JPS6157585A - Manufacture of hexahydro-3,5-dioxo-1h-pyrrolidine-2- carboxylic acid and derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds and pharmaceutical compositions useful in the treatment of senile patients, memory enhancement and treatment of induced amnesia. More specifically, the present invention relates to hexahydro-3,5-dioxo-1H-pyrrolidine-2-carboxylic acid, esters and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing these compounds, and the treatment of aging in humans. The present invention relates to a method for the treatment of memory enhancement or amnesia by electric foreground shock induction.

U.S. Pat. No. 4,572,966 describes dihydro-1H-pyrrolidine-3,5 (2H,
Pharmaceutical compositions containing 6H)-diones are disclosed.

The S-enantiomer of hexahydro-3,5-dioxo-In-pyrrolidione-2-carboxylic acid ethyl ester was produced in 1955 by K Hardegger and 011 in their description of the configuration of some derivatives of cocaine and ecgonic acid. was done (E
, H by Mr. Hardegger and Mr. H,011
e1v, 3B:312 (1955))
.

According to one aspect of the invention, compounds useful in the treatment of senility, enhancement of memory or amnesia induced by electroconvulsive shock in 8.
Alkyl having ~6 carbon atoms, feni/L/,
-(CH2)1-4 phenyl, ammonium or a cation derived from a pharmaceutically acceptable metal or organic amine).

According to another aspect of the invention, pharmaceutical compositions useful for the treatment of senility, memory enhancement or amnesia due to electrosyndrome or shock induction are effective together with a pharmaceutically acceptable carrier. of a compound having the above definition or hexahydro-3,5-dioxo-1H-pyrrolidine-2-carboxylic acid ethyl ester.

According to another aspect of the invention, the method of the invention for treating senility, enhancing memory or treating amnesia by inducing electrical foreground shock in humans comprises an effective amount of a compound having the above structural formula or It consists of administering hexahydro-3,5-dioxo-1H-pyrrolidine-2-carboxylic acid ethyl ester.

The compounds according to the present invention are prepared by the reaction sequence illustrated in the following reaction scheme (2).

Reaction Scheme I II Ill Individual stereoisomers of formula l■ are prepared from the corresponding d-acid or L-acid as shown below (R Ota 5) 5-oxo-proline (also known as pyroglutamic acid) (II) is reduced by hydrogen over a 4-radium or platinum catalyst to give the corresponding alcohol d,
L-2-okino 5-hydroxymethylpyrrolidine (I
[I) is produced. This alcohol (9) or the individual d- or L-isomers is reacted with p-)luenesulfonyl chloride in the presence of a nitrogen base such as pyridine to produce tosylate (5). This tosylate (5) is reacted with a suitable sodium dialkylmalonate salt in an inert solvent such as dry dioxane to produce the ester (IA) according to the invention.

The free acid (IB) is prepared by catalytic hydrogenolysis of the benzyl ester (re) or by hydrolysis of the tertiary butyl ester (ID) in dilute aqueous acid solution.

ICIB D Starting material of Formula II for the reaction scheme illustrated in Scheme I,
5-Oquinoproline is obtained by converting t and d from d-glutamic acid into V, 5kol, in which the method for producing the compound is described.
r Z, Zucherind by Mr. a.

Czechoslov, Rep, J 44:3
47-351 (1920).

The free acid (IS) can be prepared, for example, by suspending it in a suitable solvent, such as water, adjusting its pH with a pharmaceutically acceptable metal base, anthonium hydroxide or an organic amine base, and removing the solvent. It is converted to a metal salt, ammonium salt or organic amine salt by removal under reduced pressure. If desired, the free acid can be regenerated by treating its salt form with an acid. For example, dilute aqueous hydrochloric acid can be used to regenerate the free form of the acid from a particular salt. Although the free acid form and its various salts differ somewhat from each other in their physical properties, such as solubility in polar solvents, the free acid form and its various salts are equivalent for the purposes of the present invention. It is considered that

The term alkyl group herein means a branched or unbranched saturated hydrocarbon group.

The term "pharmaceutically acceptable metal" cation refers to ten charged ions derived from metals such as sodium, potassium, magnesium, calcium, aluminum, zinc, iron, and the like.

