JPS6016947B2 - Pyrazolidine derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to new and useful pyrazolidine derivatives.

The pyrazolidine derivative of the present invention is a novel substance that has not been described in any literature, and is represented by the following general formula (1).

However, in the formula, RI represents a lower alkyl group. Pyrazolidine derivatives are well known as antipyretic and analgesic drugs, and many derivatives have been proposed so far. The present inventors have focused on the fibrinolytic activity of pyrazolidine conductors, and have been conducting repeated studies to develop antithrombotic materials by binding or adsorbing pyrazolidine derivatives to the surface of polymeric substances. At present, pyrazolidine derivatives that have a functional group capable of binding to molecular substances and also have fibrinolytic activity are not well known.

As a result of repeated research on the synthesis of various pyrazolidine derivatives, the present inventors have synthesized a derivative represented by general formula (1) that has a number of excellent features as will be explained later. The novel pyrazolidine derivatives of the present invention include, for example, 4-n
-butyl-4-(P-carboxybenzyl)-1,2-diphenyl-3,5-dioxopyrazolidine.

All of the pyrazolidine derivatives of the present invention are characterized by not only excellent antipyretic and analgesic effects, but also particularly excellent fibrinolytic activity and excellent antithrombotic properties. Although the pyrazolidine derivative of the present invention can be synthesized by various methods, the following method is particularly desirable.

That is, the following general formula (0) [where RI is the general formula (1)]
The same as in the case of
Jium, metallic potassium, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium methoxide,
A halogen represented by the following general formula (m) [wherein X represents a halogen element such as fluorine, chlorine, bromine, or iodine] is reacted with equimolar amounts of an alkali compound such as potassium ethoxide. The desired derivative represented by the general formula (1) is synthesized by reacting with an aromatic acid.

Further, the derivative represented by the general formula (1) of the present invention is prepared by adding the compound represented by the general formula (0) to the halogenated aromatic compound represented by the general formula (m) in the presence of an alkali compound in a solvent such as alcohol. It can also be synthesized by reacting with group acids. The above reaction is usually carried out in a solvent.

Examples of solvents that can be used include water, methanol, ethanol, n-propanol, isopropanol, benzene, acetone, dioxane, ethylene chloride, chloroform, ethyl acetate, pyridine, or other general organic solvents that do not participate in the reaction. However, if necessary, these solvents may be used in combination. The pyrazolidine derivatives of the present invention include nylon, polyester, polyethylene, polyvinyl chloride, latex, polypropylene,
It can be easily coated on any polymeric compound such as polystyrene or silicone, and for example, the pyrazolidine derivative of the present invention can be used as a material for artificial blood vessels, catheters, artificial valves, artificial hearts, artificial lungs, artificial kidneys, etc. It is possible to impart excellent antithrombotic properties by coating the membrane.

In addition, the pyrazolidine derivative of the present invention may be administered orally by sprinkling it on saccharide such as sucrose, glucose, fructose, starch, etc. in an appropriate amount, or it may be dissolved in salt form in sterile distilled water and administered intravenously. You can also do it. Example 1 Phenylbutazone 924 9 and sodium hydroxide 120
The paste was dissolved over 20 ml of isopropanol, then 645 ml of P-(bromomethyl)benzoic acid was added to the solution and refluxed for 3 hours.

After removing the produced sodium bromide, the isopropanol was distilled off and the resulting pickle was dissolved in chloroform, and then the chloroform solution was diluted to 0. Washed with state hydrochloric acid. After concentrating the chloroform solution under reduced pressure, it was recrystallized from n-hexane to give 4-n-butyl-4-(P-carboxybenzyl)-1,2-diphenyl-3,5-dioxopyrazolidine (RI: n-butyl, R2: Hydrogen) was obtained.
The melting point was 192°C. In addition, as a by-product, 54-9-5-(P-carboxybenzyloxy)-41n-
Butyl-1,2-diphenyl-3-pyrazolone was also obtained.
The synthesized compound was identified by NMR.

The NMR spectrum of 4-n-butyl-4-(P-ruboxybenzyl)-11,2-diphenyl-3,5-dioxopyrazolidine in deuterated chloroform is 60-9, 61
-3~1-〇 61.9~2-1■H) butyl, 63
．． 5(2H) two phenyls bonded to nitrogen on methylene (singletl dish), 67.5(2H) aromatic proton of P-disubstituted benzene next to methylene, 68
．． 1 (IH) shows the aromatic proton of P-disubstituted benzene adjacent to the carboxylic acid (6) 10.3 (IH) shows a carboxyl proton signal.

The NMR spectrum of the by-product 5-(P-carboxybenzyloxy)-41-n-butyl-1,2-diphenyl-3-pyrazolone in deuterated chloroform is 60.
9 61.3-1.6, butyl in 62.4 (sail), 65
．． 3 (spot) with methylene, 67.3 (singleUoH
), phenyl, 67.5 and 68.1 (mountains) showed the aromatic proton of P-disubstituted benzene, and 610.3 (IH) showed the carboxyl broton signal. From the above results, the synthesized compound was identified as 41n-butyl41(P-carboxybenzyl)11,2-diphenyl3,51dioxopyrazolidine.

Reference Example A 4 wt % dioxane solution of the compound obtained in Example 1 was circulated at room temperature for 5 hours at a flow rate of 50 min in a nylon 6 tube with an inner diameter of 3 winds and an outer diameter of 5 ribs.

The tube was washed with dioxane and then dried under reduced pressure. The thrombus formation time of the nylon 6 tube coated with the pyrazolidine derivative of the present invention thus obtained was 4.
It took more than 5 minutes. In contrast, the thrombus formation time for the untreated nylon 6 tube or the medical IJ tube with the same inner diameter was 1 minute and 20 minutes, respectively. The thrombus formation time was measured using Chandler's rotating tube method [A. B. Chandler Research 7, 110 (1958)
] (Trombus formation time after human citrate blood was injected into the tube and C added +).

Claims (1)

[Claims] 1. A pyrazolidine derivative represented by the general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 represents a lower alkyl group.) 2. The pyrazolidine derivative according to claim 1, which is a compound represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼.