HK1159612B - Aminopropylidene derivative - Google Patents

Description

Aminopropylidene derivatives

Technical Field

The present invention relates to an aminopropylidene derivative and a pharmaceutically acceptable salt and hydrate thereof which are useful as an active ingredient of a pharmaceutical composition, particularly an antihistamine and the like.

Background

Histamine (histamine) is a typical chemical mediator inducing an allergic reaction, and if a substance causing an allergy enters the body, it is released from cells such as mast cells and basophils. The released histamine binds to histamine type 1 receptor (H1 receptor) protein, exerts pharmacological actions such as lowering blood pressure, enhancing vascular permeability, constriction of smooth muscle, vasodilation, and promotion of glandular secretion, and is involved in the manifestation of allergic reaction and inflammation. As described above, histamine is involved in various human diseases, and by suppressing its action, an allergic disease and an inflammation can be prevented or cured, and a drug for suppressing histamine release and a drug for inhibiting binding to a receptor (antihistamine) are widely sold and used for diseases such as bronchial asthma, allergic rhinitis, pollinosis, urticaria, and atopic dermatitis.

However, currently known antihistamines have been limited in use such as prohibition before driving because they exhibit undesirable side effects such as sedation, drowsiness, vertigo, and feelings of lassitude due to central action, thirst due to anticholinergic action, feeling of mucosal dryness, and visual accommodation disorder, and thus they are inconvenient in use. Therefore, antihistamines having excellent effects capable of solving such problems are demanded by patients and medical fields. Accordingly, the present inventors have found that the aminopropylene derivative of the present invention has less central side effects and a strong antihistaminic action.

Non-patent document 1 discloses an aminopropylene derivative having a thiabenzo (thiabenzol) azulene skeleton, in which a thiophene ring or a benzene ring is substituted with a halogen, a methoxy group, or a dimethylaminosulfonyl group, but only the synthesis thereof is reported, and no specific description is given about a pharmacological action such as an antihistaminic action.

Documents of the prior art

Non-patent document

Non-patent document 1: helvetica Chimica Acta, volume 49, No.26, page 214-

Disclosure of Invention

The purpose of the present invention is to provide a compound which has few side effects on the central nervous system such as drowsiness and is excellent and useful as an active ingredient of a pharmaceutical composition, particularly an antihistamine.

The present inventors have conducted intensive studies on an antihistamine compound having the above-mentioned characteristics, and as a result, have found that an aminopropylene derivative represented by the following structural formula (I) has an excellent antihistamine action and is a useful compound as a drug for alleviating central side effects such as drowsiness, and the present invention has been completed.

The aminopropylene derivative of the present invention has an excellent histamine receptor antagonistic action, and exhibits low intracerebral migration in an intracerebral receptor binding test when administered orally to mice, and as a result, has an effect of alleviating central side effects such as drowsiness, and therefore has desired properties as an active ingredient of a pharmaceutical composition such as an antihistamine and is highly useful.

Detailed Description

The present invention relates to an aminopropylidene derivative represented by the following general formula (I) and a pharmaceutically acceptable salt and hydrate thereof, which are useful as a medicine such as an antihistamine.

[ CHEM 1 ]

[ in the formula, R₁And R₂The same or different, represents hydrogen or a substituent selected from the following (a) to (c) (except for the case where both are hydrogen),

(a) Carbonyl substituted by hydroxy, alkoxy or hydroxyalkylamino,

(b) A carbonylalkyl substituted by a hydroxy or alkoxy group,

(c) Acrylic acid (including alkyl esters thereof),

R₃And R₄The same or different, represents hydrogen, alkyl which may be substituted by phenyl, or cycloalkyl, or R₃And R₄Together with the nitrogen atom to which they are bound form a heterocyclic ring, represents pyrrolidinyl (Pyrrolidino), piperidino which may be substituted by oxo or piperidino, piperazinyl which is substituted by alkyl or phenyl, morpholino or thiomorpholino,

a represents unsubstituted or oxo, B represents carbon or oxygen, one of X and Y represents carbon, the other represents sulfur, the dotted line represents a single bond or a double bond, and the wavy line represents a cis-isomer and/or a trans-isomer).

In the general formula (I), the alkyl group (including "alkyl group" in the above-mentioned substituents such as carbonylalkyl group, alkyl acrylate, hydroxyalkylamino group and alkylpiperazino group) preferably represents a linear or branched alkyl group having 1 to 6 carbon atoms such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, t-pentyl group, hexyl group and isohexyl group.

The alkoxy group preferably represents a linear or branched alkoxy group having 1 to 6 carbon atoms such as a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a n-pentyloxy group, or a n-hexyloxy group.

The cycloalkyl group preferably represents a cyclic alkyl group having 3 to 6 carbon atoms such as a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, or the like.

Halogen means fluorine, chlorine, bromine, iodine, etc.

Among the compounds of the present invention, preferred compounds are as follows.

(E, Z) -3- [4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-3-thiabenzo [ f)]-2-yl]Hydrochloride salt of ethyl acrylate [ Compound 1 ]]

(E, Z) -4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f)]Hydrochloride of-6-Carboxylic acid Ethyl ester [ Compound 3]

(E, Z) -4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f)]-6-carboxylic acid [ compound 4]

(E) - [ -4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-3-thiabenzo [ f ]]-2-yl]Hydrochloride salt of acetic acid [ Compound 5 ]]

(E, Z) -3- [4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-1-thioHetero-benzo [ f)]-2-yl]Hydrochloride salt of ethyl acrylate [ Compound 6 ]]

(E, Z) -3- [4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-1-thiabenzo [ f)]-2-yl]Acrylic acid [ Compound 7 ]]

(E, Z) -4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-3-thiabenzo [ f)]-2-carboxylic acid [ compound 8]

(E, Z) -4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-1-thiabenzo [ f)]Hydrochloride of (E) -2-carboxylic acid- (2-hydroxyethyl) amide [ Compound 9 ]]

(E, Z) -3- [4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-3-thiabenzo [ f)]-2-yl]Acrylic acid [ Compound 11 ]]

(E) -4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-3-thiabenzo [ f)]-2-carboxylic acid- (2-hydroxyethyl) amide [ compound 12]

(E, Z) -3- [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f)]-6-yl]Hydrochloride salt of ethyl acrylate [ Compound 13 ]]

(E, Z) -3- [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f)]-6-yl]Acrylic acid [ Compound 14 ]]

(E) - [4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-1-thiabenzo [ f ]]-2-yl]Formic acid [ compound 15 ]]

(Z) - [4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-1-thiabenzo [ f]-2-yl]Formic acid [ compound 16 ]]

(E) - [4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-1-thiabenzo [ f ]]-2-yl]Hydrochloride salt of acetic acid [ Compound 17 ]]

(Z) - [4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-1-thiabenzo [ f]-2-yl]Hydrochloride salt of acetic acid [ Compound 18 ]]

(E) - [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ]]-6-yl]Acetic acid [ Compound 19 ]]

(Z) - [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ]]-6-yl]Acetic acid [ Compound 20 ]]

(E, Z) -2- [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f)]-6-yl]Hydrochloride of ethyl-2-methylpropionate [ Compound 21 ]]

(E, Z) -2- [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f)]-6-yl]-2-methylpropanoic acid [ compound 22]

(E, Z) -2- [4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-1-thiabenzo [ f)]-2-yl]-2-methylpropanoic acid [ compound 23]

(E, Z) -2- [4- (3-dimethylaminopropylidene) -10-oxo-9, 10-dihydro-4H-1-thiabenzo [ f)]-2-yl]Hydrochloride of ethyl-2-methylpropionate [ Compound 24 ]]

(E) - { 2-methyl-2- [4- (3-methylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ]]-6-yl]} propionic acid [ Compound 25]

(E) - {4- [3- (pyrrolidin-1-yl) propylene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } acetic acid [ compound 26]

(Z) - {4- [3- (pyrrolidin-1-yl) propylidene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } acetic acid [ compound 27]

(Z) - [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-1-thiabenzo [ f ]]-6-yl]Acetic acid [ Compound 28 ]]

(E) - [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-1-thiabenzo [ f ]]-6-yl]Acetic acid [ Compound 29 ]]

(E) - [4- (3-Ethylmethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ]]-6-yl]Acetic acid [ Compound 30 ]]

(Z) - [4- (3-ethylmethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ]]-6-yl]Acetic acid [ Compound 31 ]]

(E) - {4- [3- (morpholin-4-yl) propylidene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } acetic acid [ compound 32]

(Z) - {4- [3- (morpholin-4-yl) propylidene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } acetic acid [ compound 33]

(E) - {4- [3- (piperidin-1-yl) propylidene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } acetic acid [ compound 34]

(Z) - {4- [3- (piperidin-1-yl) propylidene group]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } acetic acid [ Compound 35]

(E) -4- {4- [3- (pyrrolidin-1-yl) propylidene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } butanoic acid [ compound 36]

(Z) -4- {4- [3- (pyrrolidin-1-yl) propylidene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } butanoic acid [ compound 37]

(E) - [4- (3-Ethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ]]-6-yl]Acetic acid [ Compound 38 ]]

(Z) - [4- (3-Ethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ]]-6-yl]Acetic acid [ Compound 39 ]]

(E) - [4- (3-Benzylmethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ]]-6-yl]Acetic acid [ Compound 40 ]]

(Z) - [4- (3-benzylmethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ]]-6-yl]Acetic acid [ Compound 41 ]]

(E) - [4- (3-benzylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ]]-6-yl]Acetic acid [ Compound 42 ]]

