JPS6045626B2 - Novel 1,2,3,4-tetrahydronaphthalene derivative - Google Patents

Description

Detailed Description of the Invention The present invention is based on the general formula (I) R (CH2"I) (wherein, n is an integer of 1 to 4, R" is a hydrogen atom or a lower alkyl group, and R" is a halogen atom. , nitro group, amino group, lower alkyl group or lower alkylthio group).

The compound of the present invention is a novel compound that has not been described in any literature, and has useful pharmacological actions such as remarkable antiallergic action, platelet aggregation inhibiting action, and antithrombotic action, and is an industrially useful compound as a pharmaceutical.

To explain R'' and R'' in the general formula (I) more specifically, halogen atoms include fluorine, chlorine, bromine,
Iodine, etc., lower alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, ter
A lower alkylthio group represents an alkyl group such as t-butyl, a methylthio group, an ethylthio group, an n-propylthio group, etc.

So far, only sodium cromoglycate has been known as an antiallergic agent, particularly an atopic antiallergic agent.

However, sodium cromoglycate has the drawback that sufficient pharmacological effects cannot be expected when administered orally, and therefore, the development of an atopic allergy agent that can be administered orally is desired. Therefore, the present inventors sought a new compound that can be administered orally and has an atopic antiallergic effect, synthesized a 1,2,3,4-tetrahydronaphthalene derivative represented by general formula (I), and conducted various studies on its pharmacological effects. As a result, it was found that it has a remarkable anti-allergic effect when administered orally. Furthermore, the compound of the present invention has pharmacological effects such as platelet aggregation inhibiting action and antithrombotic action,
Discovered that it is an industrially useful compound as a pharmaceutical,
The present invention was completed.

Next, the manufacturing method of the present invention will be explained, but this is only an example, and it is of course possible to manufacture by other chemically similar methods.

Manufacturing method A However, in the formula, R1 and R2 have the same meanings as above.

R3 represents a hydrogen atom, a lower alkoxy group, or a lower alkoxycarbonyl group, X represents a halogen atom, Y represents a cyano group or a lower alkoxycarbonyl group, and n represents an integer of 1 to 4. Production method B However, in the formula, Rl, R2 and Y have the same meanings as above, and R4 represents a pyrrolidino group, a piperidino group, or a morpholino group.

Manufacturing method C However, in the formula, R1 and R2 have the same meanings as above.

Manufacturing method D However, in the formula, Rl, R2 and n represent the same meanings as above.

Next, implementation of the present invention will be specifically explained.

Production method A involves combining compound (■) and an alkylating agent in the presence of an alkali (e.g., sodium methylate, sodium ethylate, potassium, t-butyrate, sodium amide, sodium hydride, etc.) in a solvent (e.g., methanol, ethanol, tetrahydrofuran, etc.). , benzene, toluene, xylene, dioxane, dimethylformamide, dimethyl sulfoxide, hexamethylene phosphotriamide, etc.) for 3 to 3 hours or as necessary.

It is then obtained by hydrolysis using a mineral acid (eg, hydrochloric acid, sulfuric acid, etc.). Incidentally, an organic solvent such as acetic acid may be added for the purpose of maintaining uniformity of the reaction during the hydrolysis reaction. Production method B involves mixing the compound (■) and acrylonitrile or acrylic acid lower alkyl ester in an organic solvent (e.g., methanol, ethanol, tetrahydrofuran, dioxane, benzene, dimethylformamide, etc.) while passing nitrogen through the mixture for 1 to 1,200 hours North time. After heating to dilute hydrochloric acid,
Hydrolysis may be carried out using a mineral acid such as dilute sulfuric acid.

Production method C involves reacting the compound (■) with glyoxylic acid in a hydrous alcohol in the presence of an alkali hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.) at room temperature for 12 to 2 hours, and then reacting the compound (■) with glyoxylic acid for 12 to 2 hours at room temperature. Hydrogenation may be carried out in an organic solvent (for example, methanol, ethanol, alcohol, acetic acid, etc.) in the presence of a catalyst such as platinum or the like.

Production method D involves mixing the compound (■) with polyphosphoric acid at 60 to 130°C.
for 3 to 8 hours, or in the presence of an inert solvent (e.g. nitrobenzene,
carbon disulfide, 1,1,2,2-tetrachloroethane, etc.)
What is necessary is just to carry out 1-1 turbidity reaction at 0-30 degreeC.

The 7-lower alkylsulfinyl derivatives and 7-lower alkylsulfonyl derivatives of the compounds of the present invention are produced by treating the corresponding 7-lower alkylthio derivatives with hydrogen peroxide or an organic peracid.

In addition, 7-amino derivatives and 7-acylamino derivatives can be obtained by catalytically reducing the corresponding nitro derivative in the presence of a catalyst such as Raney Nickel to form a 7-amino derivative, and then reacting it with an acyl halide in the presence of an organic base (pyridine, triethylamine, etc.). obtained by. Next, experimental results regarding the platelet aggregation inhibiting effect of the compound of the present invention will be shown.

