JPS5824558A - Pyrrolidine 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 pyrroline derivatives. In particular, the present invention provides the general formula in which R1 represents hydrogen or lower alkanoyl;
3 represents hydrogen' or lower alkyl, and 81
is hydrogen, lower alkyl or formula -(cH鵞)-NR'R
”, where % represents an integer from 2 to 4, and R4 and Rs
each represents hydrogen or 7t lower alkyl, or R
4 and Rs together with the nitrogen atom represent a pyrrolizo/, 2perivinyl, piperazino or morpholine group which may optionally be substituted with one or two lower alkyl groups; The present invention relates to derivatives and acid addition salts of compounds of general formula 1 which are basic.

This compound is new and has valuable pharmacological properties.

The objects of the present invention are compounds of the general formula iris and basic mers, drugs containing the compounds, and the production of such drugs, as well as the suppression or prevention of diseases or the improvement of health, particularly the suppression or prevention of cerebral insufficiency or the improvement of intellectual ability. General formula for improving! This is the use of the acid addition salt of the compound of the general formula (2) and the basic compound of the general formula (2).

As used herein, the term "lower alkyl" refers to a straight or branched chain saturated hydrocarbon group containing at most 7, preferably at most 7 carbon atoms, such as methyl, ethyl, n -Globil, Inglovir, n-butyl,
A, subbutyl, 8-butyl, t-butyl, etc. "
111, ``lower alkanoyl'', is a linear ``lower alkanoyl'' containing at most 8 carbon atoms, preferably at most 4 carbon atoms!几 stands for a branched saturated fatty acid group such as formyl, acetyl, glopylonyl, butyryl, isobutyryl, etc.

The compounds of general formula I contain at least one asymmetrically substituted carbon atom; the invention encompasses not only the optically homogeneous enantiomeric forms of the compounds, but also mixtures thereof (especially helical forms). do.

In a preferred aspect, the invention provides that R1 and R1 are hydrogen; Compounds of general formula 1 are included.

Particularly preferred compounds of the general formula are: 1/S)-cis-N42-(2,6-dimethyl-l-piperidinyl)ethyl)-2-(3-hydroxy-2-okino-1- pyrrolisonyl) acedoazudo and (R/S)-2-(a-hydroxy-2-oxo-1-
pyrrolizonyl)acetamide.

Other preferred compounds of the general formula iris are: (R)-cis-N-(2-(2,6-nomethyl-1-piperidinyl)ethyl l-2-(3-hydroxy-2-okino-1 -pyrrolizonyl)acetamide, (S>-'/su--C-2-(2,5-vpt+ru-piperinonyl)ethyl)-2-(3-hydroxy-
2-okin-l-piCX+)(/nil)acedo2do, (R)! ! -(3-hydroxy-2-oxo-1-pyrrolizonyl)acetamide, (S)-2-(3-human axy-2-oxo-1-pyrrolizonyl)acetamide and (R/Sl-#-[2-( soingrobilamimino)ethyl]-2-(3-humanal?c2-oquinol-l-pyrrolizonyl)acedo(do.

According to the present invention, the compound of the general formula I and the acid addition salt thereof which can be prepared on the pharmaceutical basis when the compound is basic: (α) General formula H, N-Rm where R1 is as defined above. In the general formula Rm has the above meaning and Ro represents hydrogen or lower alkanoyl, or R in the formula
When 1 represents a hydrogen group, it also represents another group which can be cleaved by ammonia, and is reacted with carboxylic acid or a reactive functional derivative thereof; has the above meaning, by acylating the compound with a reagent imparting a lower alkanoyl radical, or
or (6) in the general formula, R1' and R1 have the above-mentioned meanings, and Z represents a binding group; cleavage of the binding group represented by Z from the compound;
and (mount) if necessary, the resulting soastereoisomers are separated into corresponding helices, and/or (-) if necessary, R1 represents hydrogen and/
17t is a helical form of the compound of the general formula i obtained in which R8 represents a basic group is divided into optical antipodes, and/or ψ is optionally a basic compound of the general formula I. In particular, they can be prepared by converting them into pharmaceutically acceptable acid addition salts.

According to method (a) of the present invention, compounds of formula violet can be prepared by reacting amines of formula 2 with reactive functional derivatives of carboxylic acids of formula 2 and 6. When using Gin St, this reaction is advantageously carried out in an inert organic solvent and in the presence of a condensing agent. A suitable inert organic solvent (e.g. Dichloroethane, etc., acetonitrile, V-methylformamide, etc. Examples of suitable condensing agents include socyclohexylcarmezoimide, optionally used with N-human mixosuccinic acid, 1-(lower alkyl)- 2-halopyrimylnium salt and the like.

In this case, the reaction is carried out at a temperature ranging from about 0° C. to the boiling point of the reaction mixture, but preferably at room temperature.

In the above reaction, when the reactive functional derivatives of carboxylic acids of the formula are used, the corresponding carboxylic acid esters, especially lower alkyl esters such as methyl and ethyl esters, the corresponding cardanic acid halides, especially the cardanic acid halides, the corresponding carboxylic acid halides, especially the corresponding carboxylic acid halides, 17 acid anhydrides and mixed anhydrides (e.g. with mesitylene sulfonic acid, ethyl formate, etc.), the corresponding cardanoic acid imimezolide derivatives are primarily considered to be reactive functional derivatives of Calf7tlk in the 1st layer isolated in each case. It is not necessary to do 4J, but it can be manufactured on the spot,
It can then be used immediately for reaction.

This reaction is preferably carried out in an inert organic solvent, especially F
Possibly a horsefly solvent. Depending on the refractory nature of the carb/food used, the anti-LEh' is carried out at a temperature range from about 0° C. to the boiling point of the reaction mixture.

When using a stratified free carmenic acid in the presence of a reactive condensing agent, or with a particularly reactive functional derivative of a μ-stratified free carmenic acid (e.g. the corresponding cardanic acid halide or anhydride), Only compounds in which R11 does not represent hydrogen are considered as starting materials.

In a preferred embodiment, a lower alkyl ester of carmenic acid is used as a solvent, and an excess of the amine is added as a solvent. ! - Use. Nitrogen J<Equation unspecified for atoms! If an amide of formula I is desired, the compound of formula I is ammonia and is used as such, preferably in an aqueous or alcoholic (particularly methanolic) solution. It is observed that upon use of 4J''8' ammonia, the lower alkanoyl groups which may be present in the starting material for the layering are cleaved to give compounds of the formula !, in which Rm represents all hydrogen. It is also suitable if R1' in the starting material of the formula layer is any other group that can be cleaved by converting it into ammonia.

Groups that can be cleaved by ammonia are mainly acyl groups, such as alkanoyl groups (such as the lower alkanoyl groups mentioned above).
, Halon, Alkoxy group also has Niaryloxy 4-
or an alkanoyl group substituted with a similar group (e.g., chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, etc.), an alkoxycarginyl group optionally substituted with halo, etc., or a haaryloxycarpnyl group (e.g. ethoxycaryl, trichloroethoxycaryl, trichloroethoxycaryl, etc.), aroylcarf-nyl & (e.g. pe/diylformyl), acyl groups of optically active acids e.g. (3-okino-4) , 7.7-drimethyl-2-oxabicyclo[!
, 2.1]heptol-1-yl)cal is nyl, etc.

According to this method (&), the compound of formula 1 in which R1 represents a lower alkanoyl group can be produced by treating the compound of 21b with a reagent that imparts a lower alkanoyl group. Suitable reagents for imparting lower alkanoyl groups are, for example, lower furkane carboxylic acid halides, in particular the acid halides, the corresponding anhydrides and mixed anhydrides (for example with the salts mentioned above), the corresponding lower alkane cardan imidazolides, etc. The reaction is advantageously carried out in an inert organic solvent, in particular an ether, such as tetrahydrofuran, V ethyl ether, tert-butyl methyl ether, V oxane, ethylene glycol dimethyl ether, etc. Conceivable are hydrogenated hydrocarbons, such as methylene monide, chloroform, 1,2-dichloroethane, etc., aromatic hydrocarbons, such as toluene, acetonitrile, nomethylformamide, etc.

The reaction temperature advantageously ranges from about 0°C to the boiling point of the mixture.

According to this process (a), the compound of the type in which R1 represents hydrogen can be prepared by cleaving the protective group represented by Z from a compound of formula V. Of course, only those groups which can be cleaved in a manner that selectively removes the protecting group without affecting other constituents present in the molecule are suitable. Suitable protection baselines for this method, such as readily cleavable metal-organic groups,
In particular, easily cleavable acetal and ketal protecting groups such as trialkylsilyl groups, such as trimethylsilyl group, t-butyldimethylsilyl group, etc., such as tetrahydropin-2-yl group, 4-methoxykutetrahyabilane-4
Removal of protecting groups from compounds of formula y, such as -yl groups, benyl groups, etc., is carried out in accordance with methods known per se, and, of course, when selecting the method to be used, the nature of the protecting group to be removed is determined. All considerations must be taken and only the protecting group should be selectively removed without affecting the other constituents present in the molecule. The trimethylsilyl group can be cleaved, for example, by treatment with dilute hydrochloric acid in tetrahydrofuraz and heating to the temperature in t7trz aqueous ethanol or methanol. - The above acetal and ketal protecting groups are modified under mild aqueous conditions (e.g. 0.1 N#i
acid) or acid catalysts such as hydromonic acid,
The lower alkano can be cleaved by trans-acetalization, for example with methanol or ethanol, in the presence of 3 p-toluenesulfonate, F-toluenesulfonic acid, and the like. , the pencil group can be cleaved, for example, hydrogenolytically (eg, optionally with a carrier-bound catalyst, such as platinum, platinum oxide, noradium, etc.).

1 fraction of the resulting mixture of V astereomers into the corresponding racemate! ! U itself known and in the field 'HIA
For those who do it, it is done according to known methods.

The desired separation can be effected, for example, by chromatographic methods.

R1 represents hydrogen and/or R1 represents a basic group! The racemic form of the compound is a compound whose optically active compound is a 7-acid, e.g. tartaric acid, (+)-V-0,0'-p
-Toluoyl-D-tartaric acid, (-)-(3-oxo-4
,7,7-drimethyl-2-*dt+f71o(-2-
2-1) Esterification with hebut-1-yl)carginic acid or the like, or formation of a salt with an acid, and then the 7t-siastereoisomer compound thus obtained or, for example, fractionated crystallization. Separate the birds using the Madograph method,
Ester cleavages can be resolved by liberating a shaped optically homogeneous compound by treatment with a base.

The preparation of cleaving agent-acceptable acid addition salts of compounds of formula 1 is generally carried out according to methods common and familiar to those skilled in the art. Not only inorganic acids but also organic acids can be considered, such as chloride, hydrobromide% sulfate, methanesulfone tJI, j-1 luenesulfonate, oxalate, tartrate, citric acid. These include acid salts, maleates, ascorbates, acetates, etc.

As mentioned above, another ceremony! Intermediates in the production of compounds,
That is, the above layered structure in which the protecting group is not a lower alkanoyl group and W
The compounds of are an object of the present invention.

The lower alkyl ester of the compound in the stratification is, for example, a base (e.g. sodium hydride) capable of depriving the hydrogen atom on the nitrogen atom at the t-1 position of the pyrrolizonone derivative of ZFi having the above meaning.
and the resulting anion is represented by the general formula, where R1 has the above meaning, and
and R represents lower alkyl, and can be produced by bending the compound. Thus, a compound of the general formula is obtained, in which RI, R and X have the above meanings. Compounds of formula (3) in which Z represents lower alkanoyl are lower alkyl esters of compounds of the stratified type in which RI' represents lower alkanoyl.

The lower alkyl ester of a stratified compound in which R11 represents hydrogen can be prepared by cleavage of a compound of formula (1) with a mercury group represented by Z.

Hydrolyzing the ester group in the compound of formula (2), in which R'' represents hydrogen 1, i.e., in the general formula, 88 has the above meaning, and in a prior, subsequent or simultaneous operation, It can be obtained by cleaving the protective group represented by 1 for Z. A stratified carganic acid in which 8 units represent lower alkanoyl can be obtained by reacting the compound of 2 with a reagent that imparts a lower alkanoyl group. can be obtained, for example, by treating a lower alkane with phosphoric anhydride or chloride. -1-yl) carf-nyl can be introduced in a similar manner, for example the latter group is (3-o-4.717-to17/del-2-
The sabicyclo[2,2,11hept-1-yl)cal can be introduced using nyl chloride.

The compound of formula V used as a starting material can be obtained by reacting a compound of formula 1 with an azun of formula I in analogy to method (α). In this case, only protective groups which have no influence under the reaction conditions are considered. Particularly suitable protecting groups are, for example, the 7-lyl group and the P/V group mentioned above.

Compounds of formula V can also be obtained, for example from 3-hydroxy-2-pyrrolidanone, by introducing the desired protecting group; the method of introducing the protecting group will vary depending on its nature, but is well known in the art. It is well known to those who can pass f# to .

Compounds of general formula V can also be obtained from 4-amino-2'-hydroxy@acids using the Yurako method, including monomerization and introduction of the desired protecting groups in one operation. Thus, for example, 3-(trimethylcryloxy)-2-pyrrolidino, 4-amino-2-hydroxybutyric acid in the presence of a small amount of trimethylchlorosilane can be converted to hexamethylzoclazan or bis-(trimethyl7lyl)urea or It can be obtained by reacting with bis-(trimethylsilyl)acetamide.

The stratified and y compounds contain an asymmetrically substituted carbon atom at the 3-position of the 41-yang formula.

The relevant stereochemical relationships determine the stereochemical relationships in the compound of formula 9 and 1 left from the compounds of formulas 1 and y.

The stereochemistry at the 3-position of the five-membered heterocycle of the major door and V compounds is also determined by the intermediates and/or methods used to prepare these compounds.

1 set as mentioned above! The a+)t/y derivative of is a novel compound with extremely valuable S physical properties.The compound shows negligible toxicity, and in the animal studies described below, the compound alA was produced experimentally. brain failure VC
(i! I found it possible to counteract.

