the following formula: ##STR4## wherein L is --CH.dbd.CH--, R.sup.o as a substituent on the aromatic ring has carboxyl or a derivative thereof (for example, an ester, an amide, etc.; hereafter collectively referred to as carboxylic acid group) directly or via an alkylene chain, etc. and W.sup.o is hydrogen or a substituent such as oxo (.dbd.0), methylene (.dbd.CH.sub.2), hydroxyl, alkoxyl, etc., oxepine derivatives wherein X.sub.1 --X.sub.2 .dbd.--CH.sub.2 O-- are known to show antiinflammatory, antiallergic activities, etc. [J. Med. Chem., 19, 941 (1976); ibid., 20, 1499 (1977); ibid, 21, 633 (1978); U.S. Patent No. 4,282,36(Japanese Published Unexamined Patent Application No. 21679/1983); U.S. Pat. No. 4,585,788; Japanese Published Unexamined Patent Application Nos. 152673/1986; 152674/1986 and 152675/1986]. Further, it is also known that oxepine derivatives wherein R.sup.o is hydrogen or a substituent other than the carboxylic acid group, such as alkyl, alkoxyl, halogen, etc. and W.sup.o has an alkylaminoalkyl chain via hetero atom (--NH--, --O--, --S--, etc.) show antihistaminic, antiallergic, antiasthmatic, activities, etc. [Japanese Published Unexamined Patent Application Nos. 150083/1981 (U.S. Pat. Nos. 4,396,550 and 4,465,835); 139073/1982; 126883/1983 (EP 0085870A) and 227879/1984]. It is also known that derivatives such as oxepine or thiepine (wherein X.sub.1 --X.sub.2 is --CH.sub.2 S--) wherein W.sup.o is alkylaminoalkylidene show an antidepressant action, etc. [U.S. Pat. Nos. 3,354,155 and 3,420,851; Drugs, 13, 161 (1977), Arz.-Forsch., 13, 1039 (1963); ibid.,14, 100 (1964)]. Furthermore, it is known that derivatives such as cycloheptene (wherein X.sub.1 --X.sub.2 is --CH.dbd.CH--) or thiepine wherein W.sup.o has an alkyl chain substituted with an alicyclic nitrogen-containing heterocyclic group such as piperazine, etc. at the terminal thereof via --NHCO-- have a calcium antagonizing activity [Japanese Published Unexamined Patent Application Nos. 47466/1986 (USP 4,749,703) and 153280/1987].
Further oxepine derivatives having an antiallergic activity wherein R.sup.o has carboxylic acid group and W.sup.o has an alkylaminoalkyl chain via a hetero atom are known [Japanese Published Unexamined Patent Application Nos. 28972/1985 (U.S. Pat. No. 4,596,804); 152669/1986; 152670/1986; 152671/1986; 152672/1986 (all of them correspond to EP 188802 A); 152676/1986 and 257981/1986]. Furthermore, oxepine or cycloheptene (wherein X.sub.1 --X.sub.2 .dbd.--CH.sub.2 CH.sub.2 --) derivatives showing an antihistaminic activity wherein W.sup.o is alkylaminoalkylidene are known [Japanese Published Unexamined Patent Application No. 45557/1987 (EP 2l4779A)].
In addition, thienobenzoxepine and thiepine derivatives showing an antiinflammatory activity wherein L is --S--, R.sup.o has carboxylic acid group and W.sup.o is oxo are disclosed in J. Med. Chem., 21, 633 (1978) supra.
USPTO Backgrounds
USPTO Backgrounds