JPH0314576A - 1-benzothiepin compound - Google Patents

Abstract

NEW MATERIAL:A 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; the ring expressed by formula II is cyclic amino, >=X, >=O or formula III; (n) is 0, 1 or 2) or acid addition salt thereof. EXAMPLE:4-{4-Bis[(4-fluorophenyl)methyl]piperazinyl}methyl-2,3,4,5-tet rahydro-1- benzothiepin-5-one. 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:For example, a compound expressed by formula IV, formaldehyde and a compound expressed by formula V are subjected to the Mannich reaction to afford the compound expressed by formula I.

Description

[Detailed description of the invention] [Industrial field of application] (What the invention seeks to solve! Ill!) The present inventors
With the aim of developing cardiovascular agents, we conducted intensive research to synthesize useful compounds, combined various penzochepine derivatives, and explored their pharmacological effects.As a result, we discovered l-penzochepine, which has excellent pharmacological activity. discovered a compound and perfected the invention. [Means for Solving the Problems] The present invention relates to a 1-benzochevin compound or a pharmaceutically acceptable acid addition salt thereof represented by the general formula (wherein Rl R2 are the same or different).

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, putoxy, isobutoxy, tertiary putoxy, etc., the cyclic aξ group may further have a heteroatom such as nitrogen, oxygen, sulfur, etc., such as pyrrolidinyl, morpholino, thiomorpholino, 5-7 such as piveridino, piverazinyl, homopiperazinyl, etc.
Examples include saturated ring-membered cyclic acino compounds. The cyclic aξ group may have a substituent at a substitutable position, and such substituents include a lower alkyl group (same as above),
Aralkyl groups (benzyl, phenylethyl, phenylbrobyl, or benzene ring substituted with a halogen atom, lower alkyl group, lower alkoxy group, trifluoromethyl group, etc.), acyl groups (acetyl, propionyl, butyryl, etc.), phenylethyl, phenylbrobyl, etc. ), phenyl group (optionally substituted with 1 to 3 halogen atoms, lower alkyl group, lower alkoxy group, trifluoromethyl group, hydroxyl group, etc.) or benzhydryl 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 maleate, fumarate, citrate, succinate. Examples include organic acid salts such as salt, tartrate, methanesulfonate, and p-toluenesulfonate. Further, hydrates are also included in the present invention.

Although the compound of the present invention has an asymmetric carbon and an asymmetric sulfur, all optically active substances and mixtures thereof are included within the scope of the present invention. In the present invention, the compound represented by general formula (1) is produced by the following method.

Method 1 In the general formula (I), a compound in which 〉 ), 1 (in the formula, each symbol has the same meaning as above) and formaldehyde (used as formalin or paraformaldehyde) and the general formula (in the formula, the symbols have the same meaning as above) It can be produced by subjecting a compound or its acid addition salt to a Mannich reaction. This process can be carried out under the well-known Manning reaction conditions, but is advantageously carried out in acetic anhydride at 50-100°C.
Method (3) is carried out by keeping the mixture for 1 to 10 hours, or by heating and refluxing it in a lower alcohol (methanol, ethanol, propanol, etc.) for 2 to 72 hours.

Method 2 The compound of the general formula (1-a) is a compound of the general formula, that is, the compound represented by the general formula (0), (wherein, each symbol has the same meaning as above.) The compound of 1-a) is mixed with a reducing agent (sodium borohydride, tri-tert-butoxyal ξnolithium hydride, tri-sec-butyl boron hydride, etc.) in an appropriate solvent (methanol, ethanol, isopropyl alcohol, tetrahydrofuran, etc.). sodium, lithium aluminum ξium hydride, sodium cyanoborohydride, etc.)
It can be produced by reacting with 0°C to room temperature for 0.5 to 10 hours. (In the formula, each symbol has the same meaning as above.) It can be produced by reacting a quaternary ammonium salt represented by the formula (in which each symbol has the same meaning as above) and a compound of general Any alcohol can be used as long as it is suitable, such as alcohols such as methanol, ethanol, isobrobyl alcohol, dichloromethane,
Halogenated hydrocarbons such as dichloroethane and chloroform, esters such as ethyl acetate and butyl acetate, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as acetonitrile, benzene, toluene, and xylene, acetone, methyl ethyl ketone, and methyl isobutyl. Ketones such as ketones, dimethylformamide, dimethylacetate, amides, and any mixed solvents thereof), deoxidizing agents (e.g., organic bases such as triethyl acetate, pyridine, dimethylaniline, etc.), and carbonic acid. It is carried out in the presence or absence of an inorganic base (such as sodium, potassium carbonate, or sodium bicarbonate). The reaction temperature is also not particularly limited, and is usually carried out from room temperature to around the boiling point of the solvent for 0.5 to 10 hours.

Method (4) A method for producing a compound where n=l or n=2 in general formula (1) is carried out by subjecting a compound where n=Q to an oxidation reaction. , methylene chloride, dichloroethane, chlorophonolem, etc.) in the presence of an oxidizing agent (peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, sodium periodate, etc.) at 0 to 100°C for 1 to 10
This is done by reacting for a period of time.

The compound of general formula (1) of the present invention thus obtained can be isolated and purified using 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, maleic acid, fumaric acid,
The above-mentioned pharmaceutically acceptable acid addition salts can be obtained by treatment with organic acids such as citric acid, succinic acid, tartaric acid, methanesulfonic acid, and p-toluenesulfonic acid in a conventional manner.

Moreover, optical isomers can be resolved by conventional methods.

