JP5083989B2 - Medicaments containing piperidine derivatives - Google Patents

Description

  The present invention relates to a pharmaceutical such as an antihistamine containing at least one of piperidine derivatives and pharmaceutically acceptable salts and hydrates thereof.

  Histamine (histamine) is a typical chemical mediator that induces an allergic reaction, and when a substance causing allergy enters the body, it is released from cells such as mast cells and basophils. The released histamine binds to the histamine type 1 receptor (H1 receptor) protein and exerts pharmacological actions such as blood pressure lowering, increased vascular permeability, smooth muscle contraction, vasodilatation and promotion of gland secretion, allergic reaction and inflammation Involved in the expression of. Thus, histamine is related to various human diseases, and by inhibiting its action, allergic diseases and inflammation can be prevented or cured, and drugs and receptors that inhibit histamine release Many drugs (antihistamines) that inhibit the binding are commercially available and are used for diseases such as bronchial asthma, allergic rhinitis, hay fever, urticaria, and atopic dermatitis.

  However, known antihistamines have sedative effects due to central effects, drowsiness, dizziness, malaise, etc., and undesirable side effects such as dryness due to anticholinergic effects, dryness of mucosa, impaired visual regulation, etc. For this reason, there are restrictions on use such as prohibition of taking before driving the car, which is difficult to use. Therefore, an antihistamine that solves such problems and has an excellent effect is demanded in patients and medical sites. The present inventors have found that the piperidine derivative of the present invention is useful as a medicament having few central side effects and having a strong antihistamine action.

The piperidine derivatives having a thiabenzoazulene skeleton are disclosed in Patent Documents 1 to 13, but among these, the compounds disclosed in Patent Documents 1 to 7 are different from the compounds of the present invention in the following general formula. A compound in which both R ₁ and R ₂ in (I) are hydrogen. Patent Document 8 discloses a compound in which R ₁ in the following general formula (I) is alkyl optionally substituted with acyl or hydroxy, and R ₂ is hydrogen or chlorine. Patent Documents 9 to 13 disclose Disclosed are compounds in which R ₁ in general formula (I) is hydrogen and R ₂ is halogen, alkyl or alkoxy. However, Patent Document 8 discloses an analgesic action, and Patent Document 9 discloses that it has an antagonism of drooping and catalepsy, an abnormal drop in body temperature, and an action of suppressing tremor. Further, although the compounds disclosed in Patent Documents 10 to 13 are described as having an antihistaminic action, they improve central side effects such as sleepiness that are side effects of conventional antihistamines like the compounds of the present invention. It is not disclosed. For example, ketotifen fumarate disclosed in Patent Document 10 has been frequently used as a second-generation antihistamine, but has been regarded as a precaution for side effects that induce sleepiness. Thus, a piperidine derivative having a thiabenzoazulene skeleton having few central side effects such as drowsiness and having a strong antihistamine action like the compound of the present invention has not been reported so far.

JP-A-3-294277 JP-T-2001-519789 Japanese National Patent Publication No. 6-504992 Japanese Laid-Open Patent Publication No. 1-104069 JP 57-77673 A Japanese Patent Publication No.57-60351 Japanese National Patent Publication No. 3-504855 Japanese Patent Laid-Open No. 49-69677 JP-A-51-110572 Japanese Examined Patent Publication No. 52-17030 Japanese Patent Publication No.55-8984 JP-A-48-81869 French Patent No. 1437412

  An object of the present invention is to provide a medicament such as an antihistamine with few central side effects such as sleepiness.

  As a result of intensive studies on the antihistamine compounds having the above-described characteristics, the present inventors have found that the piperidine derivative represented by the following structural formula (I) has an excellent antihistaminic activity and is central to sleepiness and the like. The present invention was completed by discovering that the compound is useful as a pharmaceutical with reduced sexual side effects.

  The piperidine derivative of the present invention has an excellent histamine receptor antagonism, and also shows low transferability in the brain in the brain receptor binding test when orally administered to mice, thereby reducing central side effects such as sleepiness. Since the effect is exerted, it has characteristics desired as an active ingredient of a pharmaceutical composition such as an antihistamine, and its usefulness is high.

〔式中、R₁は下記(a)乃至(i)から選択される置換基又は水素を表し、
(a) シアノ、
(b) アクリル酸（アルキルエステル及びヒドロキシアルキルアミドを含む）、
(c) ウレイド、
(d) アルケニル、
(e) アルキルカルボニル又はアミノカルボニルで置換されていてもよいアミノアルキル、
(f) ヒドロキシ、アルコキシ又はヒドロキシアルキルアミノで置換されているカルボニルアルキル、
(g) ヒドロキシ、モルホリノ、アルコキシ、ヒドロキシアルキルアミノアルコキシ又はシクロヘキシルオキシカルボニルオキシアルコキシで置換されているカルボニル、
(h) アルキル又はアルコキシで置換されているカルボニルアミノ、
(i) アミノ、ヒドロキシ、アルコキシ、アルケニル及びアルキル（ハロゲン、チオール、ピペリジノ、アミノ、アルコキシ、アルコキシカルボニル、アミノカルボニル又は1若しくは2のヒドロキシで置換されていてもよい）から選択される1又は2の置換基で置換されていてもよいアミノカルボニル、
R₂は下記(j)乃至(r)から選択される置換基又は水素を表し、
(j) シアノ、
(k) アクリル酸（アルキルエステル及びヒドロキシアルキルアミドを含む）、
(l) ヒドロキシ又はピペリジノで置換されているアルキル、
(m) ヒドロキシ、アルコキシ（シクロヘキシルオキシカルボニルオキシで
置換されていてもよい）、ピペリジノ又はヒドロキシアルキルアミノで置換されているカルボニルアルキル、
(n) ヒドロキシ、アルコキシ又はヒドロキシアルキルアミノで置換されているカルボニル、
(o) ヒドロキシ又はアルコキシで置換されているカルボニルアルコキシ、
(p) ヒドロキシ又はアルコキシで置換されているカルボニルアルキルスルファニル、
(q) アルコキシ、
(r) ハロゲン、
R₃は下記(s)乃至(w)から選択される置換基又は水素を表し、
(s) カルボキシ、シアノ、ピロリジル、ピペリジノ、アルコキシ、アルキルスルファニル又は1若しくは2のヒドロキシ置換されていてもよいアルキル、
(t) アルキル又はアルコキシで置換されているカルボニル、
(u) ヒドロキシ又はアルコキシで置換されているカルボニルアルコキシアルキル、
(v) アルキル、アルコキシ又はアルキルフェニルで置換されているカルボニルアルキル、
(w) アミノカルボニル又はアルカンスルホニルで置換されているアミノアルキル、
上記R₁及びR₂のいずれか一方は水素以外の置換基を表し、Aは無置換であるか又はオキソを表し、Bは炭素又は酸素を表し、X及びYはいずれか一方が炭素で他方が硫黄を表し、破線部分は単結合又は二重結合を表し、但し、R₂がハロゲン又はアルコキシである場合、Aは無置換で、R₁は水素以外の置換基、Bは酸素を表す。〕 The present invention relates to a pharmaceutical containing at least one of piperidine derivatives represented by the following general formula (I) and pharmaceutically acceptable salts and hydrates thereof.

[Wherein R ₁ represents a substituent selected from the following (a) to (i) or hydrogen,
(a) cyano,
(b) acrylic acid (including alkyl esters and hydroxyalkylamides),
(c) Ureido,
(d) alkenyl,
(e) aminoalkyl optionally substituted with alkylcarbonyl or aminocarbonyl,
(f) carbonylalkyl substituted with hydroxy, alkoxy or hydroxyalkylamino,
(g) a carbonyl substituted with hydroxy, morpholino, alkoxy, hydroxyalkylaminoalkoxy or cyclohexyloxycarbonyloxyalkoxy,
(h) carbonylamino substituted with alkyl or alkoxy;
(i) 1 or 2 selected from amino, hydroxy, alkoxy, alkenyl and alkyl (optionally substituted with halogen, thiol, piperidino, amino, alkoxy, alkoxycarbonyl, aminocarbonyl or 1 or 2 hydroxy) An aminocarbonyl optionally substituted with a substituent,
R ₂ represents a substituent selected from the following (j) to (r) or hydrogen,
(j) cyano,
(k) acrylic acid (including alkyl esters and hydroxyalkylamides),
(l) alkyl substituted with hydroxy or piperidino,
(m) hydroxy, alkoxy (optionally substituted with cyclohexyloxycarbonyloxy), carbonylalkyl substituted with piperidino or hydroxyalkylamino,
(n) a carbonyl substituted with hydroxy, alkoxy or hydroxyalkylamino,
(o) carbonylalkoxy substituted with hydroxy or alkoxy,
(p) a carbonylalkylsulfanyl substituted with hydroxy or alkoxy,
(q) alkoxy,
(r) halogen,
R ₃ represents a substituent selected from the following (s) to (w) or hydrogen,
(s) carboxy, cyano, pyrrolidyl, piperidino, alkoxy, alkylsulfanyl or 1 or 2 optionally substituted alkyl,
(t) carbonyl substituted with alkyl or alkoxy,
(u) a carbonylalkoxyalkyl substituted with hydroxy or alkoxy,
(v) carbonylalkyl substituted with alkyl, alkoxy or alkylphenyl,
(w) aminoalkyl substituted with aminocarbonyl or alkanesulfonyl;
_One of R ₁ and R ₂ represents a substituent other than hydrogen, A is unsubstituted or represents oxo, B represents carbon or oxygen, and X and Y are either carbon and the other Represents sulfur, and the broken line part represents a single bond or a double bond, provided that when R ₂ is halogen or alkoxy, A is unsubstituted, R ₁ is a substituent other than hydrogen, and B represents oxygen. ]

In the general formula (I), alkyl (alkyl ester, alkylphenyl, hydroxyalkylamide, hydroxyalkylamino, alkylcarbonyl, aminoalkyl, carbonylalkyl, hydroxyalkylaminoalkoxy, hydroxyalkylamino, carbonylalkoxyalkyl, alkylsulfanyl, carbonyl "Alkyl" in alkylsulfanyl) is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, isohexyl, etc. A linear or branched alkyl group having 1 to 6 carbon atoms is represented. The alkane of alkanesulfonyl represents a saturated hydrocarbon corresponding to the above alkyl.
Alkoxy (including “alkoxy” in hydroxyalkylaminoalkoxy, alkoxycarbonyl, carbonylalkoxy, carbonylalkoxyalkyl, cyclohexyloxycarbonyloxyalkoxy) is preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, A linear or branched alkoxy group having 1 to 6 carbon atoms such as isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, n-hexyloxy and the like is represented.
Alkenyl preferably represents a linear or branched alkenyl group having 2 to 4 carbon atoms such as vinyl, allyl, propenyl, isopropenyl, 1-butenyl, 2-butenyl and the like.
Halogen represents fluorine, chlorine, bromine, iodine or the like.
The aminoalkyl (e) of R ₁ may be substituted with alkylcarbonyl or aminocarbonyl, and the aminoalkyl (w) of R ₃ is substituted with aminocarbonyl or alkanesulfonyl, but each substituent is It substitutes for the amino group part of aminoalkyl.

Among the compounds of the present invention, preferred compounds are as follows. However, Compound 1, Compound 2, Compound 8, Compound 9, Compound 11, Compound 14, Compound 17, Compound 18, Compound 25, Compound 29, Compound 43, Compound 52, Compound 63, Compound 64, Compound 66, Compound 99, Compound 104, Compound 112, Compound 122, Compound 183, Compound 186, Compound 208, and Compound 212 are reference compounds because they do not correspond to the compound of the present invention.
2-cyano-4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulene [Compound 1]
Hydrobromide 2-bromo-4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulene [Compound 2]
[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylate [Compound 3]
Hydrochloric acid [4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid [Compound 4]
Hydrochloric acid [4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulen-2-yl] carboxylic acid [Compound 5]
3- [4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] acrylic acid hydrochloride [Compound 6]
3- [4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] acrylic acid [Compound 7]
2-Bromo-4- (1-methylpiperidin-4-ylidene) -4H-1-thiabenzo [f] azulene [Compound 8]
2-Cyano-4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulene [Compound 9]
2-t-butoxycarbonylamino-4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulene [Compound 10]
2-acetylamino-4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulene [Compound 11]
2-Aminomethyl-4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulene [compound 12] dihydrochloride
2-acetylaminomethyl-4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulene hydrochloride [Compound 13]
2-Ureido-4- (1-methylpiperidine-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulene [Compound 14]
3- [4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulen-2-yl] acrylic acid [Compound 15]
2-t-Butoxycarbonylamino-4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulene [Compound 16]
2-acetylamino-4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulene [Compound 17]
2-ureido-4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulene [Compound 18]

2-Aminomethyl-4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulene [compound 19] dihydrochloride
2-acetylaminomethyl-4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulene hydrochloride [Compound 20]
[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulen-2-yl] carboxylate [Compound 21]
3- [4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulen-2-yl] ethyl acrylate [Compound 22]
Hydrochloric acid [4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulen-2-yl] ethyl acetate [Compound 23]
[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulen-2-yl] acetic acid [Compound 24]
6-Cyano-4- (1-methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulene [Compound 25]
[4- (1-Methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl] carboxylic acid [Compound 26]
[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid-N- (2-hydroxyethyl) amide (IUPAC: N -(2-Hydroxyethyl) [4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxamide) [Compound 27]
Hydrochloric acid [4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid-N, N-bis (2-hydroxyethyl) amide (IUPAC: N, N-bis (2-hydroxyethyl) hydrochloride [4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxamide ) [Compound 28]
Dihydrochloric acid [4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylate 2- (2-hydroxyethylamino) ethyl [compound 29]
[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid-N- (3-hydroxypropyl) amide (IUPAC: N -(3-hydroxypropyl) [4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxamide) [Compound 30]
[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid amide (IUPAC: [4- (1-methylpiperidine-4 -Ilidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxamide) [Compound 31]
[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] acetic acid [Compound 32]
Dihydrochloric acid [4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid-N- [2- (piperidin-1-yl) ) Ethyl] amide (IUPAC: N- (2-piperidin-1-yl-ethyl) dihydrochloride [4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] Azulene-2-yl] carboxamide) [Compound 33]
3- [4- (1-Methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl] hydrochloric acid hydrochloride [Compound 34]
3- [4- (1-Methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl] acrylic acid [Compound 35]

3- [4- (1-Methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-2-yl] acrylate hydrochloride [Compound 36]
3- [4- (1-Methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-2-yl] acrylic acid [Compound 37]
Hydrochloric acid [4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid-N- (2-methoxyethyl) amide (IUPAC: N- (2-Methoxyethyl)-[4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxamide) [Compound 38]
Dihydrochloric acid [4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid-N- (2-aminoethyl) amide (IUPAC N- (2-aminoethyl) dihydrochloride [4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxamide) [Compound 39 ]
Hydrochloric acid [4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid-N-methoxyamide (IUPAC: N-methoxyhydrochloric acid [IUPAC: 4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxamide) [Compound 40]
[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid-N-carbamoylmethylamide (IUPAC: N- {[4 -(1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl]} carbonyl} aminoacetamide) [Compound 41]
Hydrochloric acid [4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid-N-acetic acid methylamide (IUPAC: hydrochloric acid N-{[ 4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carbonyl} aminoacetic acid methyl} [Compound 42]
Hydrochloric acid [4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid morpholinamide (IUPAC: hydrochloric acid 1-{[4- ( 1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carbonyl} morpholine) [compound 43]
Hydrochloric acid ethyl [4- (1-methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-2-yl] carboxylate [Compound 44]
[4- (1-Methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-2-yl] carboxylic acid [Compound 45]
3- [4- (1-Methylpiperidin-4-ylidene) -4H-3-thiabenzo [f] azulen-2-yl] acrylic acid [Compound 46]
Ethyl 3- [4- (1-methylpiperidin-4-ylidene) -10-oxo-9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] acrylate [Compound 47]
3- [4- (1-Methylpiperidin-4-ylidene) -10-oxo-9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] acrylic acid [Compound 48]
2-Ureidomethyl-4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulene [Compound 49]
[4- (1-Methylpiperidin-4-ylidene) -10-oxo-9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylate [Compound 50]
[4- (1-Methylpiperidin-4-ylidene) -10-oxo-9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid [Compound 51]
3- [4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulen-2-yl] acrylic acid-N- (2-hydroxyethyl) amide (IUPAC : N- (2-hydroxyethyl) -3- [4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulen-2-yl] acrylamide) [compound 52]
[4- (1-Methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-2-yl] carboxylic acid-N- (2-hydroxyethyl) amide (IUPAC : N- (2-hydroxyethyl)-[4- (1-methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-2-yl] carboxamide) [compound 53]
Hydrochloric acid [4- (1-Methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl] acetic acid [Compound 54]
[4- (1-Methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-2-yl] carboxylic acid-N- (2-hydroxyethyl) amide (IUPAC : N- (2-hydroxyethyl)-{[4- (1-methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-2-yl]} carboxamide) [Compound 55]

2- [4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] propionic acid [Compound 56]
2- [4- (1-Methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl] propionic acid hydrochloride [Compound 57]
Hydrochloric acid [4- (1-Methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-2-yl] acetic acid [Compound 58]
Hydrochloric acid [4- (1-Methylpiperidin-4-ylidene) -4H-1-thiabenzo [f] azulen-2-yl] acetic acid [Compound 59]
2- [4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulen-2-yl] propionic acid [Compound 60]
[4- (1-Ethoxycarbonylpiperidine-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylate [Compound 61]
[4- (Piperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] ethyl carboxylate [Compound 62]
[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] acetic acid-N- (2-hydroxyethyl) amide (IUPAC: N- (2-Hydroxyethyl)-{[4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl]} acetamide) [Compound 63]
2- [4- (1-Methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl] propionic acid-N- (2-hydroxyethyl) amide (IUPAC: N- (2-hydroxyethyl)-{2- [4- (1-methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl ]} Propionamide) [Compound 64]
2-Methyl-2- [4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] propionic acid [Compound 65]
3- [4- (1-Methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl] acrylic acid-N- (2-hydroxyethyl) amide (IUPAC: N- (2-hydroxyethyl)-{3- [4- (1-methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl ]} Acrylamide) [Compound 66]
[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulen-2-yl] carboxylic acid-N- (2-hydroxyethyl) amide (IUPAC: N -(2-hydroxyethyl)-{[4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulen-2-yl]} carboxamide) [Compound 67]
2-Methyl-2- [4- (1-methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl] propionic acid [Compound 68]
Hydrochloric acid [4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid-N- (2-hydroxyethyl) -N-methylamide (IUPAC: hydrochloric acid N- (2-hydroxyethyl) -N-methyl-{[4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulene-2- Il]} carboxamide) [Compound 69]
[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid-N- (2-hydroxypropyl) amide (IUPAC: N -(2-hydroxypropyl)-{[4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl]} carboxamide) [Compound 70]
[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid-N- (1-hydroxyprop-2-yl) amide (IUPAC: N- (1-hydroxyprop-2-yl)-{[4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl ]} Carboxamide) [Compound 71]
[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid-N- (1,2-dihydroxypropyl) amide (IUPAC : N- (1,2-dihydroxypropyl)-{[4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl]} carboxamide) [Compound 72]

[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid-N- (1,3-dihydroxyprop-2-yl ) Amido (IUPAC: N- (1,3-dihydroxyprop-2-yl)-{[4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulene -2-yl]} carboxamide) [Compound 73]
[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid-N-hydroxy-N-methylamide (IUPAC: N-hydroxy -N-methyl-{[4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl]} carboxamide) [Compound 74]
2-Ethoxycarbonylamino-4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulene [Compound 75]
2-Isopropoxycarbonylamino-4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulene [Compound 76]
[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid-N- (2-fluoroethyl) amide (IUPAC: N -(2-Fluoroethyl)-{[4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl]} carboxamide) [Compound 77]
[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid-N-hydroxyamide (IUPAC: N-hydroxy-{[ 4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl]} carboxamide) [Compound 78]
[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid-N- (2,2,2-trifluoroethyl) Amide (IUPAC: N- (2,2,2-trifluoroethyl)-{[4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulene-2 -Yl]} carboxamide) [Compound 79]
[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid-N- (2-methyl-1-hydroxypropi-2 -Yl) amide (IUPAC: N- (2-methyl-1-hydroxyprop-2-yl)-{[4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl]} carboxamide) [Compound 80]
[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid-N- (3,3,3,2,2- Pentafluoropropyl) amide (IUPAC: N- (3,3,3,2,2-pentafluoropropyl)-{[4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1 -Thiabenzo [f] azulen-2-yl]} carboxamide) [Compound 81]
[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid-N- (2-mercaptoethyl) amide (IUPAC: N -(2-Mercaptoethyl)-{[4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl]} carboxamide) [Compound 82]
[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid-N-amino-N- (2-hydroxyethyl) amide (IUPAC: N-amino-N- (2-hydroxyethyl)-{[4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl ]} Carboxamide) [Compound 83]
[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid-N-methyl-N-methoxyamide (IUPAC: N- Methyl-N-methoxy-{[4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl]} carboxamide) [Compound 84]
[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid-N-propylamide (IUPAC: N-propyl-{[ 4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl]} carboxamide) [Compound 85]
[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid-N-allylamide (IUPAC: N-allyl-{[4 -(1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl]} carboxamide) [Compound 86]
[4- (1-Methylpiperidin-4-ylidene) -10-oxo-9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] acetic acid [Compound 87]
[4- (1-Ethoxycarbonylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid [Compound 88]
[4- (1-Methylpiperidin-4-ylidene) -4H-3-thiabenzo [f] azulen-2-yl] carboxylic acid [Compound 89]
[4- (1-Acetylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylate [Compound 90]
[4- (1-Acetylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid [Compound 91]
Ethyl {4- [1- (2-carboxyethyl) piperidin-4-ylidene] -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl} carboxylate [Compound 92]

3- [4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulen-2-yl] propionic acid [Compound 93]
{4- [1- (2-Cyanoethyl) piperidin-4-ylidene] -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl} carboxylic acid [Compound 94]
[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-6-yl] carboxylate [Compound 95]
[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-6-yl] carboxylic acid [Compound 96]
Ethyl 3- [4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] propionate [Compound 97]
3- [4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] propionic acid [Compound 98]
3- [4- (1-Methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl] pyropionic acid piperidine amide (IUPAC: hydrochloric acid 1- { 3- [4- (1-Methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl] piropionyl} piperidine) [Compound 99]
3- [4- (1-Methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl] pyropionic acid [Compound 100]
Dihydrochloric acid ethyl {4- [1- (3-pyrrolidylpropyl) piperidin-4-ylidene] -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl} carboxylate [Compound 101]
{4- [1- (3-Pyrrolidylpropyl) piperidin-4-ylidene] -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl} carboxylic acid [Compound 102]
Hydrochloric acid ethyl [4- (1-ethylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylate [Compound 103]
6- (2-Hydroxymethyl) -4- (1-methylpiperidine-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulene [Compound 104]
Ethyl {4- [1- (2-hydroxyethyl) piperidine-4-ylidene] -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl} carboxylate [Compound 105]
Hydrochloric acid [4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-6-yl] ethyl acetate [Compound 106]
Hydrochloric acid {4- [1- (2-hydroxyethyl) piperidin-4-ylidene] -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl} carboxylic acid [Compound 107]
Hydrochloric acid [4- (1-Ethylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylic acid [Compound 108]
{4- {1- [4- (4-t-Butylphenyl) -4-oxobutyl] piperidin-4-ylidene} -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl} carvone Ethylate [Compound 109]
Hydrochloric acid ethyl {4- [1- (2-ethoxycarbonylmethoxyethyl) piperidin-4-ylidene] -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl} carboxylate [Compound 110]
Ethyl {4- [1- (2-carboxymethoxyethyl) piperidin-4-ylidene] -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl} carboxylate [Compound 111]
2-Vinyl-4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulene [Compound 112]

