JPS603305B2 - 2,3-dihydrobenzofuran derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the following general formula (1) [wherein R represents hydrogen, lower alkyl, or a halogen atom, and R2 represents hydrogen, lower alkyl, lower alkoxy, or a halogen atom].

X represents =○ or.

n represents an integer from 1 to 3.

The present invention relates to a 2,3-dinohydrobenzofuran derivative represented by the following formula and its pharmacologically acceptable acid addition salt.

In general formula (1), examples of lower alkyl groups include methyl group, ethyl group, propyl group, isopropyl group,
It represents a butyl group, an isoptyl group, etc., and examples of the lower alkoxy group include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, etc.

The pharmacologically acceptable acid salts of the compound (1) of the present invention are generally non-toxic acid salts produced by reacting the compound (1) of the present invention with an appropriate inorganic or organic acid. For example, hydrochloride, hydrobromide, sulfate, acetate, maleate, fumarate, citrate,
succinate, hakamate, tartrate, methanesulfonate,
Examples include P-toluenesulfonate. The compounds of the present invention and their pharmacologically acceptable acid salts have excellent anti-serpin activity.

There are various methods for synthesizing the compound (1) of the present invention, considering the nature of the invention, and the method described below is one of them.

[In the formula, R,, R2 and n represent the above meanings.

Y and Z represent halogen atoms. In compound (1), the case where X =○ is (la), and the case where X is (lb)
shall be.

[Step 1] 2,2-dimethyl-2,3-dihydro-benzofuran compound (0) is reacted with halogenocarbonyl halide (m) under Friedel-Crafts conditions to synthesize 5-halogenocarbonyl compound (W). .

[Step 2] The compound (W) is condensed with the N-allylpiverazine compound (V) to synthesize the compound (la) of the present invention.

[Step 3] The compound of the present invention (la) is reduced to obtain the compound of the present invention (lb
).

The reaction in step 1 is carried out under Friedel-Krauch conditions.

The catalyst is preferably aluminum chloride, ferric chloride, boron trifluoride, etc., and the solvent is preferably carbon disulfide, nitrobenzene, etc. In step 2, the reaction is carried out without a solvent or by appropriately selecting and using an inert solvent such as an aromatic hydrocarbon solvent such as benzene, toluene, or xylene, or an aliphatic lower alcohol solvent such as methanol, ethanol, or isopropanol. Can be done. During the reaction, adding a deoxidizing agent such as sodium carbonate, potassium carbonate, or pyridine to the reaction system provides favorable results in terms of yield of the target product, smoothness of the reaction, etc. In step 3, the reaction is carried out using aromatic hydrocarbon solvents such as benzene, toluene, and xylene, methanol,
Aliphatic lower alcohol solvents such as ethanol and isopropanol can be used.

As the reducing agent, commonly used reducing agents can be used, but
Preference is given to using metal hydride compounds such as sodium borohydride and lithium aluminum hydride. The obtained compound (la) (lb) can be easily converted into a pharmacologically acceptable addition salt as described above according to a conventional method.

Specific examples of the compound represented by general formula (1) include the following Table 1.
There is something like this.

Table 1 Table 1 continued) The compound (1) of the present invention and its pharmacologically acceptable acid salts have excellent anti-senpin activity.

To prove this, we present the results of the following pharmacological experiment. Test compound: 5-(4-m-chlorophenylupiverazin-1-yl)acetyl-2,2-dimethyl-2,3-dihydrobenzofuran...hereinafter 5-[Q-HydroxyB-(41m-chlorophenylupiverazin-1-yl)]ethyl-2.
2-dimethyl-2,3-dihydrobenzofuran...
・・・・・・・・・・7-chloro-5-[Q-hydroxyy-(4-p-chlorophenylupiverazin-1-yl)]propyl-2,2, hereinafter referred to as the compound B of the present invention
-Dimethyl-2,3-di/-hydrobenzofuran maleate......Hereinafter referred to as the compound C of the present invention, 5-[B-(4-m-chloropheni Lupiverazin-1-yl)] Propionyl-2,2,7-trimethyl-2,3-dihydrobenzofuran maleate......Hereinafter referred to as the compound D of the present invention Pharmacological experiment 1 Locomotor activity The animals used were DD male mice weighing 17-24 mm.

Five minutes after oral administration of the test compound (9'k9 of 40) as a 5% gum arabic suspension, three mice were placed in a black acrylic resin "openfield" (25 x 20 x 3 dimensions). They were placed in a group, and their exploratory locomotor activity was measured for 20 minutes thereafter. An experiment was conducted using 4 groups of 72 cicadas for each test compound and a control group (administered with 5% gum arabic solution).
Experimental results The locomotor activity of the control group was 1081±8
/20 minutes.