The term "pharmaceutically acceptable amine" cation includes the ten-charged ammonium ion and hexahydro-3,
Refers to analogous ions derived from organic nitrogen bases that are strong enough as bases to form salts with 5-dioxo-1H-pyrrolidine-2-carboxylic acid.

hexahydro-3,5-dioquine-IH-pyrrolidine-
Bases useful in forming pharmaceutically acceptable non-toxic addition salts of 2-carboxylic acids form a class whose range is readily understood by those skilled in the art. To illustrate, the class includes the formula (where Ra, Rb and Rca are independently alkyl having from 1 to 6 carbon atoms, cycloalkyl having from about 3 to 6 carbon atoms, aryl, from about 7 to Aralkyl having about 10 carbon atoms.

The amine cation may be a hydroxyalkyl having 2 to 4 carbon atoms or a monoarylhydroxyalkyl having about 8 to about 15 carbon atoms. Furthermore, when together with 9 atoms, any two of Ra, Rb, and Re contain carbon or oxygen; can form part of a group ring, the nitrogen heterocycle being unsubstituted or mono- or di-substituted with an alkyl group having 1 to 6 carbon atoms.

Organic amines considered to be within the scope of this invention, 1li
Examples of l ions include, for example, monomethylammonium, dimethylammonium and trimethylammonium, monoethylammonium, diethylammonium and triethylammonium, heptanopropyl (n-propyl and iso-propyl) ammonium, dipropyl (n-propyl and iso-propyl) Ammonium and tripropyl (n-propyl and iso-propyl) ammonium, ethyldimethylammonium, benzylammonium.

Dibenzylantinium, benzyldimethylammonium, cyclohexylanthonium, hiberidinium, heptylphorinium, pyrrolidinium, 4-ethylmorpholinium, 1-isopropylpyrrolidinium, 1,4-dimethylpyradinium, 1-n-butylpyridinium ,
2-methylpiperidinium, 1-ethyl-2-methylhiberidinium, monoethanolammonium, jetanolammonium and triethanolammonium,
Ethyljetanol ammonium, n-7' methyl monoethanol ammonium, tris(hydroxymethyl)
Examples include methylammonium and phenylmonoethanolammonium. Hexahydro-5,5-dioxo-1H-pyrrolidine-2-carboxylic acid and the various salts of that acid having the above definitions include, for example, hydrates, alcoholates, such as solvates with ethanol and similar alcohols. Alternatively, they may exist in unsolvated forms as well as solvated forms such as solvates with other pharmaceutically acceptable non-toxic solvents. In general, the solvated forms of the compounds of the present invention are considered to be equivalent to the unsolvated forms of the present invention.

hexahydro-3,5-dioxo-1H-pyrrolidine-
Esters and salts of 2-carboxylic acids and derivatives thereof have an asymmetric carbon atom at the position indicated by an asterisk * in the structural formula below.

Thus either center may be present in the R or S form. The present invention relates to the pure R,R form, the pure S,S form of the free acid, its esters and salts.

The pure s,P: form, the pure R,S form or mixtures containing racemic mixtures are contemplated as falling within the scope of this invention.

Specific compounds contemplated as falling within the scope of this invention include hexahyto'-3+5-:)oxo-1H-pyrrolidine-2-carboxylic acid and its esters, ammonium salts, metal salts and amine salts. One example is as follows.

hexahydro-3,5-dioxo-1H-pyrrolidine-
2-carboxylic acid methyl ester.

hexahydro-3,5-dioxo-1H-pyrrolidine-
2-Carboxylic acid n-i lopylester.

hexahydro-3,5-dioxo-1H-pyrrolidine-
2-carboxylic acid n-7' thyl ester.

hexahydro-3,5-dioxo-1H-pyrrolidine-
2-carboxylic acid 1,1-dimethylethyl ester.

hexahydro-3,5-dioxo-1H-pyrrolidine-
2-carboxylic acid n-pentyl ester.

hexahydro-3,5-dioxo-1H-pyrrolidine-
2-Carboxylic acid 2-methylbutyl ester, hexahydro-6,5-dioxo-1H-pyrrolidine-
2-carboxylic acid n-hexyl ester.

hexahydro-5,5-dioxo-[-pyrrolidine-2
-Carboxylic acid 3-methyl hard/thyl ester.