[Action and effect of the invention]

The compound of the present invention exhibits calmodulin antagonistic effects, coronary blood flow increasing effects, antihypertensive effects, etc., and is useful as a vasodilator, cerebral circulation improving agent, angina treatment agent, and antihypertensive agent for the prevention and treatment of W1 cardiovascular system diseases. It is a useful substance in treatments, etc.

When the compound of the present invention is used as a medicine, it can be safely administered to patients in the form of tablets, powders, capsules, injections, etc., usually mixed with carriers, excipients, diluents, solubilizing agents, etc. [Examples] Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1 4-dimethylantanomethyl-l-penzochepine-5-
11.3 g of methyl iodide salt of
10.4 g of 1-[bis(4-fluorophenyl]methyl]piperazine was added and refluxed for 5 hours. The solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer After washing with water, it was dried over anhydrous sodium sulfate and concentrated. The obtained oil was dissolved in acetone and hydrogen chloride gas saturated isopropyl alcohol was added to obtain 15.8 g of crude crystals. 3.0 g of this crude crystal. When recrystallized from a mixed solution of methanol-ethanol-water, white crystals of 4-(4-(bis(4-fluorophenyl)methyl)biverazinyl}methyl-2.3.4.5
2.0 g of -tetrahydride-1-penzochepin-5-one dihydrochloride was obtained. Melting point 202-204°C (decomposition) Example 2 4-dimethylaminomethyl-l-penzochebin-5-
Methyl iodide salt of On 2 2. 6 g to 5 ethanol
00d, 2-methoxyphenylpiperazine 2
3. 0 g was added and refluxed for 5 hours. 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. The obtained crystals were recrystallized from ethanol to give 20.6 g of 4-(4-(2-methoxyphenyl>biperazinyl)methyl-2.34,5-tetrahydride-1-penzochebin-5-one) as white crystals. Melting point: 115-120° C. The following compound was obtained by the same method as in the above example.

Example 3 4-(4-phenylpiperazinyl>methyl-2.3.4
．． 5-tetrahydro-1-penzochepin-5-one,
Melting point 99-100°C Example 4 4-(4-phenylpiperidino)methyl-2,3,4.
5-tetrahydro-1-penzochepin-5-one fumarate, melting point 155-160°C Example 5 4-(4-penzylpiverazinyl)methyl = 2.3,4
．． 5-tetrahydro-l-penzochepin-5-one.
Dihydrochloride quarter hydrate, melting point 193-195°C (decomposed) Example 6 4-(4-phenylpiperidino)methyl-2,3,4.
5-tetrahydro l-penzochepin 5-one 7.0
Dissolve 100 g of methanol and add 0.0 g of sodium borohydride at 0°C. 83 g was added and stirred at 0°C for 4 hours. Methanol 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 magnesium sulfate, and concentrated. When the obtained crude crystals are recrystallized from methanol, white crystals of 5-hydroxy-4-(4-
4.8 g of phenylbiveridino)methyl-2.3,4.5-tetrahydro-1-benzochepine was obtained. melting point 12
5-127°C Example 7 4-(4-(3-}refluoromethylphenyl)biperazinyl]methyl-2.3,4.5-tetrahydro-
9.3 g of 1-penzochepin-5-one in methanol 2
Sodium borohydride 1.7
g and stirred at 0°C for 3 hours. Methanol 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.

The obtained oily substance was dissolved in acetone, and hydrogen chloride gas-saturated isopropyl alcohol was added to obtain 8.8 g of crude crystals. The obtained crude crystals were recrystallized from a mixed solvent of methanol and isopropyl alcohol to give white crystals of 5-hydroxy-4-(4-(3-trifluoromethylphenyl)piperazinyl)methyl-2,3,4.5 4.0 g of -tetrahydride-1-penzochepine dihydrochloride was obtained. Melting point: 180-185°C (decomposition) Example 8 4-(4-penzylpiperazinyl)methyl 2,3.4.
5-tetrahydro l-penzochepin-5-one 1
4. 2 g was dissolved in 200 d of methanol, sodium borohydride was added at 0°C, and the mixture was stirred at 0°C for 4 hours. Methanol was concentrated 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 oil was subjected to silica gel chromatography (elution solvent: chloroform: methanol =
20:1) and concentrate the main fraction. The obtained oily substance was dissolved in acetone, and hydrogen chloride gas-saturated isobrobyl alcohol was added to obtain crude crystals.

The obtained crude crystals were recrystallized from methanol to yield white crystals of 5-hydroxy-4-(4-penzylpiperazinyl)methyl-2.3,4.5-tetrahydro-1-penzochebine dihydrochloride. 4.0 g of hemihydrate was obtained. Melting point: 243-245°C (decomposition) The following compounds are obtained in the same manner.

Example 9 5-hydroxy-4-(4-(bis(4-fluorophenyl)methyl)piverazinyl}methyl2,3,4.
5-tetrahydride-1-penduchepine, melting point 166~
168°C Example 10 5-hydroxy-4-(4-penzylbiperazino)methyl-2.3,4.5-tetrahydride-1 penzochepine, melting point 116-118°C Example 11 4-(4-(bis) (4-fluorophenyl)methyl]piperazinyl}methyl-2.3.4.5tetrahydro l-penzochepin-5-one 1-oxide Example 12 5-hydroxy-4- (4- (bis(4-fluorophenyl) methyl]piperazinyl}methyl 2,3,4.
5-Tetrahydro-1-penzochepine 1,1-dioxide

Claims (1)

[Claims] (1) General formula ▲ Numerical formulas, chemical formulas, tables, etc. Ring ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ indicates a cyclic amino group, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ , n represents 0, 1 or 2) or a pharmaceutically acceptable acid addition salt thereof.