3-benzylidene-1-carbamoyl-2-pyrrolidone compounds useful as antiinflammatory agents

The present invention relates to novel 3-benzylidene-1-carbamoyl-2-pyrroridone analogues having advantage anti-inflammatory activities, which is represented by the formula: ##STR1## wherein R.sup.1 and R.sup.2 each is independently hydrogen, alkyl, alkoxy, or halogen; R.sup.3 is hydrogen or acyl; R.sup.4 is hydrogen, alkyl, hydroxy, alkoxy, cyano, or halogen; R.sup.5 and R.sup.6 each is independently hydrogen, alkyl, aryl, aralkyl, heterocyclic group, substituted or unsubstituted amino, or OR.sup.7 wherein R.sup.7 is hydrogen, alkyl, aryl, acyl, or aralkyl, or taken together with the adjacent nitrogen atom may form heterocyclic group which may contain N, O, and/or S, and X and Y each is independently O, S, substituted or unsubstituted imino, or substituted or unsubstituted methylene. In more detail, the present invention provides an anti-inflammatory agent which is useful for the treatment of chronic inflammation and has little side effect, e.g., stomach disease.

FIELD OF THE INVENTION 
The present invention relates to novel 
3-benzylidene-1-carbamoyl-2-pyrrolidone analogues which have inhibitory 
activities against the production of leukotriene B.sub.4 (LTB.sub.4) and 
that of interleukin-1 (IL-1). In more detail, these derivatives are able 
to be applied to safe medicaments which show potent anti-inflammatory 
effects to acute and chronic inflammation and hardly cause stomach 
disease. 
BACKGROUND OF THE INVENTION 
Prior anti-inflammatory agents of non-steroid type are effective to the 
improvement in the early stages of rheumatism and acute inflammation, 
however, have some defects of being no effective to progressed rheumatic 
diseases such as osteonecrosis, the improvement in chronic rheumatic 
diseases, or the treatment of arthrosteitis etc., and of having potent 
activities to induce gastric ulcer caused by the inhibition of the 
production of prostaglandin E.sub.2 (PGE.sub.2). 
Recently it has been revealed that leukotriene (LT), esp. LTB.sub.4 etc., 
which is a metabolite produced via the metabolism of arachidonic acid 
caused by 5-lipoxygenase, is an important mediator in inflammation 
reaction. Furthermore, it has been suggested that the cause of 
inflammation relates to IL-1 which is a kind of cytokines and that also 
chronic rheumatism is much influenced by cytokines such as IL-1. 
In view of circumstances above, attentions have been paid to compounds 
having inhibitory activities against the production of LTB.sub.4 and IL-1, 
as a new type of anti-inflammatory agent. These compounds are much useful 
than known non-steroidal anti-inflammatories, in respect of that they are 
expected to have efficacy not only to acute inflammation but also to 
chronic inflammation, e.g., chronic arthrorheumatism etc. 
With an intention to develop such anti-inflammatory agents as described 
above, a wide variety of compounds are disclosed in specifications of 
Kokai 58-79944, Kokai 61-257967, Kokai 62-42977, Kokai 1-305028, Kokai 
2-4729, Kokai 2-256645, Kokai 2-270865, and Kokai 1-503782. 
As stated above, it has been desired to develop anti-inflammatory agents 
capable of inhibiting the production of mediators relating to inflammation 
such as PGE.sub.2, LTB.sub.4, and IL-1, however, such an anti-inflammatory 
agent as being useful for treating chronic inflammation and having little 
side effect, e.g., stomach disease, has not been developed yet. 
DISCLOSURE OF THE INVENTION 
The present inventors have tried to find that the compounds of the formula 
(I): 
##STR2## 
wherein R.sup.1 and R.sup.2 each is independently hydrogen, alkyl, alkoxy, 
or halogen; R.sup.3 is hydrogen or acyl; R.sup.4 is hydrogen, alkyl, 
hydroxy, alkoxy, cyano, or halogen; R.sup.5 and R.sup.6 each is 
independently hydrogen, alkyl, aryl, aralkyl, heterocyclic group, 
substituted or unsubstituted amino, or OR.sup.7 wherein R.sup.7 is 
hydrogen, alkyl, aryl, acyl, or aralkyl, or taken together with the 
adjacent nitrogen atom may form heterocyclic group which may contain N, O, 
and/or S, and X and Y each is independently O, S, substituted or 
unsubstituted imino, or substituted or unsubstituted methylene, give 
advantageous anti-inflammatory activities applicable to an agent for 
treating chronic inflammation, and that side effects thereof, e.g., 
stomach disease, are extremely weaker than prior anti-inflammatory agents, 
whereby they have completed the present invention. The present invention 
is characterized by its potent inhibitory activities against the 
production of IL-1. 
In the present specification, "alkyl" means straight or branched C.sub.1 
-C.sub.10 alkyl, and preferred is straight or branched C.sub.1 -C.sub.6 
alkyl, including, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, 
i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, s-pentyl, 
t-pentyl, n-hexyl, neohexyl, i-hexyl, s-hexyl, t-hexyl, and the like. 
As alkyl meant in the definition for R.sup.1 and R.sup.2, most preferred is 
branched C.sub.3 or C.sub.4 alkyl, i.e., i-propyl or t-butyl. As alkyl 
meant in the definition for R.sup.4, especially preferred is C.sub.1 or 
C.sub.2 alkyl, i.e., methyl or ethyl. As alkyl meant in the definition for 
R.sup.5 and R.sup.6, especially preferred is straight or branched C.sub.1 
-C.sub.3 alkyl, e.g., methyl, ethyl, n-propyl, and i-propyl. 
"Alkoxy" means the group derived from "alkyl" defined above, and preferred 
is C.sub.1 or C.sub.2 alkoxy, i.e., methoxy or ethoxy. 
"Halogen" means fluorine, chlorine, bromine, and iodine. 
"Acyl" means aromatic or aliphatic acyl. Aromatic acyl includes, for 
example, benzoyl, 4-hydroxybenzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl, 
4-nitrobenzoyl, 4-tert-butylbenzoyl, benzenesulfonyl, toluenesulfonyl etc. 
Aliphatic acyl includes, for example, formyl, acetyl, propionyl, butyryl, 
and valeryl. Preferred is aliphatic acyl, esp. acetyl. 
"Heterocyclic group" meant in the definition for R.sup.5 and R.sup.6 means 
5 to 6 membered heterocyclic group containing, one or more hetero atoms 
selected from the group consisting of oxygen, sulfur, and nitrogen as 
ring-forming atom, and which includes for example, pyrrolyl, imidazolyl, 
pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 
1,2,4-triazinyl, 1,2,3-triazinyl, isoxazolyl, oxazolyl, 1,2,3-oxadiazolyl, 
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, isothiazolyl, 
thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 
1,3,4-thiadiazolyl, tetrazolyl, furyl, thienyl, pyrrolidinyl, piperidyl, 
morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, and thiopyranyl, etc, 
and most preferred is morpholinyl or thiomorpholinyl. 
"Heterocyclic group" formed by R.sup.5 and R.sup.6 taken together means 5 
to 6 membered heterocyclic group which may further contain, one or more 
hetero atoms selected from the group consisting of oxygen, sulfur, and 
nitrogen as ring-forming atom except for the nitrogen, including, for 
example, pyrrolyl, imidazolyl, pyrazolyl, 1,3,5-triazinyl, 
1,2,4-triazinyl, 1,2,3-triazinyl, pyrrolidinyl, piperidyl, or morpholinyl, 
and thiomorpholinyl etc., and most preferred is morpholinyl or 
thiomorpholinyl. 
The substituent group meant in the term "substituted or unsubstituted 
amino" includes alkyl, hydroxy, alkoxy, acyl, and alkoxycarbonyl, where 
the said alkyl, alkoxy, and acyl have the same meaning as those described 
above, and preferred is methyl, ethyl, methoxy, ethoxy, acetyl, or 
benzoyl. Alkoxycarbonyl includes, for example, methoxycarbonyl, 
ethoxycarbonyl, tert-butoxycarbonyl, and benzyloxycarbonyl, and most 
preferred is tert-butoxycarbonyl. 
"Aralkyl" means a group of alkyl described above which is substituted by 
aryl at any position, with a proviso that aryl means C.sub.6 -C.sub.12 
aromatic ring, including, for example, phenyl, tolyl, xylyl, biphenyl, and 
naphthyl etc. The aralkyl includes, for example, benzyl, phenethyl, and 
phenylpropyl etc., and most preferred is benzyl. 
The substituent meant in the term "imino which is substituted or not" 
includes alkyl and alkoxy described above, and preferred is methyl, ethyl, 
methoxy, or ethoxy. 
The substituent meant in the term "methylene which is substituted or not" 
includes alkyl, alkoxy, hydroxy, and halogen each of which is described 
above. The said alkyl may be substituted at its terminal carbon by hydroxy 
or substituted or unsubstituted carboxy, with a proviso that the 
substituted carboxy means esterified carboxy or carboxy substituted by 
alkali metal or alkaline earth metal. Esterified carboxy means one 
described above, and preferred is methoxycarbonyl or ethoxycarbonyl. 
Alkali metal means lithium, sodium, potassium, rubidium, and cesium. 
Alkaline earth metal means beryllium, magnesium, calcium, and strontium. 
Preferred is sodium, potassium, or calcium. 
The present invention includes two kinds of isomers which are 
differentiable by the formation of its double bond, i.e., E-isomer or 
Z-isomer, or the mixture thereof. 
The representative production methods of the compounds (I) of the present 
invention are shown below. 
PRODUCTION METHOD 1 
The compounds (I) of the present invention are prepared by reacting the 
compound of the formula (II): 
##STR3## 
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, X, and Y are the same as 
defined above, with a carbamoyl reagent of the compound (III): 
EQU R.sup.8 --CO--NR.sup.5 'R.sup.6 ' (III) 
wherein R.sup.5 ' and R.sup.6 ' each is independently hydrogen, alkyl, 
heterocyclic group substituted or unsubstituted amino which may be 
protected, OR.sup.7 ' (wherein R.sup.7 ' is hydrogen, alkyl, acyl, or 
aralkyl, each of which may be protected), or taken together with the 
adjacent nitrogen atom may form heterocyclic group which may contain N, O, 
and/or S; R.sup.8 is releasing group, if necessary, followed by subjecting 
to deprotection reaction. 
It is preferable to carry out the present reaction under basic conditions. 
In the case that such a base is sodium ethoxide, sodium tert-butoxide, 
sodium hydride, sodium amide, lithium diisopropylamide, lithium 
bis(trimethylsilyl)amide, or n-butyllithium etc., the reaction is able to 
be carried out at room temperature in an aprotic polar solvent including, 
for example, tetrahydrofuran, dimethylformamide, dimethylacetamide, 
dimethyl sulfoxide, N-methylpyrrolidone, and hexamethylphosphoramide, etc. 
In the case that such a base is amines including, for example, pyridine, 
triethylamine etc., it is preferable to carry out the reaction under 
heating, if necessary, in the inert solvents including, for example, 
aromatic hydrocarbons (e.g., toluene, benzene, and chlorobenzene etc.), 
chlorinated hydrocarbons (e.g., chloroform and dichloromethane etc.), 
ketones (acetone), and ethers (tetrahydrofran). 
The amino protecting group meant in the definition for R.sup.5 ' and 
R.sup.6 ' means that usually used as amino protecting group, which 
includes, for example, trifluoroacetyl, benzyloxycarbonyl, 
tert-butoxycarbonyl, and triphenylmethyl etc. 
For the hydroxy-protecting group meant in the definition for OR.sup.7 ', 
any one stable under basic conditions can be used, which includes, for 
example, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, 
tetrahydropyranyl, methoxymethyl, methylthiomethyl, 2-methoxyethoxymethyl, 
1-ethoxyethyl, benzyl, and methoxybenzyl etc. 
The elimination group in the definition for R.sup.8 means phenyloxy which 
may be substituted by electron-withdrawing group, and which includes, for 
example, phenoxy, 4-nitrophenoxy, 4-nitrosophenoxy, 4-chlorophenoxy, 
4-acetyphenoxy, and 4-trifluoromethylphenoxy etc. 
Another production methods for some of the compounds (I) of the present 
invention are as follows: 
that the compounds (I) wherein R.sup.5 and R.sup.6 are hydrogen at the same 
time can be prepared by adding isocyanate (e.g., chlorosulfonyl 
isocyanate, trichloroacetyl isocyanate, and tert-butyl isocyanate etc.) to 
the compound (II), followed by treating with acid, and 
that the compounds (I) wherein either R.sup.5 or R.sup.6 is not hydrogen 
can be prepared by adding isocyanate which is represented, by the formula: 
O.dbd.C.dbd.N--R.sup.5 ' (wherein R.sup.5 ' is the same as defined above) 
for example methyl isocyanate, ethyl isocyanate, and 
dimethyl-tert-butylsilyloxyisocyanate etc., if necessary, followed by 
deprotection. 
PRODUCTION METHOD 2 
The compound (I) of the present invention are prepared by reacting the 
compound of the formula (IV): 
##STR4## 
wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 each is the same as defined 
above, with Wittig reagent of the formula (V): 
##STR5## 
wherein Ph is phenyl; X, Y, R.sup.5 ', and R.sup.6 ' are the same as 
defined above, under the condition for Wittig reaction. 
