JPS58210085A - Tetrahydro-3,5-dioxo-1h-pyrrolidine-7a(5h)- carboxylic acid and derivatives - 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 tetrahydro-3,5-dioxo-1H-pyrrolisif-7a(5H)-carboxylic acid and derivatives thereof as recognition active agents.

Accordingly, the present invention, in its general chemical compound aspect, relates to compounds of the structural formula Ik'lW. Here, in the above formula, n is 0 to
5 and R is OH, or 0- as a salt with a chemically acceptable metal or amine cation, or 0-alkyl containing 1 to 6 carbon atoms, provided that n is 2 is alkyl having R carbon atoms, alkoxy having 1 to 6 carbon atoms, halo, or trifluoromethyl) or NR1R2 [where R1 is hydrogen, 1 to 6 carbon atoms] Alkyl having carbon atoms or having 2 to 6 carbon atoms substituted by amine, by alkylamino or by dialkylamino, where alkyl contains 1 to 6 carbon atoms , hydroxy or alkoxy with 1 to 6 carbon atoms, mercapto or alkylmercapto with 1 to 6 carbon atoms, cycloalkyl with 5 to 6 members, alkyl with 1 to 4 carbon atoms 5- to 6-membered cycloalkyl, phenyl or 1 to 6-membered cycloalkyl
phenyl substituted with alkyl of 4 carbon atoms or containing up to 4 heteroatoms of the group consisting of nitrogen, oxygen and sulfur and amine, alkylamino or dialkylamino or 1 to 4 carbon atoms and R2 is hydrogen or alkyl having 1 to 6 carbon atoms.

In a second general aspect, the invention is directed to compounds containing the structural formula (I). where in the above formula, R is OH, O- as a salt with a pharmaceutically acceptable metal or amine cation, or o-OH2 (where X
is hydrogen, alkyl having 1 to 6 carbon atoms, 1 to 6
alkoxy, halo, or trifluoromethyl) having 1.3.4.5 carbon atoms; or 1.3.4.5
NRJR2, where R2 is hydrogen or 0-alkyl having 6 carbon atoms, provided that when n is 2, R is not
alkyl having 6 carbon atoms and R1 is hydrogen, alkyl having 1 to 6 carbon atoms, or amino, alkylamino or dialkylamino, where alkyl is hydrogen, alkyl having 1 to 6 carbon atoms; Alkyl containing 2 to 6 carbon atoms substituted by : i if all members), 2,6-dimethylphenyl, 4-amino-3-pyridinyl, 3-amino-4-pyridinyl, 4-
pyridinyl, "f7clr15-tetrazoruyl, or 1'?, R2 is bonded to the N atom, 2.
6-dimethylbi2ridinyl is formed].

In a third general concept, the present invention relates to compounds having the structure 1. where R in the above formula is OH, a pharmaceutically acceptable alkyl having a metal or amine atom, an alkyl having 1 to 6 carbon atoms, halo, or trifluoromethyl; or i, 0-alkyl having 3,4,5 or 6 carbon atoms.

The first detailed chemical compound of the present invention (proboscis 1)
: Tetrahydro-5.5-dioxo-1H-pyrrolidine-7a(5H)-propanoic acid.

The second specific chemical compound of the present invention is tetrahydro-3,5-dioxo-1H-hyolysine-7a(5H)-propanoic acid benzyl ester.

Other covalent chemical compounds of the invention are as follows.

Tetrahydro-5,5-dioquine-1H-pyrrolidine-
7a(5H)-carboxylic acid ethyl ester, tetrahydro-3,5-'-/oxo 1H-pyrrolidine-7a(
5H)-acetic acid, Tetrahuman Ll-3,5-dioxo-1H-pyrrolidine-7a(sH)-butanoic acid, Tetrahydro-6,5-dioxo-1H-pyrrolidine-
7a(5H)-Butane version benzyl ester, tetrahydro-5,5-dioquine-1H-pyrrolidine-7a(5H)
)-Prono ξ acid amide, tetrahydro-6,5-dioxo-1H-pyrrolidine-7a(5H)-propane-N
-N', N'-diisozolobyl aminoethylamide, tetrahydro-3,5-9oxo-1H-pyrrolidine-
7a(5H)-propanoic acid N-5-tetrazol-ylamide, and tetrahydro-5,5-dioxo-1H-pyrrolidine-
7a(5H)-Propane N-4-pyridinylamide.

In its pharmaceutical composition aspect, the present invention relates to compositions comprising a compound containing formula IV O in combination with a pharmaceutically acceptable carrier. where n is 0 to 6 and R4 is OH, or 0- as a terminal with a pharmaceutically acceptable gold FAt or amine cation, or 1 to 6 is 0-alkyl having carbon atoms of or o-cH2@ (where X is hydrogen,
alkyl, alkoxy, halo, trifluoromethyl having 1 to 6 carbon atoms) or NR1R2 [where R1 is hydrogen, 1 to 6 carbon atoms] 2 to 6 carbon atoms substituted by an alkyl having carbon atoms, or by an amine, by an alkylamino, or by a dialkylamine, where the alkyl contains 1 to 6 carbon atoms; Alkyl with M atoms, hydroxy or alkoxy with 1 to 6 carbon atoms, mercapto or alkylmercapto with 1 to 6 carbon atoms, cycloalkyl with 5 to 6 members, 1 to 4 carbon atoms 5- to 6-membered cycloalkyl, phenyl substituted with alkyl having 1 to 4 carbon atoms, or phenyl substituted with alkyl having 1 to 4 carbon atoms; a 5- to 6-membered heterocyclic group containing up to 4 heterocyclic groups and optionally substituted by amine, alkylamino or dialkylamino or alkyl having 1 to 4 carbon atoms; and R2 is hydrogen or alkyl having 1 to 6 carbon atoms.

The first specific pharmaceutical composition of the present invention comprises tetrahydro-3 in combination with a pharmaceutically acceptable carrier.
, 5-dioxo-1H-pyrrolidine-7a(5H)-propanoic acid.

The second specific pharmaceutical composition of the present invention is a composition comprising tetrahydro-3 in combination with a pharmaceutically acceptable carrier.
, 5-dioxo-1H-pyrrolidine-7a(5H)-propanoic acid ethyl ester.

A sixth specific pharmaceutical composition of the invention includes tetrahydro-6 in combination with a pharmaceutically acceptable carrier.
,5-dioxo-1H-pyrrolidine-7a(5H)-i
Consists of lonozoic acid hensyl ester.

Other specific pharmaceutical compositions of the invention include the following compounds in combination with pharmaceutically acceptable carriers:

Tetrahydro-6,5-dioxo-1H-pyrrolidine-
7a(5H)-carboxylic acid ethyl ester, tetrahydro-6,5-dioxo-1H-pyrrolidine-7a(5H)
)-acetic acid, tetrahydro-3,5-dioxo-1H pyrrolidine-
7a(5H)-butanoic acid, tetrahydro-6,5-dioxo-1H-pyrrolidine-
7a(5H)-butanoic acid benzyl ester, tetrahydro-3,5-dioxo-1H-pyrrolidine-7a(5H)
)-propanoic acid amide, tetrahydro-6,5-dioxo-1H-pyrrolidine-7a(5H)-propanhaN-
N',N'-diinzolobyl aminoethylamide, tetrahydro-6,5-dioxo-1H-pyrrolidine-
7a(5H)-propanoic acid N-5-tetrazol-ylamide, and tetrahydro-6,s->oxo-1H-pyrrolidine-
7a(5H)-Propanoic acid N-4-pyridinylamide.