No 1H-pyrrolidine-2-carboxylic acid 2-methyl-3-A in hexahydro-3,5-dio! methyl ester.

Hexahydro-3,5-dioxo-1a-pyrrolidinemethy-carboxylic acid phenylmethyl ester.

hexahydro-3,5-dioxo-1H-pyrrolidine-
2-carboxylic acid 2-7dynyl ethyl ester.

hexahydro-3,5-dioxo-1a-pyrrolidine-
2-carboxylic acid 3-phenylpropyl ester.

hexahydro-3,5-dioquine-1H-pyrrolidine-
2-carboxylic acid 4-phenylbutyl ester.

hexahydro-3,5-dioxo-1H-pyrrolidine-
2-Carboxylic acid sodium salt.

hexahydro-3,5-dioxo-1H-pyrrolidi/-
2-carboxylic acid potassium salt.

hexitehydro5.5-dioxo-1H-pyrrolidi/-
2-carboxylic acid magnesium salt.

hexahydro-3,5-dioxo-1H-pyrrolidi/-
2-carboxylic acid calcium salt.

hexahydro-3,5-dioquine-1H-pyrrolidine-
2-carboxylic acid ammonium salt.

Hexahydro-6,5-dioxo-1H-pyrrolidi/-
2-carboxylic acid methylammonium salt.

hexahydro-3,5-dioxo-1H-pyrrolidine-
2-carboxylic acid dimethylammonium salt.

hexahydro-3,5-dioxo-1H-pyrrolidi/-
2-carbo/trimethylammonium resistant salt.

hexahydro-3,5-dioquino-1H-pyrrolidine-
2-carboxylic acid ethyl an7nium salt.

hexahydro-3,5-dioxo-1H-pyrrolidine-
2-carboxylic acid diethylammonium salt.

hexahydro-3,5-dioxo-1H-pyrrolidine-
2-carboxylic acid triethylammonium salt.

hexahydro-5,5-dioxo-1H-pyrrolidine-
2-Carboxylic acid tri-n-propylammonium salt.

hexahydro-6,5-dioxo-1H-pyrrolidine-
2-carboxylic acid piperidinium salt, hexahydro-3,
5-dioxo-1H-pyrrolidine-2-carboxylic acid sulfolinium salt.

hexahydro-3,5-dioxo-1H-pyrrolidine-
2-carboxylic acid pyrrolidinium salt.

hexahydro-5+5-')oxo-1H-pyrrolidine-2-carboxylic acid piperazinium salt.

hexahydro-3,5-dioxo-1H-pyrrolidine-
2-carboxylic acid monoethanol ammonium salt, hexahydro-3,5-dioxo-1H-pyrrolidine-
2-carboxylic acid jetanol ammonium salt.

hexahydro-3,5-dioxo-1H-pyrrolidine-
2-Carboxylic acid triethanolammonium salt.

ΦSabidrow 3,5'-dioquine-1H-pyrrolidine-2-carboxylic acid tris(hydroxymethyl)methylammonium salt.

hexahydro-3,5-dioxo-1H-pyrrolidine-
2-Carboxylic acid hensyl ammonium salt.

hexahydro-3,5-dioxo-1H-pyrrolidine-
2-carboxylic acid phenylmonoethanol ammonium salt.

The compounds according to the invention are useful in treating senility, enhancing memory or reversing the effects of amnesia induced by electrical foreground shocks. The effectiveness of these compounds is measured in tests designed to demonstrate the ability of the compounds to reverse amnesia caused by electrostatic shock. This test is fully described in US Pat. No. 4,145,347, the disclosure of which is incorporated herein by reference. The only difference in the present invention is that the test compound is administered orally;
and the duration of the given electrical foreground shock is 1.0
It is a second.

Using this test, the following criteria are used to describe the scores for amnesia reversal. Amnesia return of 40% or more (Active-A), amnesia return of 25-39 degrees (Borderline Activity-C), and amnesia return of 0-25% (Inactive-N).

The table below shows the hexahydro-3,5-dioxo-1H-
The amnestic return of pyrrolidine-2-carboxylic acid ethyl ester is explained.