Hydrochloric acid ethyl (4-piperidin-4-ylidene-4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl) acetate [compound 113]
(4-Piperidin-4-ylidene-4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl) acetic acid [Compound 114]
4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulene-6-carboxylate [Compound 115]
Hydrochloric acid methyl [4- (1-methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-1-thiabenzo [f] azulen-6-yl] acetate [Compound 116]
[4- (1-Methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-1-thiabenzo [f] azulen-6-yl] acetic acid [Compound 117]
Hydrochloric acid {4- [1- (2-hydroxyethyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} methyl acetate [Compound 118]
{4- [1- (2-Hydroxyethyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} acetic acid [Compound 119]
4- [1- (4-Hydroxybutyl) piperidin-4-ylidene] -9,10-dihydro-4H-1-thiabenzo [f] azulene-2-carboxylic acid [Compound 120]
4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulene-6-carboxylic acid [Compound 121]
2- {4- [1- (2-hydroxyethyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} ethanol [Compound 122]
4- [4- (1-Methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl] butyric acid hydrochloride [Compound 123]
4- [4- (1-Methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl] butyric acid [Compound 124]
3- [4- (6-Carboxymethyl-10H-9-oxa-3-thiabenzo [f] azulen-4-ylidene) piperidin-1-yl] propionic acid [Compound 125]
Hydrochloric acid methyl (4-piperidin-4-ylidene-4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl) acetate [Compound 126]
Hydrochloric acid methyl [4- (1-ethylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl] acetate [Compound 127]
[4- (1-Ethylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl] acetic acid [Compound 128]
Methyl [4- (1-propylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl] acetate [Compound 129]
[4- (1-Propylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl] acetic acid [Compound 130]
Methyl [4- (1-isopropylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl] acetate [Compound 131]
[4- (1-Isopropylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl] acetic acid [Compound 132]

4- (1-Propylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulene-2-carboxylate hydrochloride [Compound 133]
4- (1-propylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulene-2-carboxylic acid [compound 134]
4- (4-Piperidin-4-ylidene-4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl) butyric acid hydrochloride [Compound 135]
4- (4-Piperidin-4-ylidene-4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl) butyric acid [Compound 136]
Hydrochloric acid (4-piperidin-4-ylidene-4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl) propyl acetate [Compound 137]
Hydrochloric acid {4- [1- (3-hydroxypropyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} methyl acetate [Compound 138]
{4- [1- (3-Hydroxypropyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} acetic acid [Compound 139]
Hydrochloric acid [4- (1-methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl] ethyl acetate [Compound 140]
4- [4- (1-Ethylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl] butyric acid hydrochloride [Compound 141]
4- [4- (1-Ethylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl] butyric acid [Compound 142]
3- (4-Piperidin-4-ylidene-4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl) hydrochloric acid hydrochloride [Compound 143]
3- (4-Piperidin-4-ylidene-4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl) acrylic acid [Compound 144]
3- (4-Piperidin-4-ylidene-9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl) acrylic acid hydrochloride [Compound 145]
3- (4-Piperidin-4-ylidene-9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl) acrylic acid [Compound 146]
Hydrochloric acid [4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulen-6-yl] ethyl acetate [Compound 147]
Hydrochloric acid [4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulen-6-yl] acetic acid [Compound 148]
4- (1-Isopropylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulene-2-carboxylate hydrochloride [Compound 149]
4- (1-Isopropylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulene-2-carboxylic acid [Compound 150]
[4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-6-yl] acetic acid [Compound 151]
2-Methyl-2- (4-piperidin-4-ylidene-9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl) propionate hydrochloride [Compound 152]

2-methyl-2- (4-piperidin-4-ylidene-9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl) propionic acid hydrochloride [Compound 153]
2- [4- (1-Ethylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] -2-methylpropionate hydrochloride [Compound 154]
2- [4- (1-Ethylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] -2-methylpropionic acid [Compound 155]
Methyl 5- [4- (1-methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl] hydrovalerate [Compound 156]
5- [4- (1-Methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl] valeric acid [Compound 157]
3- [4- (1-Ethylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] ethyl acrylate [Compound 158]
3- [4- (1-Ethylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] acrylic acid [Compound 159]
4- (1-Ethylpiperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulene-6-carboxylate [Compound 160]
4- (1-Ethylpiperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulene-6-carboxylic acid [Compound 161]
5- (4-Piperidin-4-ylidene-4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl) valeric acid [Compound 162]
Dihydrochloric acid methyl {4- [1- (3-piperidin-1-yl-propyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} acetate [Compound 163]
{4- [1- (3-Piperidin-1-ylpropyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} acetic acid [Compound 164]
Hydrochloric acid methyl [4- (1-methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yloxy] acetate [Compound 165]
[4- (1-Methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yloxy] acetic acid [Compound 166]
Hydrochloric acid {4- [1- (2-oxopropyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} methyl acetate [Compound 167]
{4- [1- (2-oxopropyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} acetic acid [Compound 168]
Hydrochloric acid {4- [1- (4-oxopentyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} methyl acetate [Compound 169]
{4- [1- (4-Oxopentyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} acetic acid [Compound 170]
Methyl [4- (1-methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-ylsulfanyl] acetate [Compound 171]
[4- (1-Methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-ylsulfanyl] acetic acid [Compound 172]

3- [4- (6-Methoxycarbonylmethyl-10H-9-oxa-3-thiabenzo [f] azulen-4-ylidene) piperidin-1-yl] propionic acid hydrochloride [Compound 173]
{4- [1- (2-ureidoethyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} methyl acetate [Compound 174]
{4- [1- (2-ureidoethyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} acetic acid [Compound 175]
4- (1-Methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulene-2-carboxylic acid 1-cyclohexyloxycarbonyloxyethyl hydrochloride [Compound 176]
Hydrochloric acid {4- [1- (2-methanesulfonylaminoethyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} methyl acetate [Compound 177]
{4- [1- (2-Methanesulfonylaminoethyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} acetic acid [Compound 178]
4- (6-Carboxymethyl-10H-9-oxa-3-thiabenzo [f] azulen-4-ylidene) piperidine-1-carboxylate t-butyl [Compound 179]
Hydrochloric acid (4-piperidin-4-ylidene-4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl) acetic acid 1-cyclohexyloxycarbonyloxyethyl [Compound 180]
4- [1- (2-Ethoxyethyl) piperidin-4-ylidene] -9,10-dihydro-4H-1-thiabenzo [f] azulene-2-carboxylate hydrochloride [Compound 181]
4- [1- (2-Ethoxyethyl) piperidin-4-ylidene] -9,10-dihydro-4H-1-thiabenzo [f] azulene-2-carboxylic acid [Compound 182]
1-methyl-4- [6- (2-piperidin-1-ylethyl) -10H-9-oxa-3-thiabenzo [f] azulen-4-ylidene] piperidine dihydrochloride [Compound 183]
4- {4- [1- [2,3-dihydroxypropyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} butyric acid hydrochloride [compound 184]
4- {4- [1- (2,3-dihydroxypropyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} butyric acid [Compound 185]
3- {4- [6- (2-Piperidin-1-ylethyl) -10H-9-oxa-3-thiabenzo [f] azulen-4-ylidene] piperidin-1-yl} propionic acid [Compound 186]
4- {4- [1- (4-oxopentyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} butyric acid hydrochloride [Compound 187]
4- {4- [1- (4-oxopentyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} butyric acid [Compound 188]
Methyl 2-methyl-2- [4- (1-methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-ylsulfanyl] propionate hydrochloride [Compound 189 ]
2-Methyl-2- [4- (1-methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-ylsulfanyl] propionic acid [Compound 190]
Hydrochloric acid {4- [1- (3-oxobutyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} methyl acetate [Compound 191]
{4- [1- (3-oxobutyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} acetic acid [Compound 192]

Hydrochloric acid {4- [1- (3-methanesulfonylaminopropyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} methyl acetate [Compound 193]
{4- [1- (3-Methanesulfonylaminopropyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} acetic acid [Compound 194]
Hydrochloric acid methyl 3- {4- [1- (2-methanesulfonylaminoethyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} propionate [ Compound 195]
3- {4- [1- (2-Methanesulfonylaminoethyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} propionic acid [Compound 196 ]
Hydrochloric acid methyl (4-piperidin-4-ylidene-4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-ylsulfanyl) acetate [Compound 197]
Hydrochloric acid {4- [1- (3-methylsulfanylpropyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} methyl acetate [Compound 198]
{4- [1- (3-Methylsulfanylpropyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} acetic acid [Compound 199]
Hydrochloric acid {4- [1- (2-methylsulfanylethyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} methyl acetate [Compound 200]
{4- [1- (2-Methylsulfanylethyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} acetic acid [Compound 201]
2-Methyl-2- [4- (1-propylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-ylsulfanyl] propionic acid [Compound 202]
3- (4-Piperidin-4-ylidene-9,10-dihydro-4H-3-thiabenzo [f] azulen-2-yl) acrylic acid [Compound 203]
[6-Fluoro-4- (1-methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-2-yl] acetic acid [Compound 204]
[6-Chloro-4- (1-methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-2-yl] acetic acid [Compound 205]
2- [6-Chloro-4- (1-methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-2-yl] -2-methylpropionic acid [compound 206]
[6-Methoxy-4- (1-methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-2-yl] acetic acid [Compound 207]
[6-Methyl-4- (1-methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-2-yl] acetic acid [Compound 208]
3- (4-Piperidin-4-ylidene-4H-1-thiabenzo [f] azulen-2-yl) propionic acid [Compound 209]
3- (4-Piperidin-4-ylidene-4H-3-thiabenzo [f] azulen-2-yl) propionic acid [Compound 210]
4-Piperidin-4-ylidene-9,10-dihydro-4H-3-thiabenzo [f] azulene-6-carboxylic acid [Compound 211]
4- (2-Bromo-9,10-dihydro-1-thiabenzo [f] azulen-4-ylidene) -1-methylpiperidine [Compound 212]

Among the compounds of the present invention, in the general formula (I), _one of R ₁ and R ₂ is preferably a compound representing hydrogen, and more preferred compounds include those described in Tables 18 and 19 below. Furthermore, the compounds described in Table 21 which are excellent in antihistaminic activity and have low brain migration are particularly preferred.

  The general method for producing the compound of the present invention is shown below. The compound of the present invention represented by the general formula (I) can be produced by the method described below. However, it will be apparent to those skilled in the art that the exact method used to produce a particular compound can vary depending on its chemical structure.