Wittig reagent (V) is prepared by reacting the compound of the formula 
(VI): 
##STR6## 
wherein Hal is halogen, X and Y each is the same as defined above, with 
Carbamoyl reagent (III) described above, to obtain the compound of the 
formula (VII): 
##STR7## 
wherein Hal, X, Y, R.sup.5 ', and R.sup.6 ' each is the same as defined 
above, followed by treating, accoding to the usual methods, with 
triphenylphosphine and base. 
Furthermore, the compounds (I) of the present invention are prepared also 
by condensing the compound (IV), under the condition for Reformatsky 
reaction, with organic zinc compound of the formula (VIII): 
##STR8## 
wherein Hal, X, Y, R.sup.5 ', and R.sup.6 ' each is the same as defined 
above, which is prepared by the reaction of the compound (VII) with 
metallic Zinc. 
The compounds of the present invention are effective for hyperthermia, 
analgesic, cold disease, acute and chronic tracheitis, inflammation caused 
by trauma or operation, arthritis, rheumatism, neuralgia, arthralgia, 
metabolic osteopathy, and the like, because of having advantageous 
anti-inflammatory effects besides that its side-effects, e.g., stomach 
disease, are very weak. The compounds of the present invention are 
especially useful for treating diseases necessary to long-term 
administration which include, chronic rheumatoid arthritis, 
osteoarthritis, and osteoporosis. 
The compounds (I) of the present invention may be formulated into the 
composition for typical use such as injection, oral, and anal 
administration etc., together with various kinds of carriers. Though the 
dosage is not regulated because it varies depending on the kind of 
disease, the degree of disease, the route of administration, the age and 
weight of a patient etc., it is usually in the range from 10 mg to 500 mg, 
preferably from 50 mg to 150 mg, per day for an adult.

The present invention is explained in more detail by the following Examples 
and Experiments, however, which will not limit the scope of the present 
invention. 
EXAMPLE 
EXAMPLE 1 
(1) The Preparation of N-carbamoyl-3-bromopyrrolidin-2-one 
A solution of 30 g of 2,4-dibromobutyryl chloride (J. Med. Chem., p1995, 
30. 1987) and 13.63 g of urea dissolved into 150 ml of benzene was heated 
at 90.degree. C. with stirring for 3 hours. The reaction mixture was 
cooled to room temperature, then a very excessive amount of ethyl acetate 
was added thereto. The layer of ethyl acetate was washed with an aqueous 
solution of sodium bicarbonate and saturated brine, then the resulting 
solution was dried over magnesium sulfate and evaporated. The obtained 
residue (28 g) was dissolved into 30 ml of tetrahydrofuran (THF) and 
cooled. To this mixture was added 4.7 g of NaH (55% in mineral oil) bit by 
bit, then the mixture was stirred at room temperature for 2 hours. The 
reaction mixture was evaporated to make the amount of the solution about 
50 ml, then which was poured into ethyl acetate. The layer of ethyl 
acetate was washed with water and saturated brine, dried over magnesium 
sulfate, and evaporated. The obtained residue was washed well with 
n-hexane, whereby 15.7 g of the objective compound was obtained in 66% 
yield. 
Mp. 127.5.degree.-129.degree. C. 
IR(KBr).nu.max cm.sup.-1 : 1726, 1700(CO). 
NMR(CDCl.sub.3) .delta. ppm: 2.19-2.41(1H,m), 2.52.-2.71(1H,m), 
3.80-4.05(2H,m), 4.52-4.59(1H,m), 5.2-5.8(1H,m), 7.8-8.3(1H,m). 
(2) The Preparation of 
N-carbamoyl-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-one 
(Ia-1) 
A solution of 2.0 g of N-carbamoyl-3-bromopyrrolidin-2-one (9.7 mmole) and 
2.78 g of triphenylphosphine (10.6 mmole) in 30 ml of THF was stirred 
under heating at 70.degree. C. for 20 hours. The reaction mixture was 
cooled down to room temperature, then the precipitated crystals were 
collected. The obtained Wittig salt (1.34 g, 2.86 mmole), 
3,5-di-tert-butyl-4-hydroxybenzaldehyde (670 mg, 2.86 mmole), and 
triethylamine (580 mg, 5.73 mmole) were dissolved into 60 ml of ethanol, 
and the mixture was stirred under heating at 70.degree. C. for 2 hours. 
The reaction mixture was evaporated, then the residue was dissolved into 
ethyl acetate, which was washed with water and saturated brine, dried over 
magnesium sulfate, and evaporated. The residue was separated by using 
silica gel chromatography (toluene:ethyl acetate=3:1) and recrystallized 
from dichloromethane-n-hexane, whereby 600 mg of the objective compound 
was obtained in 17.1% yield. The physical constants are described on Table 
1. 
EXAMPLE 2 
The Preparation of 
N-(N-methylcarbamoyl)-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin 
-2-one (Ia-2) 
Methyl isocyanate (5.0 ml) was added to 
3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-one (277 mg, 0.75 
mmole) (J. Med. Chem., p1995, 30, 1987) and the mixture was heated under 
reflux for 15 hours. The reaction mixture was evaporated under reduced 
pressure to obtain a residue, which was purified by using silica gel 
chromatography (n-hexane:ethyl acetate=4:1) and recrystallized from 
dichloromethane-ether, whereby 189 mg of the objective compound was 
obtained as white crystal in 70.3% yield. The physical constants are 
described on Table 1. 
EXAMPLE 3 
N-(N,N-dimethylcarbamoyl)-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrroli 
din-2-one (Ia-3) 
To a solution of 301 mg of 
3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidine-2-one (1.0 mmole) 
dissolved into 5 ml of DMF, NaH (60% in mineral oil, 85 mg, 2.1 mmole) was 
added under ice-cooling. The resulting mixture was stirred at room 
temperature for 30 min, then the solution was cooled again. 
N,N-Dimethylphenylcarbamate (282 mg, 1.71 mmole) which was prepared 
according to the method described in J. Org. Chem., p660, 21, 1956was 
added thereto, then the resulting solution was stirred at room temperature 
for 3 hours. The reaction mixture was poured into ethyl acetate, which was 
washed with 1N-HCl, water, and saturated brine, dried over magnesium 
sulfate, and evaporated. The obtained residue was separated by using 
silica gel chromatography (toluene:ethyl acetate=2:1) and recrystallized 
from ether-n-hexane, whereby 190 mg of the objective compound was obtained 
in 51% yield. The physical constants are described on Table 1. 
EXAMPLE 4 
N-(N-hydroxycarbamoyl)-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin 
-2-one (Ia-4) 
3-(3,5-Di-tert-butyl-4-hydroxybenzylidene)pyrrolidine-2-one (301 mg, 1.0 
mmole) and N-hydroxyphenylcarbamate-0-tert-butyldimethylsilylether (401 
mg, 15 mmole) which was prepared according to the method described in J. 
Org. Chem., p660, 21, 1956, were dissolved into 5 ml of pyridine, and the 
solution was heated under reflux for 3 hours. The reaction mixture was 
poured into ethyl acetate, which was washed with 0.1N--HCl, water, and 
saturated brine, dried over magnesium sulfate, and evaporated. The 
obtained residue was dissolved into 3 ml of THF, to which a solution of 
1M/L tetra-n-butylammonium fluoride dissolved into 1.1 ml of THF was 
added. The resulting solution was stirred for 10 min. and poured into 
ethyl actate, which was washed with 1N--HCl, water, and saturated brine, 
dried over magnesium sulfate, and evaporated. The obtained residue was 
separated by using silica gel chromatography (toluene:ethyl acetate=1:1) 
and recrystallized from dichloromethane-n-hexane, whereby 205 mg of the 
objective compound was obtained in 57% yield. The physical constants are 
described on Table 1. 
EXAMPLE 5 
N-(N-methoxycarbamoyl)-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin 
-2-one (Ia-5) 
3-(3,5-Di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-one (500 mg, 1.66 
mmole) and N-methoxyphenylcarbamate (554 mg, 3.32 mmole) which was 
prepared according to the method described in J. Org. Chem., 21, p660, 
1956, were dissolved into 8 ml of pyridine, then the solution was heated 
under reflux for 12 hours. The reaction solution was evaporated and the 
residue was dissolved into ethyl acetate, which was washed with 0.1N-HCl, 
water and saturated brine, dried over magnesium sulfate, and evaporated. 
The obtained residue was separated by using silica gel chromatography 
(toluene:ethyl acetate=10:1) and recrystallized from 
dichloromethane-n-hexane, whereby 450 mg of the objective compound was 
obtained in 72% yield. The physical constants are described on Table 1. 
EXAMPLE 6 
N-(N-hydroxy-N-methylcarbamoyl)-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)p 
yrrolidin-2-one (Ia-6) 
To a solution of 3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-one 
(500 mg, 1.66 mmole) dissolved into 5 ml of DMF, NaH (60% in mineral oil, 
200 mg, 5 mmole) was added under ice-cooling. The mixture was stirred at 
room temperature for 30 min. and cooled again, then 
N-hydroxy-N-methylphenylcarbamate-0-tert-butylsilylether (550 mg, 1.96 
mmol) which was prepared according to the method described in J. Org. 
Chem., 21, p660, 1956 was added thereto, and the resulting mixture was 
stirred at room temperature for 2 hours. The reaction mixture was poured 
into ethyl acetate, which was washed with 0.1N--HCl, water, and saturated 
brine, dried over magnesium sulfate, and evaporated. The obtained residue 
was separated by using silica gel chromatography (toluene:ethyl 
acetate=50:1) and recrystallized from dichloromethane-n-hexane, whereby 
380 mg of the objective compound was obtained in 61% yield. The physical 
constants are described on Table 1. 
EXAMPLE 7 
N-carbamoyl-5-(3,5-di-tert-butyl-4-hydroxy-benzylidene)thiazolidin-4-one 
(Ib-1) 
5-(3,5-Di-tert-butyl-4-hydroxybenzylidene)thiazolidin-4-one (479 mg, 1.5 
mmole) described in Kokai 62-42977 was suspended in dried toluene (3 ml), 
to which chlorosulfonyl isocyanate (144 .mu.l; 1.65 mmole) was added with 
stirring under nitrogen atmosphere, to obtain a transparent solution of 
orange color. Furthermore, the solution was heated at 90.degree. C. for 10 
min., from which toluene was evaporated under reduced pressure, then 3.6 
ml of mixed solution of acetic acid and water (2:1) was added thereto. The 
resulting mixture was heated at 90.degree. C. for 10 min. and poured into 
ice-water, which was subjected to extraction with dichloromethane. The 
obtained organic layer was washed with water and saturated brine, dried 
over magnesium sulfate, and evaporated. The obtained residue was separated 
by using silica gel chromatography (chloroform:acetone=20:1), whereby 377 
mg of the objective compound was obtained, which was recrystallized from 
ethanol-ether in 53% yield. The physical constants are described on Table 
1. 
EXAMPLE 8 
N-(N-hydroxycarbamoyl)-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)thiazolidi 
n-4-one (Ib-2) 
To a solution of 
5-(3,5-di-tert-butyl-4-hydroxybenzylidene)thiazolidin-4-one (319 mg, 1 
mmole) dissolved into dried pyridine (5 ml), 
N-hydroxyphenylcarbamate-0-tert-butyldimethylsilylether (419 mg, 1.57 
mmole) was added under nitrogen atmosphere with stirring, and the mixture 
was heated under reflux for 5.5 hours, then pyridine was evaporated under 
reduced pressure. An aqueous solution containing 1N hydrochloric acid was 
added to the obtained residue, which was extracted with ethyl acetate, 
washed with 1N hydrochloric acid and saturated brine, dried over sodium 
sulfate, and evaporated. The obtained residue was dissolved into 3 ml of 
THF, to which a solution of 1M/L of tetra-n-butylammonium fluoride 
dissolved into 1.1 ml of THF was added under ice-cooling. The mixture was 
stirred for 10 min. and poured into ice-water, which was subjected to 
extraction with dichloromethane. The organic layer was washed with water, 
dried over sodium sulfate, and evaporated. The obtained residue was 
separated by using silica gel chromatography (toluene:ethyl acetate=1:1), 
whereby 149 mg of the objective compound and 157 mg of the material were 
recovered, and the former was recrystallized from ether-n-hexane. Yield 
36%. The physical constants are described on Table 1. 
EXAMPLE 9 
N-(N-hydroxy-N-methylcarbamoyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)th 
iazolidin-4-one (Ib-3) 
To a solution of 
5-(3,5-di-tert-butyl-4-hydroxybenzylidene)thiazolidin-4-one (319 mg, 1 
mmole) dissolved into dried DMF (3 ml), NaH (60% in mineral oil, 120 mg, 
300 mmole) was added under nitrogen atmosphere with stirring under 
ice-cooling. The resulting mixture was warmed to room temperature and 
stirred for 30 min., then 
N-hydroxy-N-methylphenylcarbamate-O-tert-butyldimethylsilylether (422 mg, 
1.5 mmole) was added thereto under ice-cooling with stirring. The mixture 
was stirred at room temperature for 18 hours, then which was poured into 
ice-water containing 1N hydrochloric acid, extracted with ethyl acetate, 
washed with water and saturated brine, dried over sodium sulfate, and 
evaporated. The obtained residue was separated by using silica gel 
chromatography (toluene:ethyl acetate=1:1), whereby 195 mg of the 
objective compound was obtained, which was recrystallized from 
ether-n-hexane in 29% yield. The physical constants are described on Table 
1. 
EXAMPLE 10 
N-(N-methoxy-N-methylcarbamoyl-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)py 
rrolidin-2-one (Ia-7) 
To a solution of 3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-one 
(301 mg, 1 mmole) dissolved into DMF, NaH (60% in mineral oil, 90 mg, 2.25 
mmole) was added under ice-cooling. The resulting mixture was stirred at 
room temperature for 30 min. and cooled again, then 
N-methoxy-N-methylphenylcarbamate (200 mg, 1.1 mmole) was added thereto 
and the mixture was stirred at room temperature for 1 hour. The reaction 
mixture was poured into ethyl acetate, which was washed with an aqueous 
solution of 0.1N hydrochloric acid, water, and saturated brine, dried over 
magnesium sulfate, and evaporated. The obtained residue was separated by 
using silica gel chromatography (toluene:ethyl acetate=20:1), 
recrystallized from dichloromethane-n-hexane, whereby 218 mg of the 
objective compound was obtained in 56% yield. The physical constants are 
described on Table 1. 
EXAMPLE 11 
N-(N-ethyl-N-hydroxycarbamoyl-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyr 
rolidin-2-one (Ia-8) 
3-(3,5-Di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-one (301 mg, 1.0 
mmole) was dissolved into THF (5 ml), which was cooled in the acetone-Dry 
Ice bath, and a solution of 1.0 M/L lithium-bis(trimethylsilyl)amide 
dissolved into THF (2.4 ml) was added thereto. Furthermore, 
N-ethyl-N-hydroxyphenylcarbamate-O-tert-butyldimethylsilylether (443 mg, 
1.5 mmole), which was prepared according to the method described in J. 
Org. Chem., 21, P660, 1956, was added thereto, then the mixture was 
stirred at room temperature for 1 hour. The reaction mixture was poured 
into ethyl acetate, washed with an aqueous solution of 0.1N hydrochloric 
acid, water, and saturated brine, dried over magnesium sulfate, and 
evaporated. The obtained residue was dissolved into acetonitrile (4 ml), 
to which a solution of 10 ml of hydrogen fluoride-acetonitrile (an aq. 46% 
HF:acetonitrile=1:19) was added and the mixture was stirred for 10 min. 
The reaction mixture was evaporated, then the obtained residue was 
dissolved into ethyl acetate, which was washed with a saturated aq. sodium 
bicarbonate, water, and saturated brine, dried over magnesium sulfate, and 
evaporated. The obtained residue was separated by using silica gel 
chromatography (n-hexane:ethyl acetate=5:1) and recrystallized from 
dichloromethane-n-hexane, whereby 353 mg of the objective compound was 
obtained in 92% yield. The physical constants are described on Table 1. 
EXAMPLE 12 
N-(N-isopropyl-N-hydroxycarbamoyl)-3-(3,5-di-tert-butyl-4-hydroxybenzyliden 
e)pyrrolidin-2-one (Ia-9) 
3-(3,5-Di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-one (301 mg, 1.0 
mmole) was dissolved into THF (10 ml), which was cooled in the acetone-Dry 
Ice bath, and a solution of 1.0 M/L lithium-bis(trimethylsilyl)amide 
dissolved into THF (2.4 ml) was added thereto. Furthermore, 
N-hydroxy-N-isopropylphenylcarbamate-O-tert-butyldimethylsilylether (402 
mg, 1.3 mmole), which was prepared according to the method described in J. 
Org. Chem., 21, P660, 1956, was added thereto, then the resulting mixture 
was stirred at room temperature for 3 hours. The reaction mixture was 
poured into ethyl acetate, washed with aq. 0.1N hydrochloric acid, water, 
and saturated brine, dried over magnesium sulfate, and evaporated. The 
obtained residue was dissolved into acetonitrile (4 ml), to which a 
solution of 10 ml of hydrogen fluoride-acetonitrile (aq. 46% 
HF:acetonitrile=1:19) was added and the mixture was stirred for 10 min. 
The reaction mixture was evaporated, then the obtained residue was 
dissolved into ethyl acetate, which was washed with aq. saturated sodium 
bicarbonate, water, and saturated brine, dried over magnesium sulfate, and 
evaporated. The obtained residue was separated by using silica gel 
chromatography (n-hexane:ethylacetate=5:1), and recrystallized from 
dichloromethane-n-hexane, whereby 102 mg of the objective compound was 
obtained in 25.4% yield. The physical constants are described on Table 1. 
EXAMPLE 13 
(1) The Preparation of 
5-(3,5-di-tert-butyl-4-hydroxybenzylidene)oxazolidin-4-one 
5-(3,5-Di-tert-butyl-4-hydroxybenzylidene)-2-oxazolidin-4-one (4.64 g, 13.9 
mmole), which was prepared according to the method described in Kokai 
2-62864, was dissolved into dried ethanol (140 ml), to which Raney nickel 
(about 46 g) was added, then the resulting mixture was refluxed under 
nitrogen atmosphere with stirring for 1.5 hours. Raney nickel was removed 
by filtration, and the residue was washed with dichloromethane, then the 
solvent was evaporated. The obtained residue was separated by using silica 
gel chromatography (toluene:ethyl acetate=1:1), and crystallized from 
dichloromethane-n-hexane, whereby the objective compound was obtained. 
Mp. 213.degree.-217.degree. C. 
Elementary Analysis (%) for C.sub.18 H.sub.25 NO.sub.3 
Calcd.: C:71.25, H:8.31, N:4.622. 
Found: C:70.73, H:8.21, N:4.58. 
IR(KBr) .nu. max cm.sup.-1 : 3616, 3382, 3208, 1696. 
NMR(CDCl.sub.3) .delta. ppm: 1.47(s,18H), 5.37(3,1H), 5.52(s,2H), 
6.25(s,1H), 7.55 (s,2H), 8.05(b.s,1H). 
(2) N-carbamoyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)oxazolidin-4-one 
(Ic-1) 
To a suspension of 
5-(3,5-di-tert-butyl-4-hydroxybenzylidene)oxazolidin-4-one (100 mg, 0.33 
mmole) suspended in dried toluene (0.5 ml), 32 .mu.l of chlorosulfonyl 
isocyanate (0.363 mmole) was added under nitrogen atmosphere with stirring 
and the mixture was dissolved for 2 min. After the solution colored to 
brown, it was heated at 90.degree. C. for 10 min. and toluene was 
evaporated under reduced pressure. A mixed solution (0.8 ml) of acetic 
acid and water (2:1) was added thereto, and the mixture was heated at 
90.degree. C. under nitrogen atmosphere for 10 min. The resulting mixture 
was poured into ice-water, which was subjected to extraction with 
dichloromethane, then the organic layer was washed with water, dried over 
sodium sulfate, and evaporated. The obtained residue was separated by 
using silica gel chromatography (toluene:ethyl acetate=1:1), and 
recrystallized from ether-n-hexane, whereby 73 mg of the objective 
compound was obtained in 64% yield. The physical constants are described 
on Table 1. 
EXAMPLE 14 
The Preparation of 
N-(N-hydroxycarbamoyl)-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)oxazolidi 
n-4-one (Ic-2) 
To a solution of 5-(3,5-di-tert-butyl-4-hydroxybenzylidene)oxazolidin-4-one 
(100 mg, 0.33 mmole) dissolved into dried pyridine (1.7 ml), 
N-hydroxyphenylcarbamate-O-tert-butyldimethylsilylether (0.5 mmole) was 
added under nitrogen atmosphere with stirring, and the mixture was heated 
under reflux for 7 hours, then pyridine was evaporated under reduced 
pressure. Ice-water containing 2N--HCl was added to the obtained residue, 
which was subjected to extraction with ethyl acetate, then the organic 
layer was washed with water, dried over sodium sulfate, and evaporated. 
The obtained residue was dissolved into THF (1.5 ml), to which a solution 
of 1M tetra-n-butylammonium fluoride dissolved into THF (500 .mu.l, 0.5 
mmole) was added under ice-cooling with stirring. The mixture was stirred 
for 10 min. and poured into ice-water, which was subjected to extraction 
with dichloromethane. The organic layer was washed with water, dried over 
sodium sulfate, and evaporated. The obtained residue was separated by 
using silica gel chromatography (toluene:ethyl acetate=1:1), and 
recrystallized from dichloromethane-n-hexane, whereby 19 mg of the 
objective compound was obtained in 16 % yield. The starting material (63 
mg) was recovered. The physical constants are described on Table 1. 
EXAMPLE 15 
N-(N-hydroxy-N-methylcarbamoyl)-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)o 
xazolidin-4-one (Ic-3) 
To a solution of 5-(3,5-di-tert-butyl-4-hydroxybenzylidene)oxazolidin-4-one 
(100 mg, 0.33 mole) dissolved into dried DMF (1 ml), sodium hydride (60% 
in meneral oil) was added under nitrogen atmosphere, under ice-cooling 
with stirring, then the solution was warmed to room temperature and 
stirred for 30 min. The resulting mixture was again cooled with ice, to 
which N-hydroxy-N-methylphenylcarbamate-O-tert-butyldimethylsilyl ether 
(139 mg, 0.5 mmole) was added, then the mixture was stirred under nitrogen 
atmosphere at room temperature for 20 hours and poured into ice-water 
containing 3 ml of 2N hydrocloric acid. The resulting mixture was 
subjected to extraction with ethyl acetate, then the extract was washed 
with water, dried over sodium sulfate, and evaporated. The obtained 
residue was separated by using silica gel chromatography (toluene:ethyl 
acetate=4:1), whereby 35 mg of the objective compound was obtained in 28% 
yield. The material (31 mg) was recovered. The physical constants are 
described on Table 1. 
EXAMPLE 16 
1-(N-benzyloxycarbamoyl)-3-(3,5-di-tert-butyl-4 
-hydroxybenzylidene)pyrrolidin-2-one (Ia-10) 
3-(3,5-Di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-one (600 mg, 2 
mmole) and phenyl N-benzyloxycarbamate (490 mg, 2.01 mmole) were dissolved 
into 8 ml of pyridine and the solution was heated under reflux for 12 
hours. The reaction mixture was evaporated and the obtained residue was 
dissolved into ethyl acetate, which was washed with an aqueous solution of 
0.1N hydrochloric acid, water, and saturated brine, dried over magnesium 
sulfate, and evaporated. The obtained residue was separated by using 
silica gel chromatography (toluene:ethyl acetate=10:1) and recrystallized 
from dichloromethane/n-hexane, whereby 550 mg of the objective compound 
(Ia-10) was obtained in 61% yield. 
Mp.: 164.degree.-165.degree. C. 
Elementary Analysis (%) for C.sub.27 H.sub.34 N.sub.2 O.sub.4 
Calcd.: C,71.97; H,7.61; N,6.22. 
Found: C,71.99; H,7.66; N,6.29. 
I R (KBr) cm.sup.-1 : 3550,3256,1704, 1632, 1593. NMR(CDCl.sub.3).delta.: 
1.46 (18H,s); 3.07 (2H,d.t,J=2.6,7.1 Hz); 3.95 (2H, t, J=7.1 Hz); 5.0 
(2H,s); 5.57 (1H,s); 7.35-7.49 (8H, m); 10.97 (1H,s). 
EXAMPLE 17 
1-(N-benzyloxy-N-methylcarbamoyl)-3-(3,5-di-tert-butyl-4-hydroxybenzylidene 
)pyrrolidin-2-one (Ia-11) 
3-(3,5-Di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-one (3.01 g, 10 
mmole) was dissolved into THF (60 ml), which was cooled to -70.degree. C. 
To this mixture, a solution of 1.0M lithium bis(trimethylsilyl)amide 
dissolved into THF (24 ml) was added. Furthermore, 
N-benzyloxy-N-methylphenylcarbamate (2.9 g, 12 mmole) was added thereto 
and the mixture was stirred at room temperature for 1 hour. The reaction 
mixture was poured into ethyl acetate, which was washed with an aqueous 
solution of 0.1N hydrochloric acid, water, and saturated brine, dried over 
magnesium sulfate, and evaporated. The obtained residue was separated by 
using silica gel chromatography (toluene:ethyl acetate=10:1), whereby 1.5 
g of the objective compound (Ia-11) was obtained as white amorphous in 32% 
yield. 
Elementary Analysis (%) for C.sub.27 H.sub.34 N.sub.2 O.sub.4 
Calcd.: C,72.39; H,7.81; N,6.03. 
Found: C,72.51; H,7.79; N,5.94. 
IR (KBr) cm.sup.-1 : 3610, 2950, 2860, 1705, 1644. 
