JPH0314575A - 2,3-dihydro-1-benzothiepin compound - Google Patents

Abstract

NEW MATERIAL:A 2,3-dihydro-1-benzothiepin compound expressed by formula I (R<1> and R<2> are same or different and each are H, halogen, lower alkyl, lower alkoxy or hydroxyl group; R<3> and R<4> are same or different and each are H, lower alkyl, aralkyl or N-aralkylpiperidyl or R<3> and R<4> are groups which may link and, together with the adjacent nitrogen atom, form a ring; (n) is 0, 1 or 2) or acid addition salt thereof. EXAMPLE:4-(4-Benzylpiperazinyl)methyl-2,3-dihydro-1-benzothiepin. USE:A drug, capable of exhibiting calmodulin antagonistic, coronary bloodstream increasing, hypotensive action, etc., and useful as a vasodilator, ameliorant for cerebral circulation, treating agent for angina pectoris or hypotensive agent for preventing and treating diseases in circulatory systems. PREPARATION:A compound expressed by formula II (X is halogen, etc.) is reacted with a compound expressed by formula III to afford the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel and pharmaceutically useful 2,3-dihydro-1-penzochevine compound or a pharmaceutically acceptable acid addition salt thereof.

tPrior art] JP-A-61-129179, JP-A-61-13028
No. 6 and No. 61-130287 disclose 1-penzoxepin-5-one derivatives that are effective for improving and treating symptoms based on organic disorders and mental dysfunctions in the brain.

[Problem to be solved by the invention]

The inventors of the present invention have conducted intensive research to develop useful compounds for the purpose of developing cardiovascular agents.As a result of combining various penzochepine derivatives and exploring their pharmacological effects, we found that they have excellent pharmacological activity. 2,3-dihydro-
A 1-penzochepine derivative was discovered and the present invention was completed.

[Means to solve the problem]

The present invention is based on general formulas (0) and l (wherein R' and R'' are the same or different and each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a hydroxyl group, and R2 and R4 are the same or different are hydrogen atoms, lower alkyl groups, aralkyl groups, and N, respectively.
- represents an aralkylbiperidyl group, or R', R'
represents a group that is bonded to form a ring together with the adjacent nitrogen atom, and n represents O, 1 or 2. ) or a pharmaceutically acceptable acid addition salt thereof.

In this specification, halogen atoms include fluorine, chlorine, bromine, and iodine, lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, etc., and lower alkoxy groups include methoxy, Ethoxy, propoxy, isobropoxy, butoxy, isobutoxy, tertiary butoxy, etc., and aralkyl groups include benzyl, phenylethyl, phenylprobyl, or a halogen atom on the benzene ring, lower alkyl group, lower alkoxy group, trifluoromethyl group, etc. is substituted with benzyl, phenylethyl, phenylprobyl, etc., and N-aralkylpiperidyl group is 1-benzyl-4-piperidyl,
(2-phenylethyl)-4-piveridyl, 1-(3-
Examples of groups such as phenylpropyl)-4-biperidyl that form a ring together with the adjacent nitrogen atom include cyclic amino groups that may have a heteroatom such as nitrogen, oxygen, or sulfur in addition to the nitrogen atom. Examples include 5-7 noble ring saturated cyclic amino groups such as pyrrolicinyl, morpholino, thiomorpholino, piperidino, biperazinyl, and homopiverazinyl. The cyclic amino group may have a substituent at a substitutable position, and such substituents include lower alkyl groups (same as above), aralkyl groups (same as above), acyl groups (acetyl, propionyl, butyryl, etc.). ), phenyl group (optionally substituted with 1 to 3 halogen atoms, lower alkyl group, lower alkoxy group, trifluoromethyl group, hydroxyl group, etc.) or penzhydryl group (1 to 3 halogen atoms, lower alkyl group,
may be substituted with a lower alkoxy group, trifluoromethyl group, etc.).

Pharmaceutically acceptable acid addition salts of the compounds of the present invention include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, and oxalate, maleate, fumarate, and citrate. , succinate, tartrate, methanesulfonate, p-
Examples include organic acid salts such as toluenesulfonate. Further, hydrates are also included in the present invention.

Although the compounds of the present invention have asymmetric sulfur, all optically active forms and mixtures thereof are included within the scope of the present invention.

In the present invention, the compound of general formula (I) can be produced by the following method.

