JPS604172B2 - Method for producing carbostyril derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a novel carbostyril derivative, and more specifically, a method for producing a novel carbostyril derivative, and more specifically, a method for producing a novel carbostyryl derivative, in which R is a hydrogen atom or a lower alkyl group, R2 is a hydrogen atom or a lower alkyl group, R3
is a hydrogen atom, a straight or branched alkyl group, a cycloalkyl group or an aralkyl group, m and n are the same or different and are 0 or a positive integer, provided that Ism+nS5
This invention relates to a method for producing a carbostyryl derivative represented by

According to the method of the present invention, the target carbostyril derivative of the general formula (1) can be obtained by the general formula (wherein R,, R2, R3
, m and n are the same as above).

In this specification, "lower alkyl group" refers to methyl,
A lower alkyl group having 1 to 4 carbon atoms such as ethyl, propyl, butyl, "straight chain or branched alkyl group"
Straight-chain or branched alkyl groups having 1 to 8 carbon atoms such as methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl, etc., "cycloalkyl group" refers to cyclobentyl , cycloalkyl group such as cyclohexyl, "aralkyl group" is pendyl,
It means an aralkyl group such as phenethyl.

Moreover, the position of the substituent may be any of the 5th, 6th, 7th and 8th positions. In the compound of the present invention, when R2 is a lower alkyl group, the substituent thereof contains an asymmetric carbon, and therefore optical isomers may exist, and the present invention includes all such optical isomers.

In the method of the present invention, dehydrogenation of the 3,4-dihydrocarpostyryl derivative of general formula (b) is achieved by subjecting it to a dehydrogenation reaction using an oxidizing agent in a suitable solvent in a conventional manner.

The oxidizing agent used is 2,3-dichloro5,6
- Penzoquinones such as dicyanobenzoquinone (hereinafter abbreviated as DDQ), chloranil (2,3,5,6-tetrachlorobenzoquinone), gelene dioxide, palladium on carbon,
Examples include metal catalysts such as palladium black, platinum oxide, and Raney nickel, and brominating agents such as N-bromosuccinimide and bromine.

In addition, as a solvent, dioxane, tetrahydrofuran,
Ethers such as 2-methoxyethanol and dimethoxychetane, aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, butanol, amyl alcohol, hexanol, etc. alcohols, aprotic polar solvents such as N.N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. As the reaction conditions for this reaction, the reaction temperature is from room temperature to 300,000 ℃, preferably 50,000 ℃.
~20,000, the reaction time is 1 hour to 2 days, preferably 1 to 2 field hours, and the proportion of the oxidizing agent used is:
When using benzoquinones or brominating agents, the compound (
b) Equimolar to 5 times the mole, preferably equimolar to 2
If a metal catalyst is used, a normally used catalyst amount may be used.

The starting material 3,4-dihydrocarbostyryl derivative used in the process of the present invention is a new compound, and can be prepared, for example, as follows.

That is, a 3,4-dihydrocarbostyryl derivative represented by the general formula (wherein R is the same as above) is added to a 3,4-dihydrocarbostyryl derivative represented by the general formula (wherein R2, R3, m and n are the same as above, It is produced by reacting fatty acid derivatives represented by

All carpostyryl derivatives represented by the general formula (1) obtained by the method of the present invention are new compounds, have anti-inflammatory effects and platelet aggregation-inhibiting effects, and are useful as anti-inflammatory drugs and antithrombotic drugs.

Next, the method of the present invention will be specifically explained with reference to reference examples and examples.

Reference example dimethyl sulfoxide 100 [N-ethyl-5-hydroxy-3,4-dihydrocarbostyryl 19]
10 portions of sodium ethylate and 2 portions of sodium iodide are added and the mixture is heated at 80-90°C for 1 hour.