NMR (CDCl.sub.3).delta.: 1.47 (18H,s); 3.03 (2H,d.t,J=2.6, 7.0 Hz); 3.26 
(3H,s); 3.75 (2H,t,J=7.0); 4.98 (2H,s); 5.52 (1H,s); 7.34-7.48 (8H,m). 
EXAMPLE 18 
1-(N-ethoxy-N-methylcarbamoyl)-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)py 
rrolidin-2-one (Ia-12) 
Substantially in the same manner as in Example 17, 
3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-one (3.50 g, 11.6 
mmole) and N-ethoxy-N-methylphenylcarbamate (3.4 g, 17.4 mmole) were 
treated to obtain products, which were purified, and crystallized from 
isopropyl ether/n-hexane, whereby the objective compound (Ia-12) 2.80 g 
was obtained in 60% yield. Mp.: 113.degree.-114.degree. C. 
Elementary Analysis (%) for C.sub.23 H.sub.34 N.sub.2 O.sub.4.H.sub.2 O 
Calcd.: C,65.69; H,8.63; N,6.66. 
Found: C,65.89; H,8.18; N,6.79. 
NMR (CDCl.sub.3).delta.: 1.28 (3H, t, J=7.0 Hz); 1.46 (18H, s); 3.09 (2H, 
dt, J=7.4, 2.6 Hz); 3.87 (2H, t, J=7.4 Hz); 4.06 (2H, q, J=7.0 Hz); 5.53 
(1H, s); 7.36 (2H, s); 7.43(1H, t, J=2.6 Hz). 
EXAMPLE 19 
1-(N-isopropoxy-N-methylcarbamoyl)-3-(3,5-di-tert-butyl-4-hydroxybenzyliden 
e)pyrrolidin-2-one (Ia-13) 
According to the same method as in Example 17, 
3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-one (2.74 g, 9.1 
mmole) and N-isopropoxy-N-methylphenylcarbamate (2.86 g, 13.7 mmole) were 
treated to obtain products, which were purified and crystallized from 
isopropyl ether/n-hexane, whereby the objective compound (Ia-13) 1.80 g 
was obtained in 47% yield. 
Mp.: 104.degree.-106.degree. C. 
NMR (CDCl.sub.3).delta.: 1.29 (6H,d,J=5.8 Hz); 1.46 (18H,s); 3.09 
(2H,dt,J=7.4,2.4 Hz); 3.30 (3H,s); 3.87 (2H,t,J=7.4 Hz); 4.29 
(1H,sept.J=5.8 Hz); 5.53 (1H,s);7.36 (2H,s); 7.43 (1H,t,J=2.4 Hz). 
EXAMPLE 20 
1-(N-isopropyl-N-methoxycarbamoyl)-3-(3,5-di-tert-butyl-4-hydroxybenzyliden 
e)pyrrolidin-2-one (Ia-14) 
According to the same method as in Example 17, 
3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-one (602 mg, 2.0 
mmole) and N-isopropyl-N-methoxyphenylcarbamate (628 mg, 3 mmole) were 
treated to obtain products, which were purified and crystallized from 
isopropyl ether/n-hexane, whereby the objective compound (Ia-14) 643 mg 
was obtained in 77% yield. 
Mp.: 83.degree.-85.degree. C. 
NMR (CDCl.sub.3).delta.: 1.31 (6H,d,J=6.6 Hz); 1.46 (18H,s); 3.08 
(2H,dt,J=7.4,2.8 Hz); 3.78 (3H,s); 3.89 (2H,t,J=7.4 Hz); 4.10 
(1H,sept,J=6.6 Hz); 5.52 (1H,s); 7.35 (2H,s); 7.44 (1H,t,J=2.8 Hz). 
EXAMPLE 21 
1-morpholinocarbonyl-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2 
-one (Ia-15) 
To a solution of 3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-one 
(241 mg, 0.8 mmole) dissolved into DMF (2.4 ml), sodium hydride (60% in 
mineral oil, 96 mg, 2.4 mmole) was added under ice-cooling under nitrogen 
atmosphere with stirring for 30 min. Morpholinophenyl carbamate (249 mg, 
1.2 mmole) was added thereto and the mixture was allowed to stand at room 
temperature for 4 hours. The reactant was poured into ice-water, and 
extracted with ethyl acetate. The organic layer was washed with water, 
dried over magnesium sulfate, and evaporated. The obtained residue was 
recrystallized from dichloromethane/ether, whereby 300 mg of the objective 
compound (Ia-15) was obtained in 90% yield. 
Mp.: 212.5.degree.-213.5.degree. C. 
Elementary Analysis (%) for C.sub.24 H.sub.34 N.sub.2 O.sub.4 
Calcd.: C,69.53; H,8.27; N,6.76. 
Found: C,69.36; H,8.38; N,6.67. 
IR (KBr) cm.sup.-1 : 3590,3440,1688,1644,1633,1596. 
NMR (CDCl.sub.3).delta.: 1.48 (18H,s); 3.09 (2H,d.t,J=2.5,7.1 Hz); 3.56 
(4H,bs); 3.77 (6H,m); 5.53 (1H,s); 7.36 (2H,s); 7.41 (1H,t,J=2.5 Hz). 
EXAMPLE 22 
1-(N-acetoxy-N-methylcarbamoyl)-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)p 
yrrolidin-2-one (Ia-16) 
To a solution of 
1-(N-hydroxy-N-methylcarbamoyl)-3-(3,5-di-tert-butyl-4-hydroxybenzylidene) 
pyrrolidin-2-one (Ia-6) (222 mg, 0.6 mmole) dissolved into pyridine (3 ml), 
1.8 ml of acetic anhydride was added and the mixture was stirred at room 
temperature for 5 hours, then the resulting mixture was evaporated. 
Hydrochloric acid (0.5N) was added thereto, and the mixture was subjected 
to extraction with dichloromethane. The organic layer was washed with 
water, sodium bicarbonate, and water in order, dried over magnesium 
sulfate, and evaporated. The obtained residue was recrystallized from 
dichloromethane/ether, whereby 211 mg of the objective compound (Ia-16) 
was obtained in 84% yield. 
Mp. 175.degree.-176.degree. C. 
Elementary Analysis (%) for C.sub.23 H.sub.32 N.sub.2 O.sub.5.1/4H.sub.2 O 
Calcd.: C,65.61; H,7.78; N,6.65. 
Found: C,65.79; H,7.85; N,6.66. 
IR(KBr) cm.sup.-1 : 3595,3440,1797,1711,1688,1638,1596. 
NMR(CDCl.sub.3) .delta.: 1.46 (18H,s); 2.14 (3H,s); 3.10 (2H,d.t,J=2.6,7.3 
Hz); 3.37 (3H,s); 3.88 (2H,t,J=7.4 Hz);5.54 (1H,s); 7.36 (2H,s); 7.46 
(1H,t, J=2.8 Hz). 
EXAMPLE 23 
1-(N-acetoxycarbamoyl)-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin 
-2-one (Ia-17) 
N-(N-Hydroxycarbamoyl)-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin 
-2-one (Ia-4)(2 g, 5.55 mmole), acetic anhydride (680 mg, 6.66 mmole), and 
pyridine (10 ml) were reacted according to the same method as in Example 
22, whereby 1.35 mg of the objective compound (Ia-17) was obtained in 
60.5% yield. 
Mp.: 165.degree.-166.degree. C. 
Elementary Analysis (%) for C.sub.22 H.sub.30 N.sub.2 O.sub.5 
Calcd.: C,65.65; H,7.51; N,6.96. 
Found: C,65.39; H,7.50; N,6.81. 
IR(KBr) cm.sup.-1 : 3600, 3300, 2950, 1800, 1708, 1689, 1631, 1592. 
NMR(CDCl.sub.3) .delta.: 1.47 (18H,s); 2.26 (3H,s); 3.11 (2H,d.t,J=2.6, 7.3 
Hz); 3.35 (3H,s); 3.95 (2H,t,J=7.3); 5.60 (1H,s); 7.38 (2H,s); 7.51 (1H,t, 
J=2.6 Hz) 11.44 (1H,s). 
EXAMPLE 24 
3-(N-methoxy-N-methylcarbamoyl)-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)t 
hiazolidin-4-one (Ib-4) 
To a solution of 
5-(3,5-di-tert-butyl-4-hydroxybenzylidene)thiazolidin-4-one (319 mg, 1 
mmole), which was described in Kokai 62-42977, dissolved into DMF (3 ml), 
sodium hydride (60% in mineral oil, 120 mg, 3 mmole) was added under 
ice-cooling, then N,O-dimethylhydroxyphenylcarbamate (272 mg, 1.5 mmole) 
was added thereto and the mixture was stirred at room temperature for 2.5 
hours. The reaction mixture was poured into 1N HCl, which was subjected to 
extraction with ethyl acetate. The extract was washed with water, dried 
over magnesium sulfate, and evaporated. The obtained residue was separated 
and purified by using silica gel chromatography (toluene:ethyl 
acetate=1:1), then lyophilized from benzene, whereby 275 mg of the 
objective compound (Ib-4) was obtained in 68% yield. 
IR(KBr) cm.sup.-1 : 3610, 3560, 1700. 
NMR(CDCl.sub.3) .delta.: 1.47 (18H,s); 3.31 (3H,s); 3.81(3H,s); 4.87 
(2H,s); 5.52 (1H,s); 7.40 (2H,s); 7.54 (1H,s). 
EXAMPLE 25 
3-(N-methoxy-N-methylcarbamoyl)-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)o 
xazolidin-4-one (Ic-4) 
5-(3,5-Di-tert-butyl-4-hydroxybenzylidene)oxazolidin-4-one (303 mg, 1 
mmole) was reacted and treated under the similar condition as in Example 
24, then the reaction mixture was separated by using silica gel 
chromatography (toluene:ethyl acetate=1:1), then lyophilized from benzene, 
whereby 90 mg of the objective compound (Ic-4) was obtained in 23% yield. 
Elementary Analysis (%) for C.sub.21 H.sub.30 N.sub.2 O.sub.5 
Calcd.: C,64.59; H,7.74; N,7.17. 
Found: C,64.65; H,7.63; N,6.89. 
IR (KBr) cm.sup.-1 : 3620, 3540, 3440, 1738, 1700. 
NMR (CDCl.sub.3) .delta.: 1.45(18H,s), 3.30(3H,s), 3.81(3H,s), 5.42(1H,s), 
5.70 (2H,s), 6.39(1H,s), 7.54(2H,s). 
EXAMPLE 26 
(1) 1-Ethoxycarbonyl-5,5-dimethylpyrrolidin-2-one 
To a suspension of 1.43 g (35.8 mmol) of NaH (60% in mineral oil) in 12 ml 
of DMF was dropwise added over 35 minutes a solution of 1.35 g (11.93 
mmol) of 5,5-dimethylpyrrolidin-2-one in 24 ml of DMF while being stirred 
under ice-cooling. After 30 minutes, 1.7 ml (17.5 mmol) of ethyl 
chlorocarbonate was added to the mixture and allowed to stand at room 
temperature for 2 hours. The reaction mixture was extracted with ethyl 
acetate and the organic layer was washed with saturated brine then dried 
over magnesium sulfate and evaporated to give 1.746 g of the objective 
compound as oil. 
IR (CHCl.sub.3) cm.sup.-1 : 1782, 1714. 
NMR (CDCl.sub.3) .delta.: 1.31(6H,s), 1.38(3H,t,J=7 Hz), 
1.84.about.2.04(2H,m), 2.39.about.2.55 (2H,m), 4.34(2H,q,J=7 Hz). 
(2) 3-(3,5-Di-tert-butyl-4-hydroxybenzylidene)-5,5-dimethylpyrrolidin-2-one 
To a chilled solution (-70.degree. C.) of 1.657 g (8.95 mmol) of the thus 
obtained 1-ethoxycarbonyl-5,5-dimethylpyrrolidin-2-one in THF (45 ml) was 
added 9 ml of a THF solution of 1.0M lithium hexamethydisilazane under a 
nitrogen atmosphere. Five minutes later, 2.74 g (9 mmol) of 
3,5-di-tert-butyl-4-trimethylsiloxybenzaldehyde was added thereto and the 
mixture was stirred at room temperature for 2 hours. The reaction mixture 
was then poured into ice-water and extracted with dichloromethane. The 
dichloromethane layer was washed with water, dried over magnesium sulfate 
and evaporated to give a residue, which was then dissolved in 40 ml of 
toluene and combined with 280 mg of p-toluenesulfonic acid and the mixture 
was refluxed for 1.5 hours. After cooled down, the reaction mixture was 
evaporated and the resulting residue was dissolved in 30 ml of THF. Under 
ice-cooling, 3.5 ml of a THF solution of 2.0M tetra-n-butylammonium 
fluoride was added thereto and the mixture was stirred for 10 minutes. The 
mixture was poured into ice-water containing sodium bicarbonate and 
extracted with dichloromethane. The dichloromethane layer was washed with 
an aq. sodium bicarbonate, water, then saturated brine and dried over 
magnesium sulfate and evaporated to give 
1-ethoxycarbonyl-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)-5,5-dimethylpy 
rrolidin-2-one as residue, which was then dissolved in a methanol/water 
(4/1) mixed solution (100 ml). Five % solution of potassium hydroxide (5 
ml) was added thereto while being stirred under ice-cooling and stirred at 
room temperature for 3.5 hours. The reaction mixture was neutralized with 
38 ml of 2N hydrochloric acid and extracted with dichloromethane. The 
organic layer was washed with saturated brine, dried over magnesium 
sulfate and evaporated to give a residue, which was recrystallized from a 
dichloromethane/ether mixture to give 386 mg of the objective compound. 