The pharmaceutical aspect of the present invention is that the pharmaceutical composition as defined above is effective in treating total senility or reversing amnesia.
This invention relates to a method for treating senility or reversing amnesia by administering it to mammals.

Compounds of the invention in which n is 2 in formula l are tetrahydro-5
, 5-dioxo-1H-pyrrolidine-7a(5H)-propanoic acid ethyl ester by standard methods. The synthesis of this ethyl ester is
ozech, Chem, Comm, j Volume 19, No. 298
(1954) (see (3, A, Vol. 49, p. 292o)).Thus, the ethyl ester can be easily hydrolyzed by standard procedures to form the structure I in which R is OH. ' has 1, W ' generates.

Acid tetrahydro-6 having structural formula 1 (R=OH),
5-dioxo-1H-pyrrolidine-7a (5H)alkanoic acid is a compound of formula (2).A total dehydrating agent such as an alkanoic anhydride,
The arylic anhydride, alkanoyl chloride TFC, can also be prepared by reacting with an aroyl chloride in the presence of an acid acceptor or by heating. A preferred method uses acetic anhydride followed by hydrolysis with water in an inert solvent. Prior to hydrolysis with water, an intermediate compound is formed and can be isolated. This intermediate has the structural formula■
where R' is any convenient alkyl or aryl group. Starting materials having structural formula V (for n-2) were prepared as described in U.S. Pat. No. 2,502,548 V V
l n=0~' n-0~6R=H or alkyl R=HO The acid can then be converted to other compounds of structural formula 1kN by standard procedures, namely, esters, esters, and amides (C).

For example, salts can be prepared by treating an acid with an equivalent base.

Esters may be prepared by first converting the acid to an acid halide such as -C acid chloride using, for example, thionyl chloride. The acid chloride thus prepared may then be treated with the desired alcohol, preferably in the presence of a suitable acid acceptor such as triethylamine or pyridine. Amides may also be prepared by first converting the acid chloride to an acid halide, such as an acid chloride.The acid chloride thus prepared is then converted to an inert solvent, preferably methylene chloride, or depending on solubility. If necessary, n can be treated with the desired amine in a more polar aprotic solvent.

Treatment of Compound V with a dehydrating agent is a halogenated hydrocarbon (
Dichloromethane, tetrachloroethane or dichlorobenzene) may be used, but it is preferably carried out in the absence of a medium. The reactants are present in a ratio of at least one part diacid to two parts dehydrating agent, but an excess of dehydrating agent is preferred. This reaction is 25
°C to 140 °C for 1 to 16 hours, preferably io.

It can be carried out for 12-16 hours at ~140C.

The hydrolysis step is conveniently carried out in an inert solvent in which the intermediate and water can be dissolved, such as acetonitrile or tetrahydrofuran, or by vigorous stirring with water. Before this hydrolysis, the temperature was between 1 and 25°C and 85°C.
24 hours, then 6 to 8 hours at 40℃ to 60℃
! ! : To give.

The product can be isolated by filtration.

The compounds of the present invention having Takuzo Formula I (Kamishin 011) form pharmaceutically acceptable salts with organic and inorganic bases. Examples of suitable bases for salt formation are sodium hydroxide,
These include potassium hydroxide, prone sodium, calcium carbonate, potassium carbonate, and sodium bicarbonate.

The term pharmaceutically acceptable amine cation contemplates readily charged ammonium ions and similar ions derived from organic nitrogenous bases strong enough to form such cations. Bases useful in forming pharmacologically acceptable non-toxic addition salts of such compounds containing free carboxyl groups are of a type readily apparent to those skilled in the art. For purposes of illustration only, the formulas may include all cationic forms having the formula.

wherein in the above formula, Ra%Rb and R6 are each independently hydrogen, alkyl having about 1 to about 6 carbon atoms, about 5
~cycloalkyl having about 6 carbon atoms, aryl having about 6 carbon atoms, aralkyl having about 7 to about 11 carbon atoms, about 2 to about 4 carbon atoms; 1
1 hydroxyalkyl, or monoarylhydroxyalkyl containing from about 8 to about 151 carbon atoms, or together with the 9 atoms to which they are attached, any of Ra, Rb, and R8. The two are carbon, hydrogen,
It is possible to form a partial whole of a 5- to 6-sided heterocycle having oxygen or 9 atoms, and the heterocycle and the aryl group are unsubstituted or mono- or dialkyl carbon atoms. shall be present.

Therefore, Ra%Rb and R consist of pharmacologically acceptable cations derived from ammonia or basic amines. Examples are ammonium, mono-, sio- and trimethylammonium, %/-, sio-hydro-ethylammonium, mono-, di- and tripropylammonium (iso and normal), ethyldimethylammonium, benzyldimethylammonium,
Cyclohexylammonium, benzylammonium,
Dibenzylammonium, piperidinium, morpholinium, pyrrolidinium, piperazinium, 1-methylpiperidinium, 4-ethylmorpholinium, 1-isopropylpyrrolidinium, 1,4-dimethylpiperazinium, 1-n-butylpiperidinium , 2-methylbiharidinium, 1-ethyl-2-methylpiperidinium, mono-, di- and triethanolammonium, ethyljetanolammonium hn-butylmonoethanolammonium, tris(hydroxymethyl)-methylammonium, phenylmono Ethanol ammonium etc.

Pharmaceutically acceptable (-)Metal cations are intended to be ionically charged ions derived from metals such as sodium, potassium, calcium, magnesium, aluminum, zinc, iron, etc.Salts are The free form of the compound (by contacting with an equal amount of the desired base by conventional methods)
v! 4 made. The free form can be regenerated by treating the salt with acid. For example, the 8-acid water bath solution is
It can be used to regenerate the free form of water.

A dilute hydrochloric acid water bath is suitable for this purpose.

The free forms differ somewhat from their respective forms in certain physical properties, such as the degree of bathing in polar bath media, whereas the salts differ for the purposes of this invention. These are the free base forms and still images of each of them.

The compounds of the invention can be found in hydrated as well as unsolvated forms.
It can also exist in solvated forms, including other forms. Generally, forms that are solvated with pharmaceutically acceptable solvents such as water, ethanol, etc. are considered solvated for purposes of the present invention.
It is equivalent to the form that does not exist.

The alkyl groups contemplated by this invention, unless otherwise specified, encompass both straight and branched carbon chains containing from 1 to about 6 carbon atoms. Representative of such groups are methyl, ethyl, isopropyl, pentyl, 6-mesolpentyl.

Cycloalkyl radicals intended according to the invention are 5- or 6-membered alkyl radicals, such as cyclopentyl and cyclohexyl, which may optionally be replaced by 1 to 4 carbon atoms, especially methyl. It is.

The elemental radicals contemplated by the present invention are those of a 5- to 6-membered ring with 41 heteroatoms consisting of N, 0 and S, and in particular 1 to 411z1 ♀ atoms. And electricity? When two atoms are on the top, it is a ring that contains all the sulfur atoms across the acid system due to the conjugation. Examples of such products are tetrazol-5-yl, 4-pyridinyl,
6-amino-4-pyridinyl, 4-amino-5-pyridinyl, 1.2.5-) lyazol-5-yl, 1.2
．． 4-triazol-5-yl, 1,2-diazole-
6-yl, 1.5-diazol-4-yl, 1.5-diazol-2-yl, 1.3.4-thiadiazol-2
-yl and 1,3.4-oxadiazol-2-yl. These radicals can also be substituted on the ring by alkyl, especially methyl, containing 1 to 4 carbon atoms.