Method 1 (l) General formula (O),l [wherein R+. Rt and n have the same meanings as above, and X represents a halogen atom (eg, chlorine, bromine, iodine) or a reactive derivative of matah alcohol (methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.). ] A method of reacting a compound represented by the general formula (wherein R2 and R4 have the same meanings as above). The reaction is carried out using a suitable solvent (
Any substance may be used as long as it does not inhibit the reaction, such as alcohols such as methanol, ethanol, isobrobyl, and alcohol, halogenated hydrocarbons such as methylene chloride, dichloroethane, and chloroform, esters such as ethyl acetate and butyl acetate, dioxane, and tetrahydrofuran. ethers such as acetonitrile, benzene, toluene, etc., ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, oxides such as dimethylformado, dimethylacetate, and any of these. It is carried out in the presence of a deoxidizing agent (for example, an organic base such as triethylamine, pyridine, dimethylaniline, or an inorganic base such as sodium carbonate, potassium carbonate, or sodium bicarbonate) in a mixed solvent of The reaction temperature is also not particularly limited, and is usually carried out at room temperature to around the boiling point of the solvent for 0.5 to 10 hours. Method (2) A compound represented by the general formula (0), l (in the formula, each symbol has the same meaning as above) is dissolved in a suitable solvent (aromatic hydrocarbons such as benzene, toluene, xylene, methanol, ethanol, etc.). , isobrobyl alcohol, putanol, etc.) in the presence of an acid (inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, or organic acids such as benzenesulfonic acid, p-toluenesulfonic acid) near the boiling point of the solvent. A method of dehydrating by heating or causing a dehydration reaction with thionyl chloride and pyridine. Method (3) In general formula (1), when producing the compound n-1 or 2, it is carried out by subjecting the compound where n=Q to an oxidation reaction. The reaction was carried out using an appropriate solvent (formic acid, acetic acid, methylene chloride,
The reaction is carried out at 0 to 100° C. for 1 hour in the presence of an oxidizing agent (peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, sodium periodate, etc.) in dichloroethane, chloroform, etc.).

The compound of the general formula () of the present invention thus obtained can be isolated and purified by conventional methods such as recrystallization and chromatography alone or in combination.

The compound of general formula (1) of the present invention is an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, oxalic acid, maleic acid,
The above-mentioned pharmaceutically acceptable acid addition salts can be obtained by treatment with organic acids such as fumaric acid, citric acid, succinic acid, tartaric acid, methanesulfonic acid, and p-1-luenesulfonic acid in a conventional manner. . Furthermore, optical isomers can be separated by conventional methods, for example using a column. General formula (II) which is a raw material compound in the method of the present invention
) is a new compound that has not been published in any literature, for example,
A compound represented by the general formula (wherein, Rl, R! have the same meanings as above) and the general formula C I COOR' (Vl) [wherein R% is a lower alkyl group (methyl, ethyl, probyl, etc.) or Represents a phenyl group. ] can be obtained by reacting the compound represented by 1 space below 1 [Actions and Effects of the Invention] The compound of the present invention exhibits calmodulin antagonistic activity, coronary blood flow increasing activity, antihypertensive activity, etc., and is a vasodilator, a cerebral circulation improving agent, an angina treatment agent, and an antihypertensive agent. As such, it is a useful substance in the prevention and treatment of cardiovascular diseases.

When the compound of the present invention is used as a medicine, it is usually mixed with carriers, excipients, diluents, solubilizing agents, etc. to form tablets, powders, etc.
It can be safely administered to patients in the form of capsules, injections, etc.

[Example] Hereinafter, the present invention will be explained in more detail with reference to Reference Examples and Examples, but the present invention is not limited by these in any way.

Reference Example 4-Dimethylaminomethyl-2,3-dihydro-1-penzochepine l1. Og was dissolved in 200 g of dichloromethane, 6.0 g of ethyl chlorocarbonate was added, and the mixture was stirred at room temperature for 8 hours. The dichloromethane layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The obtained oily substance was subjected to silica gel chromatography (elution solvent: chloroform), and the main fraction was concentrated to obtain 7.3 g of 4-chloromethyl-2.3-dihydro-1-penzochebin.

NMR spectrum (CDCI, δppm):
2.76-2.88 (dt, 2} 1, J-61Lz, J
-2}1z), 3.08~3.22(dt,2H,J
=6}1z, J-2Hz), 4.22(s.2H),
6.68(s,1}1). 6.98 ~ 7.24 (
Example 1 4.2 g of 4-chloromethyl-2.3-dihydro-1-penzochepine was dissolved in 100% of ethanol, and 1-penzylpiperazine 7. .0g was added and refluxed for 6 hours. After the solvent was distilled off under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated.