Pharmacological experiment Inhibitory effect on platelet aggregation 1100r'Pml of guinea pig blood added with sodium citrate
Centrifuge at room temperature and transfer the supernatant to a platelet.
rich plasma (PRP).

PRPO.3 prepared by CfceIIs/MI. 9rT
Add 0.01 ml of test chemical solution to 3rC11100
Stirring was started at r'Pm, and after 2 minutes, 0.1 ml of aggregating agent collagen or arachidonic acid was added, and the platelet aggregation reaction was observed using a platelet aggregation meter.

All test compounds were dissolved in dimethyl sulfoxide to give an effective concentration of 3 x 10-5 g/ml. The aggregation inhibition rate was determined from the aggregation rate 8 minutes after addition of the flocculant. As is clear from the above test results, there is a marked blood loss in the effectiveness of the present invention. ? A negative effect was observed, resulting in blood loss]? ? Possibility of Ujinminami being used as a fraudulent agent is suggested.

As is clear from the above test results, the compound of the present invention was found to have a remarkable platelet aggregation effect, suggesting its potential as a platelet aggregation inhibitor.

Examples are shown below. Example 1 14 g of 2-ethoxycarbonyl-6,7-dimethyl-1-oxo 1,2,3,4-tetrahydronaphthalene was dissolved in 100 ml of benzene, and 3.0 g of sodium methylate was dissolved.
6g was added and heated for 1 hour.

Next, 16 g of β-bromopropionic acid ethyl ester was added and the mixture was refluxed for 1 hour. After the reaction was completed, the solvent was distilled off, 50 ml of 10% hydrochloric acid and 50 ml of acetic acid were added to the residue, and the mixture was heated for 5 hours. Then, the solvent was distilled off under reduced pressure, ice water was added to the residue, and the precipitated crystals were collected. When the crystals are recrystallized from methanol,
6,7-dimethyl-1-oxo-1,2,3,4-tetrahydro-2- as colorless, scaly crystals with a melting point of 188-190°C
17 g of naphthalene propionic acid was obtained. Example 2 10 g of 1-pyrrolidino-7-chloro-3,4-dihydronaphthalene and 5 g of acrylic acid ethyl ester were dissolved in 70 mt of dioxane and reacted in a nitrogen stream at 50 to 60°C for 5 hours.

After the reaction, the solvent was distilled off under reduced pressure and the residue was diluted with 10% hydrochloric acid (200%).
mt was added and heated for 3 hours. After the reaction was completed, crystals were precipitated when the mixture was left to cool on ice. The precipitated crystals were recrystallized from methanol to obtain 7.2 g of 7-chloro-1-oxo-1,2,3,4-tetrahydro-2-naphthalenepropionic acid in the form of colorless columnar crystals with a melting point of 177°C. Example 3 7-Methyl-1-oxo 1,2,3,4-tetrahydronaphthalene 15g 100% sodium hydroxide in a mixture of 1 glyoxylic acid modified and 150 ml ethanol
mL was gradually added dropwise under ice cooling.

After the dropwise addition, the mixture was stirred at room temperature for an hour. After the reaction is complete, ice water is added and then hydrochloric acid is added to make it acidic. The precipitated crystals are filtered out and recrystallized from concentrated methanol to give pale yellow needle-like crystals of 7-methyl-1-oxo-1,2,3,4- with a melting point of 191-197C. 18 g of tetrahydronaphthylidene acetic acid was obtained. Then, it was dissolved in 100 ml of acetic acid and hydrogenated together with 3 g of Raney nickel. After hydrogenation, acetic acid was distilled off and the residue was recrystallized from isopropyl ether to yield 16.5 g of 7-methyl-1-oxo-1,2,3,4-tetrahydro-2-naphthaleneacetic acid in the form of colorless needles with a melting point of 145-146°C. I got it. Example 4 No dihydro 3-(p-methylthiophenethyl)-2
, 5 g of 5-furandione and 300 g of polyphosphoric acid at 10
The mixture was stirred at 0°C for 2 hours.

After the reaction was completed, ice water was added and the mixture was extracted with chloroform. After washing the layer with chloroform and dehydration, the solvent was distilled off and the residue was recrystallized from methanol to give 7-methylthio-1-oxo-1,2,3,4 as pale yellow prism crystals with a melting point of 148°C.
2.6 g of -tetrahydro-2-naphthaleneacetic acid was obtained.
Examples 5 to 11 The compounds shown in the following table were synthesized according to the methods of Examples 1 to 4.

Claims (1)

[Claims] 1 General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, n is an integer from 1 to 4, R^1 is a hydrogen atom or a lower alkyl group, and R^2 is a halogen atom. , nitro group, amino group, lower alkyl group or lower alkylthio group).