To prepare pharmaceutical compositions from the compounds according to the present invention, an inert, pharmaceutically acceptable carrier can be a solid or a liquid. Solid agents include powders, tablets, dispersible granules, capsules, cannies, and herbal medicines. The solid carrier can be one or more substances that can also act as a diluent, flavoring agent, solubilizer, lubricant, binder, binder, or tablet disintegrant. The material can also be an encapsulating material. In powders, the carrier is a finely divided solid which is mixed with the finely divided active compound. In tablets, the active compound is mixed with a phase which exhibits the necessary binding properties in a suitable mill and compressed to the desired shape and size. Powders and rivets are preferably 5" or 10% to about 70% of the active ingredient in total water. Suitable solid carriers include magnesium carbonate, magnesium stearin, Merck, sugar, lactose, lactose, dextrin. , starch, seratin, toshikikanto, methylcellulose, sodium carboxymethylcellulose, low melting point wax, cacao butter, etc.It is activated using an encapsulating substance as a candy compound called "1.!L". It is intended to include formulating the compounds to provide capsules in which the active ingredient (with or without other carriers) is surrounded by the carrier and thus together with the carrier. Similarly, cachet is also included. Tablets, powders, cachets and capsules can also be used as solid forms suitable for oral administration.
I can't wait to use it again.

To prepare the whole herbal medicine, a low-melting wax such as a mixture of fatty acid dalycerides or cocoa powder is first melted, and then the active fraction is uniformly dispersed therein by thorough stirring.Then it is melted. The homogeneous mixture is poured into convenient sized molds and allowed to cool, set and solidify.

Liquid form preparations include solutions, suspensions, and emulsions. Examples include water or water-propylene glycol baths for parenteral injection. Liquid formulations may also be formulated in the form of bath solutions in polyethylene glycol water baths.
sell. Water bath solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use contain the finely divided active ingredient dispersed in water together with viscous substances such as natural rubber, synthetic rubbers, resins, methyl cellulose, sodium carboxymethyl cellulose and other well-known ingredients. You can make it by letting it happen.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid preparations for either oral or parenteral administration. Such liquid forms include baths, suspensions, and emulsions. Kon
The individual solid formulations are most conveniently provided in unit form and are used in themselves to provide a single liquid unit. Alternatively, once sufficient solids have been provided, a predetermined amount of liquid can be removed from the formulation using a syringe, spoon or other evaporative container after conversion to liquid form.
By measuring, a plurality of liquid violets can be obtained. Thus, if a liquid suit is made multiple times, the unused portions of the suit are placed at a low temperature (
-j, that is, under refrigeration). Solid preparations intended for conversion to liquid form contain, in addition to the active substance, flavoring agents, coloring agents, stabilizing agents, buffering agents, artificial and natural sweeteners, dispersing agents, thickening agents, solubilizing agents. I can't stand it. The liquid used to prepare the liquid form of the 0-cleavage agent may be water, isotonic water, ethanol, a mixture of propylene glycol, etc., and K(-n, etc.). The liquid to be used will be selected with regard to the route of administration; for example, large ethanol-containing liquid formulations are not suitable for parenteral use.

Preferably, the pharmaceutical formulation is in unit dose ml form. In such form, the preparation is divided into unit doses containing the appropriate amount of the active ingredient. 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. The unit dosage form can be a capsule, cachet, or tablet itself or can be packaged. It can also be any suitable number of these shapes.

The amount of active compound in a single tablet ranges from 1 to 500 to 1 to 7, depending on the individual application and the potency of the sticky component.
The dose may be varied or adjusted from 5 to 100 mg. If desired, the composition may also be used in other suitable forms.

When used therapeutically as a cognitively active agent, the mouth area of a 70kl mammal-class test subject is 1 to 15 mulberry per kilogram of body weight per day.
00F1g or preferably 25-75 Drag. However, these Nahi i#:1. patient's request,
It may vary depending on the severity of the condition being treated and the compound used.

Determining when is appropriate for a particular situation is within the skill of the art. In general, use less than the optimum amount of that compound to open the compound.

Then increase the size little by little until the optimum effect for the situation is achieved. Convenience-L, full day i4. if desired. It can also be divided into k divided doses and administered in portions during the day.

The effectiveness of the compound was demonstrated by a 51-year MA experiment to demonstrate the ability of the compound to completely reverse the amnesia caused by electric shock and pneumoconvulsions.

This 6. (The test is described in US 1↓1Special No. 81 No. 4,145,347, Ming. 8, and is incorporated herein by reference.) The length of the 1.4J pneumoconvulsion shock after administration was 1.0
It was seconds.

The following standards are used to interpret the amnesia reversal score%. 40% or more than 7'L (activity -8), 25-3
9% (borderline-a), and 0-24% (inert-N)
.

According to Table 1, the tetrahydrogen 0-
5.5-dioxo-1H-pyrrolidine-7a(5H)-
We report 96 cases of reversal of amnesia caused by propane throat.

1st clothes reversal 9650 40 30 56 67 22 reviews
Value AAOAA N Tetrahuman t=1-5.5-dioxo- administered orally according to Table 2 below.
The % amnesia reversal of 1H-pyrrolidine-7a(5H)-propane ester is reported.

Table 2 Easy dose (for Ki97) Reversal % (d value) C2H598 (Al 62 (Al 50 (AIOH)
20H(CHxh 0(Nl 73(At 0
(NIOH2φ 40(Al 40(Al
60tAl Table 6 reports the percentage of amnesia reversal for other orally administered test compounds.

Table 3 Inversion target (evaluation) Example A Tetrahydro-6,5-dioxo-1H-pyrrolidine-
7a Preparation of (5H)-propanoic acid Crude γ-carbomethoxyethyl-γ-nitropimelic acid dimethyl ester in methanol 800 d? 2oX as the total catalyst in the bath solution of
Pd/C2? Hydrogenate at about 50 pθ1 using f.

The resulting slurry was filtered to remove the catalyst and the P solution was evaporated under reduced pressure to produce crude 5-oxo-2,2-pyrrolidine dipropane dimethyl ester and 5-oxo-2,2
- Obtain pyrolylene propa 7m monomethyl ester.

The crude ester was mixed with 100 parts of methanol and 10 parts of water.
0rrLI! , and treated with 50% sodium hydroxide solution 1-02. The reaction mixture is stirred and heated to 100° C. to distill methanol. bath/
f! Cool thoroughly, neutralize with 130 ml of aqueous hydrochloric acid and concentrate under reduced pressure. 5-oxo-2,2-pyrrolidinedipropanoic acid Total residue containing total acetic anhydride 98 with 204v
Heat at ~10°C for 24 hours. Sodium chloride produced by neutralization is removed after the acetic anhydride reaction. Next, the P solution was drained under reduced pressure, and 200 ml of toluene was added. (Add i7 and repeat the concentration. The resulting oil is a Japanese tetrahydro-3,5-dioxo-1H-pyrrolidine-7
It is an anhydride of a(5H)-propanoic acid and acetic acid. This oil is stirred vigorously with water or reacted with water in acetonitrile and tetrahydro-6,5-dioxo-
1H-pyrrolidine-7a(5H)-propane is isolated by filtration. Tetrahydro-6,5-dioxo-1H-
Pyrrolidine-7a(5H)-furopanoic acid has a melting point of 179-181°C when purified by recrystallization from tetrahydrofuran.
yields a product with

Example B Tetrahydro-3,5-dioxo-1H-pyrrolisif
Preparation of -7a(5H)-propanoyl chloride Tetrahydro-6,5-dioxo-1H-pyrrolidine-7a(5H)-propanoic acid 5 in methylene chloride 150-
2.85 f (0,024 mol) of thionyl chloride in a suspension consisting of f (0,024 mol) and 1 drop of pyridine.
Dropwise treatment. This mixture is stirred for 3 hours. A further 2.85 M (rl, 0.24 mol) of thionyl chloride is added and the mixture is stirred for a total of 1 hour. The resulting solution is concentrated under reduced pressure to yield the product as a crystalline solid.