When the obtained crystals are recrystallized from ethanol, white crystals of 4-(4-penzylpiperazinyl)methyl-2.3-
4.5 g of dihydro-1-penzochepine was obtained. Melting point 8
0 to 82°C Example 2 4-Chloromethyl-2.3-): 7.3 g of human t'lo-1-penzochepine was dissolved in 100-g of ethanol, 10.2 g of dibutyl alcohol was added, and the mixture was refluxed for 7 hours. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The obtained oily substance was subjected to silica gel chromatography (elution solvent: chloroform:methanol-2
0:1) and the main fraction was concentrated. The obtained oily substance was dissolved in acetone and oxalic acid was added to obtain crude crystals of oxalate. The crude crystals were recrystallized from methanol to give white crystals of 4-dibutylanomethyl-283-dihydro-
2.5 g of l-penzochepine oxalate was obtained. Melting point: 138-140°C Example 3 Dissolve 6.3 g of 4-chloromethyl-2.3-dihydro-1-penzochepine in 100% of ethanol and prepare N-methyl-N-(2-(3.4-dimethoxyphenyl)ethyl). 11.7 g of adanane was added and the mixture was refluxed for 3 hours. The solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The acetic acid solution layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The obtained oil was subjected to silica gel chromatography (elution medium: chloroform:methanol = 20:1).
)k: and the main fraction was concentrated. The obtained oily rostrum was dissolved in amethane, hydrogen chloride gas and saturated isopropyl alcohol were added, and 4-(N-methyl-N-(2- (3,
4-dimethoxyphenyl)ethyl]}aminomethyl-2
．． Crude crystals of 3-dihydro-1-benzochepine hydrochloride were obtained. When the crude crystals are recrystallized from methanol, white crystals of 4-(N-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl))-ξ-nomethyl-2,3-dihydro-1-penzochepine hydrochloric acid are obtained. Obtained 2.2 g of salt, melting point 216-217°C (decomposition) Example 4 5-Hydroxy-4-(4-(2-methoxyphenyl)piverazinyl)methyl-2.3.4.5tetrahydro-1- 3.3g of benzochevine and 50R of ethanol
1, add 501 48% hydrobromic acid aqueous solution, 8
Refluxed for an hour. After neutralizing the reaction solution with potassium carbonate, the ethanol was concentrated, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The obtained oil was subjected to silica gel chromatography (elution solvent: chloroform:methanol = 50 = 1
) and the main fraction was concentrated. The obtained oil was dissolved in acetone, hydrogen chloride gas saturated isopropyl alcohol was added, and 4- (4- (2methoxyphenyl)
Piperazinyl] methyl-2 3-dihydro-1-penzochepine 2 salt! Crude salt crystals were obtained. When this crude crystal is recrystallized from methanol, white crystals of 4- (4- (
2-methoxyphenyl)piperazinyl]methyl-2.3
1.2 g of -dihydro-1-penzochevine dihydrochloride was obtained. Melting point: 225-227°C (decomposed) Example 5 5.3 g of 4-(4-penzylpiperidino)methyl-2,3-dihydro-1-penzochepine was mixed with acetic acid and water (41).
3.9 g of sodium periodate was added, and the mixture was stirred at room temperature for 2 hours. An aqueous potassium carbonate solution was added to the reaction solution to neutralize it, and then extracted with chloroform. The chloroform layer was washed twice with an aqueous sodium bisulfite solution, dried over anhydrous magnesium sulfate, and concentrated. The obtained oily substance was subjected to silica gel column chromatography. 8 medium: Chlorophonolem: Methanololem-20:
1) and the main fraction was concentrated. The obtained oily substance was dissolved in A7Tone, fumaric acid was added, and 4-(4-penzylbiperidino)methyl-2,3-dihydro-1-penzochepine 1-oxide fumarate 1/2 water was added. We obtained elementary crystals of the compound. When elementary crystals are recrystallized from methanol,
White crystals of 4-(4-penzylpiperidino)methyl-2
．． 1.2 g of 3-dihydro-1-benzochepine 1-oxide fumarate 1/2 hydrate was obtained. melting point 1i
1-113°C The following compound is obtained in the same manner as in the above example.

Example 6 4-(4-phenylbiperazinyl>methyl=2.3-dihydro l-penzochepine, melting point 100-102°C Example 7 4-(4-phenylpiperidino)methyl-2.3 -Dihydro-1-penzochepine hydrochloride, melting point 243-24
5°C (decomposed) Example 8 4-dimethylanomethyl-2,3-dihydro-1-penzochepine hydrochloride, melting point 222-223°C (decomposed) Example 9 4- (4- (bis(4-fluorophenyl) ) methyl]biperazinyl}methyl-2.3-dihydro 1-penzochepine dihydrochloride, melting point 233-235°C (decomposition) Example 10 4-(4-penzylpiperidino)methyl-2.3-dihydro 1 -Benzochepine fumarate, melting point 156~
158°C Example 11 4-(1-benzyl-4-biveridyl)aminomethyl-
2.3-dihydro-1-penzochepine dihydrochloride, melting point 279-281°C (decomposed) Example 12 4-(4-(2-methoxyphenyl)biperazinyl)methyl-2.3-dihydro-1-penzochepine l
-Oxide dihydrochloride l/4 hydrate, melting point 165~
167°C (decomposition) Example 13 4-(4-(2-methoxyphenyl)piperazinyl)methyl-2,3-dihydro-1-penzochepine 1
．． 1-dioxide

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ^3 and R^4 are the same or different and each represents a hydrogen atom, a lower alkyl group, an aralkyl group, an N-aralkylpiperidyl group, or R^
3. R^4 represents a group that is bonded to form a ring with the adjacent nitrogen atom, and n represents 0, 1 or 2. ) A 2,3-dihydro-1-benzothiepine compound or a pharmaceutically acceptable acid addition salt thereof.