To this solution was added 32 ml of ethyl y-furomobutyrate, and the mixture was heated at 100 to 110 qo for 1 hour. After the reaction,
The reaction solution was poured into 1.5 liters of saturated saline solution and extracted with chloroform (300 x 4 times). This chloroform layer was mixed with saturated saline solution, 0. Wash with aqueous sodium oxide solution and then with water, dry over anhydrous sodium sulfate, and concentrate. The resulting residue was distilled under reduced pressure to obtain colorless liquid N-ethyl-5.
21 days of mono(3-ethoxycarbonyl)propoxy-3,4-dihydrocarbostyryl was obtained. Boiling point (0.
g) 189-191q○ Example 1 N-ethyl-5-1 (3-ethoxycarponyl) propoxy 3,4-dihydrocarbostyryl 2.72 and 90%
3.4 parts of DDQ is added to 54 parts of dioxane and the mixture is refluxed for 9.5 hours and then cooled.

The precipitated crystals are removed from the furnace, and the furnace solution is distilled off. The resulting residue was dissolved in chloroform, the organic layer was washed with a saturated aqueous sodium bicarbonate solution, then with water, dried over anhydrous sodium sulfate, treated with activated carbon, the solvent was distilled off, and the remaining bamboo was fractionally distilled. Colorless *di-like N-ethyl-5-(3
-ethoxycarbonyl)propoxycarbostyryl2.
0 evening. Boiling point (0.55KHg) 191-19yo
Example 2 6-(6-benzyloxycarbonyl)hexyloxy-3,4-dihyde.

1.9 hours of rubostyril and 1.9 hours of chloranil were added to 38 hours of xylene, and the mixture was refluxed for 1 hour. The reaction mixture was treated in the same manner as in Example 1, and the resulting residue was recrystallized from methanol to obtain 1.4 mL of colorless needle-like crystals of 6-(6-benzyloxycarbonyl)hexyloxycarbostyryl. . Melting point 141-14y0 Example 35
-(4-carboxy)butoxy-3,4-dihydrocarbostyryl 2.6 and N-bromosuccinimide 2.1
The mixture was added to 50% of carbon tetrachloride, and the mixture was refluxed under concentrated steam for 1 hour and then cooled.

The precipitated crystals were collected in a furnace and mixed with 5% sodium hydroxide aqueous solution 2.
In addition to 0', let it rest for 30 minutes at room temperature, and then heat it in the oven.
The furnace solution was made acidic with IN hydrochloric acid, the precipitated crystals were removed from the furnace, and 5
Recrystallized from 0% ethanol aqueous solution to form colorless needle crystals of 5-
Take 1.5 hours of (4-carboxy)butoxycarbostyril. Melting point: 196-197° Examples 4-18 Compounds of the general formula (1) are obtained in the same manner as in Examples 1-3.

Those compounds are shown in the table below. [Pharmacological test] Platelet aggregation inhibitory effect: The platelet aggregation inhibitory effect of the compound of the present invention was evaluated by Born's method'
C. V. R. rn, Nature, pp. 927-929 (1962)].

At that time, AG-O type agglomerometer (A key regometer)
[Made by Priceton Manufacturing Company (Br$ton Man Actm Co.)]
Measured using 3.8% in blood taken from rabbits
A blood sample to which a sodium citrate aqueous solution [mixing ratio of 3.8% sodium citrate aqueous solution and blood = 1:9 (volume ratio)] was centrifuged at 100 pm (200 x g) for 1 minute. Plate bran (pla) with high platelet concentration in the upper light area
letrich plasma).

This separated dish bran is hereinafter abbreviated as PRP-1. The remaining blood sample from which PRP-1 was separated was further added to 300
Centrifuge at 1500 x g for 15 minutes to collect the top part and collect blood acid with low platelet concentration.
oorplasma).

This separated dilicic acid is hereinafter abbreviated as PPP. Said P
The number of platelets contained in RP-1
Cronkite method (BrecherCIonki met
hod) [J. Appl. Ph biol. Enter 365~
375 (1950)].