Example C Tetrahydro-6,5-diogine-1H-pyrrolidine-
Preparation of 7a(5H)-10·ξ-dispersed methyl ester 5.5 f/(0,024 mol) of tetrahydro-6,5-dioxo-1H-pyrrolidine-7a(5H)-propanoyl chloride in 200 d of dichloromethane. Triethylamine 3.3m/! (0,024 mol) and methanol 0.60 r (0,024 mol). This mixture f! : Boil for 30 minutes.

The precipitate of triethylamine hydrochloride is removed. The P solution is concentrated under reduced pressure and the residue is purified by chromatography over silica gel using 20% anhydrous diethyl ether in dichloromethane as eluent. The fractions containing the product are concentrated under total vacuum. Tetrahydro-6,5-
Dioxo-1H-pyrrolidine-7a(5H)-propanoic acid methyl ester is present as crystals having a melting power of 110-112°C.

Example D Tetrahydro-6,5-dioxo-1H-pyrrolidine-
Preparation of 7a(5H)-i lopanehahenzyl ester Tetrahydro-5,5-dioxo-1H-pyrrolidine-7a(5H)-propanoyl chloride in 200 d dichloromethane 5.5 ? (0,024 mol) bath solution total triethylamine 3.5 lnl (0,024 mol)
The mixture is stirred with 2.60 r (0,024 mol) of henzyl alcohol. The mixture is stirred for 60 minutes. The precipitate of triethylamine hydrochloride is removed. The mixture is concentrated under reduced pressure and the residue is purified by chromatography on silica gel using 10% anhydrous diethyl ether in dichloromethane as eluent. The resulting total M-containing fraction is concentrated under reduced pressure. Tetrahydro-5,
5-Dioxo-1H-pyrrolisif-7a(5H)-propanoic acid benzyl ester is observed as a crystal with a d point of 80-82°C.

Example E Tetrahydro-6,5-dioxo-1H-pyrrolidine-
Preparation of 7a(5H)-furopanoic acid 0-chlorobenzyl ester Tetrahydro-3,5 in 200 ml dichloromethane
-dioxo-1H-pyrrolidine-7a (5Lυ-propanoyl chloride 5.5y (0,024 mol)) triethylamine 3.3 ml (0,024 mol) and O-chlorobenzyl alcohol 3.41 F (0 ，
024 mol). This mixture was heated to 60 ml at room temperature.
Stir for a minute. Precipitation of triethylamine hydrochloride is removed. The IP solution is concentrated under reduced pressure and the remaining 90% is chromatographed on licage gel using anhydrous diethyl ether in dichloromethane.
I will do it. The fractions containing the product are concentrated under reduced pressure.

Tetrahydro-6,5-dioxo-1H-pyrrolidine-
7a(5H)-furopanoic acid O-chlorobenzyl ester is obtained as crystals with a melting point of 126-128°C.

Example F Tetrahydro-3,5-dioxo-1H-pyrrolidine-
Preparation of 7a(5H)--10 PanHp-chloroindyl ester of tetrahydro-5,5-dioxo-1H-pyrrolisif-7a(5H)-propanoyl chloride 5.5F (0,024 mol) in 200 d dichloromethane. The solution is stirred with triethylamine 31d (0,024 mol) and p-chlorobenzyl alcohol 3.41 F (0,024 mol). This mixture is stirred for 30 minutes at room temperature. The precipitate of triethylamine hydrochloride is removed with IFI. P
The solution is concentrated under reduced pressure and the residue is chromatographed on silica gel using 10% anhydrous diethyl ether in dichloromethane as eluent (IF). The fractions containing the product are concentrated under reduced pressure. -6,5-dioxo-1H-pyrrolidine-7a (5H)
- Propanoic acid p-chlorobenzyl ester has a melting point of 141
Obtained as crystals with a temperature of ~142°C.

Example G Tetrahydro-3,5-dioxo-1H-pyrrolidine-
Preparation of 7a(51()-propanoic acid ethyl ester)Tetrahydro-5,5-in dichloromethane 20 Otnl
Dioxo-1H-pyrrolidine-7aC5H)-propanoyl chloride 5.5? (C1,024 mol) bath solution 3.3 m/(0,024 mol) of triethylamine
and 1.19 (0,024 mol) of ethanol. This mixture is stirred for 30 minutes at room temperature. The precipitate of triethylamine hydrochloride is removed.

The P'D was rinsed under reduced pressure and the residue was dissolved in 10% dichloromethane as the silica gel EtlrFIAL agent.
Purify by chromatography using anhydrous diethyl ether. The fractions containing the product are concentrated under reduced pressure. Tetrahydro-5,5-dioxo-IH-pyrrolidine-7a(5H)-i lonomic acid ethyl ester is obtained as crystals with a melting point of 104 DEG -105 DEG C.

Example H Tetrahydro-3,5-dioxo-1H-pyrrolidine-
Preparation of 7a(5H)-propanoic acid 2-methylpropyl esterTetrahydro-6,5-dioxo-1H-pyrrolidine-7a(5H)-propanoyl chloride in 200 dichloromethane5. A solution of s t ([1,024 mol), triethylamine 3.3 d (0,024 mol) and 2-methylpropyl alcohol 1.78 f (0,0
24 mol). This mixture is stirred for 60 minutes at total room temperature. Precipitate triethylamine hydrochloride. 7 - The solution is chromatographed under vacuum and the residue is purified by chromatography on silica gel using 10% anhydrous diethyl ether in dichloromethane as eluent. The fractions containing the product are concentrated under total vacuum.

Tetrahydro-6,5-dioquine-1H-pyrroli')
7-7a(5H)-i Rossenic acid 2-methylpropyl ester is obtained as crystals with a melting point of 102-104°C.

Example etetrahydro6,5-dioxo-1H-pyrrolidine-
Preparation of 7a(5H)-phthanic acid benzyl ester Tetrahydro-3,5-dioxo-1H-pyrrolidine-7a(5H)-propanoic acid (
Synthesized as described in Example A) 10 r (0,04
A total of 5.72 (1,048 mol) of thionyl chloride is added dropwise to a suspension consisting of 8 mol) and 1 drop of pyridine. This mixed vIJ is stirred for 6 hours. Another 2.85
f (0,024 mol) of thionyl chloride is added and the mixture is stirred for 1 hour. The resulting bath ti, was concentrated under reduced pressure to give tetrahydro-6,5-dioxo-1H-
Bio IJ cy:y -7a(5H)-propanoyl chloride is obtained as a crystalline solid.

Bath solution of acid chloride 9.6 t (0.04 mol) in anhydrous diethyl ether (500 rn1.) Diazomethane 6 r (0
, 14 mol) in bi. Mix this mixture at room temperature for 1
Stir for 66 hours and concentrate to the pressure. The resulting solid was chromatographed on silica gel and the product was chromatographed at 10%
Disassociate using acetonitrile-90% chloroform. When the eluate is condensed, 4-[tetrahydro-5,5-dioxo-1H-pyrrolisif-7a(5H)] -]1
- Diazo 2-butano is obtained. Melting point 118-120
℃.