Then the mother liquor was chromatographed on silica gel (toluene/ethyl 
acetate=1/1) and recrystallized to give 559 mg of the objective compound. 
Totally, 945 mg of the objective compound was obtained in 24% overall 
yield. 
m.p. 239.degree.-242.degree. C. 
Elementary Analysis (%) for C.sub.21 H.sub.31 NO.sub.2 
Calcd.: C,76.55; H,9.48; N,4.25. 
Found: C,76.13; H,9.47; N,4.29. 
IR (KBr) cm.sup.-1 : 3400, 3160, 1679, 1637, 1592. 
NMR (CDCl.sub.3) .delta.: 1.36 (6H,s); 1.46 (18H,s); 2.91 (2H,d,J=2.8 Hz); 
5.45 (1H, s); 6.07 (1H, bs); 7.32 (2H,s); 7.33 (1H,t,J=2.8 Hz). 
(3) 
1-Carbamoyl-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)-5,5-dimethylpyrroli 
din-2-one (Id-1) 
To a suspension of 329 mg (1 mmol) of the thus obtained 
3-(3,5-di-tert-butyl-4-hydroxybenzylidene)-5,5-dimethylpyrrolidin-2-one in 
2 ml of dry toluene was added 96 .mu.l (1.1 mmol) of chlorosulfonyl 
isocyanate under a nitrogen atmosphere. The reaction mixture was heated at 
90.degree. C. for 10 minutes and evaporated to give a residue, which was 
added with 2.4 ml of acetic acid/water (2/1) and heated at 90.degree. C. 
for 10 minutes. The reaction mixture was then poured into ice-water and 
extracted with dichloromethane three times. The organic layers were 
collected and washed with water, dried over magnesium sulfate and then 
evaporated to give a residue, which was chromatographed on silica gel 
(toluene/ethyl acetate=1/1) and recrystallized from ether to give 107 mg 
of the objective compound (Id-1) in 29% yield. 
m.p. 200.degree.-203.degree. C. 
Elementary Analysis (%) for C.sub.22 H.sub.32 N.sub.2 O.sub.3.1/2H.sub.2 O 
Calcd.: C,69.26; H,8.72; N,7.34. 
Found: C,68.96; H,8.49; N,7.32. 
IR (KBr) cm.sup.-1 : 3560, 3360, 1715, 1637, 1592. 
NMR (CDCl.sub.3) .delta.: 1.47(18H,s); 1.64(6H,s); 2.89(2H,d,J=2.6 Hz); 
5.16(1H,bs); 5.56(1H,s); 7.34(2H,s); 7.52(1H,t,J=2.6 Hz); 8.82(1H,bs). 
EXAMPLE 27 
1-(N-Hydroxycarbamoyl)-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)-5,5-dimet 
hylpyrrolidin-2-one (Id-2) 
Substantially in the same manner as in Example 17, 329 mg (1 mmol) of 
3-(3,5-di-tert-butyl-4-hydroxybenzylidene)-5,5-dimethylpyrrolidin-2-one 
and 443 mg (1.5 mmol) of 
N-hydroxyphenylcarbamate-O-tert-butyl-dimethylsilyl ether were treated to 
give a residue, which was chromatographed on silica gel (toluene/ethyl 
acetate=1/1) and lyophilized from benzene to give 89 mg of the objective 
compound (Id-2) as powder in 24% yield. 
Elementary Analysis (%) for C.sub.22 H.sub.32 N.sub.2 O.sub.4 
Calcd.: C,68.01; H,8.30; N,7.21. 
Found: C,68.19; H,8.38; N,6.96. 
IR (KBr) cm.sup.-1 : 3616, 3260, 1704, 1635, 1594. 
NMR (CDCl.sub.3) .delta.: 1.47(18H,s); 1.65(6H,s); 2.92(2H,d,J=2.6 Hz); 
5.57(1H,s); 6.79(1H,bs); 7.33(2H,s); 7.49(1H,t,J=5.2 Hz); 11.01(1H,s). 
EXAMPLE 28 
(1) 1-(N-Methoxy-N-methylcarbamoyl)-5,5-dimethylpyrrolidin-2-one 
To a solution of 566 mg (5 mmol) of 5,5-dimethylpyrrolidin-2-one in 15 ml 
of DMF was added 600 mg (15 mmol) of NaH (60% in mineral oil) while being 
stirred under ice-cooling under a nitrogen atmosphere. Thirty minutes 
later, 1.359 g (7.5 mmol) of N,O-dimethylhydroxyphenyl carbamate was added 
thereto, and the reaction mixture was stirred at room temperature for 22 
hours. The reaction mixture was poured into ice-water and extracted with 
ethyl acetate. The organic layer was washed with water, dried over 
magnesium sulfate and evaporated to give a residue, which was 
chromatographed on silica gel (toluene/ethyl acetate=1/1) to give 453 mg 
of the objective compound as oil. 
IR (CHCl.sub.3) cm.sup.-1 : 1710, 1686. 
NMR (CDCl.sub.3) .delta.: 1.48(6H,s); 1.92(2H,t,J=7.7 Hz); 2.49(2H,t,J=7.7 
Hz); 3.23 (3H,s); 3.75(3H,s). 
(2) 
1-(N-Methoxy-N-methylcarbamoyl)-3-(3,5-di-tert-butyl-4-hydroxybenzylidene) 
-5,5-dimethylpyrrolidin-2-one (Id-3) 
To a chilled solution (-70.degree. C.) of 453 mg (2.26 mmol) of the thus 
obtained 1-(N-methoxy-N-methylcarbamoyl)-5,5-dimethylpyrrolidin-2-one in 
THF (12 ml) was added 2.26 ml (2.26 mmol) of a THF solution of 1.0M 
lithium hexamethyldisilazane while being stirred under a nitrogen 
atmosphere. Five minutes later, 693 mg (2.26 mmol) of 
3,5-di-tert-butyl-4-trimethylsiloxybenzaldehyde was added thereto and the 
mixture was warmed to room temperature and stirred for 2 hours. The 
reaction mixture was then poured into ice-water and extracted with 
dichloromethane. The dichloromethane layer was washed with water, dried 
over magnesium sulfate and evaporated to give a residue, which was then 
dissolved in 23 ml of toluene. To the mixture was added 145 mg of 
p-toluenesulfonic acid, which was refluxed for 1.5 hours. The solvent was 
removed under reduced pressure to give a residue, which was dissolved in 
13 ml of THF and stirred under ice-cooling. To the reaction mixture was 
added 1 ml of a THF solution of 2.0M tetra-n-butylammonium fluoride, which 
was stirred for 10 minutes. The reaction mixture was poured into ice-water 
containing sodium bicarbonate and extracted with dichloromethane. The 
dichloromethane layer was washed with an aq. sodium bicarbonate and water, 
dried over magnesium sulfate and evaporated to give a residue, which was 
then chromatographed on silica gel (toluene/ethyl acetate=9/1) and 
lyophilized from benzene to give 270 mg of the objective compound (Id-3) 
in 29% yield. 
Elementary Analysis (%) for C.sub.24 H.sub.36 N.sub.2 O.sub.4.1/4C.sub.6 
H.sub.6 
Calcd.: C,70.23; H,8.67; N,6.42. 
Found: C,70.46; H,8.60; N,6.30. 
IR (KBr) cm.sup.-1 : 3614, 3552, 1692, 1614, 1592. 
NMR (CDCl.sub.3) .delta.: 1.47(18H,s); 1.55(6H,s); 2.91(2H,d,J=2 Hz); 
3.26(3H,s); 3.78(3H,s); 5.53(1H,s); 7.32(2H,s); 7.47(1H,s). 
EXAMPLE 29 
1-(N-Hydroxy-N-methylcarbamoyl)-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)- 
5,5-dimethylpyrrolidin-2-one (Id-4) 
To a solution of 1.22 g (9.17 mmol) of aluminium chloride, 1.37 g (9.17 
mmol) of sodium iodide and 9.1 ml of acetonitrile was added a solution of 
382 mg (0.917 mmol) of the thus obtained compound (Id-3) in Example 28 in 
2.3 ml of acetonitrile. The reaction mixture was stirred at room 
temperature for 1.5 hours and poured into ice-water and extracted with 
dichloromethane. The dichloromethane layer was washed with dil. 
hydrochloric acid and water, dried over magnesium sulfate and evaporated 
to give a residue, which was recrystallized from ether/n-hexane to give 
238 g of the objective compound (Id-4) in 64% yield. 
m.p.: 176.degree.-179.degree. C. 
Elementary Analysis (%) for C.sub.23 H.sub.34 N.sub.2 O.sub.4.1/4H.sub.2 O 
Calcd.: C,67.87; H,8.54; N,6.88. 
Found: C,67.90; H,8.46; N,6.88. 
IR (KBr) cm.sup.-1 : 3562, 1681, 1654, 1628, 1590. 
NMR (CDCl.sub.3) .delta.: 1.47(18H,s);1.61(6H,s); 2.93(2H,d,J=2.4 Hz); 
3.35(3H,s); 5.56(1H,s); 7.33(2H,s); 7.51(1H,t,J=2.2 Hz); 8.80(1H,s). 
EXAMPLE 30 
(1) 1-Ethoxycarbonyl-5-methylpyrrolidin-2-one 
Substantially in the same manner as in Example 26 (1), 3.965 g (40 mmol) of 
5-methylpyrrolidin-2-one was treated to give a residue as oil, which was 
6.429 g of the objective compound in 94% yield. 
IR(CHCl.sub.3) cm.sup.-1 : 1780, 1711, 1672(s). 
NMR (CDCl.sub.3) .delta.: 1.17(3H,d,J=6.6 Hz); 1.35(3H,t,J=7.1 Hz); 
1.62-1.92(2H,m); 2.31-2.52(2H,m); 4.90(2H,q,J=7.1); 4.27-4.36(1H,m). 
(2) 3-(3,5-di-tert-Butyl-4-hydroxybenzylidene)-5-methylpyrrolidin-2-one 
Substantially in the same manner as in Example 26 (2), 3.424 g (20 mmol) of 
the thus obtained 1-ethoxycarbonyl-5-methylpyrrolidin-2-one was treated to 
give a residue, which was chromatographed on silica gel (toluene/ethyl 
acetate=1/1) and recrystallized from ether to give 1.271 g of the 
objective compound in 20% yield. 
m.p.: 179.degree.-181.degree. C. 
Elementary Analysis (%) for C.sub.20 H.sub.29 NO.sub.2 
Calcd.: C,76.15; H,9.27; N,4.44. 
Found: C,75.89; H,9.15; N,4.55. 
IR (KBr) cm.sup.-1 : 3630, 3200, 1690(s), 1678, 1637, 1597. 
NMR (CDCl.sub.3) .delta.: 1.32(3H,d,J=6.2 Hz), 1.46(18H,s), 
2.64(1H,t.d,J=3,17.2 Hz), 3.31(1H,d.q,J=2.8,8.2,Hz), 
3.87.about.3.94(1H,m), 5.45(1H,s), 6.51(1H,s), 7.32(1H,t,J=2.6 Hz), 
7.34(2H,s). 
(3) 
1-Carbamoyl-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)-5-methylpyrrolidin- 
2-one (Id-5) 
Substantially in the same manner as in Example 26 (3), 221 mg (0.7 mmol) of 
the thus obtained 
3-(3,5-di-tert-butyl-4-hydroxybenzylidene)-5-methyl-pyrrolidin-2-one was 
treated to give a residue, which was chromatographed on silica gel 
(toluene/ethyl acetate=1/1) and recrystallized from ether to give 107 mg 
of the objective compound (Id-5) in 43% yield. 
m.p.: 195.degree.-196.degree. C. 
Elementary Analysis (%) for C.sub.21 H.sub.30 N.sub.2 O.sub.3 
Calcd.: C,70.36; H,8.44; N,7.82. 
Found: C,70.10; H,8.48; N,7.67. 
IR (KBr) cm.sup.-1 : 3600, 3370, 1712, 1640, 1575. 
NMR (CDCl.sub.3) .delta.: 1.38(3H,d,J=6.4 Hz); 1.47(18H,s); 
2.64(1H,t,d,J=2.2,17 Hz); 3.23(1H,d.q,J=3.2,8.7 Hz); 4.52-4.61(1H,m); 
5.20(1H,bs); 5.57(1H,s), 7.37(2H,s);7.51(1H,t,J=2.7 Hz); 8.59(1H,bs). 
EXAMPLE 31 
1-(N-Hydroxycarbamoyl)-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)-5-methylp 
yrrolidin-2-one (Id-6) 
Substantially in the same manner as in Example 27, 473 mg (1.5 mmol) of the 
thus obtained 
3-(3,5-di-tert-butyl-4-hydroxybenzylidene)-5-methylpyrrolidin-2-one in 
Example 30 (2) was treated to give a residue, which was chromatographed on 
silica gel (toluene/ethyl acetate=1/1) and lyophilized from benzene to 
give 273 mg of the objective compound (Id-6) as powder in 49% yield. 