Inert, pharmaceutically acceptable carriers for preparing pharmaceutical compositions from the described compounds according to this invention can be either solid or liquid. Examples of solid forms include, for example, powders, one tablet, one dispersible granule, capsules, gelatin wafers, and suppositories. The solid carrier can be one or more substances that can also act as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder or disintegrant, and it can also be used in encapsulation. It can also be a substance that can. In powders, the carrier is a finely divided solid which is in a mixture 1f14 with the finely divided active compound. In tablets, the active compound is mixed with a suitable proportion of the carrier which now has the requisite binding properties and packed in the desired shape and size. Preferably, these powders and tablets contain from 5% or 10% to about 70% active ingredient. A suitable solid carrier is magnesium carbonate,
Magnesium stearate, Merck, sugar, lactose,
These include cuticle, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, etc.

The term "formulation" refers to a preparation of the active compound together with an encapsulating material as a carrier providing a capsule in which the active compound (with or without other carriers) is surrounded by and thus associated with the carrier. It means. Also included are gelatin wafers. tablet,
Powders, gelatin wafers and capsules may be used as solid dosage forms suitable for oral administration.

To prepare herbal medicines, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is homogeneously dispersed therein by stirring. The molten homogeneous mixture is then poured into conveniently sized casting furnaces and allowed to cool and solidify.

Examples of liquid form preparations include solutions.

Suspensions and emulsions may be mentioned. - Examples include solutions in water or water-propylene glycol for parenteral injection. Liquid formulations can also be prepared in solution in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants and flavors as desired.

It can be manufactured by adding stabilizers and thickeners. Aqueous suspensions suitable for oral use are prepared by dispersing the micronized active ingredient in water with viscous substances such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents. It can be done.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Examples of such liquid forms include, for example, solutions, suspensions and emulsions. These particular solid form preparations are most conveniently presented in unit dosage form and used as such to provide a single liquid dosage unit. Alternatively, if the solid is sufficient, after conversion to liquid form, a number of liquid doses can be obtained by measuring a predetermined volume of the liquid form preparation with a syringe, teaspoon, or other volumetric container. You can also make it possible to do so. When multiple liquid doses are so prepared, it is preferred to maintain the unused portions of the liquid dose at a low temperature (ie, under refrigeration) to retard possible degradation. Solid form preparations intended to be converted into liquid form contain, in addition to the active substance, one flavoring agent and one coloring agent.

Stabilizers, buffers, artificial or natural sweeteners.

It may contain a dispersant, thickener, solubilizer, etc.

The liquid used to prepare liquid form preparations can be water, isotonic water, ethanol, glycerin, propylene glycol, etc., and mixtures thereof. Naturally, the liquid used will be selected with respect to the route of administration. For example, liquid formulations containing large amounts of ethanol are not suitable for parenteral use.

Preferably, the formulation is in unit dosage form.

In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. . Also, the unit dosage form can be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these in packaged form.

The amount of active compound in a unit dose of the preparation varies from 11n9 to 500 da, preferably 5!, depending on its particular application and potency. It can be changed or adjusted by n9 to 100 strokes. If desired, the compositions can also contain other compatible therapeutic agents.

For therapeutic use as a cognitive activator, the mammalian dosage range for patients is 1 to 1 per Yu per day).
The range of 500In9 is preferably 25 to 750rn9. However, the dosage may vary depending on the needs of the patient, the severity of the condition being treated and the compound being used. Determination of the appropriate dosage for a particular condition will be apparent to those skilled in the art. Generally, treatment is initiated with lower doses that are less than the optimal dose of the compound. The dosage is then increased in small increments until the optimum effect under the circumstances is achieved. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.

Examples are presented below to enable those skilled in the art to practice the invention. However, these examples should not be considered as limiting the scope of the invention, but are merely illustrative of the invention.

Example 1 Hexahydro-5,5-dioxo-1H-pyrrolidine-
Preparation of 2-carboxylic acid ethyl ester Dioxane (10
diethyl malonate (45 mg, 4
A stirred solution of 7.5Lα (3 mol) is treated with sodium hydride (50%, 6.21% in mineral oil, 0.129 mol). After hydrogen gas generation has stopped, add dioxane (20
d in 0+d) is added to a solution of -5-tosylmethyl-2-oxo-pyrrolidine (16,1,P, 0.06 mol) (melting point 128-129°C, literature melting point 130°C). The mixture is stirred and refluxed for 6 hours, cooled and filtered. The furnace liquid was concentrated under reduced pressure and chloroform (20
0yJ) and washed with water (5-). The chloroform layer was dried (over Mg804), filtered and finally concentrated under reduced pressure at 80° C. to remove most unreacted diethyl malonate and give hexahydro-3,5-dioxo-1H-pyrrolidine- The 2-carboxylic acid ethyl ester is obtained as an oil. This oil is further purified by flash chromatography on silica (eluting with 20:1 dichloromethane:methanol).

After concentrating the desired fractions, this oil was heated for 16 hours.
Heat at 00° C. and 0.1 μm pressure.

Pure hexahydro-3,5-dioxo-I by cooling
H-pyrrolidine-2-carboxylic acid ethyl ester crystallizes out. Melting point 65-67°C.

Example 2 Hexahydro-5,5-dioxo-IH-pyrrolidine-
Preparation of 2-carbo/acid benzyl ester Dioxane (1
Dibenzyl malonate (56,E
[', 0.2 mol) of sodium hydride (50% in mineral oil, 6.2.F.

0.129 mol). d, t-5- in dioxane (200 ml) after hydrogen gas evolution stopped.
Tosylmethyl-2-oxo-pyrrolidine (16,1!i
, 0.06 mol). Stir the mixture and
Reflux for an hour, cool and filter. Solution F was concentrated under reduced pressure, dissolved in chloroform (200-), and then dissolved in water (
5-). Dry the chloroform layer (Mg8
04), treated with F and finally concentrated under reduced pressure at CLljtll and 80°C to remove most of the unreacted dibenzyl malonate to give hexahydryl-575-dioxo-IH-pyrrolidine-2-carboxylic acid. The Hensyl ester is obtained as an oil. This oil is further purified by flash chromatography on silica (2
Elution with 0:1 dichloromethane:methanol). After concentrating the desired fraction, the oil was heated at 100°C for 16 hours.
and 0.1 pressure, and after cooling, pure hexahydro-3,5-dioxo-1H-pyrrolidine-2-carboxylic acid benzyl ester is obtained.

Example 3 Hexahydro-3,5-dioquino-1H-pyrrolidine-
Preparation of 2-carboxylic acid Hexahydro- in dioxane (200 wLt)
A solution of 6,5-dioxo-1H-pyrrolidine-2-carboxylic acid hensyl ester (25,9Ji', α1 mol) is treated with hydrogen gas in the presence of 20% pa/c catalyst for 8 hours. The mixture was filtered and under reduced pressure (25
C) to obtain pure hexahydro-3,5-dioxo-1H-pyrrolidi/-2-carboxylic acid.

Example 4 Hexahydro-3,5-dioxo-1H-pyrrolidine-
Preparation of 2-carboxylic acid sodium salt Hexahydro-3,5-dioxo-1H-pyrrolidine-2-carboxylic acid (1a3J) in dioxane (200m) at θ°C.
FS0.1%/I/)+7) The solution is treated with 0.1N sodium hydroxide solution (10M, 0.1 mol) and the resulting hexahydro-3,5-dioxo-1H-pyrrolidine-2-carboxylic acid is The sodium salt solution is concentrated under reduced pressure to obtain dry sodium salt of hexahydro-3,5-dioxo-1H-pyrrolidine-2-carboxylic acid.

Example 5 Hexahydro-3,5-dioxo-1H-pyrrolidine-
Preparation of 2-carboxylic acid, potassium salt Hexahydro-6,5- in dioxane (200+d) at 0°C
Diox'so 1H-pyrrolidi/-2-carboxylic acid (1a
l, 0.1 mol) in α1N potassium hydroxide solution (
hexahydro-3,5-dioxo-1H-pyrrolidine-2-
The potassium salt solution of the carboxylic acid was concentrated under reduced pressure to dry hexahydro-3,5-dioxo-IH-? 'Obtain the potassium salt of loridine-2-carboxylic acid.

Example 6 Hexahydro 3,5-dioquine-1H-pyrrolidine-
Preparation of 2-carboxylic acid calcium salt Hexahydro-3,5- in dioxane (200 yd) at 0°C.
Dioxo-1H-pyrrolidine-2-carboxylic acid (ELM
, 0.1 mol) of α1N calcium hydroxide solution (
100 Tnt, 0.1 mol) and the resulting hexahydro-3,5-dioxo-1H-pyrrolidine-2
- Concentrate the calcium salt solution of the carboxylic acid under reduced pressure and dry it.
- Obtain a calcium salt of 2-carboxylic acid.

Example 7 Hexahydro 3,5-dioquine-1H-pyrrolidine-
Preparation of 2-carboxylic acid ammonium salt Hexahydro-6,5-dioxo-1H-pyrrolidine-2-carboxylic acid (1al,
0.1 mol) of α1N ammonium hydroxide solution (
100 m/, α1 mol) and the resulting ammonium salt of hexahydro-3°5-dioquino-1H-pyrrolidine-2-carboxylic acid is concentrated under reduced pressure to dry hexahydro-3,5-dioxo-1H- Pyrrolidine-2-
Obtain the ammonium salt of carboxylic acid.

Prescription example 1 Ingredients Amount Lactose
1113j' Corn starch 39Ii Hydroxypropyl cellulose 501 Danesium stearate 7Il Ethanol-
Water 50:50 Sufficient amount of the above hexahydro-6,5-dioxo-1H-pyrrolidine-2-carboxylic acid, sodium salt, lactose and hydroxypropyl cellulose are blended and granulated with so:so ethanol-water. The wet granules are sieved, dried and sieved again. The resulting dried granules are blended with cornstarch and magnesium stearate, and the mixture is compressed into 2251R9 tablets using an 11/32 inch standard recess punch. Approximately 6,00
0 tablets were obtained, each containing 25 m9 of hexahydro-
26.9# of hexahydro-315-E, corresponding to 3,5-dioxo-11(-pytetralysine-2-carboxylic acid)
Contains oxo-1H-pyrrolidine-2-carboxylic acid, sodium salt.

Another pharmaceutical preparation of hexahydro-6,5-dioxo-1H-pyrrolidine-2-carboxylic acid in place of the above-mentioned hexahydro-3,5-dioxo-1H-pyrrolidine-2-carboxylic acid, 1 equivalent of the sodium salt. (by substituting an acceptable salt in 225 containing dioxo-1H-pyrrolidine-2-carboxylic acid
Formulation example to obtain In9 tablets 2 Ingredients Amount Lactose 1437.4II Cornstarch 609 Hydroxypropyl cellulose 60! I Magnesium Stearate 11. 9 Hexahydro-3,5-dioxo-IH-pyrrolidine-2-carboxylic acid, calcium salt, as described above.

Blend the lactose and human, roxizolovir cellulose and granulate with so:so ethanol-water. The wet granules are sieved, dried and sieved again. The resulting dried granules are blended with corn starch and magnesium stearate and the mixture is compressed into 375 square tablets using a 13/32 inch standard recess punch. Approximately 6,000 tablets were obtained.

each of 100 hexahydro-3,5-dioxo-I
1156W corresponding to H-pytetralysine-2-carboxylic acid
Contains Ig of hexahydro-3,5-dioquine-1H-pyrrolidine-2-carboxylic acid, calcium salt.

Another pharmaceutical preparation of hexahydro-3,5-dioxo-1H-pyrrolidine-2-carboxylic acid in place of the above-mentioned hexahydro-5,5-dioxo-1H-pyrrolidine-2-carboxylic acid, 1 equivalent of the calcium salt. by replacing the acceptable salts in 575 containing 1H-pyrrolidine-2-carboxylic acid
m9 tablets are obtained.

Prescription example 3 Lactose 1105.
211 Cornstarch 9
0! iHydroxypropylcellulose
90N Magnesium Stearate
1811 Hexahy, drawn 3,5-dioxo-1H-pyrrolidine-2-carboxylic acid, calcium salt.

Blend the lactose and hydroxyzorobyl cellulose and granulate with so:so ethanol-water. The wet granules are sieved, dried and sieved again. The resulting dried 11 grains were blended with corn starch and magnesium stearate, and the mixture was drilled using a 172-inch standard recessed hole puncher.
Press into mp tablets. Approximately 6,000 tablets were obtained;
Each contains 250 # of Tehydro 3,5-dioxo-I
28289 corresponding to H-pyrrolidine-2-carboxylic acid
Contains hexahydro-3,5-dioxo-1H-pyrrolidine-2-carboxylic acid, carithum salt.

1 equivalent of the above hexahydro-3,5-dioxo-1m-pyrrolidine-2-carboxylic acid, potassium salt,
hexahydro-3,5-dioxo-IH-pyrrolidine-
By substituting another pharmaceutically acceptable salt of 2-carboxylic acid and adjusting the amount of lactose to obtain the same total amount as in the example formulation, again each is equal to 250 g hexahydro-3,5-dioxo-
500■ containing 1H-pyrrolidine-2-carboxylic acid
Tablets are obtained.

Formulation example 4 Hexahydro-3,5-dioxo-IH-pyrrolidine-
2-Carboxylic acid sodium salt 269I lactose 1707g Hexahydro-3,5-dioxo-1H-pyrrolidine-
The 2-carboxylic acid, sodium salt, lactose and magnesium stearate are blended and packed into KA4 hard gelatin capsules so that each capsule is filled with 200 μ of the powder mixture. Approximately 10,000 capsules were obtained, each containing 25 m of hexahydro-3,
Contains 26.919 hexahydro-6,5-dioso-1H-pyrrolidine-2-carboxylic acid, sodium salt, corresponding to 5-dioxo-1H-pyrrolidine-2-carboxylic acid.

The above hexahydro-3,5-dioxo-1H-pyrrolidine-2-carboxylic acid, 11:hexahydro-3,5-dioxo-IH-pyrrolidine-in place of the sodium salt
Again, each of Kisahydro! 20 containing 115-diox-7-IH-pyrrolidine-2-carboxylic acid
0 da capsules are obtained.

Prescription example 5 Sodium salt 113
SJ'lactose 1
976JF Magnesium Stearate
6811 Above hexahydro-3,5-dioxo-1
H-pyrrolidine-2-carboxylic acid, calcium salt, lactose and magnesium stearate are blended and packed into A2 hard gelatin capsules so that each capsule is filled with 200 μ of the powder mixture. Approximately 1
0,000 capsules were obtained, each containing 100 μ of hexahydro-3,5-dioxo-In-pyrrolidi/-2
-carboxylic acid corresponding to 1 11119 hexahydro-3,5-dioxo-1H-pyrrolidine-2-carboxylic acid.

Contains calcium salts.

Hexahydro-3,5-dioxo-1H-pi017
gin-2-carboxylic acid, the amount of Kla in place of the calcium salt, and the hexahydride substituted with another pharmaceutically acceptable salt of -3,5-dioxo-1H-pyrrolidine-2-carboxylic acid and in the above formulation example. By adjusting the amount of lactose to obtain a total amount identical to
0 da capsules are obtained.

Formulation example 6 Hexahydro 3,5-dioxo-IH-pyrrolidine-
2-Carboxylic acid sodium salt 2828
N-lactose 28
02, P above hexahydro-3,5-dioquine-1H
-Pyrrolidine-2-carboxylic acid, potassium salt, lactose and magnesium stearate are blended and packed into Vcm 4 hard keratin capsules so that each capsule is filled with 580 ml of the powder mixture. Approximately 1
0.000 capsules were obtained, each containing 250 Da of hexahydro-5,5-dioxo-1H-pyrrolidine-2
-Hexahite a of 2 82.8JIli' which is compatible with carboxylic acid -S,S-dioxo-1H-pyrrolidine-2
- Carboxylic acid, potassium.

Contains lamb salt.

1 equivalent of the above hexahyto'-3+5-dioxo-1B-pyrrolidine-2-carboxylic acid, in place of the potassium salt,
hexahydro-3,5-dioxo-IH-pyrrolidine-
By substituting another pharmaceutically acceptable salt of the 2-carboxylic acid and adjusting the amount of roughose to obtain the same total amount as in the example formulation, each again as described above. 58 containing an amount of 2501n9 hexahydro-3,5-dioxy/-IH-pyrrolidine-2-carboxylic acid
0 ■ capsules are obtained.