1-Diazo-2- in benzyl alcohol (50d)
A solution of 6.4 fCo (0.027 mol) of butanone is added to a suspension of Ag2011 in benzyl alcohol (100-) at 80 DEG C. under stirring. The suspension is stirred at 80° C. until the N2 evolution has ceased. The mixture is stirred at room temperature for 16 hours and filtered using filter aid. Reduced pressure (0,
After concentration under 9 m), the residue is chromatographed on silica gel and separated with 10% anhydrous diethyl ether in methylene chloride. When the bath liquid is condensed with vJ under reduced pressure, tetrahydro-6,5-7oxo 1H-pyrrolidine-7a
(5H)-Butanoic acid benzyl ester has a melting point of 102-1
It is treated as a crystalline solid with a temperature of 0.5°C.

Example J Synthesis of Tetrahydro-3,5-dioxo-1H-pyrrolidine-7a(5H)-butanoic acid prepared in the example procedure in tetrahydrofuran (30i) 7
a(5H)-butanoic acid benzyl ester 1. or(0,
0032 mol) (D?'i'BiIk 20%Pd/
Treat with hydrogen in the presence of 0.12 C catalyst. The resulting electrolyte is filtered to remove the catalyst and concentrated to crystallize the product. Recrystallization from acetonitrile yields tetrahydro-3,5-dioxo-1H-pyrrolidine-7a (5H)
-Butanoic acid is obtained, melting point 178-1801m:.

Example K Tetrahydro-6,5-dioxo-1H-pyrrolidine-
Synthesis of ethyl nisder 7a(5H)-carboxylate Methyl acrylate 172.18F (
2 mol) and Triton B 10t
The entire bath solution was heated to 60°C and 133.10 r of ethyl α-nitroacetate (CAB shop 614-18-6) was added under stirring.
(1.0 mol) is added dropwise. When addition is complete, add 5 more
1 Triton B (Aldrich Chemica
Benzyltrimethylammonium hydroxide, available from Baker Chemical Co., Ltd., J.T., Baker Chemical Co., et al., is added and the mixture is maintained at 60° C. for 16 hours. Cool the mixture and salt in water (1t)
Pour into the +J bath solution. The f6FLk was extracted with dichloromethane (2X1t), dried over anhydrous magnesium myelate, filtered, concentrated and distilled to dimethyl-i
-carboethoxy-γ-nitrobemerate is obtained. Boiling point 140-145°C 70.6rrun.

Dimethyl-γ-carboethoxy γ-nitrobemerate 240.5 F (0,
79 mol) of the bath solution is treated with hydrogen in the presence of 20% pd/c 1 o y. The mixture was filtered and concentrated to give 5-carboethoxy-5-carbomethoxyethyl-2
A Japanese mixture of -pyrrolidinone and 5-carpoethoxy-5-carboxyethyl-2-pyrrolidinone is obtained as an oil.

The oil dissolved in methanol (500g) was dissolved in water (500g).
57mj) with a solution of sodium hydroxide (566r, 1.4 mol). The mixture is stirred and the methanol is distilled off until the temperature of the bath reaches 99°C. This mixture was cooled to 10°C and concentrated hydrochloric acid 116.7r4C.
1.42 mol) to obtain an aqueous solution of 5-carboethoxy-5-carboxyethyl-2-pyrrolidinone. The water was removed by concentrating under reduced pressure and the resulting oil was added to 1 part of acetic anhydride with stirring.

The mixture is heated at 100° C. for 16 hours and filtered in a filter tank 1j. After condensation under reduced pressure, stain the oily substance 135 ~
Distill at 150°C/0.5 rrtyn. Chromatography on silica gel followed by stripping with 20% anhydrous diethyl ether in methylene chloride and the eluate #
Upon condensation, tetrahydro-5,5-dioxo-1H-pyrrolidine-7a(5H)-carboxylic acid ethyl ester is obtained. Melting point 77-82°C.

Example L Tetrahydro-3,5-dioxo-1H-pyrrolidine-
Synthesis of 7a(5H)-acetic acid β-nitropropane (g) in loloform (1t)
(CAS A 5C14-88-1) 1 1
6r (0.97 mosile) ai fA liquid 'e i&
Stir and treat with thionyl chloride 127.5F (107 moles). Rapid gas evolution occurs and the mixture is stirred for 1 hour at 5°C. Ethanol (50?, 1
．． When 0.07 mol) was added dropwise, gas generation occurred quickly. The mixture is stirred for 72 hours, concentrated and distilled to give ethyl β-nitroprobanoate. Boiling point 95-b/15
Ethyl acrylate [C'ASA140 in m1m0 tert-butanol (150m7) and Triton B1[1-
-88-5] A solution of 182F (1.84 mol) was
135.5r (ethyl β-nitropronoξnoe) at °C
0.92 mol). In addition, Triton B (2s
vx3) and ethyl acrylate (25rX3) are added over the course of 5 hours. . Cool the mixture and add water (
11) into a solution of 100 d of concentrated hydrochloric acid. Diethyl-γ-nitro-γ-carboethoxymethylpimelate is extracted using dichloromethane (4×500k).

The combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. This oily substance (1609
) dissolved in total ethanol (1,5 L) and 20%
Treat with hydrogen in the presence of Pa1079. The mixture was filtered through filter aid and compressed to 5-carboethoxyethyl-5-carboethoxymethyl-2-pyrrolidinone (
A mixture of the main products), 5-carboethoxymethyl-5-carboxyethyl-2-pyrrolidinone and 5-carboethoxyethyl-5-carboxymethyl-2-pyrrolidinone is obtained as an oil. Is this oil dissolved in 50% ethanol? (50% water vaporization) Using a lime water solution, remove ethanol while stirring under reflux.

The hydrolyzed mixture is neutralized with concentrated hydrochloric acid to obtain 5-carboxyethyl-5-carboxymethyl-2-pyrrolidinone in water. The water is removed under reduced pressure and the resulting solid is added to aqueous acetic acid (1 ky) with stirring. This mixture is heated at 100° C. for 16 hours. Filter the mixture with filter aid
F-contains and collapses under reduced pressure to give tetrahydro-3,5
The anhydride of -dioxo-1H-pyrrolidine-7a(5H)-acetic acid and acetic acid is obtained as an oil. Dissolve all of the oil in a minimal amount of acetonitrile, add an equal amount of water and stir the mixture for 16 hours.

The V compound is condensed under total pressure to obtain a solid. This solid was recrystallized from acetonitrile to obtain tetrahydro-6,5-dioxo-1H-pyrrolidine-7a(5H)-acid acid. Melting point: 177-180°C.

Example M Tetrahydro-5,5-dioxo-1H-pyrrolidine-
7a(5H)-Promenoamide A solution of 502 of tetrahydro-3,5-,dioxo-1H-pyrrolithia 7a(5H)-propanoyl chloride in 100 of menalene chloride at room temperature. Aqueous ammonia is bubbled through. The by-product NH4Ct, which crystallizes, is filtered out. On standing, the desired product crystallizes as a white precipitate. The white precipitate formed is collected and reconstituted from methanol. Crystallizes, melting point 176-175°C.

Example N Tetrahydro-5,5-dioxo-1H-pyrrolidine-
7a Preparation of (5H)-propanoic acid N-5-tetrazol-ylamide 5-amino-tetrazole in acetone 100-2.7
Tetrahydro-3,5-dioxo-1H-pyrrolidine-7a (
5H)-propanoyl chloride 6, of all were added at a dropwise rate and then triethylamine 3.6
Add r i. Immediately formed white color? j: The precipitate is collected and washed with boiling acetone and then boiling toluene, leaving the product as a white solid. This stuff has a melting point of 191-195
°C (decomposition).