  The 4- (piperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulene compound of the present invention represented by the above general formula (I) is described in JP-A-49-69677. Method, 4- (piperidin-4-ylidene) -4H-1-thiabenzo [f] azulene compounds are disclosed in JP-A-49-69677 and Helvetica Chimica Acta, Vol 49, Fasc. Emile Cherbuliez (1966) No. 26, 214- 234, 4- (piperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulene compound is obtained from Helvetica Chimica Acta, vol. 54, Fasc. 1 (1971), 277- 282, 4- (piperidin-4-ylidene) -4H-3-thiabenzo [f] azulene compounds are disclosed in JP-A 49-69677, Helvetica Chimica Acta, Vol 49, Fasc. Emile Cherbuliez (1966) No. 26, 214-234 and Helvetica Chimica Acta, Vol 54, Fasc. 1 (1971), 277-282, 4- (piperidin-4-ylidene) -10-oxo-9,10-dihydro-4H- 1-thiabenzo [f] azulene compounds are described in Helvetica Chimica Acta, vol. 59, Fasc. 3 (1976), 8 66-877, 4- (piperidin-4-ylidene) -4,10-dihydro-9-oxa-1-thiabenzo [f] azulene compound and 4- (piperidin-4-ylidene) -4,10 -Dihydro-9-oxa-3-thiabenzo [f] azulene compounds can be produced according to the method described in WO2005 / 003131.

Functionalization of the aromatic ring can be achieved by bromination using bromine or NBS (N-bromosuccinimide), lithiation reaction using an alkyl lithium reagent, Friedel-Crafts acylation reaction, Vilsmeier formylation reaction, etc. . In addition, brominated compounds are introduced with a desired functional group by a carbonylation reaction, Heck reaction, cyanation reaction, formylation reaction, Ullmann reaction, Suzuki coupling reaction, etc., using a transition metal catalyst such as palladium as appropriate. It can also be synthesized by selecting a starting material having an arbitrary substituent at a corresponding position in advance.

(1) When A is unsubstituted 4- (piperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulene compound of general formula (II), 4- (piperidin-4-ylidene) ) -4H-1-thiabenzo [f] azulene compound, 4- (piperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulene compound, 4- (piperidin-4-ylidene)- 4H-3-thiabenzo [f] azulene compound, 4- (piperidin-4-ylidene) -4,10-dihydro-9-oxa-1-thiabenzo [f] azulene compound and 4- (piperidin-4-ylidene)- A general method for producing 4,10-dihydro-9-oxa-3-thiabenzo [f] azulene compounds is shown below. The compound of general formula (II) can be obtained by alkylation reaction, Ullmann reaction or Michael reaction of the compound of general formula (III). For example, the alkylation reaction is carried out in the presence of a base such as potassium carbonate, sodium hydride or potassium butoxide in a solvent such as acetone, benzene or DMF (dimethylformamide) at a suitable temperature between room temperature and the boiling point of the solvent. , Alkyl halide or the like.

The compound of general formula (III) is obtained by alkaline hydrolysis, hydrobromic acid decomposition, and reduction reaction of the compound of general formula (IV). For example, the alkaline hydrolysis reaction is performed by heating to reflux in a solvent such as butanol or isopropanol in the presence of a strong base such as sodium hydroxide or potassium hydroxide.

The compound of the general formula (IV) can be synthesized by a carbonyl reaction of the compound of the general formula (V). For example, it is carried out by heating under reflux in a solvent such as benzene or dichloroethane in the presence of ethyl chloroformate or 2,2,2-trichloroethyl chloroformate.

The compound of the general formula (V) is appropriately converted into a cyanation reaction, a carbonylation reaction, a Heck reaction, an alkylation reaction, a formylation reaction, or a compound of the general formula (VI) using a palladium catalyst. It is obtained by Suzuki coupling reaction after converting to a boric acid compound. For example, the cyanation reaction uses copper cyanide, zinc cyanide, ferric ferrocyanide, sodium cyanate, Pd (dba) ₂ (bis (dibenzylideneacetone) palladium (0)), Pd ₂ (dba) ₃ (Tris (di Benzylideneacetone) dipalladium (0)), Pd (OAc) ₂ (palladium (II) acetate), Pd (PPh ₃ ) ₄ (tetrakis (triphenylphosphine) palladium (0)) in the presence of DPPF (1,1 '-Bis (diphenylphosphino) ferrocene), PPh ₃ (triphenylphosphine), P (o-tol) ₃ (tris (2-methylphenyl) phosphine), P (t-Bu) ₃ (tri-tert.- Butylphosphine), N, N ′-(2,6-diisopropylphenyl) dihydroimidazolium chloride and the like. The reaction can be carried out in a suitable solvent such as DMF, water, acetone, acetonitrile, toluene, THF (tetrahydrofuran) or mixtures thereof, preferably at a suitable temperature between room temperature and the boiling point of the solvent.

The compound of general formula (VI) is obtained by bromination of the compound of general formula (VII). Bromine, NBS, or the like can be used as the brominating agent. The reaction can be carried out in a suitable solvent such as acetic acid, chloroform, carbon tetrachloride, ethyl acetate, methanol or mixtures thereof, preferably at a suitable temperature between 0 ° C. and the boiling point of the solvent.

The compound of general formula (VII) is obtained by dehydration reaction or McMurry reaction after Grignard reaction of the compound of general formula (VIII). For example, the Grignard reaction is carried out by using a Grignard reagent prepared from magnesium and 4-chloro-N-methylpiperidine in an anhydrous solvent such as THF and toluene at a suitable temperature from the melting point to the boiling point of the solvent at the compound of general formula (VIII). By reacting with. Subsequent dehydration reaction can be carried out using hydrochloric acid, trifluoroacetic acid, thionyl chloride, etc. without solvent or in a suitable solvent such as water, ethanol, dichloromethane, etc., at the optimum reaction temperature from the melting point to the boiling point of the solvent. . The compound of the general formula (VIII) can be synthesized according to the method of JP-A-49-69677, Helvetica Chimica Acta, vol. 54, Fasc. 1 (1971), 277-282, WO2005 / 003131.

(2) When A is oxo 4- (piperidin-4-ylidene) -10-oxo-9,10-dihydro-4H-1-thiabenzo [f] azulene compound of general formula (IX) is represented by the general formula (X ) And the alcohol dehydration reaction at the same time. This reaction can be carried out using an inorganic acid such as hydrochloric acid or an organic acid and a water-containing solvent such as water or ethanol at a temperature between room temperature and the boiling point.

The compound of the general formula (X) is appropriately converted to a cyanation reaction, a carbonylation reaction, a Heck reaction, an alkylation reaction, a formylation reaction, or a compound of the general formula (XI) using a palladium catalyst. It is obtained by Suzuki coupling reaction after converting to a boric acid compound. For example, the cyanation reaction uses copper cyanide, zinc cyanide, ferric ferrocyanide, sodium cyanate, and in the presence of Pd (dba) ₂ , Pd ₂ (dba) ₃ , Pd (OAc) ₂ , Pd (PPh ₃ ) ₄ , DPPF, PPh ₃ , P (o-tol) ₃ , P (t-Bu) ₃ , N, N ′-(2,6-diisopropylphenyl) dihydroimidazolium chloride and the like. The reaction can be carried out in a suitable solvent such as DMF, water, acetone, acetonitrile, toluene, THF or mixtures thereof, preferably at a suitable temperature between room temperature and the boiling point of the solvent.

The compound of general formula (XI) is obtained by Grignard reaction of the compound of general formula (XII). For example, the Grignard reaction is carried out by using a Grignard reagent prepared from magnesium and 4-chloro-N-methylpiperidine in an anhydrous solvent such as THF and toluene at a suitable temperature from the melting point to the boiling point of the solvent at a compound of the general formula (XII). It can be performed by reacting with.

The compound of the general formula (XII) can be obtained by a β elimination reaction subsequent to the methanol decomposition reaction of the compound of the general formula (XIII). For example, methanol decomposition is performed by heating and refluxing in methanol. The β-elimination reaction is carried out at room temperature using a base such as DBU (1,8-diazabicyclo [5,4,0] unde-7-ene), triethylamine, or potassium butoxide in a solvent such as THF, benzene, toluene, or methanol. To a boiling point of the solvent.

The compound of general formula (XIII) is synthesized by bromination reaction using NBS or the like of the compound of general formula (XIV). For example, the bromination reaction is carried out by heating and refluxing in a suitable solvent such as chloroform, carbon tetrachloride, dichloroethane, toluene using a small amount of benzoyl peroxide as an initiator.

The compound of the general formula (XIV) is synthesized by bromination of the compound of the general formula (XV) with bromine. Bromination is carried out in a solvent such as chloroform, acetic acid and methanol at a suitable temperature from the melting point to the boiling point.

The compound of the general formula (XV) is synthesized by intramolecular Friedel-Crafts reaction of the compound of the general formula (XVI). For example, the intramolecular Friedel-Crafts reaction remains as a carboxylic acid, or after conversion to acid chloride or mixed anhydride, if necessary, polyphosphoric acid, aluminum chloride, titanium chloride, tin chloride, BF ₃ · OEt ₂ In the presence of a Lewis acid such as (boron trifluoride / diethyl ether complex), use a solvent such as THF, dichloromethane, chloroform, dichloroethane, carbon disulfide, nitrobenzene, etc. Performed at an appropriate temperature.

The compound of the general formula (XVI) can be synthesized by Aldol reaction, Wittig reaction, Wittig-Horner reaction, Peterson reaction, etc. of the compound of general formula (XVII). For example, when the Wittig reaction is used, the compound of general formula (XVII) is brominated with a methyl group using NBS and then reacted with triphenylphosphine to obtain a phosphonium salt. At this time, the bromination reaction is carried out by heating and refluxing in a solvent such as carbon tetrachloride or dichloroethane using a small amount of benzoyl peroxide or the like as a reaction initiator. The reaction of benzyl bromide obtained by bromination reaction and triphenylphosphine is carried out by heating in a solvent such as benzene, toluene, dichloroethane and the like. The obtained phosphonium salt can be converted into an ylide using a base such as butoxy potassium or sodium hydride, condensed with thiophene aldehyde, and finally reduced to a compound of the general formula (XVI) by reducing the double bond. At this time, the reaction between the phosphonium salt and thiophene aldehyde is carried out at a suitable temperature from the melting point to the boiling point of the solvent in a solvent such as THF, acetonitrile, benzene, and toluene. Reduction of the double bond of the Wittig reaction product is performed by catalytic reduction using a palladium catalyst or a Willkinson complex, catalytic hydrogen transfer reaction or hydrazine reduction.

  The compound represented by the general formula (I) includes various salts when pharmaceutically acceptable salts exist, such as hydrochloric acid, oxalic acid, fumaric acid, p-toluenesulfonic acid, Mention may be made of addition salts with acids with maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, nitric acid and the like. The salt of the carboxyl group can also include a suitable alkali metal salt such as sodium, potassium, calcium and the like. These salts can be produced from each free compound by known methods, or can be converted into each other. In addition, even when it exists in the form of a stereoisomer such as a cis-trans isomer, an optical isomer, a conformer, a hydrate or a metal complex compound, any stereoisomer, hydrate and complex thereof. The invention also encompasses compounds.

  The compound of the present invention can be made into a medicine in combination with a suitable pharmaceutical carrier or diluent, and can be formulated by any ordinary method, and as an oral preparation such as a tablet, capsule, powder, liquid, etc. Or as a parenteral for subcutaneous, intramuscular, rectal or intranasal administration. In prescribing, the compound of the present invention may be used in the form of a pharmaceutically acceptable salt thereof, may be used alone or in combination as appropriate, and may be combined with other pharmaceutically active ingredients.

  For oral administration, as it is or with suitable additives such as lactose, mannitol, corn starch, potato starch and other conventional excipients, binders such as crystalline cellulose, cellulose derivatives, gum arabic, corn starch and gelatin , Corn starch, potato starch, disintegrants such as carboxymethylcellulose potassium, lubricants such as talc and magnesium stearate, other bulking agents, wetting agents, buffering agents, preservatives, fragrances, etc. It can be a granule or a capsule.

  Depending on the type of disease and the patient, it is formulated into a dosage form other than those optimal for the treatment, such as injections, suppositories, inhalants, aerosols, syrups, eye drops and ointments can do.