Elementary Analysis (%) for C.sub.21 H.sub.30 N.sub.2 O.sub.4 
Calcd.: C,67.35; H,8.08; N,7.48. 
Found: C,67.66; H,8.07; N,7.14. 
IR (KBr) cm.sup.-1 : 3610, 3400, 3250, 1700, 1630, 1593. 
NMR (CDCl.sub.3) .delta.: 1.39(3H,d,J=6.4 Hz); 1.47(18H,s); 
2.67(1H,t.d,J=2,17.2 Hz); 3.28(1H,d.q,J=3,8.2 Hz); 4.51-4.60(1H,m); 
5.58(1H,s); 6.80(1H,bs); 7.36 (2H,d,J=3.4 Hz); 7.49(1H,t,J=3 Hz); 
10.81(1H,s). 
EXAMPLE 32 
(1) 2-Methoxycarbonylisoxazolidin-3-one 
To a suspension of 466 mg (11.66 mmol) of NaH (60% in mineral oil) in 20 ml 
of DMF was dropwise added 20 ml of a DMF solution of isoxazolidin-2-one 
while being stirred under ice-cooling for 30 minutes. To the reaction 
mixture was added 858 .mu.l (11.1 mmol) of methyl chlorocarbonate at 
-30.degree. C. while being stirred under ice-cooling for 2 hours. The 
reaction mixture was evaporated under reduced pressure to give a residue, 
which was added with dichloromethane. The thus obtained suspension was 
filtered and the filtrate was evaporated to give a crude product, which 
was chromatographed on silica gel (n-hexane/ethyl acetate=2/1) to give 
1.290 g of the objective compound in 80% yield. 
Elementary Analysis (%) for C.sub.5 H.sub.7 NO.sub.4 
Calcd.: C,41.38; H,4.86; N,9.65. 
Found: C,40.96; H,4.96; N,9.91. 
NMR (CDCl.sub.3) .delta.: 2.98(2H,t,J=7.8 Hz); 3.94(3H,s); 4.77(2H,t,J=7.8 
Hz). 
(2) 
2-Methoxycarbonyl-4-(3,5-di-tert-butyl-4-hydroxybenzylidene)isoxazolidin-3 
-one 
To a chilled solution (-78.degree. C.) of 1.55 g (7.96 mmol) of the thus 
obtained 2-methoxycarbonylisoxazolidin-3-one in THF (100 ml) was added 8.4 
ml of a THF solution of 1.0M lithium hexamethyldisilazane, and the mixture 
was stirred at -78.degree. C. for 30 minutes. To the reaction mixture was 
added 2.5 ml of a THF solution of 2.44 g (8.76 mmol) of 
3,5-di-tert-butyl-4-hydroxybenzaldehyde-O-methoxymethyl ether and the 
mixture was stirred at -78.degree. C. for 30 minutes and then 8.4 ml of 1N 
hydrochloric acid and ethyl acetate were added thereto. The ethyl acetate 
layer was washed with water and saturated brine, dried over magnesium 
sulfate and evaporated under reduced pressure to give a residue, which was 
dissolved in 200 ml of toluene and combined with 400 mg of 
p-toluenesulfonic acid and the mixture was refluxed under flask equipped 
with the Dean-Stark water separator for 3 hours. After cooled down, the 
reaction mixture was added with ethyl acetate and washed with saturated 
sodium hydrogencarbonate. The ethyl acetate layer was washed with water, 
dried over magnesium sulfate and evaporated under reduced pressure to give 
a residue, which was crystallized from a ether/n-hexane mixture to give 
1.57 g of the objective compound in 55% yield. 
m.p.: 191.degree.-192.degree. C. 
Elementary Analysis (%) for C.sub.20 H.sub.27 NO.sub.5.1/2H.sub.2 O 
Calcd.: C,64.85; H,7.62; N,3.78 
Found: C,65.14; H,7.47; N,3.81 
NMR (CDCl.sub.3) .delta.: 1.46(18H,s); 3.99(3H,s); 5.35(2H,d,J=2.6 Hz); 
5.67(1H, s); 7.14(2H,s); 7.53(1H,t,J=2.6 Hz) 
(3) 4-(3,5-di-tert-Butyl-4-hydroxybenzylidene)isoxazoldin-3-one 
To a solution of 1.364 g (3.77 mmol) of the thus obtained methoxy carbonyl 
compound in methanol (136 ml) was added 7.54 ml of a solution of 1.0M 
sodium methoxide in methanol while being stirred vigorously at room 
temperature and the mixture was stirred for 5 minutes. To the reaction 
mixture were added dichloromethane and ice-water. The dichloromethane 
layer was washed with water, dried over magnesium sulfate and evaporated 
to give a residue, which was chromatographed on silica gel (n-hexane/ethyl 
acetate=2/1) to give 610 mg of the objective compound in 53% yield. A part 
of product was recrystallized from a dichloromethane/n-hexane mixture. 
m.p.: 180.degree.-183.degree. C. 
Elementary Analysis (%) for C.sub.18 H.sub.25 NO.sub.3.1/2H.sub.2 O: 
Calcd.: C,69.20; H,8.39; N,4.48 
Found: C, 69.21: H, 8.17; N,4.44 
NMR (CDCl.sub.3) .delta.: 1.46(18H,s); 5.32(2H,d,J=2.6 Hz); 5.56(1H,brs.); 
7.13(2H, s); 7.31(1H,t,J=2.6 Hz) 
(4) 2-Carbamoyl-4-(3,5-di-tert-butyl-4-hydroxbenzylidene)isoxazolidin-3-one 
(Ie-1) 
To a solution of 212 mg (0.7 mmol) of the thus obtained 
4-(3,5-di-tert-butyl-4-hydroxybenzylidene)isoxazolidin-3-one in toluene (6 
ml) was added 67 .mu.l (0.77 mmol) of chlorosulfonyl isocyanate while 
being stirred with heating at 100.degree. C. and allowed to react for 10 
minutes. The reaction mixture was evaporated to give a residue, which was 
added with 4 ml of a acetic acid/water (2/1) mixture and stirred with 
heating at 100.degree. C. for 10 minutes. The reaction mixture was 
evaporated to give a residue, which was dissolved in ethyl acetate. The 
reaction mixture was washed with water and saturated brine and evaporated 
under resuced pressure to give a residue, which was chromatographed on 
silica gel (n-hexane/ethyl acetate=2/1) to give 127 mg of the objective 
compound (Ie-1) in 52% yield. A part of product was recrystallized from a 
dichloromethane/n-hexane mixture. 
m.p.: 178.degree.-181.degree. C. 
Elementary Analysis (%) for C.sub.19 H.sub.26 N.sub.2 O.sub.4 3/4H.sub.2 O: 
Calcd.: C,63.40; H,7.70; N,7.78 
Found: C,63.58; H,7.48; N,7.58 
NMR (CDCl.sub.3) .delta.: 1.47(18H,s); 5.37(2H,d,J=2.6 Hz); 5.69(1H,s); 
7.15(2H,s); 7.49(1H,t,J=2.6 Hz) 
EXAMPLE 33 
(1) 1-Acetyl-3-(3,5-di-isopropyl-4-hydroxybenzylidene)pyrrolidin-2-one 
To a solution of 5.90 g (6 mmol) of 
(1-acetyl-2-oxopyrrolidin-3-yl)triphenylphosphonium bromide in ethanol (12 
ml) were added 1.24 g (6 mmol) of 3,5-di-isopropyl-4-hydroxybenzaldehyde 
and 1.67 ml (12 mmol) of triethylamine, and the mixture was stirred with 
heating at 60.degree. C. for 2 hours. The reaction mixture was evaporated 
to give a residue, which was added with ethyl acetate and water. The ethyl 
acetate layer was washed with water, dried over magnesium sulfate and 
evaporated to give a residue, which was chromatographed on silica gel 
(toluene/ethyl acetate=4/1) to give 857 mg of the objective compound in 
45% yield. 
Elementary Analysis (%) for C.sub.19 H.sub.25 NO.sub.3 : 
Calcd.: C,72.35; H,7.99; N,4.44 
Found: C,72.40; H,8.07; N,4.49 
NMR (CDCl.sub.3) .delta.: 1.30(12H,d,J=7.0 Hz); 2.63(3H,s); 
2.94-3.29(4H,m); 3.90 (2H,t,J=7.0 Hz); 7.25(2H,s); 7.52(1H,t,J=2.6 Hz) 
(2) 3-(3,5-di-Isopropyl-4-hydroxybenzylidene)pyrrolidin-2-one 
To a solution of 810 mg (2.57 mmol) of the thus obtained 
1-acetyl-3-(3,5-di-isopropyl-4-hydroxybenzylidene)pyrrolidin-2-one in 5 ml 
of methanol and 10 ml of THF was added 2 ml of 1N aq. sodium hydroxide at 
room temperature and the mixture was stirred for 3 hours. the reaction 
mixture was poured into ice-water containing ethyl acecate and 3 ml of 1N 
hydrochloric acid. The ethyl acetate layer was washed with water and 
saturated brine, dried over magnesium sulfate and evaporated under reduced 
pressure to give a residue, which was crystallized from a ether/n-hexane 
mixture to give 800 mg of the objective compound as yellowish white 
crystal in 100% yield. 
m.p.: 201.degree.-202.degree. C. 
Elementary Analysis (%) for C.sub.17 H.sub.23 NO.sub.2 1/4H.sub.2 O: 
Calcd.: C,73.48; H,8.52; N,5.04 
Found: C,73.43; H,8.44; N,5.00 
NMR (CDCl.sub.3) .delta.: 1.28(12H,d,J=6.8 Hz); 3.06-3.29(4H,m); 
3.56(2H,t,J=6.8 Hz); 4.95-5.34(1H,broad); 6.16-6.40(1H,broad); 7.22(2H,s); 
7.22(2H,s); 7.33(1H,t,J=2.6 Hz) 
(3) 
1-(N-Hydroxy-N-methylcarbamoyl)-3-(3,5-di-isopropyl-4-hydroxybenzylidene)p 
yrrolidin-2-one (Ia-18) 
Substantially in the same manner in Example 22, 273 mg (1 mmol) of the thus 
obtained 3-(3,5-di-isopropyl-4-hydroxybenzylidene)pyrrolidin-2-one was 
treated to give a residue, which was crystallized from a ether/n-hexane 
mixture to give 120 mg of the objective compound (Ia-18) in 35% yield. 
m.p. 182.degree.-183.degree. C. 
Elementary Analysis (%) for C.sub.19 H.sub.26 N.sub.2 O.sub.4 
Calcd.: C,65.88; H,7.56; N,8.09 
Found: C,65.63; H,7.61; N,8.09 
NMR (CDCl.sub.3) .delta.: 1.29(12H,d,J=7.0 Hz); 3.03-3.25(4H,m); 
3.34(3H,s); 3.97(2H,t,J=7.0 Hz); 7.24(2H,s); 7.49(1H,t,J=2.6 Hz); 
9.70(1H,s) 
EXAMPLE 34 
1-Carbamoyl-3-(3-ethoxy-4-hydroxybenzylidene)pyrrolidin-2-one (Ia-19) 
To a solution of 939 mg (2 mmol) of 
(1-carbamoyl-2-oxopyrrolidin-3-yl)triphenylphosphonium bromide in ethanol 
(16 ml) were added 332 mg (2 mmol) of 3-ethoxy-4-hydroxybenzaldehyde and 
558 .mu.l (4 mmol) of triethylamine, and the mixture was stirred at 
60.degree. C. for 2 hours. The reaction mixture was evaporated to give a 
residue, which was dissolved in diisopropyl ether and treated with 4 ml of 
1N aq. sodium hydroxide. The aqueous layer was made acid with 1N 
hydrochloric acid under ice-cooling and the product was dissolved in ethyl 
acetate, washed with water and saturated brine, dried over magnesium 
sulfate and evaporated to give a residue, which was crystallized from a 
dichloromethane/n-hexane mixture to give 143 mg of the objective compound 
(Ia-19) in 26% yield. 
m.p.: 204.degree.-205.degree. C. 
Elementary Analysis (%) for C.sub.14 H.sub.16 N.sub.2 O.sub.4 : 
Calcd.: C,60.86; H,5.84; N,10.14 
Found: C,60.76; H,5.91; N,10.10 
NMR (CDCl.sub.3) .delta.: 1.49(3H,t,J=7.8 Hz); 3.06(2H,dt,J=7.4 & 2.8 Hz); 
3.95(2H,t,J=7.4 Hz); 4.16 (2H,q,J=7.0 Hz); 5.20(1H,brs); 5.96(1H,s); 
6.96-7.26(3H,m), 7.43(1H,t,J=2.8 Hz); 8.52(1H,brs) 
EXAMPLE 35 
(1) 1-(N-tert-Butyldimethylsilyloxy-N-methylcarbamoyl)pyrrolidin-2-one 
To a chilled solution (-70.degree. C.) of 2 g (23.5 mmol) of 
2-oxopyrrolidine in 10 ml of THF was added 24 ml of a THF solution of 1.0M 
lithium bis-(trimethylsilyl)amide under a nitrogen atmosphere. Then 6.62 g 
of N-hydroxy-N-methylcarbamate-O-tert-butyldimethylsilyl ether was added 
thereto and the mixture was stirred at room temperature for 3 hours. The 
reaction mixture was poured into ethyl acetate and the mixture was washed 
with 0.1N hydrochloric acid, water, and saturated brine and dried over 
magnesium sulfate and evaporated to give a residue, which was 
chromatographed on silica gel (toluene/ethyl acetate=10/1) to give the 
objective compound as colorless oil in 70% yield. 
NMR (CDCl.sub.3) .delta.: 0.21(6H,s); 0.97(9H,s); 2.08(2H,quinted,J=7.6 
Hz); 2.49 (2H,t,J=7.9); 3.24 (3H,s); 3.76(2H,t,J=7.6 Hz); 2.49 
(2H,t,J=7.9); 3.24 (3H,s); 3.76(2H,t,J=7.0 Hz) 
(2) 
1-(N-Hydroxy-N-methylcarbamoyl)-3-(3,5-di-tert-butyl-4-hydroxybenzoyl)pyrr 
olidin-2-one (Ia-20) 
To a chilled solution (-78.degree. C.) of 2 g (7.34 mmol) of the thus 
obtained 
1-(N-tert-butyldimethylsilyloxy-N-methylcarbamoyl)pyrrolidin-2-one in THF 
(5 ml) was added 8.1 ml (8.1 mmol) of a THF solution of 1.0M lithium 
bis(trimethylsilyl)amide under a nitrogen atmosphere, and the mixture was 
stirred for 1 hour. To the reaction mixture was dropwise added 5 ml of a 
THF solution of 1.55 g (5 mmol) of 
methyl-3,5-di-tert-butyl-4-methoxymethyloxybenzoate while being stirred at 
room temperature for 20 hours. The reaction mixture was poured into ethyl 
acetate, washed with 0.1N hydrochloric acid and saturated brine, dried 
over magnesium sulfate and evaporated to give a residue, which was 
dissolved in 12 ml of acetone and added with 0.6 ml of conc. hydrochloric 
acid. The reaction mixture was stirred at room temperature for 20 hours, 
and poured into ethyl acetate, washed with water and saturated brine, 
dried over magnesium sulfate and evaporated to give a residue, which was 
chromatographed on silica gel (toluene/ethyl acetate=10/1) to give 200 mg 
of the objective compound (Ia-20) as white amorphous in 10% yield. 
Elementary Analysis (%) for C.sub.21 H.sub.30 N.sub.2 O.sub.5 : 
Calcd.: C,64.60; H,7.74; N,7.17. 
Found: C,64.77; H,7.75; N,6.93. 
IR (KBr) cm.sup.-1 : 3560, 2955, 1700-1662. 
NMR (CDCl.sub.3) .delta.: 1.48(18H,s); 2.27-2.45(1H,m); 2.63-2.80(1H,m); 
3.27(3H,s); 3.85-4.09(2H,m); 4.62(1H,d.d.,J=6.4,8.9 Hz); 5.86(1H,s); 
7.94(2H,s); 8.87(1H,s). 
EXAMPLE 36 
(1) 1-(N-Benzyloxycarbamoyl)-3-bromopyrrolidin-2-one 
A solution of 3.28 g (20 mmol) of 3-bromopyrrolidin-2-one and 5.346 g (22 
mmol) of N-benzyloxyphenylcarbamate (J. Org. Chem., 21, 660, (1956)) in 20 
ml of pyridine was refluxed for 12 hours. The reaction mixture was 
evaporated to give a residue, which was dissolved in ethyl acetate. The 
ethyl acetate layer was washed with 1N hydrochloric acid, water and 
saturated brine under ice-cooling, dried over magnesium sulfate and 
evaporated to give a residue, which was chromatographed on silica gel 
(toluene/ethyl acetate=2/1) and recrystallized from a 
dichloromethane/n-hexane mixture to give 3.62 g of the objective compound 
in 60% yield. 
m.p.: 137.degree.-142.degree. C. 
IR (KBr) cm.sup.-1 : 3272, 1719, 1694. 
NMR (CDCl.sub.3) .delta.: 2.29-2.41 (1H, m); 2.54-2.71 (1H, m); 3.91-3.97 
(2H, m); 4.46-4.51 (1H, m); 4.96 (2H, s); 7.35-7.44 (5H, m); 10.43 (1H, 
s). 
(2) {1-(N-Benzyloxycarbamoyl)-2-oxopyrrolidin-3-yl}triphenylphosphonium 
bromide 
To a solution of 2.222 g (7.1 mmol) of the thus obtained 
1-(N-benzyloxycarbamoyl)-3-bromopyrrolidin-2-one in 50 ml of 
tetrahydrofuran was added 1.862 g (7.1 mmol) of triphenylphosphine, and 
the mixture was stirred at 80.degree. C. for 24 hours. The reaction 
mixture was cooled with ice to deposit crystals, which were filtered off 
with cooled tetrahydrofuran, to give 3.177 g of the objective compound in 
83% yield. 
m.p.: 235.degree.-238.degree. C. 
IR (KBr) cm.sup.-1 : 3400, 3302, 1717, 1584. 
NMR (CDCl.sub.3) .delta.: 1.99-2.29 (1H, m); 3.05-3.24 (1H, m); 3.76-3.84 
(1H, m); 4.08-4.22 (1H, m); 4.85 (2H, q, J=10.6 Hz); 7.35 (5H, s); 
7.59-8.00 (16H, m); 10.10 (1H, s). 
(3) 
1-(N-Benzyloxycarbamoyl)-3-(3,5-di-methoxy-4-hydroxybenzylidene)pyrrolidin 
-2-one 
To a solution of 2.88 g (5 mmol) of the thus obtained wittig base in 99% 
ethanol (30 ml) were added 911 mg (5 mmol) of 
3,5-di-methoxy-hydroxybenzaldehyde and 1.4 ml (10 mmol) of triethylamine, 
and the mixture was stirred at 70.degree. C. for 1.0 hour. The reaction 
mixture was evaporated to give a residue, which was crystallized from a 
ethanol/n-hexane (=1/1) mixture to give 1.90 g of the objective compound 
in 85% yield. 
m.p.: 167.degree.-170.degree. C. 
NMR (CDCl.sub.3) .delta.: 3.11 (2H, dt, J=7.4,2.8Hz); 3.93 (6H, s); 3.97 
(2H, t, J=7.4 Hz); 5.00 (2H, s); 5.83 (1H, s); 6.74 (2H, s); 7.32-7.51 
(6H, m); 10.87 (1H, s). 
(4) 
1-(N-Hydroxycarbamoyl)-3-(3,5-di-methoxy-4-hydroxybenzylidene)pyrrolidin-2 
-one (Ia-21) 
To a solution of 800 mg (2 mmol) of 
1-(N-benzyloxycarbamoyl)-3-(3,5-di-methoxy-4-hydroxybenzylidene)pyrrolidin 
-2-one in a mixture of anisole (12 ml) and nitromethane (12 ml) was added a 
solution of 1.6 g (12 mmol) of aluminium chloride in anisole (4 ml) under 
a nitrogen atmosphere while being stirred under ice-cooling and the 
mixture was stirred at room temperature for 2 hours. The reaction mixture 
was poured into 6 ml of cooled 2N hydrochloric acid and the mixture was 
stirred for 1 hour and extracted with ethyl acetate. The ethyl acetate 
layer was washed with saturated brine, dried over magnesium sulfate and 
evaporated to give a residue, which was recrystallized from a methylene 
chloride/ether mixture to give 387 mg of the objective compound in 63% 
yield. 
m.p.: 203.degree.-204.degree. C. 
NMR (DMSO-d.sub.6) .delta.: 3.05-3.17 (2H, m); 3.72-3.88 (2H, m); 3.81 (6H, 
s); 6.90 (2H, s); 7.25-7.32 (1H, m); 8.96-9.28 (2H, broad); 10.44 (1H, 
broad, s). 
EXAMPLE 37 
1-Carbamoyl-3-(3,5-dimethyl-4-hydroxybenzylidene)pyrrolidin-2-one (Ia-22) 
2.46 g (5.24 mmol) of 
(1-carbamoyl-2-oxopyrrolidin-3-yl)triphenylphosphonium bromide (obtained 
from the reaction of 1-carbamoyl-3-bromopyrrolidin-2-one prepared in the 
same manner as in Example 1 (1) with triphenylphosphine), 787 mg (5.2 
mmol) of 3,5-dimethyl-4-hydroxybenzaldehyde, and 1.1 g (10.08 mmol) of 
triethylamine were dissolved in 50 ml of ethanol and the solution was 
stirred at 80.degree. C. for 3 hours. After cooled down, the deposited 
crystals were filtered off and the filtrate was recrystallized from a 
ethyl acetate/n-hexane mixture to give 420 mg of the objective compound in 
31% yield. 
m.p.: 239.5.degree.-241.5.degree. C. 
Elementary Analysis (%) for C.sub.14 H.sub.16 N.sub.2 O.sub.3 
Calcd.: C,64.60; H,6.20; N,10.76. 
Found: C,64.56; H,6.22; N,10.70. 
IR (KBr) cm.sup.-1 : 3450, 1705, 1682. 
NMR (d.sub.6 -DMSO) .delta.: 2.20 (6H, s); 2.99 (2H, dt, J=3,7 Hz); 3.76 
(2H, t, J=7 Hz); 7.19 (3H, broad); 7.41 (1H, broad); 8.06 (1H, broad); 
8.85 (1H, broad). 
EXAMPLE 38 
(1) 1-Acetyl-3-(4-acetoxy-3,5-di-tert-butylbenzylidene)pyrrolidin-2-one 
To a solution of 450 mg (1.5 mmol) of 
3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-one in 10 ml of 
acetic anhydride was added 0.3 ml of conc. sulfuric acid and heated at 
170.degree. C. for 3 hours. The reaction mixture was evaporated under 
reduced pressure to give a residue, which was powdered with a 
ether/n-hexane mixture to give 505 mg of the objective crude compound as 
brown powder. This was employed for the subsequent reaction without 
purification. 
NMR (CDCl.sub.3) .delta.: 1.37 (18H, s); 2.37 (3H, s); 2.63 (3H, s); 3.05 
(2H, dt, J=7.6,2.8 Hz); 3.89 (2H, t, J=7.6 Hz); 7.49 (2H, s); 7.54 (1H, t, 
J=2.8 Hz). 
(2) 3-(4-Acetoxy-3,5-di-tert-butylbenzylidene)pyrrolidin-2-one 
To a solution of 386 mg (1 mmol) of the thus obtained crude compound in 40 
ml of methanol and 20 ml of tetrahydrofuran was added 0.1 ml (0.1 mmol) of 
a methanol of 1 m/L sodium methoxide while being stirred under ice-cooling 
and the reaction mixture was stirred at room temperature for 1 hour and 
poured into ice-water containing ethyl acetate and 1 ml of 1N hydrochloric 
acid. The ethyl acetate layer was washed with saturated brine, dried over 
magnesium sulfate and evaporated under reduced pressure to give 345 mg of 
the objective crude compound as foam. This compound was employed for the 
subsequent reaction without purification. 
NMR (CDCl.sub.3) .delta.: 1.36 (18H, s); 2.37 (3H, s); 3.18 (2H, dd, 
J=6.4,2.8 Hz); 3.59 (2H, t, J=6.4 Hz); 6.23 (1H, brs); 7.37 (1H, t, J=2.8 
Hz); 7.48 (2H, s). 
(3) 
1-(N-Hydroxy-N-methylcarbamoyl)-3-(4-acetoxy-3,5-di-tert-butylbenzylidene) 
pyrrolidin-2-one (Ia-23) 
Substantially in the same manner as in Example 11, 226 mg (0.66 mml) of the 
thus obtained crude compound and 222 mg (0.79 mmol) of 
N-hydroxy-N-methylphenylcarbamate-O-tert-butyldimethylsilyl ether were 
treated and crystallized from a methylene chloride/hexane mixture to give 
66 mg of the objective compound (Ia-23) in 56% yield. 
m.p.: 176.degree.-177.degree. C. 
NMR (CDCl.sub.3) .delta.: 1.37 (18H, s); 2.37 (3H, s); 3.13 (2H, dt, 
J=7.4,2.8 Hz); 3.35 (3H, s); 3.98 (2H, t, J=7.4 Hz); 7.47 (2H, s); 7.51 
(1H, t, J=2.8 Hz); 9.57 (1H, s). 
EXAMPLE 39 
(1) 1-(N-tert-Butoxycarbonylaminocarbamoyl)-3-bromopyrrolidin-2-one 
A mixture of 4.1 g (25 mmol) of 3-bromopyrrolidin-2-one and 6.94 g (27.5 
mmol) of tert-butylphenylhydrazine dicarboxylate in 50 ml of pyridine was 
refluxed for 10 hours. The reaction mixture was evaporated to give a 
residue, which was dissolved in acetic acid under ice-cooling, washed with 
1N hydrochloric acid, water and saturated brine and dried over magnesium 
sulfate and evaporated. The obtained residue was chromatographed on silica 
gel (n-hexane/ethyl acetate=1/1) and crystallized from a siopropyl 
ether/dichloromethane mixture to give 4.429 g of the objective compound as 
white crystal in 55% yield. 
m.p.: 122.degree.-123.degree. C. 