(Z) - [4- (3-benzylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ]]-6-yl]Acetic acid [ Compound 43 ]]

(E) - [4- (3-Cyclopentylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ]]-6-yl]Acetic acid [ Compound 44 ]]

(Z) - [4- (3-cyclopentylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ]]-6-yl]Acetic acid [ Compound 45 ]]

(E) - [4- (3-isopropylaminopropylene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ]]-6-yl]Acetic acid [ Compound 46 ]]

(Z) - [4- (3-isopropylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ]]-6-yl]Acetic acid [ Compound 47 ]]

(E) -3- [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f)]-6-yl]Propionic acid [ compound48]

(Z) -3- [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f)]-6-yl]Propionic acid [ compound 49 ]]

(E) - {4- [3- (4-methylpiperazin-1-yl) propylene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } acetic acid [ Compound 50]

(Z) - {4- [3- (4-methylpiperazin-1-yl) propylene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } acetic acid [ Compound 51]

(E) -3- {4- [3- (pyrrolidin-1-yl) propylidene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } propanoic acid [ Compound 52]

(Z) -3- {4- [3- (pyrrolidin-1-yl) propylidene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } propanoic acid [ Compound 53]

(E) - {4- [3- (4-phenylpiperazin-1-yl) propylidene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } acetic acid [ compound 54]

(Z) - {4- [3- (4-phenylpiperazin-1-yl) propylidene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-Yl } acetic acid [ Compound 55]

(E) -3- [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-1-thiabenzo [ f)]-6-yl]Hydrochloride salt of propionic acid [ Compound 56 ]]

(Z) -3- [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-1-thiabenzo [ f)]-6-yl]Hydrochloride salt of propionic acid [ Compound 57 ]]

(E) -3- {4- [3- (pyrrolidin-1-yl) propylidene]-4, 10-dihydro-9-oxa-1-thiabenzo [ f]-6-yl } propanoic acid [ compound 58]

(Z) -3- {4- [3- (pyrrolidin-1-yl) propylidene]-4, 10-dihydro-9-oxa-1-thiabenzo [ f]-6-yl } propanoic acid [ compound 59]

(E) -4- [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ]]-6-yl]Butyric acid [ Compound 60 ]]

(Z) -4- [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f)]-6-yl]Butyric acid [ Compound 61 ]]

(E) - {4- [3- (4-oxopiperidin-1-yl) propylidene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } acetic acid [ Compound 62]

(Z) - {4- [3- (4-oxopiperidin-1-yl) propylidene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } acetic acid [ Compound 63]

(E) - [4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-3-thiabenzo [ f ]]-6-yl]Acetic acid [ Compound 64 ]]

(Z) - [4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-3-thiabenzo [ f ]]-6-yl]Hydrochloride salt of acetic acid [ Compound 65 ]]

(E)-{4-[3-([1，4’]Bipiperidin-1' -yl) propylene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]Dimethyl acid salt of (E) -6-yl acetic acid [ Compound 66 ]]

(Z)-{4-[3-([1，4’]Bipiperidin-1' -yl) propylene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]Dimethyl acid salt of (E) -6-yl acetic acid [ Compound 67 ]]

(E, Z) - {4- [3- (thiomorpholin-4-yl) propylidene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } acetic acid [ Compound 68]

(E, Z) -2-methyl-2- {4- [3- (pyrrolidin-1-yl) propylidene]-9, 10-dihydro-4H-1-thiabenzo [ f]-2-yl } propanoic acid [ compound 69]

(E) - {4- [3- (pyrrolidin-1-yl) propylene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]Hydrochloride of (E) -6-yl } acetic acid [ Compound 70 ]]

(Z) - {4- [3- (pyrrolidin-1-yl) propylidene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]Hydrochloride of (E) -6-yl } acetic acid [ Compound 71 ]]

Among the above-described compounds of the present invention, more preferable compounds include those described in tables 9 and 10 below, and still more preferable compounds are those described in table 12 which have excellent antihistaminic action and low intracerebral migration.

The following shows a general process for preparing the compounds of the present invention. The compound of the present invention represented by the above general formula (I) can be produced by the method described below. However, it is known to the person skilled in the art that: the exact method employed for the manufacture of a particular compound will vary depending upon its chemical structure.

In the compounds of the present invention represented by the above general formula (I), 4- (aminopropylidene) -9, 10-dihydro-4H-1-thiabenzo [ f)]The compound can be produced according to the method described by Helvetica Chimica Acta, Vol 49, Fasc. EmileChecherbuliez No.26, 214-234(1966) or the method described by Collection. Czech. chem. Commum. Vol.59, 667-674(1994), 4- (aminopropylidene) -9, 10-dihydro-4H-3-thiabenzo [ f-]The compound may be according to H4- (aminopropylidene) -4H-1-thiabenzo [ f ] was prepared by the method described in experimental Chimica Acta, Vol.54, Fasc.1, 277-282(1971)]Compound and 4- (aminopropylidene) -4H-3-thiabenzo [ f]The compound can be produced according to the method described by Helvetica Chimica Acta, Vol.49, Fasc. Emile Cherbuliez No.26, 214-233(1966), 4- (aminopropylidene) -4, 10-dihydro-9-oxa-1-thiabenzo [ f)]Compound and 4- (aminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f]The compound can be produced by the method described in Japanese patent laid-open No. Sho 63-10784 or WO2005/003131, 4- (aminopropylidene) -10-oxo-9, 10-dihydro-4H-1-thiabenzo [ f]The compounds can be prepared according to the method described by Helvetica Chimica Acta, Vol.59, Fasc.3, 866-877 (1976). The introduction of the substituent can be achieved by selecting a starting material having an arbitrary substituent at a corresponding position in advance.

The compound of the general formula (I) can be produced by the Wittig reaction, Wittig-Horner reaction, McMurry reaction of the compound of the general formula (II). For example, in the case of using the Wittig reaction, the reaction can be carried out according to the methods described in J.org.chem.Vol.44, 22, 3760-20865 (1979), J.Med.chem.Vol.35, 2074-2084(1992), and the like. That is, the compound of the general formula (I) can be produced by reacting a compound of the general formula (II) with a corresponding 3-aminopropylphosphonium salt or the like in an anhydrous solvent such as THF (tetrahydrofuran), toluene, diethyl ether, CPME (cyclopentyl methyl ether) or the like, preferably at an appropriate temperature between 0 ℃ and the boiling point of the solvent, in the presence of a base such as n-butyllithium, potassium butoxide or the like.

[ CHEM 2 ]

Further, the compound of the general formula (II) can be converted to the compound of the general formula (I) by subjecting the compound of the general formula (III) produced to a Grignard reaction and then to a dehydration reaction. The preparation can be carried out according to the method described by Helvetica Chimica Acta, Vol 54, Fasc.1, 277-283 (1971). For example, the Grignard reaction can be carried out by reacting with a compound of the general formula (II) using a corresponding Grignard reagent such as 3-aminopropyl magnesium halide in an anhydrous solvent such as THF, toluene, diethyl ether, CPME, etc., at an appropriate temperature between the melting point and the boiling point of the solvent. The subsequent dehydration reaction can be carried out using hydrochloric acid, trifluoroacetic acid, thionyl chloride or the like, in a suitable solvent such as water, ethanol, dichloromethane or the like, without a solvent, at a suitable reaction temperature between the melting point and the boiling point of the solvent.

Further, as another method, the method described in Collection, Czech, chem, Commum, Vol.59, 667-one 674(1994) can be used. That is, a Grignard reagent prepared from magnesium, bromocyclopropane, or the like is reacted with a compound of the general formula (II) in an anhydrous solvent such as THF, toluene, CPME, or the like at an appropriate temperature between the melting point and the boiling point of the solvent to obtain a compound represented by the general formula (IV), and then, using hydrobromic acid, trimethylsilyl bromide, thionyl chloride, or the like, water, acetic acid, dichloromethane, chloroform, 1, 4-dimethylcyclopropane, or the like, the compound is reacted with a compound of the general formula (II)The compound of the formula (V) is converted by a halogenation reaction in an appropriate solvent such as an alkane at an appropriate temperature ranging from 0 ℃ to the boiling point of the solvent. Then, the obtained halide is reacted with acetone, methanol, ethanol, THF, 1, 4-bisThe compound (I) is produced by reacting the compound (I) with a corresponding amine compound in a solvent such as an alkane or acetonitrile, preferably at an appropriate temperature ranging from room temperature to the boiling point of the solvent. In the amination reaction, potassium carbonate, sodium hydride, triethylamine, or the like can be suitably used as a base, if necessary.

The compound of the formula (II) can be produced by the methods described in Japanese patent laid-open No. 49-69677, Helvetica Chimica Acta, Vol.54, Fasc.1, 214-233(1966), Helvetica Chimica Acta, Vol.54, Fasc.1, 277-282(1971), WO2005/003131, Japanese patent application No. 2008-019121 and the like.

Functionalization of the aromatic ring can also be achieved by lithiation reaction with an alkyllithium reagent, Friedel-Crafts acylation reaction, Vilsmeier formylation reaction, or the like with a compound of the general formula (I), a compound of the general formula (II), or a compound of the general formula (III) or (IV) synthesized using the Grignard reagent described above. Further, a compound in which an aromatic ring is brominated is selected as a starting material, and the compound is changed into a desired functional group by a carbonylation reaction, a Heck reaction, a cyanation reaction, a formylation reaction, an Ullmann reaction, a suzuki coupling reaction, or the like, with or without using a transition metal catalyst such as palladium. The reaction can be carried out by the method described in J.Am.chem.Soc., Vol.124, 12557-12565(2002), Tetrahedron Lett., Vol.40, 8193-8195(1991), etc.