Example O Tetrahydro-6,5-dioxo-1H-pyrrolidine-
Preparation of 7a(5H)-propanoic acid N-N'IN'-diisopropylaminoethylamide monot=mc=N-[2-[His(
1-methylethyl)amine]ethylamine C6,5r
) of tetrahydro-6,5-dioxo-1H-pyrrolidine-7a (5H
)-propanoyl chloride (5,0?) at room temperature. After stirring under reduced pressure for 16 hours, the solvent is removed under water and the residue is dissolved in acetonitrile, treated with charcoal and filtered through Celite. When cooled,
The crystalline product is isolated by filtration. Melting point 184-1
a6c.

Example P Tetrahydro-3,5-dioxo-1H-pyrrolidine-
Preparation of 7a(5H)-propanoic acid N-4-pyridinylamide Tetrahydro-6,5 in 100 d of methylene chloride
-Dioxo-1H-pyrrolidine-7a(5H)-propanoic acid 21. ir, dicyclohexylcarbodiimide 21
．． 79 and 4-dimethylaminopyridine (catalyst) 1
0 [I Q suspension in 4-aminopyridine 9.4 V
Process with. The mixture is stirred for 16 hours and the by-product N,N'-synchrohexyl urine system total p is separated. The product was chromatographed on a sorbent gel L 409E 2-
feJ=X using propanol-methylene chloride F gold
and refine it. When recrystallized from water, raw materials have a melting point of 28
It was isolated as a white solid at a temperature of 5-287°C.

Book Mlfi'k, SolLzo 扛Activity/ffl Minute 7.1.
0.2.5.25 and 5olng stimulating tablets, 1
．． Further illustrated by capsules, parenteral formulations, rectal herbal formulations, suspension formulations and syrups for reconstituted formulations for oral administration containing 0.2.5.25 and 50 genera9.

Example 1 Pyrrolidine-7a(5H)-propanoic acid lactose
1124F Corn Starch 692 Hydroxypropyl Cellulose 30r Magnesium Stearate 7v Ethanol-
Water (50:50) appropriate amount of tetrahydro-3,5
-Dioxo-1H-pyrrolidine-7a(5H)-propanoic acid, lactose and hydroxypropylcellulose are mixed together and granulated using ethanol-water (50:50)'. Wet fc, sieve the grains, dry and sieve again. The resulting dried granules are mixed with whole magnesium stearate and corn starch and the mixture is compressed into 225 m9 tablets using a 32 inch standard concave punch. The abbreviation is tetrahydro-6,5-dioxo-IH-pyrrolidine-7a
Equivalent to approximately 6000 tablets each containing a total of 25.01 g of (5H)-propanoic acid.

Example 2 0 Lysine-7a(5H)-propanoic acid lactose 1
2491 Corn starch 591 Hydroxypropyl cellulose 3 (1
Magnesium stearate 7
2 Ethanol-Water (50:50) Appropriate amount of Tetrahydro-6,5-dioxo-1H-pyrrolidine-7a (5T()-propanoic acid, lactose and hydroxypropylcellulose) were mixed together and ethanol-water (50:50) was added.
50:50)' (i = used to form granules.

The wet granules are sieved to dry and sieved again. The obtained dry granules are mixed with whole magnesium stearate and corn starch and this mixture is
Compress into 225 punch tablets using a 1/32 inch standard concave punch.

Yield #: Tetrahydro-3,5-dioxo-1H-pyrrolidine-7a(5H)-propanoic acid 2. Equivalent to approximately 6,000 tablets containing s or f in total.

Example 5 Pyrrolidine-7a(5H)-propane lactose
126El corn starch 692 hydroxypropyl cellulose 6ov stearic acid/magnesium acid 7? Ethanol-
Water (50:50) appropriate amount of tetrahydro-6,
5-dioxo-1H-pyrrolidine-7a(5H)-propanoic acid, lactose and hydroxypropylcellulose are mixed together and granulated using ethanol-I (water (50:50)).

The wet granules are sieved to dry and sieved again. The resulting dried granules are mixed with whole magnesium stearate and cornstarch and the mixture is compressed into 225-sized tablets using a standard 11/32 inch concave punch.

The heating and cooling is tetrahydro-3,5-dioxo-IH-pyrrolisif-7fl(5H')-propa:y M 1. O
My total tablet content is equivalent to about 600 o@.

Example 4 Ingredients pyrrolidine-7a(5H)-propanoic acid lactose
974f cornstarch
391 Hydroxypropyl Cellulose 3Of Magnesium Stearate
71 ethanol-water (50:5
0) Appropriate amount of tetrahydro 3.5-
Dioxo-1H-pyrrolidine-7a(5H)-propanoic acid, lactose and hydroxypropylcellulose'til
J1 and ethanol-water (50:50)'(+-
to form granules.

The wet granules are sieved to dry and sieved again. The resulting dry granules are mixed with magnesium stearate and cornstarch and this mixture is
225 Q using a 1/32 inch standard concave punch
compressed into tablets.

The yield was 50.5% of tetrahydro-0-3.5-dioxo-IH-pyrrolidine-7a(5H)-propanoic acid. Equivalent to approximately 6000 tablets containing each Oyry.

Example 5 Pyrrolidine-7a(5H)-propanoic acid lactose
1725t magisium stearate 272
Mix the mixture and fill 200 yay portions of this powder mixture into A4 hard gelatin capsules. The yield is tetrahydro-3,5-dioxo-1H-pyrrolidine-
7a(5H)-propane=2s,.

Capsules containing a total of about 100 mg], 000 pieces.

Example 6 Ingredients Pyrrolidine-7a (5H)-propanoic acid lactose
Mix the 1948r Magnesium Stearate 277 mixture and fill 200 portions of this powder mixture into A4 hard gelatin capsules. Ti Tetrahydro 5
．． Capsules containing approximately 2.5 μm of 5-dioxo-1H-pyrrolidine-7a(5H)-propanoic acid each oo
Equal to o pieces.

Example 7 Ingredients Pickled pyrrolidine-7a(5H)-propane-branched lactose
The 1963y Magnesium/Um Stearate 271 mixture is mixed and a total of 200 mg of this powder mixture is filled into A4 hard gelatin capsules. The yield is tetrahydro-
6,5-dioxo-1H-pyrrolidine-7a (5H)
- Approximately 10 capsules containing propanoic acid milk tea
Expected to reach ,000 pieces.

Example 8 Pyrrolidine-7a(5H)-propanoacid milk 'a1
473y Magnesium stearate 2
7? Mix the mixture and fill 200 rags of this powder mixture into &4 hard gelatin capsules. The yield is equivalent to about io, ooo capsules containing a total of 5 o, 0 9 each of tetrahydro-3,5-dioxo-1H-pyrrolidine-7a(5H)-propa7ic acid.

The invention is illustrated by the following 29 lti intestinal locust examples. This zaru can contain from 30r1g to 500Q of active ingredient.

Example 9 Pyrrolidine-h<5H)-propanoic acid Witepsol H351,97?
Witepsol H35'r melted by heating to 38 °C, added tetrahydro-5,5-dioxo-1H-pyrrolidine-7a(5H)-propanoic acid and [combined until completely dispersed, and Place into molds at 34°C.

The present invention will be further illustrated by the following @turbid formulation examples. This suspension may contain the active ingredients 50Q151d-1f'15d.