Claims (1)

[Claims] 1) Formula ▲ Numerical formula, chemical formula, table, etc. ▼ I (In the formula, A is hydrogen, methyl, alkyl having 3 to 6 carbon atoms, phenyl, -(CH_2)-1- 4 phenyl, ammonium or a cation derived from a pharmaceutically acceptable metal or organic amine). 2) Compounds according to item 1 above, wherein A is hydrogen, methyl, alkyl having 3 to 6 carbon atoms, phenyl or -(CH_2)1-4 phenyl. 3) A compound according to item 1 above, wherein A is a cation derived from a pharmaceutically acceptable metal. 4) A compound according to item 3 above, wherein the metal is selected from sodium, potassium, magnesium, calcium, aluminum, zinc or iron. 5) A compound according to item 1 above, wherein A is a cation derived from ammonium or a pharmaceutically acceptable organic amine. 6) A compound according to the above item 5, wherein A is an ammonium ion. 7) A is monomethylammonium, dimethylammonium and trimethylammonium, monoethylammonium, diethylammonium and triethylammonium, monopropyl (n-propyl and iso-propyl) ammonium, dipropyl (n-propyl and iso-propyl) ammonium and tripropyl (n-
propyl and iso-propyl) ammonium, ethyldimethylammonium, benzylammonium, dibenzylammonium, benzyldimethylammonium, cyclohexylammonium, piperidinium, morpholinium, pyrrolidinium, 4-ethylmorpholinium,
1-isopropylpyrrolidinium, 1,4-dimethylpiperazinium, 1-n-butylpiperidinium, 2-methylpiperidinium, 1-ethyl-2-methylpiperidinium, monoethanolammonium, diethanolammonium and A compound according to paragraph 5 selected from triethanolammonium, ethyldiethanolammonium, n-butylmonoethanolammonium, tris(hydroxymethyl)methylammonium and phenylmonoethanolammonium. 8) A compound as described in item 1 above having the name hexahydro-3,5-dioxo-1H-pyrrolidine-2-carboxylic acid. 9) A compound as described in item 1 above having the name hexahydro-3,5-dioxo-1H-pyrrolidine-2-carboxylic acid methyl ester. 10) A compound as described in item 2 above having the name of hexahydro-3,5-dioxo-1H-pyrrolidine-2-carboxylic acid tertiary butyl ester. 11) A compound as described in item 2 above having the name hexahydro-3,5-dioxo-1H-pyrrolidine-2-carboxylic acid benzyl ester. 12) A compound as described in item 3 above having the name hexahydro-3,5-dioxo-1H-pyrrolidine-2-carboxylic acid sodium salt. 13) A compound as described in item 3 above having the name hexahydro-3,5-dioxo-1H-pyrrolidine-2-carboxylic acid potassium salt. 14) A compound as described in item 3 above having the name hexahydro-3,5-dioxo-1H-pyrrolidine-2-carboxylic acid magnesium salt. 15) A compound as described in item 3 above having the name hexahydro-3,5-dioxo-1H-pyrrolidine-2-carboxylic acid calcium salt. 16) A compound according to the above item 4 having the name of hexahydro-3,5-dioxo-1H-pyrrolidine-2-carboxylic acid ammonium salt. 17) Catalytic reduction of 5-oxo-proline to 2-oxo-5-hydroxymethylpyrrolidine, which is reacted with p-toluoylsulfonyl chloride to p-toluoylsulfonyl derivative, which is subsequently converted to the formula NaCH (
COOR)_2 (wherein R is alkyl having 1 to 6 carbon atoms) and optionally the resulting ester is hydrogenolyzed or hydrolyzed to give hexahydro -3,5
-dioxo-1H-pyrrolidine-2-carboxylic acid,
Further, if desired, the formula is converted into a salt by reacting it with a pharmaceutically acceptable metal, ammonium hydroxide, or a pharmaceutically acceptable organic amine. There are formulas, chemical formulas, tables, etc. I (formula wherein A is hydrogen, alkyl having 1 to 6 carbon atoms, phenyl, -(CH_2)1-4 phenyl, ammonium or a cation derived from a pharmaceutically acceptable metal or organic amine). A method for producing a compound having 18) An effective amount of a compound according to paragraph 1 above, together with a pharmaceutically acceptable carrier, useful for the treatment of senility, enhancement of memory or treatment of amnesia induced by electroconvulsive shock in humans. A pharmaceutical composition containing. 19) An effective amount of hexahydro-3,5, together with a pharmaceutically acceptable carrier, useful for the treatment of senility, memory enhancement or electroconvulsive shock-induced amnesia in humans.
- A pharmaceutical composition containing dioxo-1H-pyrrolidine-2-carboxylic acid ethyl ester.