For example, as the alkylation reaction, ester derivatives such as ethyl acetate, t-butyl acetate, and ethyl isobutyrate can be used, and as the base, potassium butoxide, potassium hydride, LiHMDS (lithium hexamethyldisilazane), LiNCy can be used₂(lithium dicyclohexylamide), etc., in Pd (dba)₂(bis (dibenzylideneacetone) palladium (0)), Pd₂(dba)₃(tris (dibenzylideneacetone) dipalladium (0)), Pd (OAc)₂(Palladium (II) acetate), Pd (PPh)₃)₄(tetrakis (triphenylphosphine) palladium (0)) in the presence of a gold transition catalyst, DPPF (1, 1' -bis (diphenylphosphino) ferrocene), PPh₃(iii) (triphenyl)Phosphine), P (o-tol)₃(tris (2-methylphenyl) phosphine), P (t-Bu)₃A ligand such as (tri-tert-butylphosphine) and N, N' - (2, 6-diisopropylphenyl) dihydroimidazolium chloride, and a compound in which the aromatic ring is brominated. The reaction can be carried out in a solvent such as toluene, benzene, pentane, cyclohexane, or a mixture thereof, preferably at an appropriate temperature ranging from room temperature to the boiling point of the solvent.

The compounds of the above general formula (I) also include mixtures of cis-trans isomers, which can be separated by using liquid chromatography or preferential crystallization with or without the use of an appropriate counter ion, and the like. For example, in the case of using high performance liquid chromatography, a mixture of an organic solvent such as methanol or acetonitrile and, if necessary, an aqueous solution to which formic acid or trifluoroacetic acid is added, which is appropriately mixed, is used as an eluent in a column packed with octadecylsilylated silica gel or the like.

The compound represented by the above general formula (I) includes various salts thereof in the presence of a pharmaceutically acceptable salt thereof, and examples thereof include additional salts with acids such as hydrochloric acid, oxalic acid, fumaric acid, p-toluenesulfonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, nitric acid, formic acid, and the like. The carboxylate may further include an appropriate alkali metal salt of sodium, potassium, calcium, or the like. These salts can be prepared or exchanged with each other by a known method using the free compounds. In addition, when present in the state of a stereoisomer, a hydrate or a metal complex of cis-trans isomer, optical isomer, conformational isomer or the like, the present invention also includes any of the stereoisomers, hydrates and complexes thereof.

The compound of the present invention can be combined with an appropriate pharmaceutical carrier or diluent to prepare a pharmaceutical product, and can be formulated by any conventional method, and can be formulated as an oral preparation such as a tablet, capsule, powder, or soluble liquid preparation, or as a non-oral preparation for subcutaneous, intramuscular, intrarectal, or intranasal administration. The compounds of the present invention can be used in the form of pharmaceutically acceptable salts thereof at the time of prescription, and can be used alone or in appropriate combinations, and further can be used as a compounding agent with other pharmaceutically active ingredients.

The oral preparation can be prepared into tablets, powders, granules or capsules by appropriately combining a binder such as crystalline cellulose, a cellulose derivative, acacia, corn starch or gelatin, a disintegrant such as corn starch, potato starch or potassium carboxymethyl cellulose, a lubricant such as talc or magnesium stearate, other extenders, wetting agents, buffers, preservatives, flavors, etc., directly or with an appropriate additive, for example, conventional excipients such as lactose, mannitol, corn starch or potato starch.

The pharmaceutical composition may be formulated into other dosage forms suitable for the treatment of the diseases, depending on the type of the diseases and the patients, for example, injections, suppositories, inhalants, aerosols, syrups, eye drops, ointments and other external preparations.

The preferred administration amount of the compound of the present invention varies depending on the administration subject, dosage form, administration method, administration period, etc., and in order to obtain the desired effect, the compound of the present invention may be orally administered to an adult in an amount of 1 to several times a day, generally 0.5 to 1000mg, preferably 1 to 500 mg. In the case of non-oral administration (for example, injection), the amount administered per day is preferably at a dose level of 3 to 10 times the above-mentioned each amount administered.

Examples

The present invention will be specifically described below with reference to examples, but the present invention is not limited thereto.

Melting points were determined by adding the sample to a glass capillary and using a melting point apparatus model ヤマト MP-21. The temperature agent was not corrected. MS spectra were measured by POLARIS Q (Thermo Quest Co.).¹The chemical shift value of H-NMR measured with an ARX500 nuclear magnetic resonance apparatus (Bruker) in a deuterated organic solvent was measured using TMS (0 ppm) added as an internal standardppm denotes. In addition, in the case of measurement in heavy water, the peak of water 4.67ppm was used as an internal standard. Silica gel column chromatography was performed using silica gel PSQ 100B or NH-DM1020 (Fuji ツリツア Chemicals). Thin layer chromatography was performed using Silica gel F254(Merck, No.5715) or TLC plate NH (Fuji ツリツア chemistry), using a UV lamp and 5% phosphomolybdic acid-ethanol chromogenic reagent. The separation of the mixture of geometric isomers was carried out by high performance liquid chromatography using 880-PU (japanese spectroscopy) as an infusion pump, 875-UV (japanese spectroscopy) as a detector and STR PREP-ODS (20mm i.d. × 250mm) as a separation column (news and chemical).

Example 1.

3- (4-oxo-9, 10-dihydro-4H-3-thiabenzo [ f)]Preparation of (E) -2-yl) acrylic acid ethyl ester

In the presence of 2-bromo-9, 10-dihydro-3-thiabenzo [ f]To a solution of (7.00g) of (E) -4-ketone in DMF (50mL) was added triethylamine (34mL), ethyl acrylate (27.5mL), palladium acetate (0.4g), P (o-Tol)₃(1.5g) was stirred and mixed overnight at 80 ℃ under an argon atmosphere. After a saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling the solvent off under reduced pressure was purified by silica gel column chromatography (chloroform-methanol 9: 1) to obtain 6.39g (85%) of the title compound as an amorphous solid.

¹H-NMR(DMSO-d₆)：1.26(t，J＝7.1Hz，3H)，3.10-3.19(m，4H)，4.19(q，J＝7.1Hz，2H)，6.55(d，J＝16.1Hz，1H)，7.40-7.44(m，2H)，7.55-7.59(m，2H)，7.80-7.82(m，1H)，8.59(s，1H).

Example 2.

(E, Z) -3- [4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-3-thiabenzo [ f)]-2-yl]Hydrochloride salt of ethyl acrylate [ Compound 1 ]]Preparation of

A1.6 mol/L n-butyllithium-hexane solution (42mL) was added to a solution of dimethylaminopropyltriphenylphosphonium bromide hydrobromide (23.5g) in THF (100mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the solution was added a THF (100mL) solution of the compound obtained in example 1 (6.11g), and further stirred and mixed overnight. The solvent was distilled off under reduced pressure, and a saturated aqueous ammonium chloride solution was added to the residue to conduct extraction 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 (chloroform: methanol ═ 9: 1), and the obtained purified product was dissolved in 1, 4-bis (phenol-formaldehyde)To an alkane (20mL), 4mol/L hydrogen chloride-bis (HCl) was addedThe alkane solution (1.1mL) was stirred and mixed at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, the precipitated crystals were filtered and dried to obtain 0.51g (6%) of a mixture of the title compound (E-form and Z-form).

Example 3.

(E, Z) - [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f)]-6-yl]Preparation of tert-butyl acetate

Hexamethyldisilazane under argon atmosphere and ice-cooling(3.53g) to a 1.6mol/L n-butyllithium-hexane solution (14mL) was added dropwise. To the solution was added dropwise n-butyl acetate (1.2mL) and the mixture was stirred for 30 minutes. Adding Pd (dba)₂(0.30g), N' - (2, 6-diisopropylphenyl) dihydroimidazolium chloride (0.22g), (E, Z) - [3- (6-bromo-10H-9-oxo-3-thiabenzo [ f)]-4-ylidene) propyl]Dimethylamine (2.01g), and the mixture was warmed to room temperature and stirred overnight. Saturated aqueous ammonium chloride was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate: 19: 1) to obtain 0.80g (36%) of a mixture of the E-form and Z-form of the title compound as an oil.

MS(EI)：m/z 400[M⁺+1].¹H-NMR(DMSO-d₆)：1.35-1.42(m，9H)，2.07-2.66(m，10H)，3.51-3.55(m，2H)，5.05-5.12(m，2H)，5.84-6.06(m，1H)，6.77-7.53(m，5H).

Example 4.

(E, Z) - [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f)]-6-yl]Production of acetic acid

Trifluoroacetic acid (2.0mL) was slowly added to the compound obtained in example 3 (1.53g), and mixed with stirring at room temperature for 2 hours. Trifluoroacetic acid was distilled off under reduced pressure, and after a 5% aqueous potassium carbonate solution was added to the residue, the pH was adjusted to 7 using dilute hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.20g (91%) of an oil of a mixture of the E-form and Z-form of the title compound.

Example 5.

(E) - [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ]]-6-yl]Acetic acid [ Compound 19 ]]And (Z) - [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl]Acetic acid [ Compound 20 ]]Preparation of

The compound (1.20g) obtained in example 4 was dissolved in 30mL of a 0.2% aqueous formic acid solution/methanol mixture, and a sample solution obtained by filtration through a 0.45 μm membrane filter was separated and purified by liquid chromatography (eluent: 0.2% aqueous formic acid solution/methanol mixture (3: 2)). The flow rate was 6.5 mL/min, and the measurement wavelength was 254 nm. Compound 19 was dissolved in 20 to 24 minutes, and compound 20 was dissolved in 15 to 18 minutes. The solvent of the effluent of each fraction was distilled off under reduced pressure, and the precipitated white crystals were filtered and dried to obtain 0.53g (44%) and 0.28g (23%) of compound 19 and compound 20, respectively.

