KR820001963B1 - Process for preparing pyrroliding dderivative - Google Patents

Abstract

Pyrrolidinones(I), useful for treatment of cerebral insufficiency and improve intellectual efficiency, were prepd. by cyclization of 4-(P-methoxybenzoylamino)butyric acid. For example, 20.0 g 4-(P-methoxybenzoylamino)butyric acid. was refluxed for 2 hr in a mixed soln. of 50 ml toluene and 9.2 ml thionyl chloride to give 1-(P-methoxybenzoyl)-2-pyrrolidinone(m.p. 119-120≰C).

Description

Method for preparing pyrrolidine derivative

The present invention is represented by the following structural formula (I), 1- (p-methoxybenzoyl) -2-pyrroli having important pharmacological effects in the control or prevention of metastasis, or in the treatment and prevention of hyperactivity, especially cerebral insufficiency. Dinon series compounds and their intermediates and methods of preparing these pharmaceutical formulations.

According to the present invention, 1- (p-methoxybenzoyl) -2-pyrrolidinone represented by structural formula (I) can be prepared by cyclizing 4- (p-methoxybenzoylamino) burric acid. In the cyclization reaction of 4- (p-methoxybenzoylamino) butyric acid, 1 mole of water comes off, so it is treated with a normal carbocyclization reaction with dehydrating agents such as heating and / or polyphosphoric acid, phosphorus pentachloride and thionyl chloride. Depending on the method of use, it is made in an inert organic solvent such as an aromatic hydrocarbon (eg toluene), ether (eg tetrahydrofuran) or halogenated cyclohydrogen (eg chloroform). 4- (p-methoxybenzoylamino) butyric acid is also treated in the present invention and can be prepared by appropriately cyclizing 4-aminobutyric acid (e.g. using p-methoxybenzoyl chloride in the presence of an acid binder such as sodium hydroxide). .

As mentioned above, 1- (p-methoxybenzoyl) -2-pyrrolidinone having structural formula (I) is a novel compound having several important medicinal benefits. The compound is mildly toxic and has been shown to cure various cerebral insufficiency symptoms experimentally induced by the animal experiments described below.

A) Experiment of acquisition of `` avoidance reaction '' after treatment with excess carbonic acid

The experimental device is a "shuttle box" with a grid of 10 cm in the middle and an electrical grid on the bottom. In the box that became the reactor, there is a good speaker.

One hour or three hours after the injection of the sample or control compound into the mice, they are placed in pure carbon dioxide for 12 seconds (experimental animals: 120 to 150 g rats: 10 animals per group). The third group of 10 animals was the control group, which did not undergo experimental manipulation or carbon dioxide treatment. Three minutes after CO2 treatment, all three groups of rats in the shuttle box learned to reflect both unconditionally and unconditionally in the shuttle box: 10 seconds of static-5 seconds of noise (`` avoidance '')-15 seconds of noise + Valkunk ("Escape"): This operation is repeated six times.

In each of these six experiments, each rat's reaction time (the time it takes for the rat to jump on the rod) is measured. Calculate it so that

Only the "active" amount of the sample is the amount which shows significant activity during each six experiments. In other words, when this sample volume is used, animals with carbon dioxide and sample treatment perform much better than animals treated with carbon dioxide and the same reactions as animals without samples or carbon dioxide treatment.

B) "Passive Avoidance" Memory Loss Test by Electric Shock

The test apparatus is a skinner box with an electrically conductive grid floor and a gray square platform at one corner. Males weighing between 100 and 120 grams are placed on this gray podium. Every time they come down to the bottom of the grid, they receive an electric shank and the rats treated three or five times learn the so-called `` passive avoidance '', which is the one that is reluctant to descend from the podium. Divide the rats into three groups of 20 animals each. One group adds an electric shank (45 mA, 2 seconds) to both your company and intraperitoneally administers sodium chloride solution. The second group applies an electric shank to both firms and injects the sample into the peritoneum. The third group only injects sodium chloride solution. After three hours, each rat is placed on the podium and the length of stay (up to 60 seconds) is measured. Significant activity of the sample compared to the two control groups was calculated using the Lang test method.

