Histamine is a representative chemical mediator which induces allergic reaction and is released from cells such as mast cells or basophils when an allergenic substance comes into the body. The released histamine binds to a histamine 1-type receptor (H1 receptor) protein and achieves the pharmacological action such as reduction of blood pressure, promotion of vascular permeability, contraction of smooth muscle, dilation of blood vessel or promotion of gland secretion participating in expression of allergic reaction and inflammation. As such, histamine is related to various human diseases and it is possible to prevent or treat allergic disease and inflammation by suppressing its action. Drugs (antihistaminic drugs) which suppress the histamine release or inhibit the histamine binding to a receptor have been abundantly put into the market and used for the diseases such as bronchial asthma, allergic rhinitis, pollinosis, urticaria and atopic dermatitis.
However, the antihistaminic drugs which have been known up to now express undesirable side effects such as sedative action, drowsiness, dizziness, feeling of malaise, anticholinergic thirst, dry feeling of mucosa or visual accommodation disorder. Accordingly, there are restrictions for its use such as prohibition of ingestion before driving a car and that is a cause of its inconvenient use. Therefore, there has been a demand by patients and the medical practice for antihistaminic agent wherein such a problem is solved and an excellent effect is available. The present inventors have found an excellent synthetic method for a thiabenzoazulene-propionic acid having less central side effect and a potent antihistaminic action whereupon the present invention has been achieved.
With regard to piperidine derivatives having a thiabenzoazulene skeleton where the site between the 9- and 10-positions is a double bond, Patent Document 1 discloses a compound having neuroleptic effect and central depressing effect where the 2-position of the thiabenzoazulene skeleton is substituted with methyl, alcohol or alkyl ketone and the 1-position of piperidine is substituted with alkyl. Patent Document 2 discloses a compound having sedative action, sleep promoting action and muscle relaxing action where the 2-position of the same thiabenzoazulene skeleton is substituted with methyl or chlorine and the 1-position of piperidine is substituted with alkyl ketone. However, there has been no report concerning a synthetic method for a compound where propionic acid is bound to the 2-position of a thiabenzoazulene skeleton which is able to be synthesized by a producing process of the present invention.