Example 6.

(4-cyclopropyl-4-hydroxy-4, 10-dihydro-9-oxa-3-thiabenzo [ f)]Preparation of (E) -6-yl) acetic acid methyl ester

To metallic magnesium (2.5g), a solution of bromocyclopropane (8.3mL) in anhydrous THF (50mL) was added dropwise while heating. After completion of the dropping, anhydrous THF (20mL) was added, and the mixture was refluxed for 2 hours, then cooled, and the resulting solution was added dropwise to (4-oxo-4, 10-dihydro-9-oxa-3-thiabenzo [ f ] cooled in an ice bath]-6-yl) acetic acid methyl ester (10.0g) in dry THF (30 mL). After stirring and mixing for 30 minutes, a saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate ═ 5: 1) to obtain 9.0g (79%) of the title compound as an oil.

¹H-NMR(DMSO-d₆)：0.16-0.18(m，1H)，0.29-0.31(m，1H)，0.44-0.47(m，1H)，0.60-0.62(m，1H)，1.74-1.78(m，1H)，3.60-3.65(m，5H)，4.78(d，J＝15.4Hz，1H)，5.36(d，J＝15.4Hz，1H)，6.10(s，1H)，6.72-6.73(m，1H)，7.07-7.51(m，4H).

Example 7.

(E, Z) - [4- (3-bromopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f)]-6-yl]Preparation of methyl acetate

To a solution of the compound (9.0g) obtained in example 6 in dichloromethane (100mL) was added dropwise a solution of bromotrimethylsilane (3.6mL) in dichloromethane (20mL) at room temperature to carry out bromination. After stirring and mixing for 1 hour, a saturated aqueous sodium bicarbonate solution was added, and the organic layer was separated. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (hexane-ethyl acetate 9: 1) to obtain 9.3g (87%) of a mixture of the title compound E-body and Z-body as an oil.

¹H-NMR(DMSO-d₆)：2.76-3.10(m，2H)，3.60-3.79(m，7H)，5.06-5.14(m，2H)，5.83-6.06(m，1H)，6.79-7.56(m，5H).

Example 8.

(E, Z) - {4- [3- (pyrrolidin-1-yl) propylene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]Preparation of methyl (6-yl) acetate

Pyrrolidine (0.4mL), potassium carbonate (0.7g), and potassium iodide (0.9g) were added to a solution of the compound obtained in example 7 (1.00g) in THF (20mL), and the mixture was refluxed overnight. After cooling, saturated aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (hexane-ethyl acetate 5: 1) to obtain 0.50g (51%) of a mixture of the E-form and Z-form of the title compound as an oil.

MS(EI)：m/z 383[M⁺].¹H-NMR(DMSO-d₆)：1.63-1.67(m，4H)，2.35-2.58(m，8H)，3.60-3.69(m，5H)，5.05-5.12(m，2H)，5.80-6.09(m，1H)，6.78-7.53(m，5H).

Example 9.

(E, Z) - {4- [3- (pyrrolidin-1-yl) propylene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]Preparation of (E) -6-yl acetic acid

To a solution of the compound (2.80g) obtained in example 8 in ethanol (30mL) was added 1mol/L sodium hydroxide (22mL), 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 pH7 with dilute hydrochloric acid and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The oily substance obtained by distilling off the solvent under reduced pressure was solidified with diethyl ether to obtain 2.21g (82%) of a mixture of the E-form and Z-form of the title compound as crystals.

Example 10.

(E) - {4- [3- (pyrrolidin-1-yl) propylene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } acetic acid [ compound 26]And (Z) - {4- [3- (pyrrolidin-1-yl) propylene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } acetic acid [ compound 27]Preparation of

Using the mixture of E-form and Z-form (1.99g) obtained in example 9, separation and purification were carried out in the same manner as in example 5 to obtain 1.09g (55%) and 0.31g (16%) of each of the white crystals of Compound 26 and Compound 27.

Example 11.

(E, Z) - [3- (6-bromo-10H-9-oxa-3-thiabenzo [ f) hydrochloride]-4-ylidene) -propyl]Dimethylamine [ compound 2 ]]Preparation of

Using 6-bromo-10H-9-oxa-3-thiabenzo [ f]-4-ketone (5.10g), and by carrying out the same operations as in examples 6 and 7, from the obtained compound and a 50% aqueous solution of dimethylamine, and by the same operations as in example 8, [3- (6-bromo-10H-9-oxa-3-thiabenzo [ f ] was obtained]-4-ylidene) propyl]3.62g (58%) of a mixture of dimethylamine E-form and Z-form as an oil. The isomer mixture thus obtained (1.0g) was dissolved in 1, 4-bisTo an alkane (10mL), 4mol/L hydrogen chloride-bis (HCl) was addedThe alkane solution (3.0mL) was stirred and mixed at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, the precipitated crystal was filtered and dried to obtain 0.85g (77%) of a hydrochloride of a mixture of the E-form and Z-form of the title compound.

Example 12.

(E, Z) - [ 6-cyano-4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ]]]Preparation of

To a solution of Compound 2(11.6g) in DMF (150mL) was added zinc hydrocyanate (2.27g), Pd₂(dba)₃(1.14g) and DPPF (3.47g) were stirred and mixed overnight at 120 ℃ under an argon atmosphere. After cooling, water was added to the reaction mixture, and insoluble matter was filtered off and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 9: 1) to obtain 1.70g (17%) of a mixture of the E-body and Z-body of the title compound as an oil.

MS(EI)：m/z 311[M⁺+1].¹H-NMR(DMSO-d₆)：2.09-2.13(m，6H)，2.31-2.58(m，4H)，5.16-5.23(m，2H)，6.13-6.16(m，1H)，6.81-7.96(m，5H).

Example 13.

(E, Z) -4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f)]-6-carboxylic acid [ compound 4]Preparation of

To a solution of the compound (1.70g) obtained in example 12 in ethanol (25mL) was added 1mol/L sodium hydroxide (27mL), and the mixture was refluxed for 6 hours. Hereinafter, 1.26g (70%) of a mixture of the title compound E-form and Z-form was obtained by the same treatment as in example 9.

Example 14.

(E, Z) -4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f)]Hydrochloride of-6-Carboxylic acid Ethyl ester [ Compound 3]Preparation of

After a solution of compound 4(0.50g) in ethanol (50mL) was cooled in an ice bath, thionyl chloride (1.1mL) was added and mixed with stirring at 80 ℃ overnight. The reaction mixture was cooled, the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution and a saturated brine. After drying 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 9: 1) to obtain an oil of a mixture of the free title compound E-body and Z-body. Thereafter, 0.37g (64%) of a mixture of the E-form and Z-form of the title compound was obtained as crystals by the same procedure as in the preparation of the hydrochloride salt of example 11.

Example 15.

(E) - [4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-3-thiabenzo [ f ]]-2-yl]Hydrochloride salt of acetic acid [ Compound 5 ]]Preparation of

Using a mixture of 2-bromo-9, 10-dihydro-3-thiabenzo[f](E, Z) - [3- (2-bromo-9, 10-dihydro-3-thiabenzo [ f ] obtained by the same procedure as in example 11 on 4-one]-4-ylidene) propyl]Dimethylamine (2.00g) was prepared in the same manner as in example 3 to give [4- (3-dimethylaminopropylene) -9, 10-dihydro-4H-3-thiabenzo [ f ]]-2-yl]0.30g (20%) of an oil of a mixture of E-form and Z-form of acetic acid. Thereafter, by the same operation as in the preparation of the hydrochloride salt of example 11, 0.15g (45%) of the title compound as white crystals was obtained.

Example 16.

(E, Z) -3- [4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-1-thiabenzo [ f)]-2-yl]Hydrochloride salt of ethyl acrylate [ Compound 6 ]]Preparation of

In the presence of a catalyst consisting of 2-bromo-9, 10-dihydro-1-thiabenzo-4-ketone free (E, Z) - [3- (2-bromo-9, 10-dihydro-1-thiabenzo [ f ] obtained by the same procedure as in example 11]-4-ylidene) propyl]To a solution of dimethylamine (2.82g) in DMF (60mL) under argon, 8.5mL of ethyl acrylate, triethylamine (11mL), palladium acetate (0.14g), and P (o-Tol) were added₃(0.47g) was stirred and mixed at 80 ℃ overnight. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. Will haveThe 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 silica gel column chromatography (hexane-ethyl acetate 9: 1) to obtain 2.29g (77%) of an oil of a mixture of free E-form and Z-form of the title compound. Using this isomer mixture (0.76g), 0.57g (68%) of the title compound, E-form and Z-form, was obtained in the same manner as in the preparation of hydrochloride of example 11.

Example 17.

(E, Z) -3- [4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-1-thiabenzo [ f)]-2-yl]Acrylic acid [ Compound 7 ]]Preparation of

The same procedures used in example 9 were repeated except for using the free compound (1.53g) obtained in example 16 to obtain 0.94g (66%) of the title compound as crystals of a mixture of E-form and Z-form.

Example 18.