The active dosage of the sample is the amount that shows a significant protective activity against the electric shock (ie, the experimental animals treated with the active amount of the sample and the electric shank have a long residence time, like the animals without the electric shank, On the other hand, animals treated with sodium chloride and electric shank have short stay times).

C) Delayed trial of haloperidol-induced "knockout" time for "sequential evasion" reactions using squirrel monkeys

Among the two-rowed Skinner box, a male squirrel monkey (Saimiri sciureus) weighing 0.6-1.2 kg each housed separately is trained to "sequential avoidance".

'' Avoid-shank ''-interval of 40 seconds; `` Shank-shank ''-interval of 20 seconds; Foot-shock of up to 5 seconds. In monkeys with basic training, 1.0 mg / kg oral of haloperidol is measured orally to measure the "knukout" time (the time taken to "block" or "escape" the behavior. Monkeys showing stable “knock out” times are selected and used for titer testing of sample compounds as a cerebral activity enhancer. Sample compounds are injected at varying times before halopyridol treatment.

The active amount of a sample is the amount by which a significant "knock out" time has occurred in a three-hour test when the sample is properly administered prior to haloperidol treatment.

D) Oxygen Deficiency Treatment Test

Males weighing between 300 and 350 g are used in this test. Experimental animals are anesthetized with halotane and tracheotomy followed by epidural electrodes on each side. After this operation, anesthesia is continued and all wounds and compressions are infiltrated with Xylocaine, and d-Dubocurarine is wetted for artificial respiration. Continue to record the electroencephalogram (EEG) throughout the entire process of this experiment. To cause oxygen deficiency, the coin EEG is recorded for 30 seconds and then aspirated again.

Experimental terms are defined below.

1. "Remaining time" = ST: time required to record coin EEG under nitrogen stream

2. "Recovery time" = RT: Time taken from indoor air aspiration to first electrical activity in the cortex

The sample compound is administered 60 to 120 minutes before the first oxygen deficiency occurs. ST and RT values of the mice treated respectively are compared with the control group by Lang test. Extension of the ST value and / or shortening the RT value is considered a protective effect against oxygen deficiency.

The "active amount" of a sample compound is an amount which shows remarkable protective activity.

1- (p-methoxybenzoyl) -2-pyrrolidide according to the present invention with very low acute toxicity [LD 50> 5000 mg / kg po (mouse)] in the above-described test shows significant activity at :

1- (p-methoxybenzoyl) -2-pyrrolidinone of formula (I) may be used as a medicament. As a pharmaceutical preparation, it is used as a tablet, a skin coating, dragee, a hard gelatin capsule, a soft gelatin capsule, a solution, an emulsifier, a suspension, etc. However, it may be administered rectally as a suppository or in a parenteral preparation such as an injectable solution.

1- (p-methoxybenzoyl) -2-pyrrolidinone may be used in combination with pharmaceutically inert organic or inorganic tablet excipients for the preparation of economics, skin preparations, dragees or hard gelatin capsules. As these excipients, lactose, corn starch or derivatives thereof, talc, stearic acid and salts thereof are used.

Excipients for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semisolids and liquid polyols.

Suitable excipients for preparing solutions or granules include water, polyols, sugars, invert sugar, glucose and the like.

Suitable excipients for preparing injectable solutions include water, alcohols, polyols, glycerin, vegetable oils and the like.

Suitable excipients for preparing suppositories include natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

In addition, pharmaceuticals and formulations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, coloring agents, flavoring agents, osmotic salt buffers, coatings or antioxidants. Of course, it may also contain other therapeutically effective compounds.

According to the present invention, 1- (p-methoxybenzoyl) -2-pyrrolidinone of formula (I) is used to control or prevent cerebral insufficiency, which often occurs in cerebral seizures, old age, and alcoholism. It can be used to improve. Dosages vary and increase or decrease as needed in each case. In general, in the case of oral administration, it is usual to administer 10 mg to 2500 mg of 1- (p-methoxy-benzoyl) -2-pyrrolidinone per day, but more may be administered.

The following examples are presented for the purpose of describing the present invention and are by no means intended to be limiting.