The effect of each test compound on locomotor activity was expressed as a percentage inhibition relative to the control group. Table 2 Pharmacological Experiment 2 Anti-serpin action animals used were DD male mice weighing 17-24 mm.

Reserpine 2.5 p/k9 was administered intraperitoneally, administration 18
Esophageal temperature (To) was measured after hours. The test compound (9 of 10/k9) was orally administered to these mice as a 5% gum arabic suspension, and the esophageal temperature (Tt) was measured 2 hours later. 4 reserpine preconditioned mice for each analyte compound
Using an example. A thermistor thermometer is used to measure body temperature.
The test was carried out at a room temperature of 22 to 23 oo. Note that a 5% gum arabic solution was administered to the control group. Experimental Results The degree of influence of the test compound on body temperature reduction by reserpine administration is as follows: △Ti = (Tt-To) test compound - (
Tt-To) control.

If △Tt>2.0ko0, (10); 2.0qOZ△
T>n. For the case of 0℃ (10); 1.000~△TZ-1
．． The case of 0qo is shown as (0); the case of -1.0qo>ΔTt is shown as (1). Table 3 Pharmacological Experiments 1 and 2 showed that the compounds A, B, C, and D of the present invention had excellent anti-serpin activity and had almost no effect on locomotor activity.

As described above, compound (1) represented by compounds A, B, C, and D of the present invention, and its pharmacologically acceptable acid salts, have a strong anti-serpin effect and are effective against automatic movement. Since it has almost no effect, it can be used as an antidepressant to treat depression.

The compound (1) of the present invention and its pharmacologically acceptable acid salts can be prepared alone or in vehicles such as fillers, carriers, diluents, etc. commonly used in the technical field of formulations, using conventional formulation techniques. It is formulated together with.

Examples of the dosage form include tablets, powders, granules, capsules, syrups, solutions, injections, and suppositories. Next, the present invention will be explained by illustrating a method for synthesizing the compound represented by general formula (1). Example 1 5-(4-phenylpiverazin-1-yl)acetyl-2,2-dimethyl-2,3-dihydrobenzofuran {
a) 5-chloroacetyl-2,2-dimethyl-2,3
-Synthesis of dino-hydrobenzofuran 14.7 mols (0.11 mol) of pulverized anhydrous aluminum chloride and 2 mols of carbon disulfide
12.4 moles (0.11 mol) of chloroacetyl chloride was added under ice to the mixture of 2,2-dimethyl-2,3-dihydrobenzofuran (0.11 mol) while stirring. A solution of 1 mol) dissolved in 50 ml of carbon disulfide was added dropwise while maintaining the concentration at 15-20 qo.

After adding the entire amount to the bottle, the column was kept at room temperature for 4 hours to distill off carbon disulfide, and then the residue was poured into ice water. Next, 5 parts of concentrated sulfuric acid was added, heated on a water bath for 20 minutes, and then extracted with dichloromethane. The extract was washed with water, dried (MgSo4), and then distilled under reduced pressure to obtain a pale yellow viscous liquid with a boiling point of 1°C to 137°C (0.4°C) (yield: 31%). By recrystallizing from ethanol-hexane, the desired product was obtained as small colorless needles. Melting point: 67-69qO Elemental analysis value: C, 2nd, C as 302CI Theoretical value (song) 64.14 5.84 Actual value (%) 64.26 5.73 Infrared absorption spectrum fin x arc - 1:1680 (C=〇) Nuclear magnetic resonance spectrum (CDC13) 6:7.8 legs (2 days, m, C4-H
andC6-H) 6.70 ■ (IH, d, C7-day, J
= Spot Z) 4.6 ■ Wind (ga, s, COCH2CI) 3.0
blood (ga, s, C3-ga) 1.5 blood (string, s, C2 primary H3) (b) 5-(4-phenylpiverazin-1-yl)acetyl-2,2-dimethyl-2・Synthesis of 3-dihydrobenzofuran Add 5-chloroacetyl to Z of 100 toluene
2,2-dimethyl-2,3-dihydrobenzofuran 4
．． 5 (0.02 mol), N-phenylupiverazine 3
．． 3 mols (0.02 mol) and 3 mols of sodium carbonate were added, and the mixture was refluxed under concentrated steam for 5 hours.

After cooling, the inorganic matter was removed in the furnace, the furnace liquor was extracted with dilute hydrochloric acid, the acidic extract was made alkaline with concentrated sodium hydroxide, and the separated oil was extracted with ether. The extract was washed with water and dried (M$
After 04), the solvent was distilled off and the product was recrystallized from ethanol to obtain the desired product 4.4 (yield: 63%). Cocoon & point:
1 paper - 14000 Elemental analysis value: C day 2 is 202 C day N Theoretical value (%) 75.83 7.49 7.99 Actual value 75.31 7.50 7.99 Infrared absorption svector tsuba 1-1: 1665 (C:〇) Mass vector m/e: 350 (M 10), 175 (Msep
eak) Nuclear magnetic resonance spectrum (CDC13) 6:8.
0-6. Pulse blood (9 days, m, aron skin ic H) 3.8
Gofu (ga, s,) 3.4-2. Flower blood (8 days, m, ) 3.10 blood (ga, s, C3-pan) 1.5 Q blood (bait, s, C2-XH3) Example 2 5-[Q-Hydroxy 81 (4- phenylpiverazin-1-yl)]ethyl-2,2-dimethyl-2,3-
Dihydrobenzofuran 5-(4-phenylpiverazine-1-1-yl)acetyl-2,2-dimethyl-2,3-dihydrobenzofuran (3.5 mmol) (0.01 mol) was dissolved in 60 methanol. , Hiroshi (5-1 pi○) under the sea,
1.0 ml of sodium borohydride was gradually added.

After stirring at room temperature for 1 hour, the mixture was heated under reflux on a water bath for 1 hour. After cooling, add 100 tons of water and collect the resulting precipitate in an oven, wash with water, air dry, and recrystallize from ethanol to obtain the desired product (2.7 hours).
A yield of 76% was obtained. Melting point: 156 - 1570 Elemental analysis value: Theoretical value (Grandchild) as C 28N202 C day N 74.96 8.0,1 7.95 Actual value (object) 75.02 7.81 7. 1,600 Infrared Absorption Subekurure Mother 1 Kazo-: 317 o (oH) Mass Vector m/e: 352 (M 10), 334 (M 11 20), 175 (Nosepeak) Nuclear Magnetic Resonance Spectrum (CDC13) 6 :8.0-6.7 legs (thin, m, ar
omatic H) 4.7 blood (IH, t, CHCH2
) 3.8 legs (IH, broad S,.

day, D20exchangeable) 3.4-2. Range blood (ban, m, ) 3.0 string blood (ga, s, C3-pan) 1.4 rut plate (thin, s, C2-XH3) Example 3 5-[8-(4-phenylpi) verazin-1-yl)] propionyl-2,2,7-trimethyl-2,3-dihydrobenzofuran'a) 5-(8-chloro)ph.

. Synthesis of pionyl-2,2,7-trimethyl-2,3-dihydrobenzofuran2,2,7-trimethyl-2,
3-dihydrobenzofuran 32.6 moles (0.2 mol)
and 8-chloropropionyl chloride 27.9 hours (
Anhydrous aluminum chloride (0.22 mol) dissolved in 500 units of carbon disulfide and pulverized while cooling to below 0°C (29.3 mol)
C. (0.22 mol) was added gradually. After the entire amount was added, the mixture was returned to room temperature and refluxed for 2 hours. After the reaction was completed, the residue obtained by distilling off carbon disulfide was poured into 300 m of ice water containing 1 ow' of concentrated hydrochloric acid, and heated on a water bath for 1 hour. The oil deposited in the lower layer was extracted with dichloromethane, washed with water, dried (M04), and then the solvent was removed. The residue was recrystallized from ethanol-hexane to obtain the desired product (yield 68%). Melting point: 79-81℃ Elemental analysis value: C, 4 days, ? 02CI as Umron Value Association C
Day 66.52 6.79 Actual measurement value (%) 66.73 6.86 {b}
5-[8-(4-phenylpiverazin-1-yl)]
Synthesis of propionyl-2,2,7-trimethyl-2,3-dihydrobenzofuran maleate 5-(8-oo)-propionyl-2,2,7-trimethyl-2.
3-dihydrobenzofuran 5.1 moles (0.02 mol)
, N-phenylupiverazine 3.3 moles (0.02 mol)
Dissolved in 100% of benzene, and added 2.0% of soda carbonate to this.
The water was refluxed for 7 hours, including 5 nights.