(E, Z) -4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-3-thiabenzo [ f)]-2-carboxylic acid [ compound 8]Preparation of

Using a catalyst consisting of 2-bromo-9, 10-dihydro-3-thiabenzo [ f]-4-ketone (E, Z) - [3- (2-bromo-9, 10-dihydro-3-thiabenzo [ f ] obtained by the same procedure as in example 11]-4-ylidene) propyl]Dimethylamine (6.33g), which was prepared in the same manner as in examples 12 and 13As a result, 2.12g (37%) of a crystal of a mixture of the E-form and Z-form of the title compound was obtained.

Example 19.

(E, Z) -4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-1-thiabenzo [ f)]Hydrochloride of (E) -2-carboxylic acid- (2-hydroxyethyl) amide [ Compound 9 ]]Preparation of

Will be substituted by 2-bromo-9, 10-dihydro-1-thiabenzo [ f]-4-one, (E, Z) - [4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-1-thiabenzo [ f ] as a mixture of E-forms and Z-forms obtained in the same manner as in example 18]-2-yl]A solution of formic acid (0.70g), N-hydroxysuccinimide (0.25g) and hydrochloride salt of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (0.41g) in dichloromethane (20mL) was mixed with stirring at room temperature overnight. The reaction mixture was washed with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium bicarbonate solution and a saturated brine, and the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride (20mL), and 2-hydroxyethylamine (0.13mL) was added and mixed with stirring at room temperature overnight. The reaction mixture was washed with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium bicarbonate solution and a saturated brine, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol ═ 19: 1) to obtain 0.50g (56%) of an oil of a mixture of free E-body and Z-body of the title compound. Thereafter, 0.29g (34%) of a mixture of the E-form and Z-form of the title compound was obtained as crystals in the same manner as in the preparation of the hydrochloride salt of example 11.

Example 20.

(E, Z) -2-bromo-4- (3-dimethylaminopropylidene) -4, 9-dihydro-1-thiabenzo [ f)]Hydrochloride of (E) -10-ketone [ Compound 10 ]]Preparation of

Using 2-bromo-10-methoxy-1-thiabenzo [ f]-4-ketone (2.04g), and by the same operation as in example 11, 1.31g (50%) of a mixture of E-form and Z-form of the title compound was obtained as crystals.

Example 21.

(E, Z) -3- [4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-3-thiabenzo [ f)]-2-yl]Acrylic acid [ Compound 11 ]]Preparation of

The same procedures used in example 9 were repeated except for using compound 1(0.99g) obtained in example 2 to give 0.60g (71%) of the title compound as crystals of a mixture of E-form and Z-form.

Example 22.

(E) -4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-3-thiabenzo [ f)]-2-carboxylic acid- (2-hydroxyethyl) amide [ compound 12]Preparation of

The same procedures as in example 19 were carried out using compound 8(0.50g) obtained in example 18 to obtain 0.14g (25%) of the title compound as white crystals.

Example 23.

(E, Z) -3- [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f)]-6-yl]Hydrochloride salt of ethyl acrylate [ Compound 13 ]]Preparation of

The same procedures used in example 16 were repeated except for using compound 2(3.05g) obtained in example 11 to give 3.03g (86%) of the title compound as crystals of a mixture of E-form and Z-form.

Example 24.

(E, Z) -3- [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f)]-6-yl]Acrylic acid [ Compound 14 ]]Preparation of

Using compound 13(1.92g), 1.25g (77%) of a mixture of the E-form and Z-form of the title compound was obtained as crystals in the same manner as in example 9.

Example 25.

(E) - [4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-1-thiabenzo [ f ]]-2-yl]Formic acid [ compound 15 ]]And (Z) - [4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-1-thiabenzo [ f]-2-yl]Formic acid [ compound 16 ]]Preparation of

Para-substituted benzene of 2-bromo-9, 10-dihydro-1-thiabenzo [ f]-4-Ketone A mixture of the E-form and Z-form of the title compound (1.20g) obtained in the same manner as in examples 11, 12 and 13 was isolated and purified in the same manner as in example 5 to obtain 0.53g (44%) and 0.28g (23%) of compound 15 and compound 16 as white crystals, respectively.

Example 26.

(E) - [4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-1-thiabenzo [ f ]]-2-yl]Hydrochloride salt of acetic acid [ Compound 17 ]]And (Z) - [4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-1-thiabenzo [ f]-2-yl]Hydrochloride salt of acetic acid [ Compound 18 ]]Preparation of

Using (E, Z) - [3- (2-bromo-9, 10-dihydro-1-thiabenzo [ f ]]-4-ylidene) propyl]Dimethylamine (6.0g) was prepared in the same manner as in examples 3 and 4, and the oily mixture of the free E-form and Z-form of the title compound was solidified with diethyl ether. Recrystallizing the obtained mixture of E-form and Z-form with ethyl acetate-ethanol mixture to obtain (E) - [4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-1-thiabenzo [ f]-2-yl]Acetic acid 1.02g (18%). The solvent of the filtrate after recrystallization was distilled off under reduced pressure, and the obtained residue was separated and purified in the same manner as in example 5 to obtain (Z) - [4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-1-thiabenzo [ f ]]-2-yl]Acetic acid oil 0.25g (4%). Using the respective isolated and purified compounds, 0.80g (73%) and 0.21g (75%) of white crystals of each of compound 17 and compound 18 were obtained in the following manner in the same manner as the preparation method of hydrochloride of example 11.

Example 27.

(E, Z) -2- [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f)]-6-yl]Hydrochloride of ethyl-2-methylpropionate [ Compound 21 ]]Preparation of

Dicyclohexylamine (1.45g) was ice-cooled under argon atmosphere, and a 1.6mol/L n-butyllithium-hexane solution (5.0mL) was added dropwise. To the solution, 0.9mL of ethyl isobutyrate was added dropwise), and the mixture was stirred and mixed for 30 minutes. Adding Pd (dba)₂(0.26g)、10％P(t-Bu)₃-hexane solution (1.0mL), (E, Z) - [3- (6-bromo-10H-9-oxo-3-thiabenzo [ f)]-4-ylidene) propyl]Dimethylamine (1.60g), and the mixture was warmed to room temperature and stirred overnight. Saturated aqueous ammonium chloride was added to the reaction mixture, followed by extraction 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 obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate ═ 19: 1). Thereafter, 1.24g (65%) of a mixture of the E-form and Z-form of the title compound was obtained as crystals in the same manner as in the preparation of the hydrochloride salt of example 11.

Example 28.

(E, Z) -2- [4- (3-dimethylaminoalkylidene)Propyl) -4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl]-2-methylpropanoic acid [ compound 22]Preparation of

The same procedures used in example 9 were repeated except for using compound 21(0.98g) to give 0.32g (39%) of the title compound as crystals of a mixture of E-form and Z-form.

Example 29.

(E, Z) -2- [4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-1-thiabenzo [ f)]-2-yl]-2-methylpropanoic acid [ compound 23]Preparation of

From (E, Z) - [3- (2-bromo-9, 10-dihydro-1-thiabenzo [ f ]]-4-ylidene) propyl]Dimethylamine, (E, Z) -2- [4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-1-thiabenzo [ f ] obtained by a reaction with a palladium catalyst in the same manner as in example 27 was used]-2-yl]Ethyl 2-methylpropionate (1.03g), according to the same operation as in example 9, 0.32g (33%) of a mixture of the E-form and Z-form of the title compound was obtained as crystals.

Example 30.

(E, Z) -2- [4- (3-dimethylaminopropylidene) -10-oxo-9, 10-dihydro-4H-1-thiabenzo [ f)]-2-yl]Hydrochloride of ethyl-2-methylpropionate [ Compound 24 ]]Preparation of

Using a catalyst consisting of 2-bromo-10-methoxy-1-thiabenzo [ f]-4-ketone 2-bromo-4-cyclopropyl-10-methoxy-4H-1-thiabenzo [ f ] obtained in the same manner as in example 6]-4-ol (3.20g), and by the same operation as in example 27, (2-cyclopropyl-4-hydroxy-10-methoxy-4H-1-thiabenzo [ f)]1.78g (50%) of an oil of a mixture of E-form, Z-form of ethyl (2-yl) -2-methylpropionate. Thereafter, by the same procedure as in the preparation of the hydrochloride salt of example 11, 0.67g (33%) of an amorphous solid of a mixture of the E-form and Z-form of the title compound was obtained.

Example 31.

(E) - { 2-methyl-2- [4- (3-methylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ]]-6-yl]} propionic acid [ Compound 25]Preparation of

From (E, Z) - [3- (6-bromo-10H-9-oxa-3-thiabenzo [ f ]]-4-ylidene) propyl]Methylamine, the same operation as in example 27 was carried out, and the same operation as in example 9 was carried out with respect to the obtained compound (2.74g), so as to obtain 1.68g (66%) of a mixture of the title compounds E-form and Z-form. Using this isomer mixture, separation and purification were carried out in the same manner as in example 5 to obtain 0.60g (34%) of the title compound.

Example 32.

(Z) - [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-1-thiabenzo [ f ]]-6-yl]Acetic acid [ Compound 28 ]]And (E) - [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-1-thiabenzo [ f]-6-yl]Acetic acid [ Compound 29 ]]Preparation of

Para-substituted (4-oxo-4, 10-dihydro-9-1-thiabenzo [ f)]Methyl (E) -6-yl) acetate A mixture of the E-form and Z-form of the title compound (1.63g) obtained in the same manner as in examples 11 and 9 was isolated and purified in the same manner as in example 5 to obtain 0.39g (23%) and 0.58g (36%) of compound 28 and compound 29 as white crystals, respectively.

Example 33.