Example 10 Ingredients Lid Pyrrolidine-7a(5H)-Saccharin Sodium Propanoate 0.5F Trihydroxystearin
0.75r propylparaben
0.1? imitation cherry flavor
24 Neobee M-5100- and an appropriate amount of propylparaben to a portion of Neobee M-5, trihydroxystearin is added and the mixture is homogenized for a total of 50 minutes while maintaining the temperature at 50-60°C. This mixture was cooled down and tetrahydro-5
, 5-dioxo-1H-pyrrolidine-7a(5H)-propanoic acid, sodium saccharin and imitation cherry flavor. Complete answer 1 using Neobee M-54.

The invention is further illustrated by the following reconstitution syrup example. This Shirotsu In50M915ml~500R97
May contain 5 ml of active ingredient.

Example 11 Pyrrolidine-7a(5H)-propanoic acid granulated sugar (
Bottler's grade) 60f artificial peppermint Freher (water bathable) I], 4r water
A suitable amount of tetrahydro-3,5-dioxo-1H-pyrrolidine-7a(5H')-propanoic acid, granulated sugar and artificial palmmint flavor are dry blended to make 100d. Fill this mixture into bottles with a scale of iiooml. Add water when dispensing the prescribed amount! Volume up to 6 volumes and shake to dissolve all solids.

This syrup has 250 i + 915 g of active ingredients. Refrigerate this mixture and use within 7 days.

The invention is further illustrated by the following 22 rectal sitting examples.

This herbal medicine can contain 301g~500119g of active ingredient gold@M.

Example 12 Pyrrolidine-7a(5H)-propanoic acid ethyl ester Witepsol (W1tθpsol) H351,97?
Witepsol H35 (decomposed by lA!il by heating to 38°C, tetrahydro-5,5-dioxo-
1H-pyrrolidine-7a(5H)-propanoic acid ethyl ester is added and mixed until completely dispersed, then poured into molds at 63-64°C.

The invention is further illustrated by the following suspension formulation examples. This iMtffi liquid is 5011g/5mZ ~1 r15
d active ingredients.

Example 13 Ingredients lPyrrolidine-7a(5H)-furonoic acid ethyl ester saccharin sodium o5v trihydroxystearin 0.75
f Propylparaben 012 imitation Thierry flavor 2- Neobse M-51 Doat and appropriate amount Propylparaben whole Neobse M-5 dissolved in a portion, trihydroxystearin whole egg and temperature 50-60
This mixture is homogenized for a total of 60 minutes while being maintained at .degree. The mixture is completely cooled and tetrahydro-5,5-dioxo-1H-hyrolidine-7a (5H)-furopane ether ester, saccharin sodium, and imitenyon cherry flavor are added. Complete the capacity using Neobee M-5.

The invention is further illustrated by the following reconstituting syrup examples. This syrup is 50gg15. z~500Q15m
All active ingredients in / can be used.

Example 14 Ester granulated sugar (bottler's grade) 60
v Artificial peppermint flavor (water bathing)
0.4f water
A suitable amount of 100 mg of tetrahydro-6,5-dioxo-1H-pyrrolidine-7a(5H)-furopanoic acid ethyl ester, granules and artificial peharmint flavor are dry blended. This mixture' is filled into bottles having a scale of 100 d. During dispensing, water is added to bring the volume to volume I and shaken until all solids are dissolved. This syrup contains 500 ml of active ingredients. Refrigerate this mixture completely and use within 7 days.

The invention is further illustrated by the following 21 rectal sitting examples.

This raw chestnut can contain somg ~ 50011 g of active ingredient.

Example 15 Ingredient Phase Luester Witepsol (Wit, epsol) H551,97
fWitepsol H35t - Melt by heating to 38°C, tetrahydro-0-5.5-dioxo-1H-
Add pyrrolidine-7a(5H)-propanoic acid benzyl ester and mix until completely dispersed, and
Enter the mold at 3-34°C.

The invention is further illustrated by the following suspension formulation examples. This 7-shu solution may contain all the active ingredients of the genus 5o, g15-1115ml.

Example 16 Sodium ester saccharin 0.5? Trihydroxystearin 0.75F Propyl Paraben 0.12 Imitation Thierry Flavor 2ml Neobee M-510C7 and Probilbaraben are dissolved in a portion of Neobee M-5, trihydroxystearin is added and the temperature is increased to 50°C. ~60
Homogenize this mixture v/J for 30 minutes while maintaining at <0>C. The mixture is completely cooled and tetrahydro-6,5-dioxo-1H-pyrrolidine-7a(5H)-propanoic acid benzyl ester, sodium saccharin and imitation cherry flavor 2 are added. Neobee M-5
Complete the valley ik using .

The invention is further illustrated by the following reconstitution syrup examples. This syrup is 5o/5ml-500m! ?
/ 5 ml of total active ingredient.

Example 17 Le Esther Granium Artificial Peharmint Flavor (Water Bath) 0
．． 1' water 10
0i and 1tetrahydro-6,5-dioquine-i
Dry blend H-pyrrolidine-7a(5H)-10nosenoic acid hensyl ester, granulated sugar and artificial peppermint flavor. This mixture is filled into a bottle marked with 100 mA. During dispensing, water is added to bring up the volume and shaken until all solids are dissolved. This syrup contains 250"9/5 mef of active ingredient. Refrigerate the mixture and use within 7 days.

The following 21 examples of rectal suppositories fully illustrate the present invention.

This herbal medicine may contain a total of 50 Q to 500119 active ingredients.

Example 18 Ingredients Amount lolobenzyl ester Witepsol H551,97
? Witepsol H35k rfll'W by heating to 38°C, add tetrahydro 5,5-dioxo-1H-pyrrolidine-7a(5H)-propanoic acid 0-chlorobenzyl ester and mix until completely dispersed, It is then put into a mold at 66-34°C.

The following formulation examples further illustrate the invention. This suspension may contain 5 o g15-1915 mA of active ingredient.

Example 19 0 lobenzyl ester saccharin sodium 0.5r trihydroxystearin 0.75
F Propyl Paraben 0.12 Imitation Thierry Flavor 2d Neobee M-5100a! ! Tona TJM propylparaben is dissolved in a portion of all Neobee M-5,
Add trihydroxystearin and increase temperature to 50-6
The mixture is homogenized for 30 minutes while maintaining at 0°C.

The mixture was cooled and tetrahydro-6,5-dioxo-1H-pyrrolidine-7a(5H)-propanoic acid
- Add chlorobenzyl ester, sodium saccharin and imitation cherry flavor.

The volume was made up to tk% using Neobee M-5.

The invention is further illustrated by the following reconstituting syrup examples -
do. This syrup is 50 genus y / 5 ml - 500
Q15 ml of active ingredient can be 8'M.

Example 20 Lolobenzyl ester granulated sugar (Potler class X) 602 Artificial artificial peppermint flavor bath) 0.4r water
100- and an appropriate amount of tetrahydro-3,5-dioxo-1H-pyrrolidine-
7a (5H) --! Dry blend the lopanoic acid 0-chlorobenzyl ester, granulated sugar and artificial peharmint flavor. This mixture is filled into a bottle having a scale of 100-. When dispensing, water is added to the desired volume and shaken until all solids are dissolved. This syrup contains 50 Q75 ml'c of active ingredient. Refrigerate this mixture completely and use within 7 days.

The following 22 examples of rectal sitting exercises clarify this theory.

This herbal medicine may contain 30 mg to 500 mg of active ingredient.