The following operation was carried out in the same manner as in Example 1'b} to obtain a pale yellow oil. This was converted into a maleate salt and recrystallized from ethyl acetate to obtain the desired product 7.5 times (yield 76%). Melting point: 168-16900 Elemental analysis value: C% day 3bu 202・C4 is C as 04
Day N theoretical value (%) 67.98 6.94 5.6
6 actual measurements) 67.89 6.94 5.60 Infrared absorption spectrum analysis revealed a blind arc ';1665 (C Ni0,
free field se) Example 4 51 -Phenylpiverazine-1-yl)]Propionyl-2.2.
7-Trimethyl-2,3-dihydrobenzofuran was treated in the same manner as in Example 2 and recrystallized from benzene-hexane to obtain the desired product (yield: 66%).

Melting point Mi 148-149q○ Elemental analysis value: C day N theoretical value as C day 32N202) 75.74 8.49 7.36 Actual value (%) 75.67 8.48 7.39 Example 55- y-(4-phenylpiverazin-1-yl)
]Butyryl-2,2-dimethyl-2,3-dihydrobenzofuran (a} 5-(y-chloro)butyryl-2.
Synthesis of 2-dimethyl-2,3-di/hydrobenzofuran] 29.6 units (0.2 mol) of 2,2-dimethyl-2,3-dihydrobenzofuran and 31.0 units of y-chlorobutyryl chloride (0.22 mol) in Example 3 {a}
Perform the same operation as above to obtain a boiling point of 171-175°C (0.
A viscous steel liquid exhibiting 6 Hg) was obtained.

The desired product (yield: 66%) was obtained by recrystallizing this from ethanol-hexane. Melting point: 33-3 de○ Elemental analysis value: C, 4 days, C day as 702CI Theoretical value 66.52 6.79 Actual value (%) 66.77 6.82 (b} 5-1
y-phenylpiverazin-1-yl)] butyryl 2.
Synthesis of 2-dimethyl-2,3-di/hydrobenzofuran 5 -(y-chloro)butyryl-2,2-dimethyl-2,3-dihydrobenzofuran 2.5 units (0.01 mol) and N-phenylene Lupiverazine 3.3 evenings (0.02
mol) and stirred at room temperature overnight, then heated on a boiling water bath for 5 hours and lit with a candle.

After cooling, the reaction mixture was dissolved in diethyl ether and washed with water.
Dry (MgS04). The crystalline residue obtained by removing the ether was recrystallized from benzene-hexane to obtain the desired product 2.3 times (yield: 60%). Cocoon & points: 11
4-115℃ Elemental analysis value: C Day N Theoretical value (%) 7305 7.68 7.10 Actual value (grandchild) 73.31 7.73 7.18 Infrared absorption spectrum Calibration fence validity 1 En→:・665 (C:〇) Example 6 5-[Q-Hydroxy Kazuya-1 (4-phenylpiverazin-1-yl)] Butyl-2,2-dimethyl-2,3-dihydrobenzofuran 5 -[y-(4-phenylpiverazin-1-yl)]butyryl-2,2-dimethyl-2
- 3-dinohydrobenzofuran was treated in the same manner as in Example 2 and recrystallized from benzene-hexane to obtain the desired product (yield 67%).

Melting point: 133-134℃ Elemental analysis value: C Masuhi 32N202 C day N

Claims (1)

[Claims] 1 General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R_1 represents hydrogen, lower alkyl, or a halogen atom, and R_2 represents hydrogen, lower alkyl, lower alkoxy, or a halogen atom. . X represents =O or ▲There are mathematical formulas, chemical formulas, tables, etc.▼. n represents an integer from 1 to 3. ] A 2,3-dihydrobenzofuran derivative represented by: 2. A 2,3-dihydrobenzofuran derivative according to claim 1, which is represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. 3. A 2,3-dihydrobenzofuran derivative according to claim 1, which is represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. 4. The 2,3-dihydrobenzofuran derivative according to claim 1, which is represented by the formula ▲ Numerical formulas, chemical formulas, tables, etc. are available. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ 5 Formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ The 2,3-dihydrobenzofuran derivative according to claim 1, which is represented by the following. 6. A 2,3-dihydrobenzofuran derivative according to claim 1, which is represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. 7. The 2,3-dihydrobenzofuran derivative according to claim 1, which is represented by the formula ▲ Numerical formulas, chemical formulas, tables, etc. are available. 8. A 2,3-dihydrobenzofuran derivative according to claim 1, which is represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. 9. A 2,3-dihydrobenzofuran derivative according to claim 1, which is represented by the formula ▲ Numerical formulas, chemical formulas, tables, etc. are available. 10 The 2,3-dihydrobenzofuran derivative according to claim 1, which is represented by the formula ▲ Numerical formulas, chemical formulas, tables, etc. are available. 11 The 2,3-dihydrobenzofuran derivative according to claim 1, which is represented by the formula ▲ Numerical formulas, chemical formulas, tables, etc. are available.