(E) - [4- (3-Ethylmethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ]]-6-yl]Acetic acid [ Compound 30 ]]And (Z) - [4- (3-ethylmethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl]Acetic acid [ Compound 31 ]]Preparation of

A mixture (1.00g) of the E-form and Z-form of the title compound obtained in example 7 and N-ethylmethylamine in the same manner as in examples 8 and 9 was isolated and purified in the same manner as in example 5 to obtain 0.21g (21%) and 0.09g (9%) of compound 30 and compound 31 as white crystals, respectively.

Example 34.

(E) - {4- [3- (morpholin-4-yl) propylidene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } acetic acid [ compound 32]And (Z) - {4- [3- (morpholin-4-yl) propylene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } acetic acid [ compound 33]Preparation of

From the compound obtained in example 7 and morpholine, a mixture of the title compound (1.52g) as the E-form and Z-form was isolated and purified in the same manner as in example 5 in the same manner as in example 8 and 9 to obtain 0.42g (28%) and 0.15g (10%) of compound 32 and compound 33 as white crystals, respectively.

Example 35.

(E) - {4- [3- (piperidin-1-yl) propylidene]-4, 10-dihydro-9-oxa-3-thiabenzo-6-yl } acetic acid [ compound 34]And (Z) - {4- [3- (piperidin-1-yl) propylene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } acetic acid [ Compound 35]Preparation of

From the compound obtained in example 7 and piperidine, a mixture of the title compound (1.25g) in E-form and Z-form was isolated and purified in the same manner as in example 5 in the same manner as in example 8 and 9 to obtain 0.70g (56%) and 0.08g (6%) of compound 34 and compound 35 as white crystals, respectively.

Example 36.

(E) -4- {4- [3- (pyrrolidin-1-yl) propylidene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } butanoic acid [ compound 36]And (Z) -4- {4- [3- (pyrrolidin-1-yl) propylene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } butanoic acid [ compound 37]Preparation of

From 4- (4-oxo-4, 10-dihydro-9-oxa-3-thiabenzo [ f)]Methyl (E) -6-yl) butyrate, the mixture (1.31g) of the E-form and Z-form of the title compound thus obtained was isolated and purified by the same procedures as in example 5 in the same manner as in example 6, 7, 8 and 9 to obtain 0.60g (46%) and 0.16g (12%) of each of amorphous solids of compound 36 and compound 37.

Example 37.

(E) - [4- (3-Ethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ]]-6-yl]Acetic acid [ Compound 38 ]]And (Z) - [4- (3-ethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl]Acetic acid [ Compound 39 ]]Preparation of

From the compound obtained in example 7 and ethylamine hydrochloride, a mixture (0.66g) of the title compound obtained as an E-form and a Z-form was isolated and purified in the same manner as in example 5 in the same manner as in example 8 and 9 to obtain 0.46g (70%) and 0.08g (12%) of compound 38 and compound 39 as white crystals, respectively.

Example 38.

(E) - [4- (3-Benzylmethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ]]-6-yl]Acetic acid [ Compound 40 ]]And (Z) - [4- (3-benzylmethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl]Acetic acid [ Compound 41 ]]Preparation of

A mixture (1.54g) of the E-form and Z-form of the title compound obtained in the same manner as in examples 8 and 9 was isolated and purified by the same manner as in example 5 from the compound obtained in example 7 and N-benzylmethylamine to obtain 0.65g (42%) and 0.10g (6%) of compound 40 and compound 41 as white crystals, respectively.

Example 39.

(E) - [4- (3-benzylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ]]-6-yl]Acetic acid [ Compound 42 ]]And (Z) - [4- (3-benzylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ]]-6-yl]Acetic acid [ chemical combination ]Object 43]Preparation of

From the compound obtained in example 7 and benzylamine, the same procedures as in examples 8 and 9 were repeated to obtain a mixture (1.51g) of the title compound (E-form and Z-form), which was isolated and purified by the same procedures as in example 5, thereby obtaining 0.62g (41%) of an amorphous solid of compound 42 and 0.23g (15%) of compound 43 as white crystals.

Example 40.

(E) - [4- (3-Cyclopentylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ]]-6-yl]Acetic acid [ Compound 44 ]]And (Z) - [4- (3-cyclopentylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl]Acetic acid [ Compound 45 ]]Preparation of

From the compound obtained in example 7 and cyclopentylamine, a mixture (1.00g) of the title compound obtained as an E-form and a Z-form was isolated and purified in the same manner as in example 5 in the same manner as in example 8 and 9 to obtain 0.54g (54%) and 0.10g (10%) of compound 44 and compound 45 as white crystals, respectively.

Example 41.

(E) - [4- (3-isopropylaminopropylene) -4, 10-dihydro-9-oxa-3-thiabenzo-6-yl]Acetic acid [ Compound 46 ]]And (Z) - [4- (3-isopropylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl]Acetic acid [ Compound 47 ]]Preparation of

From the compound obtained in example 7 and isopropylamine, a mixture (2.02g) of the title compound obtained in E-form and Z-form was isolated and purified in the same manner as in example 5, using the same procedures as in examples 8 and 9, to give 0.38g (19%) and 0.05g (2%) of compound 46 and compound 47 as white crystals, respectively.

Example 42.

(E) -3- [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f)]-6-yl]Propionic acid [ compound 48 ]]And (Z) -3- [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f)]-6-yl]Propionic acid [ compound 49 ]]Preparation of

From 3- (4-oxo-4, 10-dihydro-9-oxa-3-thiabenzo [ f)]Methyl (E, Z) -3- [4- (3-bromopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ] was obtained by the same procedures as in examples 6 and 7]-6-yl) propionic acid methyl ester. The same procedures as in examples 8 and 9 were repeated using the mixture of E-form and Z-form and dimethylamine hydrochloride, and the mixture of E-form and Z-form (1.32g) of the title compound was isolated and purified by the same procedures as in example 5 to obtain 0.33g (25%) of an amorphous solid of compound 48 and 0.06g (5%) of compound 49 as white crystals.

Example 43.

(E) - {4- [3- (4-methylpiperazin-1-yl) propylene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } acetic acid [ Compound 50]And (Z) - {4- [3- (4-methylpiperazin-1-yl) propylene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } acetic acid [ Compound 51]Preparation of

From the compound obtained in example 7 and 1-methylpiperazine, the same procedures as in examples 8 and 9 were carried out, and a mixture (0.61g) of the E-form and Z-form of the title compound obtained was isolated and purified by the same procedures as in example 5 to obtain 0.25g (41%) and 0.03g (5%) of each of the compound 50 and the compound 51 as white crystals.

Example 44.

(E) -3- {4- [3- (pyrrolidin-1-yl) propylidene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } propanoic acid [ Compound 52]And (Z) -3- {4- [3- (pyrrolidin-1-yl) propylene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } propanoic acid [ Compound 53]Preparation of

From 3- (4-oxo-4, 10-dihydro-9-oxa-3-thiabenzo [ f)]Methyl (E) -6-yl) propionate prepared in the same manner as in examples 6, 7, 8 and 9, and the title compound obtained in the same manner as described above was mixed with the E-form or Z-formThe compound (1.21g) was isolated and purified by the same procedures as in example 5 to obtain 0.33g (27%) of compound 52 as white crystals and 0.06g (5%) of compound 53 as an amorphous solid.

Example 45.

(E) - {4- [3- (4-phenylpiperazin-1-yl) propylidene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } acetic acid [ compound 54]And (Z) - {4- [3- (4-phenylpiperazin-1-yl) propylene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } acetic acid [ Compound 55]Preparation of

From the compound obtained in example 7 and 1-phenylpiperazine, according to the procedure of examples 8 and 9, a mixture (1.08g) of the obtained title compound in E-form and Z-form was isolated and purified in the same manner as in example 5 to obtain 0.11g (10%) and 0.05g (5%) of compound 54 and compound 55 as white crystals, respectively.

Example 46.

(E) -3- [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-1-thiabenzo [ f)]-6-yl]Hydrochloride salt of propionic acid [ Compound 56 ]]And (Z) -3- [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-1-thiabenzo [ f)]-6-yl]Hydrochloride salt of propionic acid [ Compound 57 ]]Preparation of

From 3- (4-oxo-4, 10-dihydro-9-oxa-1-thiabenzo [ f)]Methyl (E, Z) -3- [4- (3-bromopropylidene) -4, 10-dihydro-9-oxa-1-thiabenzo [ f ] was obtained by the same procedures as in examples 6 and 7]-6-yl) propionic acid methyl ester. The procedure of examples 8 and 9 was repeated using the mixture of E-form and Z-form and dimethylamine hydrochloride, and the mixture of E-form and Z-form (0.89g) of the title compound thus obtained was separated and purified in the same manner as in example 5 to obtain free compound 56 and compound 57 as amorphous solids. Then, by the same procedure as in the preparation of the hydrochloride salt of example 11, 0.10g (11%) and 0.08g (9%) of white crystals of compound 56 and compound 57 were obtained, respectively.

Example 47.

(E) -3- {4- [3- (pyrrolidin-1-yl) propylidene]-4, 10-dihydro-9-oxa-1-thiabenzo [ f]-6-yl } propanoic acid [ compound 58]And (Z) -3- {4- [3- (pyrrolidin-1-yl) propylene]-4, 10-dihydro-9-oxa-1-thiabenzo [ f]-6-yl } propanoic acid [ compound 59]Preparation of

From 3- (4-oxo-4, 10-dihydro-9-oxa-1-thiabenzo [ f)]Methyl (E) -6-yl) propionate was prepared in the same manner as in examples 6, 7, 8 and 9, and the mixture (1.20g) of the E-form and Z-form of the title compound was isolated and purified in the same manner as in example 5 to obtain Compound 58 and Compound 59Amorphous solids 0.37g (31%) and 0.22g (18%).