  The desired dose of the compound of the present invention varies depending on the administration subject, dosage form, administration method, administration period, etc. In order to obtain the desired effect, the compound of the present invention is generally 0.5 to 1000 mg, preferably 1 for adults. Up to 500 can be administered orally in 1 to several divided doses per day. In the case of parenteral administration (for example, injection), the daily dose is preferably a dose level of 3 to 1/10 of the respective dose.

EXAMPLES Next, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto. However, Example 1 related to Compound 212, Example 2 related to Compound 1 and Example 8 related to Compound 2 are reference examples.
The melting point was measured with a Yamato MP-21 melting point measuring instrument after putting the sample in a glass capillary (the thermometer was not corrected). MS spectra were measured with POLARIS Q (Thermo Quest). ¹ H-NMR was measured with a Bruker ARX500 nuclear magnetic resonance apparatus, and the chemical shift value was expressed in ppm based on TMS (δ = 0 ppm) added as an internal standard. Silica gel column chromatography was performed using silica gel BW-127ZH (Fuji Silysia Chemical) for chromatography. Thin layer chromatography used Silica gel F254 (Merck, No. 5715), and detected using a UV lamp and a 5% phosphomolybdic acid-ethanol coloring reagent.

Example 1.
Preparation of 4- (2-bromo-9,10-dihydro-1-thiabenzo [f] azulen-4-ylidene) -1-methylpiperidine [Compound 212]
To a solution of 4- (9,10-dihydro-1-thiabenzo [f] azulen-4-ylidene) -1-methylpiperidine (5.76 g, 19.5 mmol) in chloroform (50 mL) at 0 ° C. with bromine (1.0 mL, 19.5 mmol) was added dropwise. After stirring at room temperature for 2 hours, saturated aqueous sodium hydrogen carbonate was added, and the organic layer was separated. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (chloroform-methanol = 9: 1) to obtain 5.6 g (91%) of the title compound as white crystals.
Mp. 141-142 ° C. MS (EI): m / z 375 [M ⁺ +2], 373 [M ⁺ ]. ¹ H-NMR (DMSO-d ₆ ) δ: 1.90-2.79 (m, 13H), 3.18-3.22 (m, 2H), 6.85 (s, 1H), 6.98-7.30 (m, 4H).

Example 2
4- (2-Cyano-9,10-dihydro-1-thiabenzo [f] azulen-4-ylidene) -1-methylpiperidine hydrochloride [Compound 1] The compound obtained in Example 1 (5.0 g, 14.7 mmol) in DMF (25 mL) under an argon atmosphere, Zn (CN) ₂ (0.94 g, 8.8 mmol), Pd ₂ (dba) ₃ (0.61 g, 0.74 mmol), DPPF (0.89 g, 1.8 mmol) was added and stirred at 80 ° C. overnight. Insoluble material was removed by filtration, saturated brine (50 mL) was added to the filtrate, and the product was extracted with ethyl acetate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform-methanol = 9: 1), and the resulting oil was treated with 4 mol / L hydrogen chloride-dioxane to give the title compound. 1.9 g (40%) was obtained as crystals.

Example 3
Preparation of 4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulene-2-carboxylic acid [compound 4] of hydrochloric acid Compound 1 (1.5 g, 4.2 mmol) A 2 mol / L aqueous sodium hydroxide solution (20 mL) was added to an ethanol (10 mL) solution, and the mixture was stirred overnight with heating under reflux. Ethanol was distilled off under reduced pressure, 6 mol / L hydrochloric acid was added to the resulting residue, and the precipitated crystals were collected by filtration and washed thoroughly with water. This was dried at 50 ° C. over phosphorus pentoxide under reduced pressure to obtain 0.96 g (67%) of the title compound.

Example 4
Preparation of ethyl 4- (1-methylpiperidine-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulene-2-carboxylate [Compound 3] Then thionyl chloride (0.24 mL, 0.32 mmol) was added dropwise. Compound 4 (100 mg, 0.29 mmol) was added to the solution, and the mixture was stirred at room temperature for 30 minutes and then heated to reflux for 2 hours. After allowing to cool, the solvent was distilled off under reduced pressure, and the precipitated crystals were separated by filtration and dried to give 107 mg (100%) of the title compound as white crystals.

Example 5 FIG.
Preparation of ethyl [4- (1-ethoxycarbonylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylate [Compound 61] Compound 3 (22.0 g, To a solution of 59.9 mmol) in dichloroethane (140 mL) was added ethyl chlorocarbonate (57 mL, 599 mmol), and the mixture was stirred overnight with heating under reflux. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform) to obtain 26.3 g (100%) of the title compound.

Example 6
Preparation of ethyl [4- (piperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] carboxylate [Compound 62] Compound 61 (10.5 g, 24.7 mmol) A 33% hydrogen bromide-acetic acid solution (23 mL, 133.2 mmol) was added to the acetic acid (90 mL) solution, and the mixture was heated to reflux for 5 hours. After allowing to cool, the solvent was distilled off under reduced pressure, and the precipitated crystals were separated by filtration and dried to obtain 8.8 g (82%) of the title compound.

Example 7
{4- {1- [4- (4-t-Butylphenyl) -4-oxobutyl] piperidin-4-ylidene} -9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl} carvone Preparation of ethyl acid [Compound 109] Compound 62 (3.0 g, 6.9 mmol) in DMF (75 mL) solution in triethylamine (2.1 mL, 15.1 mmol), 1- (4-tert-butylphenyl) -4-chlorobutane-1 -On (1.98 g, 8.3 mmol) was added and stirred at 80 ° C. for 21 hours. After evaporating the solvent under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 0.9 g (23%) of the title compound.

Example 8 FIG.
Preparation of 2-bromo-4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulene [compound 2] hydrobromide
Bromine (0.52) was added to a solution of 4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulene (3.0 g, 10.2 mmol) in chloroform (30 mL) at 0 ° C. mL, 10.2 mmol) was added dropwise. After stirring at room temperature for 2 days, saturated aqueous sodium hydrogen carbonate was added, and the organic layer was separated. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (chloroform-methanol = 9: 1) to obtain 3.8 g (100%) of the title compound as white crystals.

Example 9
Preparation of ethyl 3- [4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-3-thiabenzo [f] azulen-2-yl] acrylate [Compound 22] Compound 2 (9.2 g , 24.5 mmol) in DMF (160 mL), triethylamine (35.5 mL, 255 mmol), ethyl acrylate (26.8 mL, 246 mmol), palladium acetate (0.4 g, 1.8 mmol), tri (o-toluyl) phosphine (1.5 g, 5.0 mmol) was added, and the mixture was stirred overnight at 80 ° C. under an argon atmosphere. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by column chromatography (chloroform-methanol = 9: 1) to obtain 7.6 g (79%) of the title compound as white crystals.

Example 10
Preparation of 4- (6-bromo-10H-9-oxa-3-thiabenzo [f] azulen-4-ylidene) -1-methylpiperidine
A Grignard reagent prepared from 4-chloro-N-methylpiperidine (20 mL, 150 mmol) and magnesium metal (3.6 g, 150 mmol), dibromoethane (0.1 mL), THF (200 mL) was added to 6-bromo-10H. -9-oxa-3-thiabenzo [f] azulen-4-one (21.6 g, 100 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, and a saturated aqueous ammonium chloride solution was added to the solution to stop the reaction. Then, the product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was dissolved in dichloromethane (300 mL), trifluoroacetic acid (77 mL, 1.0 mol) was added, and the mixture was stirred overnight. The solvent was distilled off under reduced pressure, and saturated aqueous sodium hydrogen carbonate was added. The product was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (hexane-ethyl acetate = 3: 2) to obtain 16.2 g (81%) of the title compound.
MS (EI): m / z 378.0 [M ⁺ +1]. ¹ H-NMR (DMSO-d ₆ ) δ: 2.09-2.77 (m, 11H), 4.85 (d, J = 15.5 Hz, 1H), 5.42 (d, J = 15.5 Hz, 1H), 6.81-7.45 (m, 5H).

Example 11
Production of 2- [4- (1-methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl] propionic acid [compound 57] hydrochloride under argon atmosphere Hexamethyldisilazane (5.0 mL, 31.2 mmol) was ice-cooled and 1.6 mol / L butyllithium-hexane solution (19.5 mL, 31.2 mmol) was added dropwise. After stirring for 30 minutes, propionate-t-butyl (2.1 g, 16.1 mmol) was added dropwise to the solution and stirred for 30 minutes. Further, Pd (dba) ₂ (0.45 g, 0.8 mmol), N, N '-(2,6-diisopropylphenyl) dihydroimidazolium chloride (0.34 g, 0.8 mmol) was added, and the mixture was stirred for 10 minutes, and then 4- ( A solution of 6-bromo-10H-9-oxa-3-thiabenzo [f] azulen-4-ylidene) -1-methylpiperidine (3.0 g, 8.0 mmol) in toluene (25 mL) was added dropwise. After stirring overnight at room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent of the organic layer was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate). The purified compound was dissolved in dioxane (10 mL), 4 mol / L hydrogen chloride-dioxane solution (12.5 mL, 50 mmol) was added, and the mixture was stirred overnight. The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration to obtain 1.5 g (69%) of the title compound.

Example 12
Preparation of 2-bromo-9,10-dihydro-1-thiabenzo [f] azulen-4-one
Bromine (8.5 mL, 165 mmol) was added dropwise to a solution of 9,10-dihydro-1-thiabenzo [f] azulen-4-one (23.2 g, 108 mmol) in chloroform (300 mL), and the mixture was stirred for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 22.0 g (69%) of the title compound.
MS (EI): m / z 294 [M ⁺ +2], 292 [M ⁺ ]. ¹ H-NMR (DMSO-d ₆ ) δ: 3.19 (s, 4H), 7.38-7.42 (m, 2H), 7.52-7.55 (m, 2H), 7.78-7.79 (m, 1H).

Example 13
Preparation of 2,9,10-tribromo-9,10-dihydro-1-thiabenzo [f] azulen-4-one To a solution of the compound obtained in Example 12 (53.9 g, 184 mmol) in dichloroethane (500 mL) NBS (65.4 g, 367 mmol) and benzoyl peroxide (0.1 g, 0.5 mmol) were added, and the mixture was heated to reflux for 4 hours. The reaction mixture was allowed to cool, saturated potassium carbonate was added, and the organic layer was separated. The organic layer was further washed with saturated potassium carbonate and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 76.8 g (93%) of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 5.96 (d, J = 5.3 Hz, 1H), 6.22 (d, J = 5.3 Hz, 1H), 7.67-7.74 (m, 4H), 8.03-8.05 (m , 1H).

Example 14
Preparation of 2-bromo-10-methoxy-1-thiabenzo [f] azulen-4-one A solution of the compound obtained in Example 13 (90.2 g, 200 mmol) in methanol (1100 mL) was heated to reflux overnight. After allowing to cool, DBU (63.4 g, 417 mmol) was further added, and the mixture was further heated to reflux overnight. The reaction mixture was allowed to cool, and the precipitated crystals were collected by filtration and dried to obtain 55.7 g, 173 mmol (2 steps, 87%) of the title compound.
MS (EI): m / z 322 [M ⁺ +2], 320 [M ⁺ ]. ¹ H-NMR (DMSO-d ₆ ) δ: 4.02 (s, 3H), 6.98 (s, 1H), 7.61- 7.62 (m, 1H), 7.77-7.80 (m, 1H), 7.90-7.96 (m, 2H), 8.46-8.47 (m, 1H).