Example 1

30.9 g of 4-aminobutyric acid, 24.0 g of sodium hydroxide and 300 ml of deionized water are added while stirring 10.2 g of p-methoxybenzoyl chloride at 30 ° C. in one portion. After 2 hours, the mixture was acidified by adding 75 ml concentrated hydrochloric acid at a temperature of 10 ° C. or lower. The precipitate is filtered off, washed with deionized water, dehydrated on phosphorus pentoxide in an oven at 65 ° C. and recrystallized from 45 ml of acetone / low boiling petroleum ether (3: 1). 4- (p-methoxybenzoylamino) butyric acid having a melting point of 120.5 ° to 122 ° C is obtained.

10 g of phosphorus pentoxide and 6 ml of orthophosphoric acid (at least 85%) are combined and warmed up. To this reaction was added 2.0 g of 4- (p-methoxybenzoylamino) butyric acid at room temperature. The mixture was warmed at 50 DEG C for 60 minutes and then reacted with ice to extract with ethyl acetate. The organic layer is first washed with cold water, then cold sodium bicarbonate solution, and finally with water to dehydrate on sodium sulfate. Diethyl ether was added to the residue, followed by mixing and separation to obtain 1- (p-methoxybenzoyl) -2-pyrrolidinone having a solvent point of 120 ° C to 122 ° C.

Example 2

20.0 g of 4- (p-methoxybenzoylamino) butyric acid, 50 ml of toluene, 9.2 ml of thionyl chloride mixture was refluxed for 2 hours, treated with decolorized activated carbon and evaporated. The residue is dissolved in methylene chloride and chromatographed on neutral aluminum oxide gel. Recrystallization of 1- (p-methoxybenzoyl) -2-pyrrolidinone flowing out to methylene chloride has a melting point of 119 ° to 120 ° C.

Diethyl ether is added, the mixture is mixed well and the resulting filter cake is taken in ethyl acetate. This ethyl acetate service is washed with sodium bicarbonate solution and water, dehydrated over sodium sulfate and evaporated to dryness. Subsequent vacuum sublimation of the residue yields 1- (p-methoxybenzoyl) -2-pyrrolidinone having a melting point of 119 ° to 120 ° C.

Example 3

1- (p-methoxybenzoyl) -2-pyrrolidinone is mainly used as a tablet with the following composition:

Finely ground main components, powdered lactose and a portion of white corn starch are mixed well together. The mixture is sieved, added with a polyvinylpyrrolidone solution dissolved in water, kneaded well, and granulated to dry. The granules, the remaining corn starch and magnesium stearate are combined and sieved and mixed with each other. The mixture is compressed to produce tablets of the appropriate type and size.

Example 4

1- (p-methoxybenzyl) -2-pyrrolidinone is used as a main ingredient to prepare tablets having the following composition:

Finely ground main component, part of white corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed. Sift the mixture, combine the rest of the white corn starch with water to form appropriate granules, dry and sift. To this, sodium carboxymethyl starch and magnesium stearate are added and mixed, and the mixture is compressed to form a tablet with a cutting line.

Example 5

1- (p-methoxybenzoyl) -2-pyrrolidinone is used as a main ingredient to prepare tablets having the following composition:

Finely ground main component, part of white corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed. The mixture is sifted and combined with the rest of the white corn starch and water to form granules and sifted to dryness. To this, sodium carboxymethyl starch and magnesium stearate are added, mixed and compressed to form tablets with a cutting line.

Example 6

1- (p-methoxybenzoyl) -2-pyrrolidinone is used as a main component to prepare double ampoules with the following composition:

The diluent is combined into the main ingredient ampoule prior to injection. This yields 10 ml of ready-to-use injectable solution containing 100 mg of main ingredient.

Example 7

1- (p-methoxybenzoyl) -2-pyrrolidinone is used as a main component to prepare a double ampoule having the following composition:

The diluent is combined into the main ingredient ampoule prior to injection. This gives 10 ml of ready-to-use injectable solution containing 100 mg of active ingredient.

Example 8

1- (p-methoxybenzoyl) -2-pyrrolidinone is used as a main component to prepare a double ampoule having the following composition:

The diluent is combined into the main ingredient ampoule prior to injection. This gives 10 ml of a ready-to-use injectable solution containing 100 mg of active ingredient.

Claims (1)

A process for preparing 1- (p-methoxybenzoyl) -2-pyrrolidinone represented by the following structural formula (I), characterized by cyclization of 4- (p-methoxybenzoylamino) butyric acid.