Example 48.

(E) -4- [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ]]-6-yl]Butyric acid [ Compound 60 ]]And (Z) -4- [4- (3-dimethylaminopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f)]-6-yl]Butyric acid [ Compound 61 ]]Preparation of

From 4- (4-oxo-4, 10-dihydro-9-oxa-3-thiabenzo [ f)]Methyl (E, Z) -4- [4- (3-bromopropylidene) -4, 10-dihydro-9-oxa-3-thiabenzo [ f ] was obtained by the same procedures as in examples 6 and 7]-6-yl) butyric acid methyl ester. The same procedures as in examples 8 and 9 were repeated using the mixture of E-form and Z-form and dimethylamine hydrochloride to obtain a mixture of E-form and Z-form of the title compound (1.52g), which was isolated and purified by the same procedures as in example 5 to obtain 0.33g (22%) of compound 60 as white crystals and 0.09g (6%) of compound 61 as an amorphous solid.

Example 49.

(E) - {4- [3- (4-oxopiperidin-1-yl) propylidene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } acetic acid [ Compound 62]And (Z) - {4- [3- (4-oxopiper)Pyridin-1-yl) propylene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } acetic acid [ Compound 63]Preparation of

From the compound obtained in example 7 and 4-piperidone, by carrying out the same operations in the order of examples 8 and 9, a mixture (0.60g) of the E-form and Z-form of the title compound obtained was isolated and purified by the same operations as in example 5 to obtain 0.28g (47%) and 0.10g (17%) of each of the compound 62 and the compound 63 as white crystals.

Example 50.

(E) - [4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-3-thiabenzo [ f ]]-6-yl]Acetic acid [ Compound 64 ]]And (Z) - [4- (3-dimethylaminopropylidene) -9, 10-dihydro-4H-3-thiabenzo [ f]-6-yl]Hydrochloride salt of acetic acid [ Compound 65 ]]Preparation of

From (4-oxo-9, 10-dihydro-4H-3-thiabenzo [ f)]Ethyl (E, Z) - [4- (3-bromopropylene) -9, 10-dihydro-4H-3-thiabenzo [ f ] was obtained by the same procedures as in examples 6 and 7]-6-yl]Ethyl acetate. Using the mixture of E-form and Z-form and 50% aqueous dimethylamine solution, the same procedures as in examples 8 and 9 were repeated to obtain a mixture of E-form and Z-form of the title compound (0.91g), which was isolated and purified by the same procedures as in example 50.35g (38%) of compound 64 as white crystals and 0.20g (22%) of free amorphous solid of compound 65. The same procedures as those for preparing the hydrochloride salt of example 11 were carried out using the free compound 65 to obtain 0.15g (68%) of the title compound 65 as white crystals.

Example 51.

(E)-{4-[3-([1，4’]Bipiperidin-1' -yl) propylene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]Dimethyl acid salt of (E) -6-yl acetic acid [ Compound 66 ]]And (Z) - {4- [3- ([1, 4']Bipiperidin-1' -yl) propylene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]Dimethyl acid salt of (E) -6-yl acetic acid [ Compound 67 ]]Preparation of

From the compound obtained in example 7 and 4-piperidinopiperidine, by carrying out the same operations in the order of examples 8 and 9, a mixture (0.83g) of the E-form and Z-form of the title compound obtained was isolated and purified by the same operations as in example 5 to obtain 0.44g (53%) and 0.14g (16%) of each of amorphous solids of compound 66 and compound 67.

Example 52.

(E, Z) - {4- [3- (thiomorpholin-4-yl) propylidene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]-6-yl } acetic acid [ Compound 68]Preparation of

The same procedures as in examples 8 and 9 were repeated except for using the compound obtained in example 7 (2.00g) and thiomorpholine to give 0.83g (37%) of the title compound as crystals of a mixture of E-form and Z-form.

Example 53.

(E, Z) -2-methyl-2- {4- [3- (pyrrolidin-1-yl) propylidene]-9, 10-dihydro-4H-1-thiabenzo [ f]-2-yl } propanoic acid [ compound 69]Preparation of

Using a mixture of 6-bromo-9, 10-dihydro-3-thiabenzo [ f]-4-ketone (E, Z) -1- [3- (6-bromo-9, 10-dihydro-3-thiabenzo [ f ] obtained by the same procedure as in examples 6, 7 and 8]-4-ylidene) propyl]Pyrrolidine (3.01g) was used in the same manner as in examples 27 and 9 to obtain 1.53g (51%) of a mixture of E-form and Z-form of the title compound.

Example 54.

(E) - {4- [3- (pyrrolidin-1-yl) propylene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]Hydrochloride of (E) -6-yl } acetic acid [ Compound 70 ]]Preparation of

The same procedures as those for the preparation of the hydrochloride salt of example 11 were carried out using the compound 26(1.09g) obtained in example 10 to obtain 1.10g (92%) of the title compound as white crystals.

Example 55.

(Z) - {4- [3- (pyrrolidin-1-yl) propylidene]-4, 10-dihydro-9-oxa-3-thiabenzo [ f]Hydrochloride of (E) -6-yl } acetic acid [ Compound 71 ]]Preparation of

The same procedures as those for the preparation of the hydrochloride salt of example 11 were carried out using compound 27(0.31g) obtained in example 10 to obtain 0.31g (90%) of the title compound as white crystals.

The physical property data of the compounds of the present invention prepared in the above examples are shown in tables 1 to 8.

[ TABLE 1 ]

[ TABLE 2 ]

[ TABLE 3 ]

[ TABLE 4 ]

[ TABLE 5 ]

[ TABLE 6 ]

[ TABLE 7 ]

[ TABLE 8 ]

Example 56.

In vitro human histamine H1 receptor binding assay

Recombinant human histamine H1 receptor plasmid (インビトロジエン, Inc.), using Lipofectamine2000(インビトロジエン, Inc.), to HEK293A cells were transfected. Cells stably expressing the human histamine H1 receptor were selected using ジエネテイシン (Geneticin, インビトロジエン). Cells were cultured using Dulbecco's Modified Eagle Medium containing 10% fetal calf serum, 0.1mmol/L MEM non-essential amino acid solution, 2mmol/L glutamic acid and 0.7mg/mL ジエネテイシン at 37 ℃ with 5% CO₂Continuously culturing in an incubator. Cells stably expressing human histamine H1 receptor were prepared to 3X 10 using 50mmol/L Tris-HCl (pH 7.5) (hereinafter referred to as buffer) containing 0.1% bovine serum albumin⁶Cell samples were prepared per mL. To each well of the 96-well plate were added 50. mu.L of the buffer solution, 50. mu.L of the solution of the test substance at various concentrations and 50. mu.L of the solution³H]The bilamine (pyriamine) solution (final concentration 3nmol/L) was stirred, and then 100. mu.L of the cell specimen (3X 10) was added⁵One/well), the reaction was started.

After incubation at room temperature for 60 minutes, the reaction mixture was filtered through a cell harvester (IH-110, manufactured by イノテツク) on a UniFilter GF/C plate (manufactured by パツカ - ド) immersed in 0.5% polyethyleneimine, and the reaction mixture was washed with a buffer. After the washed Plate was sufficiently dried, 20. mu.L of a scintillator (MaxiLight, manufactured by Hidex) was added to each well, and the number per minute (cpm) was measured by a multifunction microplate Reader (Plate Chameleo II, manufactured by Hidex). The nonspecific binding was cpm obtained by adding 30. mu. mol/L of pyrilamine (pyrilamine). The test was performed with n-3 and repeated at least 3 times.

An example of the results is shown in Table 9. The compounds of the present invention show very potent activity In the In vitro human histamine H1 receptor binding assay.

[ TABLE 9 ]

Number of Compounds	IC50(nmol/L)
		Compound 3	22.2
Compound 9	55.7
		Compound 13	32.4
Compound 19	56.9
		Compound 21	74.7
Compound 22	60.0
		Compound 23	74.6
Compound 24	13.2
		Compound 26	19.2
Compound 27	70.2
		Compound 28	43.4
Compound 29	70.7
		Compound 30	57.6
Compound 34	31.4
		Compound 40	19.1
Compound 42	99.8
		Compound 50	89.1
Compound 54	10.9
		Compound 55	19.6
Compound 56	29.0
		Compound 57	56.3
Compound 58	23.0
		Compound 59	36.0
Compound 62	60.5
		Compound 64	8.56
Compound 65	14.0
		Compound 66	31.2
Compound 68	45.2
		Compound 69	53.8
Compound 70	14.3
		Compound 71	63.4

Example 57.

Histamine in rats induces vascular permeability hyperactivity (in vivo antihistamine)

180g of SD male rats (SPF) were subjected to a pre-feeding for 1 week or more and a fasting for 1 night for the test, in an artificial lighting environment set at 22 ℃ and 55% humidity for 12 hours (lighting period, 8 am to 8 pm). Histamine.2 hydrochloride (hereinafter referred to as histamine) and Evans blue (Evans blue) were dissolved in a physiological saline solution for use. The test substance was dissolved or suspended in 0.5% sodium carboxymethylcellulose in water for injection and orally administered to rats (administration amount 5mL/kg body weight). After 1 hour of administration, physiological saline solution and histamine solution (20. mu.g/0.05 mL/part) were subcutaneously injected into the back of a rat, which had been shaved with electric scissors, under ether anesthesia at two places. A0.5% physiological salt solution of Evans blue (1mL/200g body weight) was injected into the tail vein just before subcutaneous injection of histamine.