Example 15.
Preparation of 2-bromo-10-methoxy-4- (1-methylpiperidin-4-yl) -4H-1-thiabenzo [f] azulen-4-ol
The Grignard reagent prepared from 4-chloro-N-methylpiperidine (2.7 mL, 20 mmol) and magnesium metal (0.49 g, 21 mmol), dibromoethane (0.2 mL), THF (20 mL) was obtained in Example 14. The resulting compound (4.27 g, 13.3 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, and saturated ammonium chloride aqueous solution was added to the solution to stop the reaction, and then the product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 2.8 g (50%) of the title compound.
MS (EI): m / z 422 [M ⁺ +3], 420 [M ⁺ +1]. ¹ H-NMR (DMSO-d ₆ ) δ: 0.41-0.43 (m, 1H), 0.77-0.87 (m , 2H), 1.18-1.52 (m, 3H), 1.83-1.92 (m, 1H), 1.99 (s, 3H), 2.50-2.55 (m, 1H), 2.64-2.66 (m, 1H), 5.83 (s , 1H), 6.40 (s, 1H), 7.22-7.26 (m, 2H), 7.31-7.34 (m, 1H), 7.38-7.39 (m, 1H), 7.72-7.73 (m, 1H).

Example 16
Preparation of [4-hydroxy-10-methoxy-4- (1-methylpiperidin-4-yl) -4H-1-thiabenzo [f] azulen-2-yl] ethyl acetate Hexamethyldisilazane ( 16.8 g, 104 mmol) was ice-cooled, and 1.6 mol / L butyllithium-hexane solution (65 mL, 104 mmol) was added dropwise. After stirring for 30 minutes, ethyl acetate (5 mL, 51 mmol) was added dropwise to the solution and stirred for 30 minutes. Further, Pd (dba) ₂ (1.5 g, 2.6 mmol), N, N ′-(2,6-diisopropylphenyl) dihydroimidazolium chloride (1.1 g, 2.6 mmol) were added, and the mixture was stirred for 10 minutes, and then Example 15 A toluene (100 mL) solution of the compound obtained in (5.0 g, 12 mmol) was added dropwise. After stirring overnight at room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent of the organic layer was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 3.1 g (60%) of the title compound.
MS (EI): m / z 428 [M ⁺ +1]. ¹ H-NMR (DMSO-d ₆ ) δ: 0.41-0.78 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H), 1.30 -1.83 (m, 5H), 1.99 (s, 3H), 2.50-2.63 (m, 2H), 3.84-3.92 (m, 5H), 4.08 (q, J = 7.1 Hz, 2H), 5.68 (s, 1H ), 6.33 (s, 1H), 7.10 (s, 1H), 7.20-7.74 (m, 4H).

Example 17.
Preparation of [4- (1-methylpiperidin-4-ylidene) -10-oxo-9,10-dihydro-4H-1-thiabenzo [f] azulen-2-yl] acetic acid [Compound 87] Obtained in Example 16 To a solution of the obtained compound (2.0 g, 4.7 mmol) in ethanol (24 mL) was added hydrochloric acid (8 mL), and the mixture was heated to reflux overnight. After the solvent was distilled off, water (20 mL) and sodium hydroxide (0.8 g, 20 mmol) were added to the residue, and the mixture was stirred overnight at room temperature. The liquid was adjusted to pH = 6.5 with hydrochloric acid, and the precipitated crystals were separated by filtration and dried to obtain 0.68 g (39%) of the title compound.

Example 18
Production of ethyl (4-hydroxyphenylsulfanyl) acetate
To a solution of 4-mercaptophenol (23.1 g, 183 mmol) in DMF (450 mL) were added ethyl bromoacetate (21.5 mL, 194 mmol) and potassium carbonate (50.7 g, 367 mmol), and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain 30.3 g (78%) of the title compound.
MS (EI): m / z 212 [M ⁺ ]. ¹ H-NMR (DMSO-d ₆ ) δ: 1.11 (t, J = 7.1 Hz, 3H), 3.60 (s, 2H), 4.03 (q, J = 7.1 Hz, 2H), 6.72-6.74 (m, 2H), 7.25-7.27 (m, 2H), 9.64 (s, 1H).

Example 19.
Preparation of methyl 3- (4-ethoxycarbonylmethylsulfanylphenoxymethyl) thiophene-2-carboxylate To a solution of the compound obtained in Example 18 (28.1 g, 132 mmol) in DMF (300 mL), 3-bromomethylthiophene- Methyl 2-carboxylate (28.2 ml, 120 mmol) and potassium carbonate (36.6 g, 264 mmol) were added, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain 35.1 g (80%) of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.11 (t, J = 7.1 Hz, 3H), 3.70 (s, 2H), 3.83 (s, 3H), 4.04 (q, J = 7.1 Hz, 2H), 5.41 (s, 2H), 6.96-7.38 (m, 5H), 7.89-7.90 (m, 1H).

Example 20.
Preparation of 3- (4-carboxymethylsulfanylphenoxymethyl) thiophene-2-carboxylic acid To a solution of the compound obtained in Example 19 (35.1 g, 96 mmol) in methanol (250 mL) was added sodium hydroxide (19.2 g, 480 mmol) Aqueous solution was added and heated to reflux for 2 hours. After allowing to cool, the solvent was distilled off under reduced pressure, and water was added to the residue. The solution was neutralized with hydrochloric acid, and the precipitated crystals were separated by filtration and dried to obtain 30.0 g (97%) of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 3.64 (s, 2H), 5.41 (s, 2H), 6.94-7.36 (m, 5H), 7.79-7.80 (m, 1H), 13.04 (brs, 2H) .

Example 21.
Preparation of (4-oxo-4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-ylsulfanyl) acetic acid Compound (29.0 g, 89 mmol) obtained in Example 20 from dichloroethane (300 mL) To the solution was added trifluoroacetic anhydride (28.0 mL, 201 mmol), and the mixture was stirred at 60 ° C overnight. The solvent was distilled off under reduced pressure, and water was added to the residue. The precipitated crystals were separated by filtration and dried to obtain 26.7 g (98%) of the title compound.
MS (EI): m / z 307 [M ⁺ +1]. ¹ H-NMR (DMSO-d ₆ ) δ: 3.81 (s, 2H), 5.31 (s, 2H), 7.20-8.10 (m, 5H) , 12.78 (brs, 1H).

Example 22.
Preparation of methyl (4-oxo-4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-ylsulfanyl) acetate DMF (26.1 g, 85 mmol) of the compound obtained in Example 21 (200 mL) Methyl iodide (6.5 mL, 104 mmol) and potassium hydrogen carbonate (17.0 g, 170 mmol) were added to the solution, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain 24.0 g (88%) of the title compound.
MS (EI): m / z 320 [M ⁺ ]. ¹ H-NMR (DMSO-d ₆ ) δ: 3.64 (s, 3H), 3.91 (s, 2H), 5.31 (s, 2H), 7.20-7.27 (m, 2H), 7.63-7.66 (m, 1H), 7.97-8.10 (m, 2H).

Example 23.
Preparation of methyl [4-hydroxy-4- (1-methylpiperidin-4-yl) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-ylsulfanyl] acetate magnesium (2.8 g, 116 mmol), 4-chloro-1-methylpiperidine (15.5 mL, 116 mmol), Grignard reagent prepared from THF (180 mL) was ice-cooled, and the compound obtained in Example 22 (18.5 g, 58 mmol) Of THF (120 mL) was added dropwise. After reacting for 30 minutes, saturated ammonium chloride was added and the product was extracted with ethyl acetate. The organic layer was washed successively with saturated ammonium chloride and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to obtain 4.4 g (18%) of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 0.78-0.80 (m, 1H), 1.34-1.64 (m, 5H), 2.05 (s, 3H), 2.26-2.29 (m, 1H), 2.63-2.75 ( m, 2H), 3.61 (s, 3H), 3.80-3.87 (m, 2H), 4.74 (d, J = 15.5 Hz, 1H), 5.38 (d, J = 15.5 Hz, 1H), 6.06 (s, 1H ), 6.70-6.71 (m, 1H), 7.09-7.48 (m, 4H).

Example 24.
Preparation of methyl [4- (1-methylpiperidin-4-yl) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-ylsulfanyl] acetate Compound obtained in Example 23 ( To a solution of 5.7 g, 14 mmol) in dichloromethane was added trifluoroacetic acid (10 mL), and the mixture was stirred overnight at room temperature. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to give a free compound. Then 4 mol / L hydrogen chloride-dioxane (8.0 mL, 32 mmol) was added. Stir for 1 hour. The solvent was distilled off under reduced pressure, and ether was added to the residue for crystallization. The precipitated crystals were separated by filtration and dried to obtain 4.1 g (69%) of the title compound.
Mp. 210-212 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 2.36-3.60 (m, 11H), 3.60 (s, 3H), 3.81-3.93 (m, 2H), 4.87 (d, J = 15.3 Hz, 1H), 5.45 (d, J = 15.3 Hz, 1H), 6.85-7.53 (m, 5H), 10.67 (brs, 1H).

Example 25.
Preparation of [4- (1-methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-ylsulfanyl] acetic acid [Compound 172] Obtained in Example 24 An aqueous solution of sodium hydroxide (1.4 g, 680 mmol) was added to a solution of the compound (2.9 g, 6.7 mmol) in ethanol (40 mL), and the mixture was heated to reflux for 2 hours. After allowing to cool, the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was neutralized with hydrochloric acid. The precipitated crystals were separated by filtration and dried to obtain 1.3 g (50%) of the title compound.

Example 26.
Preparation of 4- (1-methylpiperidin-4-ylidene) -9,10-dihydro-4H-1-thiabenzo [f] azulene-2-carboxylic acid 1-cyclohexyloxycarbonyloxyethyl hydrochloride [Compound 176] To a solution of 3.0 g, 8.84 mmol) in DMF (50 mL), add triethylamine (6.2 mL, 44.2 mmol), potassium iodide (4.4 g, 26.5 mmol), and 1-chloroethylcyclohexyl carbonate (2.2 g, 10.6 mmol) .80 Stir overnight at ° C. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1). The obtained free amino acid was dissolved in dioxane (20 mL), 4 mol / L hydrogen chloride-dioxane was added, and the mixture was stirred for 1 hour. The solvent was distilled off under reduced pressure, and ether was added to crystallize the hydrochloride. The crystals were separated by filtration and dried to obtain 1.8 g (2 steps 37%) of the title compound.

Example 27.
Preparation of 4- (2-bromo-10H-9-oxa-3-thiabenzo [f] azulen-4-ylidene) -1-methyl-piperidine
To a solution of 1-methyl-4- (10H-9-oxa-3-thiabenzo [f] azulen-4-ylidene) piperidine (19.3 g, 65.0 mmol) in chloroform (300 mL) was added bromine (5 mL, 98 mmol) was added dropwise. After stirring at 0 ° C. for 2 hours, a saturated aqueous sodium hydrogen carbonate solution was added and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (chloroform: methanol = 9: 1). Crystallization from petroleum ether yielded 11.2 g (46%) of the title compound.
Mp. 101-103 ℃. ¹ H-NMR (CDCl ₃ ) 2.10-2.71 (m, 11H), 4.76 (d, J = 15.4 Hz, 1H), 5.36 (d, J = 15.4 Hz, 1H), 6.93 ( s, 1H), 7.08-7.12 (m, 3H), 7.26-7.29 (m, 1H).

Example 28.
Preparation of [4- (1-methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-2-yl] acetic acid t-butyl ester Silazane (11.97 g, 74.2 mmol) was ice-cooled, and 1.6 mol / L n-butyllithium-hexane solution (46.6 mL, 74.6 mmol) was added dropwise. To the solution, t-butyl acetate (4.9 mL, 36.7 mmol) was added dropwise and stirred for 30 minutes. Pd (dba) ₂ (1.05 g, 1.8 mmol), N, N ′-(2,6-diisopropylphenyl) dihydroimidazolium chloride (0.80 g, 1.9 mmol), the compound obtained in Example 27 (7.0 g, 18.6 mmol) was added and the mixture was warmed to room temperature and stirred overnight. Water was added to the reaction mixture, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The organic layer was evaporated under reduced pressure, and the residue was purified by column chromatography (hexane: ethyl acetate = 9: 1) to give 3.30 g (43%) of the title compound as an oil.
MS (EI): m / z 412 [M ⁺ +1]. ¹ H-NMR (DMSO-d ₆ ) δ: 1.40 (s, 9H), 2.11-2.28 (m, 6H), 2.39-2.57 (m, 3H), 2.68-2.74 (m, 2H), 3.70 (s, 2H), 4.76 (d, J = 15.4 Hz, 1H), 5.36 (d, J = 15.4 Hz, 1H), 6.58 (s, 1H), 7.05-7.10 (m, 3H), 7.25 (dd, J = 2.3, 8.5 Hz, 1H).

Example 29.
Preparation of hydrochloric acid [4- (1-methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-2-yl] acetic acid [Compound 58] 4 mol / L hydrogen chloride-dioxane solution (10 mL, equivalent to 40 mmol hydrogen chloride) was added to a dioxane (30 mL) solution of the above compound (2.21 g, 5.4 mmol), and the mixture was stirred at 40 ° C. for 8 hours. The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration to obtain 1.70 g (81%) of the title compound as crystals containing 0.5 equivalent of dioxane.

Example 30. FIG.
Preparation of {4- [1- (4-oxopentyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} acetic acid methyl ester
(4-Piperidin-4-ylidene-4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl) methyl acetate (2.50 g, 7.0 mmol), anhydrous potassium carbonate (2.15 g, 15.6 mmol ), 5-chloro-2-pentanone (2.4 mL, 20.9 mmol) was added to a solution of potassium iodide (1.41 g, 8.5 mmol) in DMF (50 mL), and the mixture was stirred at 80 ° C. overnight. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried using anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (chloroform: methanol = 19: 1) to obtain 2.40 g (78%) of the title compound as an oil.
MS (EI): m / z 439 [M ⁺ ]. ¹ H-NMR (DMSO-d ₆ ) δ: 1.63 (tt, J = 7.1, 7.1 Hz, 2H), 2.09 (s, 3H), 2.17-2.33 (m, 5H), 2.36-2.47 (m, 3H), 2.49-2.61 (m, 2H), 2.65-2.72 (m, 2H), 3.59 (s, 3H), 3.61 and 3.65 (ABq, J = 15.7 Hz , 2H), 4.82 (d, J = 15.3 Hz, 1H), 5.40 (d, J = 15.3 Hz, 1H), 6.79 (d, J = 5.2 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H ), 7.03 (d, J = 8.2 Hz, 1H), 7.13 (dd, J = 2.0, 8.2 Hz, 1H), 7.42 (d, J = 5.2 Hz, 1H).

Example 31.
Production Example of {4- [1- (4-Oxopentyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} acetic acid [Compound 170] 2 mol / L aqueous sodium hydroxide solution (5 mL, equivalent to 10 mmol of sodium hydroxide) was added to an ethanol (20 mL) solution of the compound obtained in 30 (2.40 g, 5.5 mmol), and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off, water was added to the residue, and the aqueous solution was adjusted to pH = 7 with dilute hydrochloric acid. The precipitated crystals were separated by filtration and dried to obtain 1.30 g (56%) of the title compound.

Example 32.
2-Methyl-2- [4- (1-methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-ylsulfanyl] propionic acid [Compound 190] 2-methyl-2- [4- (1-methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-ylsulfanyl] methyl propionate [ Compound 189] (0.88 g, 1.8 mmol) in ethanol (20 mL) was added a solution of sodium hydroxide (0.82 g, 20.6 mol) in water (10 mL) and heated to reflux for 6 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in water, neutralized with dilute hydrochloric acid, and the precipitated crystals were collected by filtration and dried to obtain 0.67 g (72%) of the title compound as crystals.

Example 33.
4- (2-Bromo-9,10-dihydro-1-thia-benzo [f] azulen-4-ylidene) piperidine-1-carboxylic acid ethyl ester Compound obtained in Example 1 (21.0 g, 56 mmol) in toluene (200 mL) was added ethyl chlorocarbonate (32 mL, 336 mmol) and heated to reflux for 6 hours. After allowing to cool, the reaction mixture was added to a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (hexane: ethyl acetate = 19: 1) to give the title compound as an oil As a product, 15.0 g (62%) was obtained.
MS (EI): m / z 433 [M ⁺ +2], 431 [M ⁺ ]. ¹ H-NMR (DMSO-d ₆ ) δ: 1.17 (t, J = 7.1 Hz, 3H), 2.10-2.23 ( m, 2H), 2.38-2.48 (m, 2H), 2.68-2.83 (m, 2H), 2.92-3.26 (m, 4H), 3.52-3.78 (m, 2H), 4.04 (q, J = 7.1 Hz, 2H), 6.90 (s, 1H), 7.02-7.13 (m, 1H), 7.16-7.36 (m, 3H).

Example 34.
4- [2- (2-Ethoxycarbonylvinyl) -9,10-dihydro-1-thiabenzo [f] azulen-4-ylidene] piperidine-1-carboxylic acid ethyl ester Compound obtained in Example 33 8.80 g, 17.0 mmol) in DMF (50 mL) under an argon stream, ethyl acrylate (18.5 mL, 170 mmol), triethylamine (24 mL, 170 mmol), palladium acetate (0.3 g, 1.3 mmol) and tri (O-Toluyl) phosphine (2.0 g, 6.6 mmol) was added and stirred at 80 ° C. overnight. After allowing to cool, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (hexane-ethyl acetate = 9: 1) to obtain 6.1 g (79%) of the title compound as an oil.
¹ H-NMR (DMSO-d ₆ ) δ: 1.18 (t, J = 7.0 Hz, 3H), 1.23 (t, J = 7.0 Hz, 3H), 2.11-2.16 (m, 1H), 2.20-2.28 (m , 1H), 2.38-2.48 (m, 2H), 2.78-2.86 (m, 2H), 2.96-3.14 (m, 1H), 3.20-3.32 (m, 3H), 3.55-3.61 (m, 1H), 3.68 -3.74 (m, 1H), 4.04 (q, J = 7.0 Hz, 2H), 4.15 (m, 2H), 6.06 (d, J = 15.7 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H) , 7.16-7.24 (m, 2H), 7.27 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 15.7 Hz, 1H).

Example 35.
4- [2- (2-Ethoxycarbonylethyl) -1-thiabenzo [f] azulen-4-ylidene] piperidine-1-carboxylic acid-t-butyl ester Compound obtained in Example 34 (6.10 g, 30% hydrogen bromide-acetic acid solution (3.8 mL, equivalent to 67.5 mmol hydrogen bromide) was added to a solution of 13.5 mmol) in acetic acid (50 mL), and the mixture was stirred at 120 ° C. for 4 hours. The reaction mixture was allowed to cool to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in etal (50 mL). A 2 mol / L aqueous sodium hydroxide solution (14 mL, equivalent to 28 mmol sodium hydroxide) And stirred at room temperature for 3 hours. After the solvent was distilled off, water was added to the residue, and the aqueous solution was adjusted to pH = 7 with dilute hydrochloric acid and extracted with chloroform. The organic layer was washed with saturated brine, the solvent was distilled off under reduced pressure, and di-t-butyldicarbonate (3.0 g, 13.7 mmol) was added to a dichloromethane (50 mL) solution of the residue. Stir for hours. Water was added, the organic layer was separated and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. To a DMF (50 mL) solution of the residue were added potassium hydrogen carbonate (4.0 g, 40.5 mmol) and ethyl iodide (1.1 mL, 13.5 mmol), and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (hexane: ethyl acetate = 19: 1) to obtain 2.9 g (45%) of the title compound as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.24 (t, J = 7.1 Hz, 3H), 1.45 (s, 9H), 2.08-2.14 (m, 1H), 2.20-28 (m, 1H), 2.30-2.36 (m, 2H), 2.65 (t, J = 7.6 Hz, 2H), 2.84-3.01 (m, 1H), 3.02 (m, 1H), 3.12 (t, J = 7.6 Hz, 1H), 3.56-3.70 ( m, 2H), 4.14 (q, J = 7.1 Hz, 1H), 6.59 (s, 1H), 6.76 (d, J = 11.5 Hz, 1H), 6.84 (d, J = 11.5 Hz, 1H), 7.10 ( d, J = 7.6 Hz, 1H), 7.23-7.28 (m, 1H), 7.31-7.36 (m, 2H).

Example 36.
3- (4-Piperidin-4-ylidene-4H-1-thiabenzo [f] azulen-2-yl) propionic acid ethyl ester Preparation of the compound (2.9 g, 6.0 mmol) of dioxane (30 mL) Hydrogen chloride-dioxane (7.5 mL, corresponding to 30 mmol of hydrogen chloride) was added to the solution, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (chloroform-methanol = 19: 1) to obtain 2.0 g (88%) of the title compound as an oil.
¹ H-NMR (DMSO-d ₆ ) δ: 1.15 (t, J = 7.1 Hz, 3H), 1.82-1.89 (m, 1H), 2.03-2.10 (m, 1H), 2.11-2.18 (m, 1H) , 2.26-2.32 (m, 1H), 2.44-2.58 (m, 1H), 2.60-2.68 (m, 2H), 2.70-2.82 (m, 1H), 3.02 (t, J = 7.3 Hz, 2H), 3.44 -3.52 (m, 1H), 3.65-3.74 (m, 1H), 4.04 (q, J = 7.1 Hz, 2H), 6.67 (s, 1H), 6.85 (d, J = 11.5 Hz, 1H), 6.89 ( d, J = 11.5 Hz, 1H), 7.09 (d, J = 7.5 Hz, 1H), 7.25-7.30 (m, 1H), 7.34-7.38 (m, 2H).

Example 37.
3- (4-Piperidin-4-ylidene-4H-1-thiabenzo [f] azulen-2-yl) propionic acid [Compound 209] Ethanol of the compound (2.0 g, 5.3 mmol) obtained in Example 36 A 2 mol / L aqueous sodium hydroxide solution (10 mL, equivalent to 20 mmol of sodium hydroxide) was added to the (30 mL) solution, and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off, water was added to the residue, and the pH was adjusted to 7 with dilute hydrochloric acid. The precipitated crystals were separated by filtration and dried to obtain 1.1 g (59%) of the title compound.

The compounds of the present invention other than the above were also prepared in the same manner according to the above general production method and the method described in the Examples, using appropriate raw materials instead of the raw materials in the Examples. Tables 1 to 17 show physical property data of the compounds of the present invention obtained by production. However, Compound 1, Compound 2, Compound 8, Compound 9, Compound 11, Compound 14, Compound 17, Compound 18, Compound 25, Compound 29, Compound 43, Compound 52, Compound 63, Compound 64, Compound 66, Compound 99, Compound 104, Compound 112, Compound 122, Compound 183, Compound 186, Compound 208, and Compound 212 are reference compounds because they do not correspond to the compound of the present invention.

Example 38.
In vitro human histamine H1 receptor binding experiment Recombinant human histamine H1 receptor plasmid (made by Invitrogen) was transfected into HEK293A cells using Lipofectamine2000 (Invitrogen). Human histamine H1 receptor stably expressing cells were selected using Geneticin (Invitrogen). The cells were treated with Dulbecco's Modified Eagle Medium containing 10% fetal bovine serum, 0.1 mmol / L MEM Non-Essential Amino Acids Solution, 2 mmol / L L-glutamine and 0.7 mg / mL geneticin, 5% CO _{2 at} 37 ° C. The culture was continued in an incubator. Human histamine H1 receptor stably expressing cells were prepared to be 3 × 10 ⁶ cells / mL using 50 mmol / L Tris-HCl (pH 7.5) (hereinafter buffer) containing 0.1% bovine serum albumin. A cell specimen was used. Add 50 μL of buffer solution, 50 μL of various concentrations of test substance solution and 50 μL of [ ³ H] pyrilamine solution (final concentration: 3 nmol / L) to each well of a 96-well plate, and then stir 100 μL cell specimens (3 × 10 ⁵ cells / well) were added to initiate the reaction.

After incubation at room temperature for 60 minutes, the reaction was stopped by filtration using a cell harvester (IH-110, Innotech) on a UniFilter GF / C plate (Packard) immersed in 0.5% polyethyleneimine. Washed with liquid. After thoroughly washing the plate after washing, add 20 μL of scintillator (MaxiLight, manufactured by Hidex) to each well, and count per minute (cpm) into a multi-label microplate reader (Plate Chameleo II, manufactured by Hidex). Measured. Nonspecific binding was defined as cpm when 30 μmol / L of pyrilamine was added. Experiments were performed with n = 3 and repeated at least 3 times.
An example of the results is shown in Table 18. However, Compound 63, Compound 64, Compound 104, Compound 112, and Compound 122 are reference compounds because they do not correspond to the compound of the present invention. The compound of the present invention showed very strong activity in an in vitro human histamine H1 receptor binding experiment.

Example 39.
Rat histamine-induced hypervascular response (in vivo antihistamine action)
180 g SD male rats (SPF), solid feed and tap water in an environment set at 22 ° C, 55% humidity and artificial lighting for 12 hours a day (8am to 8pm light) Was used for the experiment. Histamine dihydrochloride (hereinafter referred to as histamine) and Evans Blue were dissolved in physiological saline at the time of use. The test substance was dissolved in water for injection or suspended in 0.5% sodium carboxymethylcellulose and orally administered to rats (administration volume 5 mL / kg body weight). One hour after administration, physiological saline and histamine solution (20 μg / 0.05 mL / location) were injected intradermally into the back of each rat shaved with an electric clipper under ether anesthesia. 0.5% Evans blue saline solution (1 mL / 200 g body weight) was injected into the tail vein just before intradermal injection of histamine.

Thirty minutes later, the animals were decapitated and lethal to death, the skin was peeled off, and the amount of dye leaked from the blue dyed area was measured. To measure the amount of the leaked pigment, cut out two skins at the site of the leaked pigment, add 1 mL of 2 mol / L potassium hydroxide solution in a test tube, leave it to stand overnight at 37 ° C and dissolve, then 0.67 mol / L 6 mL of a 1: 3 mixture of L phosphoric acid and acetone was added and shaken vigorously for 10 minutes. Thereafter, the mixture was filtered, and the absorbance at 620 nm of the filtrate was measured. Absorbance obtained from two sites injected with physiological saline as a blank value was used for correction. The amount of dye leakage was calculated from an Evans blue calibration curve at 620 nm.
An example of the results is shown in Table 19. The compound of the present invention showed a very strong antagonistic activity in the rat histamine-induced vascular permeability enhancement reaction.

Example 40.
Mouse brain H1 receptor occupancy (ex vivo)
A 6-week-old ICR male mouse was preliminarily raised for at least 1 week by freely ingesting solid feed and tap water in an environment set up with artificial lighting at a temperature of 22 ° C, humidity of 55% and 12 hours a day, Fasted overnight and used for experiments. The test substance was dissolved in water for injection or suspended in a 0.5% carboxymethylcellulose solution and orally administered to mice (dosing volume 0.1 mL / 10 g body weight). One hour after oral administration, the mice were decapitated and the whole brain except the cerebellum and medulla was immediately removed. The isolated brain tissue was homogenized using polytron (manufactured by Kinematica) in ice-cooled 50 mmol / L phosphate buffered saline (pH 7.4, 100 mg / 1.9 mL).

In a test tube for reaction (TPX-tube), 180 μL of brain homogenization solution and 10 μL of ³ H-pyrilamine solution (final concentration 2 nmol / L) and unlabeled pyrilamine solution (final concentration 200 μmol / L) or 50 mmol / L phosphate buffer After adding 10 μL of physiological saline and incubating at room temperature for 45 minutes, 2.0 mL of ice-cooled 50 mmol / L phosphate buffered physiological saline was added to stop the reaction. The reaction solution was filtered through a GF / B filter (manufactured by ADVANTEC), placed in a vial, and dried at 60 ° C. overnight. After drying, add 10 mL of scintillator (AL-1, toluene base, manufactured by Dojindo Laboratories) and measure Disintegration per minute (dpm) with a liquid scintillation counter (TRI-CARB 2700TR, manufactured by Packard, USA) 5 minutes / vial).

An example of the results is shown in Table 20. In this experiment, it was shown that the compound of the present invention required a high concentration in order to occupy the receptor in the brain, and the ability to enter the brain was low. From this result, it was clarified that the compound of the present invention exhibits an antihistamine action in a peripheral manner without transferring into the brain, and central side effects such as sleepiness can be reduced.

Table 21 shows values obtained by dividing the ID ₅₀ value (Table 20) in the brain receptor binding test by the ED ₅₀ value (Table 19) in the histamine-induced vascular permeability enhancement reaction test from the results of Examples 39 and 40 above. . The larger the ID ₅₀ value in the receptor binding test in the brain (Table 20), the lower the transferability in the brain, that is, the lower the central side effects such as sleepiness, and the ED _{50 in the} histamine-induced vascular permeability enhancement test. The smaller the value (Table 19), the stronger the antihistamine action. Therefore, the larger the value of ID ₅₀ value / ED ₅₀ value, the stronger the antihistamine action, and it can be used as an index indicating that there are few central side effects such as sleepiness. As shown in Table 21, the compound of the present invention has a large value of ID ₅₀ value / ED ₅₀ value even compared with ketotifen, which is an existing antihistamine, and therefore the compound of the present invention has a strong antihistamine action. In addition, it can be said that it has desirable characteristics as an active ingredient of a pharmaceutical composition, particularly an antihistamine, which has few central side effects such as sleepiness.

The piperidine derivative of the present invention has a strong histamine H1 receptor binding ability as shown in Table 18, and, as shown in Table 19, a strong histamine receptor in rat histamine-induced vascular permeability enhancement reaction. It showed body antagonist activity. Further, as is apparent from Table 20, the brain receptor binding test administered orally to mice also shows low translocation into the brain, and the piperidine derivative of the present invention is preferable in terms of reducing central side effects such as sleepiness. It is. As is clear from the values in Table 21 that evaluate both the histamine receptor antagonistic activity and the ability to migrate into the brain, the piperidine derivative of the present invention is a potent histamine receptor antagonist and is central to sleepiness and the like. Since there are few side effects, it has the characteristic suitable for the active ingredient of pharmaceutical compositions, such as a desired antihistamine, and its usefulness is very high.

Claims (16)

A medicament comprising at least one of piperidine derivatives represented by the following general formula (I) and pharmaceutically acceptable salts and hydrates thereof.

[Wherein R ₁ represents a substituent selected from the following (a) to ( f ) or hydrogen ,
(a) acrylic acid (including an alkyl ester le),
(b ) aminoalkyl optionally substituted with alkylcarbonyl or aminocarbonyl,
(C) hydroxy or an alkoxy carbonyl which is substituted by alkyl,
(D) hydroxy, carbonyl A Rukoki sheet or substituted with cyclohexyloxycarbonyloxy alkoxy,
(E) A Rukoki deer Ruboniruamino,
( f ) 1 or 2 selected from amino, hydroxy, alkoxy, alkenyl and alkyl (optionally substituted with halogen, thiol, piperidino, amino, alkoxy, alkoxycarbonyl, aminocarbonyl or 1 or 2 hydroxy) An aminocarbonyl optionally substituted with a substituent,
R ₂ represents a substituent selected from the following ( g ) to ( k ) or hydrogen ,
(g) acrylic acid (including an alkyl ester le),
(h ) a carbonylalkyl substituted with hydroxy or alkoxy (optionally substituted with cyclohexyloxycarbonyloxy ) ,
(I) hydroxy or carbonyl substituted with an alkoxy,
( j ) carbonylalkoxy substituted with hydroxy or alkoxy,
( k ) a carbonylalkylsulfanyl substituted with hydroxy or alkoxy ,
R ₃ represents a substituent selected from the following ( l ) to ( p ) or hydrogen,
( l ) carboxy, cyano, pyrrolidyl, piperidino, alkoxy, alkylsulfanyl or alkyl optionally substituted by 1 or 2 hydroxy,
( m ) a carbonyl substituted with alkyl or alkoxy,
( n ) a carbonylalkoxyalkyl substituted with hydroxy or alkoxy,
( o ) carbonylalkyl substituted with alkyl, alkoxy or alkylphenyl,
( p ) aminoalkyl substituted with aminocarbonyl or alkanesulfonyl,
_One of R ₁ and R ₂ represents a substituent other than hydrogen, A is unsubstituted or represents oxo, B represents carbon or oxygen, and X and Y are either carbon and the other There represents a sulfur, a broken line part to display the single bond or a double bond. ]   The medicament according to claim 1, comprising at least one of piperidine derivatives in which A is unsubstituted and pharmaceutically acceptable salts and hydrates thereof. The medicament according to claim 2, comprising at least one of piperidine derivatives in which one of R ₁ or R ₂ is carbonylalkyl substituted with hydroxy and the other is hydrogen, and pharmaceutically acceptable salts and hydrates thereof. The medicament according to claim 3, comprising at least one of piperidine derivatives wherein R ₁ is carbonylalkyl substituted with hydroxy, and pharmaceutically acceptable salts and hydrates thereof. The medicament according to claim 3, comprising at least one of piperidine derivatives wherein R ₂ is carbonylalkyl substituted with hydroxy, and pharmaceutically acceptable salts and hydrates thereof. The medicament according to claim 2, comprising at least one of piperidine derivatives wherein R ₁ is hydrogen and R ₂ is carbonylalkylsulfanyl substituted with hydroxy, and pharmaceutically acceptable salts and hydrates thereof.   The medicament according to any one of claims 2 to 6, comprising at least one of a piperidine derivative wherein B is carbon and a pharmaceutically acceptable salt and hydrate thereof.   The medicament according to any one of claims 2 to 6, comprising at least one of a piperidine derivative wherein B is oxygen and a pharmaceutically acceptable salt and hydrate thereof. The medicament according to any one of claims 2 to 8, comprising at least one of piperidine derivatives wherein R ₃ is hydrogen and pharmaceutically acceptable salts and hydrates thereof. The medicament according to any one of claims 2 to 8, comprising at least one of piperidine derivatives in which R ₃ is unsubstituted alkyl, and pharmaceutically acceptable salts and hydrates thereof. The medicament according to any one of claims 2 to 8, comprising at least one of piperidine derivatives in which R ₃ is alkylcarbonylalkyl, and pharmaceutically acceptable salts and hydrates thereof.   [4- (1-Methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-2-yl] acetic acid and pharmaceutically acceptable salts and hydrates thereof A medicament containing at least one of the above.   {4- [1- (4-Oxopentyl) piperidin-4-ylidene] -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-yl} acetic acid and its pharmaceutically acceptable A medicament comprising at least one of a salt and a hydrate.   2-Methyl-2- [4- (1-methylpiperidin-4-ylidene) -4,10-dihydro-9-oxa-3-thiabenzo [f] azulen-6-ylsulfanyl] propionic acid and its pharmaceutically A medicament comprising at least one of acceptable salts and hydrates.   A medicament comprising at least one of 3- (4-piperidin-4-ylidene-4H-1-thiabenzo [f] azulen-2-yl) propionic acid and pharmaceutically acceptable salts and hydrates thereof.   The medicine according to any one of claims 1 to 15, which is an antihistamine.