The test equipment consists of a grid floor (30*401) that can conduct electricity and a gray-white glass grid foam (
Untrained male rats (100-120cm), skinner boyc (@Skinsgr boyc) (1sw 15w'0.8cm), were individually placed in a hole on a platform, and the rats were placed on a grid floor. Immediately after crawling down, electric leg shock Gα8 A)
9, the normal reaction of an untrained rat is to jump back to the platform. However, in order for the rat to try to crawl again, the foot shock treatment must be repeated 3-5 times for each animal, performing 3-5 of these repetitions for each movement. Tomogo, rat welfare so-called [passive avoidance ffi! J (jas
4wsavo(das6g response)y
Learn, i.e. the rat no longer tries to get down on the grate floor,
The reason for this is that I knew that I would be in a terrible situation if it rained.

Immediately thereafter, 31 groups of 30 animals were tagged. The first group was injected with scopolaban α3q/Akebono <i-p
-) L, as well as distilled water (!sd/9, ν·O). @Group 2: Scopolamine O, 3mg/￥x Nitrogen
t injection (<-F-)L, and oral dose of test substance 1
Gave. The third #9 was given only distilled water (p-a.).

After 2 hours, each rat was placed on the platform in the "Skinner Dunks". The assessment criteria for this test 111' for the determination of short-term memory preparations was that the animal remained on the platform for 60 seconds! or not (thus the result t-leather for each animal [can be remembered as ``yes''), the difference between the results obtained in the first and second groups. Statistical significance is Chi-8 square
Determined using tests.

75% of ft animals treated with distilled water only
The animal remembers the “passive avoidance response” for 2-4 hours after learning to stay on the platform7? :, Scopolamine to, aq/m, (.

p-) and distilled water (p, O)-treated animals.
In 92% of cases, the degenerative effect on short-term memory is 3.
Substances capable of antagonizing the 6wi deficiency established in ~4 hours, i.e., the animal must remain on the platform, resulted from an injection at 70.3197 hours of Schopola scoliosis. Inhibition of short-term memory - can be reversed. Many positive results ("yes") were observed for scopolami/(α3q/1cpi p-) and distilled water (p-a
A dosage of a preparation is designated as "active" towards scopolamine if it is clearly different from the results of control animals treated with only 1.-).

The following table shows the dosages at which compounds of formula I exhibited significant activity in several tests. Additionally, this table includes data on acute toxicity (w after a single oral administration to mice).
LD in q/kIF! +1) is included.

Loud compounds and formulas that are basic! The pharmaceutically acceptable acid addition salts of the compounds can be administered as pharmaceutical agents, eg, in the form of capsules, solutions, emulsions or suspensions. However, it is also possible to administer the preparation rectally (eg in the form of a herbal medicine) or parenterally (eg in the form of an injection bath).

As mentioned above, a pharmaceutically acceptable acid addition resistant drug of Daito's compound or a compound of Formula 1 which is basic may be used as an object of the present invention, as well as a method for producing such a drug. The process for preparing the medicament includes the addition of one or more pharmaceutically acceptable acid addition salts of a compound of the formula or a basic compound and optionally 111% or more of other treatments. Valuable substanceff renus method (gαt#%1c
al) consisting of making it into a dosage form.

In preparing tablets, coated tablets, dragees, and hard gelatin capsules, the compounds of formula 1 can be treated with pharmaceutically inert inorganic or organic excipients. As such excipients, for example, for tablets, dragees and hard gelatin capsules, lactose, corn flour derivatives, Merck, stearic acid or salts thereof, etc. can be used.

Suitable excipients for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semisolid and liquid polyols, and the like.

Suitable excipients for preparing solutions and syrups are, for example, water, polyols, sucrose, invert sugar, dulcose, etc.

Excipients suitable for herbal medicines include, for example, natural or hydrogenated oils, waxes,
These include fats, semi-solid and liquid polyols.

)#! In addition, pharmaceutical preparations contain preservatives, bathing agents, stabilizers, wetting agents, emulsifiers, sweeteners, coloring agents, flavoring agents, salts to change the osmotic pressure, buffering agents, coating agents or antioxidants. Contains agent
can be set. The preparation can also contain other therapeutically valuable substances.

According to the invention, 2! Compounds of formula 1 and compounds of formula 1 which are basic are acceptable in formulation; b-acid addition is useful for inhibiting or preventing cerebral insufficiency, or for improving intellectual performance, e.g., cerebral stroke, geriatrics, It can be used in cases of alcohol poisoning, etc. The throw arrangement can vary within wide limits and is, of course, adapted to the individual needs in each case.

Generally, for oral administration, a daily dosage of about 105)500 η is appropriate, although examples below this upper limit are illustrative of the present invention if indicated. It is not intended to limit the scope of the invention.

In the examples, all temperatures are expressed in degrees Celsius.

Example l (α) Approximately 55% dispersion of sodium hydride in mineral oil 3
8.3 gi, with stirring at a temperature between 45 and 50°C.
(R/'?)-3-) in anhydrous acetonitrile 520-
Dimethylsilyloxy-2-pyrrolisonone 51.911
and ethyl bromoacetate in portions within 136s/KIO minutes. That iron.

The mixture was brought to reflux with stirring within 30 minutes, stirred for a further 1 hour at reflux, then evaporated to 90 P solution and ethyl (R/5)-2-(3 -) Residue containing riftylsilyloxy-2-oxo-l-pyrrolizonylon acetate dissolved in 50 °C of tetrahydrofuran
, 1N hydrochloric acid in this solution? 1d, 7.2j' of sodium hydrogen carbonate was added to an IB trowel, and the mixture was stirred at room temperature for 7 minutes and evaporated into the eel. The residue was extracted three times with acetonitrile, and the combined acetonitrile extracts were evaporated. The remaining 1 ft is filled with silica dull (top grain size α2~αS)
m) Uederi e1! I put it on Togelahui. Ethyl (A'/5)-1- eluted with methylene chloride and ethyl acetate
(3-Hydroxy-2-oxo-1-bioI)',Z-yl)acetate-r-f ethyl acetate/n-hex/(1:2
), this crystal has a melting point of 80.5~81''C.

(h) Ethyl (R/5)-z-(a-hydroac-
2-oxo-1-pyrrolizonyl)acetate zsoIl
After treatment with about 115% ammonium hydroxide solution, the mixture was stirred at room temperature for 1 hour. The mixture was treated with acetonitrile and evaporated. Residue trr
Setonitrile was treated twice and evaporated in each case. (R
/5) -2-(3- and doloquinol-2-oquinol-pyrrolizonyl)acetamide was obtained, which was recrystallized from methanol/diethyl ether (1:2), 163
Dissolved at ~164°C.

Example 2 Ethyl (R/5)-2-(3-hydroxy-2-oquinol-l-piOIJzonyl)acetate-)4.5# was converted into cis-2-(2,6-dimethyl- l-piperinonyl)ethylamine y? J 11/ with a5 hours 100℃
heated to. After that, add soethyl acetate to the mixture,
The mixture was stirred and filtered, leaving a filter residue (asy)2. z+
7 cals (particle size 0.2 to α5fl) was subjected to a 30J' column atomography.

Bath removed with methylene chloride and methanol 7t(R/S)-
cis-/l/-(2-(gos-?/methyl-1-piperizonyl)ethyl)-2-(3-hydroxy-2-ogisol-10 IJzonyl)acetamide.

After recrystallization from ethyl acetate, it has a melting point of 131-132°C.

Example 3 Ethyl (ItlS)-2-(3-?nidoakiku2-okin-1--roIJe/nyl)acetate 45I! under nitrogen! -(N isopropyl ester)ethyl ester and heated to 100°C for 5 hours and chromatographed the crude product on aluminum oxide (neutral, active). enol (l:l and ethanol (R/
5) -N-C2-<visopropylminino)ethyl)-
After eluting 2-(3-hydroxy-2-oquino-1-pyrroliV-nyl)acetamide and stirring in JV ethyl ether for 7t, this had a melting point of 91-93°C and a boiling point of g30.
~250°C/αO1 mHy (bulb-tube).

Example 4 (α) Hexamethyldusilazane 89- and trimethylchlorosilane were added to a suspension of (R)-4-reminnow 2-hyperoxybutylene 5top in 340 ml of 5w1k anhydrous xylene. . The mixture was heated to boiling for 4 hours with stirring, then evaporated 1, the residue was extracted 4 times with toluene 7t, the combined toluene extracts kX were evaporated under vacuum, and the residue was distilled in 3 steps.

Boiling point 90-100℃/αotam#g (ball-'f)
(R)-3-trimethylsilyloxy)-2-pyrrolidinone was obtained.

(6) Except for using (1-3-(trimethylsilyloxy)-2-pyrrolizonone) as a source material,
The method of Example 1%m<α) was repeated. After recrystallization from ethyl acetate/n-hexidone, melting point 84-8S'CO
2+#(R)-(+'J-2-(3-hitokukiku2-
Okino 1-Pias V-Nyl) acetate was obtained;
α) “Knee + 5 g @, [α31!@=+g2°
, [α1fls-+ 255°shi\7 (V Methyformia (do, 6=LO).

(6) Ethyl (R)-(+)-g-(3-hydroxy-2-oxo-
! - piazonyl) acetate, (R)-(+)
-! -(3-Hydroxy-2-o-1-pyrroliVyl)acetamide is obtained, which has a melting point of 197-1
98℃; [α]F=+81@, ('')L-+s7'', C
1l$s=+3os@(V methylformamide% C=
1. o) had v.

Example 3 Following the method described in Example 2, ethyl (R)-(+)-
From 2-(3-human axy-2-oquinol l-pyrrolizoel l acetate, (1-(+1-cis-/V-(2-
(2,8-N me?L-1-pi,e IJvnyl)ethyl)-2-(3-hydroxy-2-oxo-1-pyrrolizonyl)acetamide was obtained with a melting point of 11 and a melting point of 101.
-102”: [α] Closer +43° ((X)L
=+52@, [α]L=+162° (acetonitrile, e=Lo O) 1 may be present.

Practical Example 6 (α) In the same manner as in Example 40 (α),
From (S)-(-)-a-amino-2-hydroxybutyric acid, ethyl (S)-(-)-2-(3-hydroxy-2-
Okino 1-pyrroli V nyl) acetate was obtained; melting point 85-8&5°C; [α] Fuu SS@, (d] Rs=
-84°, [dlj! 5--zze.

(Chloroform, e = 1.0”) @(b) Ethyl<8)-(-
)-2-(3-human adf seal l-via a17/nil)
From the acetate, (S)-(-)-2-(3-human acetamide, 2-okino-1-pyrrolizonyl)acetamide is obtained, which has a melting point of 197-1911°C: [l'',:
=c-82', (lIfs=-os", [α):!s
=-313@(V methylformua(do, a=LOo)'
h- had.

EXAMPLE Ethyl (1-(-
1-1-(3-human 2-oxo-1-pyrroli V
From nyl acetate, (S)-<-)-VX-N-(2
-(2,6-'/lf-1-piperidinyl)ethyl)-2-(3-hydroxy-snow-okino-1--asV
fL% This %O has a melting point of 10
1-103℃; [α]? =-44@, [αIJ! s=
-53°, (α)Hs=-tss@(acetonitrile, 6; 1G)k*.

Example 8 Ethyl (R/5)-2-(3-hydroxy-2-oxo-1-pyrrolizonyl)acetate 1. Peel treated with 10-40% solution of methylamine in olk water.

Stir for 1 hour at room temperature and evaporate the mixture.

The residue was shaken 5 times with acetonitrile and then removed in water.
Reevaporation was carried out in each case. The residue was treated with ethyl ether. - Too niche, melting point 129-13α
N-methyl-2-(3-hydroxy-2-okino-1-pyrrolidinyl) acedoline r1 (isolated) at 5°C.

Example 9 Ethyl (R/5)-2-(3-hydroxy-2-okino-1-pyrrolizonyl)acetate! L5g and l, 2-
The mixture of ethylene diabane I L2& was allowed to stand at room temperature for 20 hours and the excess 1,2-ethylenediamydane was evaporated under vacuum. The distillate was dissolved in hot acetonitrile (40°C), stirred at room temperature for 2 hours, and then stirred in a water bath for 1 hour to give 7t.
N42-(amino)ethyl)-2-(3-hydroxy-2-oquinol-1-pyrrolidinyl)acetamide having a melting point of 110 DEG-112 DEG C. was separated by filtration.

Example lO Ethyl (R/S)-2-(3-hydroxy-2-okino-1-pyrrolizonyl)acetate ioI! and cis-4
-(2,6-vmethyl-1-piperidinyl)butyl ai
Heat to 100° C. for 15 h under nitrogen. Add this mixture to aluminum oxide (activity cylinder, neutral)
Chromatographed on 'toy. Bath-removed with ethanol, 9(R/&)-7x-N-[4-(2,6-V
l-piperidinyl)butyl]-2-(3-hydroxyl-2-oxo-1-pyrrolidinyl)acetotin F was dissolved from V ethyl ether and had a melting point of 90~90.
The temperature was 92℃.

Example 11 Ethyl (R/5)-2-(a-hydroxy-2-oxo-1-pyrrolizonyl)acetamide 101 and N-(2
-aminoethyl)pipericin 1B71'JrHeated to 100<0>C for 4 hours under nitrogen. Excess amount of N-(2-aminoethyl) bilysin was distilled off under high vacuum.
The remaining 1M (R/5)-N-[2-(1-piperidinyl)ethyl]-2-(3-hydroxy-2-oquin-l-pyarizonyl)acetamide had a melting point of 110 after crystallization from ethyl acetate. ~111″Cy was shouldered.

Example 12 Ethyl (R/5)-2-(3-oxo-1-pyrrolidinyl)acetate 40y and #-(3
-aminoethyl) morpholine & 1g under nitrogen
This mixture was chromatographed with 50 g of silica glue (particle size α2-0.5 Jll) and eluted with ethanol (HI).
5) -N-(3-(1-morpholinyl)gurogyl]-2
-(3-hydroxy-2-oΦso-1-pyrrolizonyl)
Acetamide has a melting point of 94~ after recrystallization from ethyl acetate.
Example 13 Ethyl (HI5)-2-(3-hydroxy-2-oxo-1-golizonyl)acetate λ0. y and (j2-
(v ethylamino) ethylamino 1 fluoride Mix this * with aluminum oxide (neutral, activity level) 4! Chromatography on ij'. [crude <HI3)-N-C-2-(soethylamino)ethyl]-2-(3-hydroxy-2-oxo-
The 1-pyrrolisonyl) acetamide was again chromatographed on 25I aluminum oxide (neutral, active). The product was eluted with ethyl acetate and ethanol and then distilled in a ball-tube at about 250°C/αO3 mHg.

Example 14 (α) Kobil (HI5)-2-(3-hydroxy-2
-oxo-1-pyrrolisonyl) acetate 1 & 0 dissolved in absolute alcohol 150- and absolute alcohol 38-
To the 1,95% solution of sodium 1,951, 1,5% of ion-free water was added, and the mixture was stirred overnight at room temperature. Occurrence 1'F:,! @Add 250-diethyl ether to the suspension, filter the mixture and add 2,(R
/S)-2-(3-hydroxy-2-oxo-1-
The sodium salt of pyrrolisonyl)acetic acid was obtained. This salt mixture was stirred overnight at room temperature in 2 d of acetonitrile and 12 d of 25% hydrochloric acid. This mixture was then evaporated. Evaporation f
iffi' was treated twice with acetonitrile and reevaporated in each case. The residue was boiled under reflux in 320ml of acetonitrile, filtered while hot, and the P solution was stirred in a water bath for 3 hours and 7t. By filtration, melting point 153
~11S4°C tv(it/5)-2-(3-hyF(!-?C2-oxo-1-pyrrolizonyl)acetic acid was isolated.

(6) Dissolved in t/methylformamide 6- tZoku clohexylcarbosiimide L3ON? 72:(HI5)-2- was dissolved in 20d of V methylformamide at 0°C.
<B-Hydromedicine 2-Oxo 1-Pily/ = t
h) Acetic acid LO1 and 947%'/X-2-(!, II
-zomethyl-1-biirizonyl) engineering f luain L03j
lK exchange friend. This mixture was stirred for 4 days at about t-1ii, and water containing no 7f of iodine was stirred for 4 days. It was treated with 23 g of water and evaporated under vacuum using a water R pump. The residue was treated five times with toluene and reevaporated in each case. The residual components that are soluble in chloroform are treated with aluminum oxide (active,
Neutral), 60 1iF). The alcohol bath solution was again chromatographed over aluminum oxide (activity [1, neutral) 151]. In the fractions eluted with acetonitrile and ethanol,
According to the gas chromatogram and mass spectrum, (R
/S)-cis-N-[2-(2.6-'/methyl-1-piperidinylJethyl)-2-(3-hydroxy-2
-oxo-1-pyrrolizonyl) acetate.

Example 15 (a) (A'/5)-2-(a-human C1-?C2-oxo-1-pyrrolizonyl)acetic acid oi, anhydrous tetrahydrofuran 80- and acetyl cuclide 5- while stirring 4 hours. Boil it under afi.

The mixture was then evaporated. The residue was filtered through silica gel (particle size A2-A5). D
5) -2-(3-7-1!V-2-oxo-1-pyrrolidinyl)acetic acid was removed.

(&)! -Chloro 1-methyl-rizonium Iomade L81 #t-Tenukamethylene/1odK was suspended in (S/5)-2-(3-nacetoxy 2) at room temperature.
-oquinol-pyrrolidinyl)acetic acid L! Added l. A solution of 94.7% 7-2-(16-damethyl-l-piperidinyl)ethylane 70981 and triethylamine λ0 dyd in methylene chloride 20 d was reduced within 15 minutes at t-o C, and the mixture was then stirred at room temperature for 18 h. Stirred. Let this mixture tube evaporate and remove the residue from aluminum oxide (
The mixture was chromatographed on a neutral plate. Elute with chloroform and remove the substance with silica glue (particle size 0.2~
0.5 m)). (R/S)-cis-717'-(2-
(2,6-dimethyl-1-biperizonyl)ethyl)-2
-(3-acetoxy-2-oxo-1-pyrrolinonyl)
After crystallization from zoethyl ether in acetamide, melting point: 120-122°C.

Example 16 (S/5)-2-(3-acetoxy-2-ol-
pyrrolisonyl)acetic acid (1.0 N'J (anhydrous tetrahydroflough), then add N,N'-carginyldiimidal 0.89F'11 times (90).This mixture was stirred until gas evolution ceased. The mixture was stirred at room temperature. Then, 94.7% cis-2-(2゜6-dimethyl-1-piperidinyl)ethylazine (L811ft-) was added, the mixture was allowed to stand at room temperature overnight, and then evaporated to remove the residue. Aluminum oxide (active layer-1 neutral) was chromatographed with soybean and eluted with methylene chloride ('R/S).
-cis-N-(2-(2,s-dimethyl-1-piperidinyl)ethyl)-2-(3-acetoxy-2-oxo-
1-Biclidinyl acetamide, along with diethyl needle, had a temperature of 121-1.22°C.

Example 17 (a) Ethyl (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)arytate L? Ojt
Methylene chloride 30- and acetyl chloride 0.53
The mixture was then boiled for 25 hours under reflux with stirring in a boiling point. The mixture was then evaporated. Remaining git bulb - steaming in the tube 7
t, boiling point 22S'C/(Lot-H ethyl (S/5
)-2-(a-acetoxy-2-ol-pyrrolidinyl)acetate is also obtained.

(6) Ethyl (S/5)-2-(a-acetoxy-
2-oxo-1-pyrrolidinyl) acetate 0.40j
F' was treated with a saturated solution of ammonia in methanol 45-. The mixture was left at room temperature for 1 hour and then evaporated. The remaining 1 fi't was treated with acetonitrile four times and reevaporated in each case. (S/5)-2-(S-hydroyac-2-oxy-1-pyrrolidinyl)acetamide was obtained, which was composed of methanol/diethyl ether (1
': After recrystallizing from 3), it melts at 163-164°C.

Example 18 (S/5)-2-(3-acetoxy-2-oquinol-
pyrrolidinyl)acetic acid, O# t-toluene 20- and thionyl chloride 0.54- and boiled under reflux for 2 hours. After evaporation of this mixture, the residue was sieved twice with toluene and in some cases the toluene was evaporated under full vacuum to give the crude (R/5)-2-(3-acetoxy-2- The residue α51 containing oxo-1-pyrrolizonyl) acetic acid chloride was left overnight in a saturated solution of ammonia in methanol. After evaporation of the solvent, the residue was subjected to atomography on silica gel (particle size α2-0.5 am) SII. Eluent [methylene chloride/meth/-ol (1:1
)) (R/5)-2-(a-human Ia x-2-okino-1-pyrrolizonyl)acedoide can be detected.

Example 19 Noshik-a-hexyl-u*ly-y dissolved in tetraroform 20
Nii Wl, 641f (R185-2-(2-oxy'-1-pyrrolizonyl)acetic acid L!iF in 3-acetate
, chloroform 40- and N-hydroxysuccinimide 0°86II at room temperature.

After 4 hours, the solid fraction '1f-F was separated, and the P solution was filtered and passed through again. Fgt evaporation. The residue was treated with 40 liters of a saturated solution of ammonia in methanol at room temperature. The mixture was stirred at room temperature for 5 minutes, then 10 d of ion-free water was added to it, and recrystallized two more times from this mixed trill. (R/5)-2-(3-
Hydroxy-2-oxy-1-pyrrolizonyl)acetamide was obtained. .

Example 20 (R/5)-2-(3-hydroxy-2-oxo-1-
Pyrrolizonyl) e#x, soy was dissolved in 50% of blackened form and 10% of dimethylformamide. N- to this
Hydroxysuccinimide 1,08 & was added. Then, cyclohexyl calyceide 208I dissolved in chloroform 25 was added, the mixture was stirred at room temperature for 4 hours, and the precipitated solid kF was separated. Solution F was condensed to a volume of about 20%, then refiltered, 90P solution was evaporated, and the remaining 1Q was 947% cis-2-(2,6-nomethyl-1).
-piperizonyl)ethylabane L70j'.

This mixture was left at room temperature overnight to remove excess cis-2,-
(2,6-somethyl-1-pyrrolizonyl)ethylal'
rJcg! Removed below. The residue was chromatographed on 60 μl of aluminum oxide (activity!, basic) and the fractions eluted with chloroform and alcohol were evaporated.

Diethyl ether/ethyl acetate (2:
1) Stir in 33-hole. (R/S)-cis-/
V-(!-(1!, 6-cymethyl-1-&perigiel)
ethyl)-2-(3-hydroquine-1-biazonyl)acetamide (melting point 116-120°C) was obtained, which was obtained by cycling over aluminum oxide (activity level: After crystallization and recrystallization from ether acetate, it melted at 126-128°C.

Example 21 (R/5)-z-(3-hydroxy-2-okino-1-pyrrolizo/)acetic acid zOy dissolved in 50-ml of loloform and 1.74+t/l of triethylamine were added dropwise. -2
After stirring for 120 minutes at a temperature between -10°C and 7%, 9ζ7% cis-2-(2,s) dissolved in chloroform-10-
-ymethyl-1-pyrrolizonyl)ethylamide72. O'
llt#j4 was lowered. This mixture was left overnight at room temperature.
This mixture was then purified by chromatography over 12 Ojl of aluminum oxide (activated charcoal, neutral) and eluted with acetonitrile and ethanol to give the residue (61)'fe(R/S)-cis-7V-(2 -(2,6-
Dimethyl-1--periV-nyl)ethyl)-2-(3-hydro-2-okino-1-pyrrolidinyl)acetamide was purified after repeated chromatography on aluminum oxide and 4N crystallization from ethyl acetate.
Melts at ~130°C.

Example 22 Cis-2-(3s-
<it/S)-t-(
From 2 g of 3-acetoxy-2-oxo-1-L'lolidinyl)acetoand, (R/5)-2-(3-hi)'c
1-? 2-oquinol-pyrrolidinyl)acetamide was added.

riOW) Although Seiji Jl was not performed due to Dharafi,
However, it was disintegrated in chloroform. Melting point 161-163
The product was obtained at ℃.

Example 2-3 In the same manner as in Example 21, (R/5)-1-(3
A crude mixture was obtained from -acetoxy-2-okino-1-pyro"rizonyl)acetic acid. This mixture was chromatographed on aluminum oxide (activity, neutral) 4011 and eluted with aa-form. ft(R/S)
-cis-7V-[:2-(2,6-cymethyl-1-biyrizonyl)ethyl]-2-(3-acetoxy-j-oxydi-1-pyrrolizonyl)acetamide, after disintegration in diethyl ether, has a melting point of 121-122℃ 1jiL
, was.

Example 24 In a similar manner to the method of Example 21, (R/5)-z-(3-human axy-2-oxo-1-pyrrolidinyl)acetic acid was prepared from 5)
-N-(2-(V-nyl)ethyl)-2-(3
-Hydroxy-2-oxo-1-pyrrolizonyl)acetamide was obtained. Microanalysis shows the following values.

Experimental C11H meeting, 0. N: Molecular weight 25! Calculated value for L32: C3eL45%-;#&211%;A/:16
．． 46%.

Actual value: csat t%; Zf & 29% H7V: ta3
2%0 Example t5 ←) According to the method described in 15(α) of Example 1, (R
゛/5)-3-Trimethylcryloxy-2-゛pyrrolizonone and hethyl 2-promoglopionate, boiling point: 10°C. Ethyl (R/
S)-2-(3-Hydroxy-2-O*/-1-pyrrolidinyl)gropionate.

(6) According to the method described in Section (6) of Implementation iQJ 1, ethyl (7?/5)-2-(a-hydroxy-2-
oxo-1-pyrrolizonyl) glopionate after chromatographic filtration on silica dal (particle size 0,2 to α5-), stripping with acetonitrile/ethanol (l:1) and crystallization from atonitrile. Melting point 13
(R/5)-2-(3-hydroxy-
2-oxo-1-pyrrolizonyl)probionabad was obtained.

Example 26 Ethyl (R/5)-2-(s-hydroxy-2-oxo-l-pyrrolizonyl)globionate i,5iir less-2-(2,6-G'methyl-1-biirizonyl)ethylamine! 45j' at room temperature for 24 hours. Thereafter, an amount of cis-2-(2,617methyl-1-piperidinyl)ethylane was distilled off under high vacuum, and the remaining fIi15F) t-silica dal (particle size 0.2 to α5
Chromatography was carried out on 30y. Elute with methanol to give (R/S)-cis-N-r-2-(2,6-
dimethyl-1-piperiVyl)ethyl]-2-(3-hydro-2-oquinol-l-pyrrolishell)propio/
The amide has a melting point of 129-13 after recrystallization from ethyl acetate.
0'C1- had.

Implementation fi! F (a) According to the method described in [(α) of Example 1, (
R/5)-s-trimethylnoryloxy-2-pyrroli V
from non and ethyl-2-bromobutyrate, boiling point 10
B'C/α02am#g (ball-tube) ethyl CR15)
-2-<3-hydroxy-2-okino-1-vicrizonyl)butyrate was obtained.

(According to the method described in the example, ethyl (R/5)
-2! -(3-Hydroxy-2-oxo-1-pyaridinylumptylate 205.9 to 205.9, after a madographical scrutiny, amorphous <87s)"-cis-/'/-(2-
(2,6-zomethyl-l-piperiVyl)ethyl)-2
-(3-human a-xy-2-oquino-1-pyaridinyl)
Buthirua is fL7t.

Example 28 In the same manner as in ffJ(6) of Example 1, 2
Ethyl (R/5)- with 5% ammonium hydroxide solution
Recrystallized from acetonitrile from 2-(3-hydroxyc-2-oxo-1-pyrrolidinyl)butyrate to give l/S>-2-(3-human a), melting point 121-122°C.
xy-2-1dF-1-pyrrolidinyl)butyramide was obtained.

Example 2fI (α) Ethyl (1-t/5)-2-(3-hydroxy-2-okino-1-pyrrolidinyl)acetate zoyv
Dissolved in bilicin 40- and then at O ~ +5 °C (-)-(
3-Okino4. ? ,? -) riftyl-2-oxaC cyclo(22,11hegtol-1-yl)carf-nyl chloride [[α]Hs=-23': chloroform, c=lO
I added λ54IIk one by one. Stir overnight at room temperature and add 7t.
f&, this mixture was evaporated. 4 in residue toluene
In each case, the residue was treated with aluminum oxide (activation level, neutral) and evaporated, the fraction eluted with chloroform was evaporated. It was crystallized from

1111 points 89-91”C ethyl 2-/3-[(3-
Oxy-4,7,7-? Riftyl-2-oxabikukuo
A diastereoisomeric mixture of [2,2,1]hept-1-yl)caryloxyph-2-okyne-1-pyrrolizonyl/acetate was obtained.

(6) The components * of the above two tanks are in the n-
of 12% tetrahydrofuran and α2% Ino! A commercially available (Marek) pre-filled hyper-lichronorp (H4bar-L) was
ichroaorb) RT DI OL column (2
50g/4m, particle size lOμmL), ethyl g-/
54(3-oxo4.7.?-trimethyl-2-oxacyclo(2,2,1)hebut-1-yl)carmenyloxy]-2-oxo1-vicridinyl/cyastereo of arytate High performance liquid chromatography of isomer mixtures could be performed.

Ethyl 1)-z-/s-((3-okino 4,7,
'r7) dimethyl-2-oxafushik a (g, 2.1
) heg)-1-4l) The melting point of caryl oxyler 2-oquin-l-pyrrolizonyl/acetate is the same as that of benzene/
Ml-heki-? y (1G?~t after recrystallization from 1:27
at os°C.

(e) Ethyl [7-2-/3-((3-okino4
．． T, 7-drimethyl-2-oxapicic σ[2,2,
1] -2-oxo-1-biyrizonyl/acetate in t-1-ylncarmenylate was stirred at room temperature for 2 hours in a solution of ammonia in methanol. This mixture was tube evaporated. The residue was treated four times with acetonitrile and in each case reevaporated (7t, by trituring the residue twice in ethyl acetate, melting point 195~
(A')-(+)-2-(a-pyrrolizonyl)acetamide at 116°C was obtained, [α]π=+78", [α]lm=10 94°, [α
]I%, = + a O2”: (dimethylformamide, 6 m LO).

Example 30 (R2H)-2-(3-hydroxy-2-oquinol-
(pyrrolizonyl)acetamide 1.5,9 was heated with acetyl chloride 1 & 5- and chloroform 25- for 20 minutes under centrifugal flow. This mixture was released t#. Treated 4 times with residual toluene, in each case without significant evaporation.
/5) -2-(a-acetoxy-2-oquino-1-pyrrolizonyl)acetando is obtained, which is dissolved at 116-117°C after recrystallization from ethyl ether.
It was.

31 CRlS)-cis-A'42-(2,a-#chiru1-
piperinonyl)ethyl)2g-(a-hydroxy-2-
Oquinol l-pyrrolizonyl acedozo IIr heated under reflux for 3 hours in 60 ml of chloroform and 1.5 ml of acetyl chloride and 7'? After evaporation of the -6 volatile components, the residue was treated three times with toluene and reevaporated in each case under vacuum. The residue was chromatographed on aluminum oxide (activity ■, neutral) and extracted with rearroform to give L(R/S)-cis-/V-[2-(2°6-dimethyl-1-piperidinyl). )ethyl]-2-(3
-Acetoand (2-oxo-1-pyrrolizonyl) has a melting point of 121 after recrystallization from diethyl ether.
It has a temperature of ~122°C.

Example 32 <R/h)-cis-N~(2-(2,6-dimethyl-l
-Biirizonyl)ethyl]-2-('3'-hydroxy-2-oxo-1-pyrrolizonyl)'acetand0.
394 I! The mixture was boiled under reflux for 4 hours with N-acetylated mesol α222y in toluene. Add this mixture '$A to aluminum oxide (active vertical metal, neutral) 2
Chromatographed on IF. (R/S)-cis-A/-(2-(2,6-nomethyl-l-biperizonyl)ethyl]-2-[-acetoxy-2-o-nor-l-pyrrolizonyl)acetamide eluted with diethyl chloride. After crystallization from ether, melting point 120-121℃
It had "Example 33 Ethyl (R/5)-2-(3-)riftylsilyloxy-2
-oxo-1-pyrrolizonyl-)acetate was obtained. (R/S)-2-(3-trimethyl7lioxy2-
After treatment of oxo-1-pyrrolinonyl)acetamide with 25% ammonium hydroxide solution and acidic hydrolysis W4, crude (R/5)-2-(3'-hydroqui-2-oquinol-l-pyrrolizonyl)acetamide is obtained. Uf'L7
t, chromatographed on cricavir (particle size α2-α5 M) and acetonitrile/methanol (1:
, with about 80-90% purity (R
/5)-2-(3-hydro-co-2-okine-1-pia
rizonyl)acetamide was able to be detected.

Implementation %l 34 (R/S)-cis-#-(2-(2,6-dimethyl-1
-piperidinyl)ethyl)-2-(3-acetoxy-2
-oxo-1-pyrrolizonyl)acetamide 0.3 A
It was stirred for 2 hours at room temperature in a saturated solution of ammonia in t-methanol. After evaporation of methanol, residue I
IIt? treated three times with toluene, in each case Kg evaporated A
Zeta. Disintegration in diethyl ether, melting point 129-13
(R/S)-cis-N-C2-<2.6-dimethyl-1-pipet7ynirnethyl)-2-(3-hydroxy-2-oxol-1-pyrrolizonyl)acetamide at 0°C was obtained.

Example 35 (α)(−)-(3-okino4.7.7-drimethyl-2-oxabicifa[2=2.1]hegt-1-yl)carnyl chloride [[α]soyi= -23”
; f) OOhoA' A, a=! O]0.86j'k
<it/S) dissolved in pyridine 1G- at O~+5°C
-cis-#-(2-(2,6-dimethyl-1-piperidinyl)ethyl)l! -(3-hydroyac-2-oxo-
1-pyrrolidinyl) acedoazedo1. The mixture was added in portions to Oy (7j), stirred at room temperature for 4 hours, and then pyridized and completely evaporated. The residue was treated three times with toluene, and the solution was evaporated in each case. Aluminum oxide (residue, neutral)
Glomatodalaphy was carried out on soy. Cis/V-”(2-(16-nomethyl-1)
-piperidinyl)ethyl)-2-/3-[(3-oxo-4,7,?-)sabicyclo(2,
2,1) Hebut-1-yl) carnioloxy]-2-oquinol-1-picridinyl/acetyl 7(d) contained a mixture of the theastereoisomers of this substance t1! Submitted to processing.

(e) Minutes of the two components*n, 24 in s-hexane
% tetrahydrofuran and 0.4% isopropyl amine/
-Commercial (Marck) pre-packed tt7H Hi/#-Licrosolp j-tTD1O while eluting with
In L Kara A (250x4m+, particle size I Gam), cis-N-(2-(2,6-nomethyl-1-piperidinyl)ethyl]-2-/34(3-oxo4.7.?
-trimethyl-2-oxabicyclo(2,2,1)hept-1-yl)-2-oxo-1-
What is produced by high-speed liquid atomography of a mixture of theaseroisomers of pyrrolizonyl/acedoide?

(e) (R) -cis-/l/42-(2,6-zo5
Methyl-21-piperidinyl)ethyl)-2-/3-[
(3-okino4.7.7-)rifthyl-2-1oxabicyclo[2,2,1)heguto1-(l)carponyloxy]-2-ochuso1-ni'mouth17 Nyl/ From acedoide, treat with aqueous ammonia to obtain (R)-cis-
N-[e-(2m s-zomethyl-l-piperidinyl]ethyl)-1-(3-hydro-2-okino-1-
pyrrolizonyl)acetamide could be obtained. Melting point 101~lo! °C (crystallized from ethyl acetate; [α)”,
;=+43°, [α]Jffis-+sg@, [α1f
fs = + 1 g 2°.

(acetonitrile, e=to-o).

(ψ C3)-cis-#-(2-(ffi, 6-zomethyl-l-biberisonyl)ethyl]-2-/3-[(3-
Okino 4.7.7-Dorimethyl-2-oxabicyclo (2,2,13 hegto 11 l carmenyl
From 2-oquinol-l-pyrrolizonyl/acetoand, treatment with aqueous ammonia gives (S)-cis-/l/-[1(2
,6-nomethyl-1-piperidinyl)ethyl)-2-(
3-Hydroxy-2-oxo-1-pyrrolizonyl)acedoide could be obtained. Melting point 101-103℃ (
crystallized from ethyl acetate); [α) IM=-44@, [α
)ll, --ss @ , [α] ] snow g, =
-tss@(acetonitrile, (1-LQ).

Example 36 <R/S)-cis-A/-(2-(2,6-dimethyl-
l-piperidinyl)ethyl]-2-(3-doxy-
2-oxo-1-pyrrolidinyl)acedoide 197j
Ft was dissolved in ethanol lO-. To this was added 14@mk of a 7.93N solution of hydrogen chloride in ethanol. The mixture was then evaporated and the residue dried under high vacuum.

(R/J)-cis-#-[2
-(2,6-dimethyl-l-piperidinyl)ethyl)-
1-(3-Hydroxy-2-oxo-1-pia 17zonyl)acetamide base salt was obtained. Microanalysis showed the following values: Empirical formula Ct @ H @ MaN, C), ・HCL; molecule f
i33: Calculation for 18g +11: C5 &96; H & 45%: Nl'j, 59
%0Actual value: 5198;#&57'10;NI! 40
%.

Example A As active substance (R/
S)-cis-#-42-(2,6-dimethyl-l-piperidinyl)ethyl)-2-(3-hydroxy-2-oxo-1-pyrrolisonyl)acedeamide could be used: Active substance 1q lactose
100TIq corn flour
1&5jll? Magnesium Stearin α5Ils1170q Finely ground active substance, ground lactose and a portion of corn starch were mixed. This mixture is sieved and then treated with corn starch paste.

The resulting mixture was granulated, dried and sieved. Mixed with sifted granular Kestearin, fk magnesium and compressed this mixture into *w170■ and excessive size T self weight 43-9゜

Claims (1)

[Claims] In the general formula L, %Ri represents hydrogen or t represents lower alkanoyl, and R
8 represents hydrogen or lower alkyl 1, and R1 is hydrogen, lower alkyl or the formula -(Cff*)%-Nlt
'R' represents an integer of %Fiz~4, and R4 and Rs each represent hydrogen or lower alkyl '9, or Rs and Rs together with a nitrogen atom Acid addition salts of pyrrolidine conductors and bases of pyrrolidine, represented by pyrrolidine, piperi Vy, biperazone or morpholine groups t'' optionally substituted with l@ or two lower alkyl groups. 2, 8'' represents hydrogen, R1 represents hydrogen, and R3 represents hydrogen, 2-(f/isofapylamino)ethyl or 2-(2,6-1/methyl-1-piperilinyl)ethyl - A compound according to claim 1, which represents a compound according to claim 1. The compound according to claim 111, which is 2-oxo-1-pyrroliV-nyl)acetamide. 4 (R/5)-2-(3-Hrcl-7-g-okino-1-pyrrolidinyl)acetamide The compound according to claim 1.
The compound according to claim 1, which is Kiku 2-okine-1-pyrrolidinyl)acetamide. a, (S)-cis-A/-[2-(2,6-zomethyl-l-piperiVnyl)ethyl-2-(3-hydroxy-2-oxo-1-pyrrolizonyl)acetamide; A compound according to item 1. ? , (A')-2-(3-41"oxy-2-oxo-1-pyrroliVyl)acetamide. IL (5')-2-(3 -nidokuki/-2-,t
The compound according to claim 1, which is xy-1-pyrrolisonyl)acetamide. The compound according to claim 1, which is (R/S)-#-[2-(zoisoglobylamino)ethyl)-2-(3-hydroxy-2-oquinopyrrolizonyl)acetamide. . 10. In the general formula, %R3 represents hydrogen, fc represents lower alkanoyl, and R11 represents hydrogen and lower alkanoyl, which can be easily cleaved by ammonia! Carmenic acid represented by the group t-. 1t In the general formula, R3 represents hydrogen or a lower alkyl group, R1 represents hydrogen, a lower alkyl group, or a group of the formula (CH*)-NE'R'', where 5 represents an integer from 2 to 4. , and R4 and R1 each represent hydrogen or lower alkyl, or 86 and R1 together with the nitrogen atom optionally represent pyrrolizo/, which may optionally be substituted with one or two lower alkyl groups. Compound 0 12 as a pharmaceutically active substance Claim 1-
A compound according to any one of Item 9. 1 & Special IFF as an active substance antagonizing brain dysfunction or improving intellectual performance Compounds according to any of claims 1 to 9. Table 1 (α) General formula %Formula % Formula % where R3 has the meaning described in claim 1. death,
and RII represents hydrogen or lower alkanoyl' or, when Hs in formula IvC represents hydrogen'lk, represents another group that can be cleaved by ammonia, carginic acid or its reactive function Should it be reacted with a derivative? (6) In the general formula, R3 and Ha have the meanings described in claim 1, the compound of (6) is acylated with a reagent that imparts a lower alkanoyl group, or (6) in the general formula, R1 and R1 have the meanings described in the first claim, and Z is 1113! cleavage of the holding group represented by Z from the compound representing I;
and () If necessary, the resulting norastereoisomers are separated into the corresponding race(-), and/or (-) if necessary, R1 represents hydrogen and/or R1 is a base. The racemic form of the compound of the general formula I, which is obtained by n representing the sex 4, is resolved into its optical antipodes, and /'fc is ψ If necessary, the compound of the general formula I, which is basic, is A method for producing the compound according to any one of claims 1 to 9, which is converted into a pharmaceutically acceptable acid addition salt. 1!L RH is hydrogen or 7t is lower alkanoyl The method according to claim 14. A drug containing the compound according to any one of claims 1 to 9. 17. Claims 1 to 9 A drug that antagonizes brain insufficiency or improves intellectual ability, containing a compound according to any one of the following. 1B - Any of claims 1 to 9 for suppressing or preventing disease or improving health. Use of the compound described in any one of Items 1 to 9. 1N Use of the compound described in any of Items 1 to 9 for suppressing or preventing cerebral insufficiency or improving intellectual ability. 2. Claim 14: A compound according to any one of claims 1 to 9 prepared by a method according to claim 15 or an apparently chemically equivalent method thereof.