After 30 minutes, the animals were decapitated, bled to death, and the skin was peeled off to measure the amount of leaked pigment from the blue-stained area. The amount of the leaked dye was measured by cutting 2 spots of the skin from the site where the dye leaked, adding 1mL of a 2mol/L potassium hydroxide solution to the test tube, standing overnight at 37 ℃, dissolving the solution, adding 6mL of a 1: 3 mixture of 0.67mol/L phosphoric acid and acetone, and vigorously shaking the mixture for 10 minutes. Then, the mixture was filtered, and the absorbance of the filtrate at 620nm was measured. As a blank value, the absorbance obtained from 2 sites injected with physiological saline was used for calibration. The amount of dye leakage was calculated from a standard curve of Evans blue at 620 nm.

An example of the results is shown in Table 10. The compound of the present invention shows very strong antagonistic activity in rat histamine-induced vascular permeability-enhancing reaction.

[ TABLE 10 ]

Number of Compounds	ED50(mg/kg)
		Compound 16	0.299
Compound 18	0.063
		Compound 19	0.24
Compound 20	0.45
		Compound 22	Ca.1
Compound 24	Ca.1
		Compound 25	5.70
Compound 26	0.156
		Compound 27	0.226
Compound 28	＜0.1
		Compound 29	＜0.1
Compound 30	Ca.0.3
		Compound 31	Ca.1
Compound 33	Ca.0.3
		Compound 34	Ca.0.3
Compound 35	Ca.0.1
		Compound 43	1.31
Compound 50	1.34
		Compound 57	Ca.0.1
Compound 58	Ca.0.1
		Compound 59	Ca.0.3
Compound 70	0.42
		Compound 71	0.83
Ketotifen	0.54

Example 58.

Mouse intracerebral H1 receptor occupancy (ex vivo)

Male mice of ICR line, 6 weeks old, were free to ingest solid feed and tap water under artificial lighting conditions set at a temperature of 22 ℃, a humidity of 55% and 1 day for 12 hours, pre-reared for 1 week or more, and were kept on a diet overnight for the test. The test substance was dissolved in water for injection or suspended in a 0.5% carboxymethyl cellulose solution, and orally administered to mice (administration amount 0.1mL/10g body weight). After oral administration for 1 hour, the head is broken, and the cerebellum and the whole brain except medulla oblongata are rapidly removed. The harvested brain tissue was homogenized in an ice-cooled 50mmol/L phosphate-buffered physiological saline solution (pH7.4, 100mg/1.9mL) using a homogenizer (ポリトロソ) (Kinematica).

To a reaction test tube (TPX-tube) were added 180. mu.L of the brain homogenate and³10. mu.L of H-bilamine solution (final concentration 2nmol/L) and 10. mu.L of unlabeled bilamine solution (final concentration 200. mu. mol/L) or 50mmol/L phosphate-buffered physiological saline were incubated at room temperature for 45 minutes, and then ice-cooled 50mmol/L phosphate was addedThe reaction was stopped by buffering 2.0mL of physiological saline solution. The reaction solution was filtered through a GF/B filter (manufactured by ADVANTEC Co., Ltd.), and the filtrate was put into a vial and dried at 60 ℃ overnight. After drying, 10mL of scintillator (scintillator) (AL-1, toluene-based, manufactured by Dojindo chemical Co., Ltd.) was added, and the decay per minute (dpm) was measured with a liquid scintillation counter (manufactured by ド, TRI-CARB 2700TR, パツカ, USA) (5 minutes/vial).

An example of the results is shown in Table 11. In this test, the compound of the present invention occupies intracerebral receptors and requires a high concentration, showing low intracerebral migration. These results show that the compounds of the present invention do not migrate into the brain, and the peripheral part selectively exhibits an antihistamine action, thereby reducing central side effects such as drowsiness.

[ TABLE 11 ]

Number of Compounds	ID50(mg/kg)
		Compound 16	45.8
Compound 18	2.1
		Compound 19	6.08
Compound 20	109.3
		Compound 22	18.7
Compound 24	174.0
		Compound 25	＞200
Compound 26	80.9
		Compound 27	＞200
Compound 28	5.85
		Compound 29	23.7
Compound 30	95.0
		Compound 31	＞200
Compound 33	21.1
		Compound 34	34.8
Compound 35	65.7
		Compound 43	＞80
Compound 50	＞80
		Compound 57	＞80
Compound 58	110.2
		Compound 59	＞200
Compound 70	51.4
		Compound 71	＞80
Ketotifen	0.51

ID of the receptor binding assay in brain based on the results of examples 57 and 58 above₅₀Value (Table 11) divided by ED in the histamine-induced vascular permeability enhancement reaction test₅₀The values (Table 10) are shown in Table 12. ID of intracerebral receptor binding assay₅₀The larger the value (Table 11), the lower the intracerebral migration, that is, the smaller the central side effects such as drowsiness, and the ED in the histamine-induced vascular permeability-enhancing reaction test₅₀The smaller the value (Table 10), the stronger the antihistaminic action. Thus ID₅₀value/ED₅₀The larger the value, the stronger the antihistamine action and can be used as an index showing less central side effects such as drowsiness. As shown in Table 12, this is theComparison of the inventive Compounds with Ketotifen (Ketotifen), an existing antihistamine, ID₅₀value/ED₅₀The compound of the present invention exhibits a strong antihistaminic action and can have desired properties as an active ingredient of a pharmaceutical composition with less central side effects such as drowsiness, particularly an antihistamine.

[ TABLE 12 ]

Number of Compounds	ID50(mg/kg)/ED50(mg/kg)
		Compound 16	153.2
Compound 18	33.3
		Compound 19	25.3
Compound 20	242.9
		Compound 22	18.7
Compound 24	174.0
		Compound 25	＞35.1
Compound 26	518.6
		Compound 27	＞885
Compound 28	＞58.5
		Compound 29	＞237
Compound 30	316.7
		Compound 31	＞200
Compound 33	70.3
		Compound 34	116.0
Compound 35	657.0
		Compound 43	＞61.1
Compound 50	＞59.7
		Compound 57	＞800
Compound 58	110.2
		Compound 59	＞666.7
Compound 70	122.4
		Compound 71	＞96.4
Ketotifen	0.9

Industrial applicability

As shown in Table 9, the aminopropylene derivatives of the present invention have a strong binding ability to histamine H1 receptor, and as shown in Table 10, exhibit a strong antagonistic activity against histamine receptor in the rat histamine-induced vascular permeability-enhancing reaction. Further, as shown in table 11, the aminopropylene derivative of the present invention shows low intracerebral migration even in an intracerebral receptor binding test in which mice are orally administered, and is preferable from the viewpoint of reducing central side effects such as drowsiness. These compounds have both histamine receptor antagonistic activity and intracerebral migration, and as is clear from the values in table 12 to be evaluated, the aminopropylene derivative of the present invention is a potent histamine receptor antagonistic substance and has less central side effects such as drowsiness, and therefore has the desired characteristics suitable for the active ingredient of a pharmaceutical composition such as an antihistamine and is extremely useful.

Claims (6)

1. An aminopropylene derivative represented by the following general formula (I) and a pharmaceutically acceptable salt thereof,

in the formula, R₁Represents a substituent selected from the following (a) to (c),

(a) carbonyl substituted by hydroxy, alkoxy or hydroxyalkylamino,

(b) A carbonylethyl group substituted with a hydroxyl group, a carbonylpropyl group substituted with a hydroxyl group, a carbonylisopropyl group substituted with a hydroxyl group, or a carbonylalkyl group substituted with an alkoxy group,

(c) An acrylic acid or an alkyl acrylate, or a mixture thereof,

R₂represents hydrogen, and is represented by the formula,

R₃and R₄The same or different, represents hydrogen, alkyl which may be substituted by phenyl, or cycloalkyl, or R₃And R₄Together with the nitrogen atom to which they are bound form a heterocyclic ring, represents pyrrolidinyl, piperidino which may be oxo-or piperidino-substituted, piperazinyl which is alkyl-or phenyl-substituted, morpholino or thiomorpholino,

a is unsubstituted, B is oxygen, X is carbon, Y is sulfur, the dotted line represents a single bond, the wavy line represents a cis-isomer and/or trans-isomer,

the alkyl group is a straight chain or branched alkyl group having 1 to 6 carbon atoms,

the alkoxy group is a linear or branched alkoxy group having 1 to 6 carbon atoms,

the cycloalkyl is a cyclic alkyl group having 3 to 6 carbon atoms.

2. Aminopropylene derivatives and pharmaceutically acceptable salts thereof according to claim 1, wherein R is₁Is a carbonylethyl group substituted with a hydroxyl group, a carbonylpropyl group substituted with a hydroxyl group or a carbonylisopropyl group substituted with a hydroxyl group.

3. A pharmaceutical product comprising at least one of the aminopropylidene derivative and a pharmaceutically acceptable salt thereof according to claim 1 or 2.

4. The pharmaceutical product of claim 3, which is an antihistamine.

5. The pharmaceutical product according to claim 3, for treating at least one disease selected from the group consisting of bronchial asthma, allergic rhinitis, pollinosis, urticaria and atopic dermatitis.

6. Use of the aminopropylidene derivative according to claim 1 or 2 and a pharmaceutically acceptable salt thereof for the production of a medicament for treating at least one disease selected from the group consisting of bronchial asthma, allergic rhinitis, pollinosis, urticaria and atopic dermatitis.