Lorobenzyl ester Witepsol H2S
1.97 fWitepsol H35 (r melted by heating to 38°C, added tetrahydro-5,5-dioquine-1H-pyrrolidine-7a (5H)-propanoic acid p-chlorobenzyl ester and thoroughly dispersed) Mix until temperature and pour into molds at 66-54°C.

The following examples of MiJJI agents further illustrate the present invention.

This suspension may contain a total of 75 ml of active ingredient.

Example 22 Sodium saccharin 0.52 Trihydroxystearin 0.75 F Propylparaben 01v Imitation Thierry Flavor 2d Neobe
e) Dissolve propylparaben commonly known as M-510C1+4 in -g of Neohy M-5, add trihydroxystearin and homogenize the mixture for 30 minutes while maintaining the temperature at 50-60°C. The mixture is cooled down and tetrahydro-3,5-dioquine-1H-pyrrolidine-7a(5H)-i lono-ξ acid p-chlorobenzyl ester, sodium saccharin and imitated cherry flenoz- are added.

Complete the capacity using Neobee M-5 gold.

The invention is fully illustrated by the following reconstituting syrup examples. This syrup can contain from 508,975 ml to 500"g/5 nrJ! of active ingredient depending on the active ingredient used.

Example 23 Granulated sugar (bottler's grade) 6o? Artificial peppermint flavor (water-soluble 1 cow) o,
sr water 100m
Tetrahydro-6,5-dioxo-1H-
Pyrrolidine-7a(5H)-ilopane[f1)-chlorobenzyl ester, granulated sugar and artificial benoξ-
Dry blend the mint flavor. This mixture sound 100
Fill into bottles with ml graduations. When dispensing, water is added to the desired volume and shaken to remove all solids. This syrup (active ingredients: 500 Q/
Contains a total of 5 ml. Use this mixture within 7 days after storage.

Claims (1)

[Scope of Claims] 1) Compounds having the entire structural formula, where n is 0 to 6 and R is OH or a salt with a pharmaceutically acceptable metal or amine cation. or O-alkyl having 1 to 6 carbon atoms (provided that if n is 2, R shall not be 〇-ethyl) or 0-OH2@ (where and X is hydrogen, 1 to 6 (It!,
or NR1R2 where R1 is hydrogen;
Alkyl having 1 to 6 carbon atoms, or by amino, by alkylamino or dialkylamino (
where alkyl contains 1 to 6 carbon atoms) substituted with alkyl containing 2 to 6 carbon atoms, hydroxy, or alkoxy containing 1 to 6 carbon atoms, mercapto or alkyl mercapto having 1 to 6 carbon atoms, 5 to 6 membered cycloalkyl,
5- to 6-membered cycloalkyl substituted with alkyl of 1 to 4 carbon atoms, phenyl or phenyl substituted with alkyl of 1 to 4 carbon atoms,
or a heteroatom of the group consisting of nitrogen, oxygen and sulfur 4
a 5- to 6-membered heterocyclic radical containing up to 4 carbon atoms and optionally substituted by amine, alkylamino or dialkylamino, where alkyl has 1 to 4 carbon atoms; and R2 is hydrogen or alkyl containing 1 to 6 carbon atoms). 2) A compound as defined in claim 1 having the structural formula, where R is OH, as a salt with a pharmaceutically acceptable metal or amine cation; 0- or 0-OH2@ (where X is hydrogen, alkyl having 1 to 6 carbon atoms, bualkoxy having 1 to 6 carbon atoms, halo, or trifluoromethyl)
or 1.3.4.0-alkyl having 5 or 6 carbon atoms, or NR1R2 [where R2 is hydrogen or alkyl having 1 to 6 carbon atoms] and R1 is substituted by hydrogen, alkyl having 1 to 6 carbon atoms, or amine, by alkylamino or by dialkylamino, where alkyl contains 1 to 6 carbon atoms. 2～
Alkyl containing 6 carbon atoms, 2,6-dimethylphenyl, 4-amino-6-pyridinyl, 6-amino-4
-pyridinyl, 4-pyridinyl, or 5-tetrazol-yl, or Rj R2 is combined with the N atom to form 2,6-dimetherbiperidinyl)
. 'fr: a compound as defined in Claim 1 having the formula above, wherein R is OH, but 0- as a salt with a pharmaceutically acceptable metal or amine cation;
or o-cH (where X is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo, or trifluoromethyl) , or 0-alkyl containing 1.3.4.5 or 6 carbon atoms). 4) Tetrahydro-3,5-dioxo-1H-pyrrolidine-7a(5H)-propanoic acid, tetrahydro-3,5
-dioxo-1H-pyrrolidine-7a(5H)--10
Panic acid hensyl ester, and tetrahydro-6,5
-rL compound as defined in claim 1 selected from the group consisting of -dioxo-1H-pyrrolidine-7a(5H)-propane N-4-pyridinylamide. 5) a structural formula in combination with a pharmaceutically acceptable carrier, where n is O~>6 and R4 is OH or a pharmaceutically acceptable metal or amine cation; 0- as a salt of or having 1 to 6 carbon atoms
-alkyl or 0-OH2@ (where X
is hydrogen, alkyl containing 1 to 6 carbon atoms, 1 to 6
NR1R2 [where R1 is hydrogen, alkyl having 1 to 6 carbon atoms,
Or by amines, by alkylaminos! alkyl having 2 to 6 carbon atoms, hydroxy, '1. fC, substituted with alkoxy with 1 to 6 carbon atoms, mercapto or alkylmercapto with 1 to 6 carbon atoms, cycloalkyl with 5 to 6 members, alkyl with 1 to 4 carbon atoms; 5- to 6-membered cycloalkyl, phenyl or phenyl substituted with alkyl of 1 to 4 carbon atoms, or having up to 4 heterozygous atoms of the group consisting of nitrogen, oxygen and sulfur; and R2 is a 5- to 6-membered Pi group optionally substituted by amine, alkylamino or dialkylamino (wherein alkyl has 1 to 4 carbon atoms); hydrogen or alkyl having 1 to 6 carbon atoms],
A for the treatment of senility or induced by electroconvulsive shock
A pharmaceutical composition for reversing amnesia. 6) δn induced by treatment of aging or electrostatic dyeing
The treatment of senility in such moaning rats or night spasm shock consisting of administering a pharmaceutical composition as defined in claim 5 to a rat in need of reversal of amnesia. A method for reversing amnesia induced by t. 7) Tetrahydro-6 in humans in need of treatment of senility or reversal of amnesia caused by electrolyte therapy.
, 5-dioxo-1H-pyrrolidine-7a(5H)-propanoic acid, tetrahydro-5,5-dioxo-1H-pyrrolidine-7a(5H)-propane cough ether ester,
Tetrahydro-6,5-dioxo-1H-pyrrolidine-
7a(5H)-propanoic acid is an ester, or tetrahydro-5,5-dioxo-1H-pyrrolidine-7
Treatment of aging in humans consisting of effective administration of a(5H)-pro,zonic acid N-4-pyridinylamide!
or a method for reversing amnesia induced by electrical foreground shocks. 8) Formula (where n is 0 to 3 and 7 and R is hydrogen or 1 to 6
In the presence of an acid acceptor or at elevated temperature, a compound having the formula R'OOOH (wherein R' is an alkyl or aryl having 1 to 6 carbon atoms) ) and the resulting product is hydrolyzed to form a compound (R=OH)'i as defined in claim 1. and, if desired, converting this product into a compound, ester or amide as defined in claim 1 by conventional methods. Method of manufacturing compounds.