In order to perform an adenosine diphosphate-induced aggregation inhibition test (hereinafter abbreviated as ADP-induced aggregation inhibition test), a sample containing 300,000 platelets was prepared by diluting PRP-1 with PPP ( This prepared sample is shown below.
(abbreviated as P-2).

In addition, in order to perform a collagen yield aggregation inhibition test, P
A sample containing 450,000 platelets was prepared by diluting RP-1 with PPP (hereinafter referred to as PRP-3).
). ADP-induced aggregation inhibition test: 0.01' of a solution containing a predetermined concentration of the compound to be tested and 0.6 of the above PRP-2 were added to a cell for measuring platelet aggregation containing a rotor, and the cell was placed in the cell chamber of a platelet aggregometer kept at 37°C (the rotation speed of the rotor was adjusted to 110 pm), and after 1 minute, 7.5 x 10-
0.07 of the 5MADP solution was added and the change in light transmission was recorded.

The 7.5×10-5 MADP solution used in the above test was
It was prepared by adding ADP powder (manufactured by Sigma) to Oren Veronal buffer (pH 7.35).

The aggregation rate at the time when platelet aggregation reached the maximum (the time when the light transmittance reached the maximum) was calculated using the following formula. Aggregation rate = b Shasan o a,: Light transmittance of PRP-2 b,: Light transmittance of PPP c,: When platelet aggregation is caused by the above method and platelet aggregation reaches the maximum In the above method, platelets were agglomerated in the same manner by adding only a solvent in which the test compound was dissolved instead of the test compound solution, and the aggregation rate was determined in the same manner, and this was used as the control aggregation rate.

From the aggregation rate of the test compound obtained above and the aggregation rate of the control, the platelet aggregation inhibition rate of the test compound was calculated according to the following formula.

Rejection rate (%)〒A33 ×, o.

A,: Control aggregation rate B,: Aggregation rate of test compound Collagen-induced aggregation inhibition test: 0.01' of a solution containing a predetermined concentration of the compound to be tested is placed in a cell for measuring platelet aggregation containing a rotor. and PRP-3 0.6' were added, and the cell was placed in the cell chamber of a platelet aggregometer kept at 37°C (the rotation speed of the rotor was adjusted to 110pm), and after 1 minute, .5×10
-0.07' of 5M collagen solution was added and the change in light transmission was recorded.

The 7.5 x 10-5M collagen solution used in the above test was prepared by grinding 9 parts of 100 parts of the collagen solution, adding it to 5M of Oren-Veronal buffer (Book 7.35), and separating the resulting supernatant solution. did.

The aggregation rate at the time when platelet aggregation reached the maximum (the time when the light transmittance reached the maximum) was calculated using the following formula.

Aggregation rate = Tortoise X100 a2: Light transmittance of PRP-3 b2: Light transmittance of PPP c2: Light transmittance when platelet aggregation is maximized by causing platelet aggregation using the above method In the method described above, instead of the test compound solution, only the solvent in which the test compound was dissolved was added to cause platelets to aggregate in the same manner, and the aggregation rate was determined in the same manner, and this was used as the control aggregation rate.

From the aggregation rate of the test compound obtained above and the aggregation rate of the control, the platelet aggregation inhibition rate of the test compound was calculated according to the following formula.

Inhibition rate (%) 2A Sanpo 9X・oo A2: Aggregation rate of control B2: Aggregation rate of test compound Platelet aggregation inhibitory effect was measured using the inhibition rate (%) obtained above.

The results are shown in the table below. In the table, the inhibitory effect on ADP-induced aggregation is shown in column a, and the inhibitory effect on collagen-induced aggregation is shown in column b. As is clear from the above results, the compound of the present invention has a particularly excellent inhibitory effect on ADP-induced aggregation compared to the control acetylsalicylic acid.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1 is a hydrogen atom or a lower alkyl group, R_
2 is a hydrogen atom or a lower alkyl group, R_3 is a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, or an aralkyl group, m and n are the same or different and each is 0 or a positive integer, provided that 1 There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (in the formula, R_1, R_2, R_
3, m and n are the same as above).