NMR (CDCl.sub.3) .delta.: 1.49 (9H, s); 2.26-2.44 (1H, m); 2.54-2.73 (1H, 
m); 3.95-4.00 (2H, m); 4.53 (1H, dd, J=7.2,3.4 Hz); 6.29 (1H, broad s); 
9.56 (1H, broad s). 
(2) 
{1-(N-tert-Butoxycarbonylhydrazinocarbonyl)-2-oxopyrrolidin-3-yl}triphenyl 
phosphonium bromide 
To 3.88 g (12.04 mmol) of the thus obtained 
1-(N-tert-butoxycarbonylaminocarbamoyl)-3-bromopyrrolidin-2-one and 3.157 
g (12.04 mmol) of triphenylphosphine was added 7 ml of tetrahydrofuran and 
the mixture was heated at 90.degree. C. for 7 hours to give a compound as 
wax, which was washed with tetrahydrofuran to give 4.077 g of the 
objective crude compound as waxy residue. 
(3) 
1-(N-tert-Butoxycarbonylhydrazinocarbonyl)-3-(3,5-di-tert-butyl-4-hydroxyb 
enzylidene)pyrrolidin-2-one (Ia-24) 
To a solution of 4.077 g of the thus obtained crude wittig base in 80 ml of 
absolute ethanol were added 1.64 g (7.0 mmol) of 
3,5-di-tert-butyl-4-hydroxybenzaldehyde and 1.95 ml (14 mmol) of 
triethylamine and the mixture was heated at 70.degree. C. for 3 hours. The 
reaction mixture was evaporated to give a residue, which was added with 
ethyl acetate and water and the mixture was stirred. The ethyl acetate 
layer was washed with water, dried over magnesium sulfate and evaporated 
under reduced pressure to give a residue, which was recrystallized from a 
dichloromethane/diisopropyl ether mixture to give 515 mg of the objective 
compound (Ia-24) as white crystal in 9.3% yield. Then the mother liquor 
was chromatographed on silica gel (n-hexane/ethyl acetate=4/1) and 
recrystallized from a dichloromethane/diisopropyl ether mixture to give 
607 mg of the objective compound as white crystal in 11.0% yield. 
m.p.: 228.degree.-229.degree. C. 
NMR (CDCl.sub.3) .delta.: 1.47 (18H, s); 1.49 (9H, s); 3.08 (2H, dt, 
J=6.8,2.6 Hz); 3.95 (2H, t, J=6.8 Hz); 5.58 (1H, s); 6.35 (1H, broad s); 
7.37 (2H, s); 7.48 (1H, t, J=2.6 Hz); 10.04 (1H, broad s). 
EXAMPLE 40 
1-(N-Hydrazinocarbonyl)-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidi 
n-2-one (Ia-25) 
To a solution of 2.023 g (4.40 mmol) of the compound (Ia-24) obtained in 
Example 39 in 20 ml of dichloromethane was added 5 ml of trifluoroacetic 
acid under ice-cooling. The reaction mixture was stirred at room 
temperature for 3 hours and evaporated under reduced pressure to give a 
residue, which was dissolved in ethyl acetate, washed with water, dried 
over magnesium sulfate and evaporated under reduced pressure. The obtained 
residue was chromatographed on silica gel (n-hexane/ethyl acetate=1/1) and 
crystallized from a ethyl acetate/n-hexane mixture to give 1.15 g of the 
objective compound as white crystal in 73% yield. 
m.p.: 225.degree.-226.degree. C. 
NMR (CDCL.sub.3) .delta.: 1.44 (18H, s); 3.09 (2H, dt, J=6.8, 2.6 Hz); 3.95 
(2H, t, J=6.8 Hz); 5.57 (1H, s); 7.37 (2H, s); 7.46 (1H, t, J=2.6 Hz); 
9.57 (1H, s). 
EXAMPLE 41 
(1) 3-Bromo-1-(N-dimethylaminocarbamoyl)pyrrolidin-2-one 
Substantially in the same manner as in Example 39 (1), 8.2 g (50 mmol) of 
3-bromopyrrolidin-2-one and 9.91 g (55 mmol) of 
N-dimethylaminophenylcarbamate in 100 ml of pyridine were treated to give 
7.96 g of the objective compound as white crystal in 63.6% yield. 
m.p.: 78.degree.-79.degree. C. 
NMR (CDCl.sub.3) .delta.: 2.26-2.44 (1H, m); 2.50-2.68 (1H, m); 2.66 (6H, 
s); 3.90 -4.00 (2H, m); 4.53 (1H, dd, J=10.6, 3.6 Hz); 9.04 (1H, s). 
(2) {1-(N-Dimethylaminocarbamoyl)-2-oxopyrrolidin-3-yl}phosphonium bromide 
Substantially in the same manner as in Example 39 (2), 4.25 g (17 mmol) of 
the thus obtained 3-bromo-1-(N-dimethylaminocarbamoyl)-pyrrolidin-2-one 
and 4.46 g (17 mmol) of triphenylphosphine were treated to give 8.31 g of 
the objective crude compound as waxy residue. 
(3) 
1-(N-Dimethylaminocarbamoyl)-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyr 
rolidin-2-one (Ia-26) 
Substantially in the same manner as in Example 39 (3), 8.31 g of the thus 
obtained {1-(N-dimethylaminocarbamoyl)-2-oxopyrrolidin-3-yl-phosphonium 
bromide, 3.79 g (16.2 mmol) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 
4.51 ml (32.4 mmol) of triethylamine were treated to give 2.91 g of the 
objective compound (Ia-26) in 46.4% yield. 
m.p.: 133.degree.-134.degree. C. 
NMR (CDCl.sub.3) .delta.: 1.47 (18H, s); 2.70 (6H, s); 3.04 (2H, d.t., 
J=6.8, 2.8 Hz); 3.96 (2H, t, J=6.8 Hz); 5.56 (1H, s); 7.36 (2H, s); 7.43 
(1H, t, J=2.8 Hz); 9.58 (1H, s). 
EXAMPLE 42 
(1) 3-Bromo-1-{N-(4-morpholino)carbamoyl}pyrrolidin-2-one 
Substantially in the same manner as in Example 39 (1), 8.2 g (50 mmol) of 
3-bromopyrrolidin-2-one and 12.22 g (55 mmol) of 
N-morpholinophenylcarbamate in 100 ml of pyridine were treated to give 
6.72 g of the objective compound as white crystal in 46% yield. 
m.p.: 118.degree.-119.degree. C. 
NMR (CDCl.sub.3) .delta.: 2.27-2.42 (1H, m); 2.52-2.73 (1H, m); 2.92 (4H, 
t, J=4.8 Hz); 3.83 (4H, t, J=4.8 Hz); 3.90-3.99 (2H, m); 4.54 (1H, dd, 
J=7, 3.4 Hz); 9.16 (1H, s). 
(2) [1-{N-(4-Morpholino)carbamoyl}-2-oxopyrrolidin-3-yl]phosphonium bromide 
Substantially in the same manner as in Example 39 (2), 4.09 g (14 mmol) of 
the thus obtained 3-bromo-1-{N-(4-morpholino)carbamoyl}pyrrolidin-2-one 
and 3.67 g (14 mmol) of triphenylphosphine were treated to give 7.46 g of 
the objective crude compound as waxy residue. 
(3) 
1-{N-(4-Morpholino)carbamoyl}-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)py 
rrolidin-2-one (Ia-27) 
Substantially in the same manner as in Example 39 (3), 7.46 g of the thus 
obtained [1-{N-(4-morpholino)carbamoyl}-2-oxopyrrolidin-3-yl]-phosphonium 
bromide, 3.16 g (13.5 mmol) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 
3.76 ml (27 mmol) of triethylamine were treated to give 5.96 g of the 
objective compound as white crystal in 99% yield. 
m.p.: 195.degree.-196.degree. C. 
NMR (CDCl.sub.3) .delta.: 1.47 (18H, s); 2.96 (4H, t, J=4.8 Hz); 3.05 (2H, 
d.t., J=6.6H, 2.8 Hz); 3.85 (4H, t, J=4.8 Hz); 3.95 (2H, t, J=6.6 Hz); 
5.76 (1H, s); 7.37 (2H, s); 7.44 (1H, t, J=2.8 Hz); 9.70 (1H, s). 
Physical constants of the compounds Ia-1-9, Ib-1-3 and Ic-1-3 obtained in 
Example 1-15 are shown in the following Table 1 No. 1-No. 5. 
TABLE 1 
__________________________________________________________________________ 
Elementary 
Analysis 
Compd. 
m.p. 
IR.sub.84 max Calcd. (%) 
No. (.degree.C.) 
(cm.sup.-1) 
NMR .delta. ppm Found (%) 
__________________________________________________________________________ 
Ia-1 134.about. 
(KBr) (CDCl.sub.3) 1.47(18H, s), 3.06(2H, d. 
(C.sub.20 H.sub.28 N.sub.2 O.sub.3) 
136 3600, t, J=3, 7Hz), 3.95(2H, t, J=7Hz), 
C, 69.74; 
3540(OH), 
5.20.about.5.35(1H, broad), 5.57(1H, s), 
H, 8.19; 
3388(NH), 
7.38(2H, s), 7.48(1H, t, J=3Hz), 
N, 8.13; 
2950(CH), 
8.48.about.8.65(1H, broad). 
C, 69.35; 
1706(CO), H, 8.26; 
N, 7.96. 
Ia-2 200.about. 
(KBr) (CDCl.sub.3) 1.47(18H, s), 2.95(3H, d. 
(C.sub.21 H.sub.30 N.sub.2 O.sub.3) 
201 3570, t, J=4.8Hz), 3.04(2H, dt, J=2.8, 
C, 70.36; 
3330, 7.1Hz), 3.95(2H, t, J=7.1Hz), 5.54 
H, 8.44; 
1710, (1H, s), 7.37(2H, s), 7.44(1H, t, J= 
N, 7.81; 
1638, 3Hz), 8.50.about.8.70(1H, broad). 
C, 70.54; 
1547. H, 8.47; 
N, 7.78. 
Ia-3 180.5.about. 
(KBr) (CDCl.sub.3) 1.47(18H, s), 3.05(6H, s), 
(C.sub.22 H.sub.32 N.sub.2 O.sub.3) 
183 3430, 3.09(2H, d, t, J=2.6, 7.1Hz), 3.89 
C, 70.94; 
2960, (2H, t, J=7.1Hz), 5.51(1H, s), 7.36 
H, 8.66; 
1712, (2H, s), 7.40(1H, t, J=2.6Hz). 
N, 7.52; 
1659. C, 70.89; 
H, 8.57; 
N, 7.40. 
Ia-4 202.about. 
(KBr) (CDCl.sub.3) 1.46(18H, s), 3.09(2H, d. 
(C.sub.20 H.sub.28 N.sub.2 O.sub.4) 
205 3630, 3600, 
t, J=2.2, 7.0Hz), 3.95(2H, t, J=7.0 
C, 66.64; 
3400, 3240 
Hz), 5.58(1H, s), 7.37(2H, s), 
H, 7.83; 
2950, 1700 
7.46(1H, t, J=2.2Hz). 
N, 7.77; 
1639. C, 66.52; 
H, 7.89; 
N, 7.76. 
Ia-5 187.5.about. 
(KBr) (CDCl.sub.3) 1.47(18H, s), 3.09(2H, d. 
(C.sub.21 H.sub.30 N.sub.2 O.sub.4. 
188.5 
3620, t, J=2.4, 7.3Hz), 3.85(3H, s), 3.95 
0.1H.sub.2 O) 
3270, (2H, t, J=7.3Hz), 5.59(1H, s), 7.37 
C, 67.03; 
2970, (2H, s), 7.45(1H, t, J=2.4Hz), 
H, 8.09; 
1706, 10.97(1H, s). N, 7.44; 
C, 66.95; 
H, 8.05; 
N, 7.47. 
Ia-6 164.about. 
(KBr) (CDCl.sub.3) 1.47(18H, s), 3.13(2H, d. 
(C.sub.21 H.sub.30 N.sub.4 O.sub.4) 
166 3565, t, J=2.4, 7.3Hz), 3.34(3H, s), 3.98 
C, 67.36; 
2960, (2H, t, J=7.3Hz), 5.59(1H, s), 7.37 
H, 8.07; 
1682, (2H, s), 7.49(1H, t, J=2.4Hz). 
N, 7.48; 
1655, C, 67.41; 
1630. H, 8.18; 
N, 7.35. 
Ia-7 130.about. 
(KBr) (CDCl.sub.3) 1.48(18H, s), 3.10(2H, d. 
(C.sub.22 H.sub.32 O.sub.2 O.sub.4) 
132 3510, t, J=2.6, 6.8Hz), 3.29(3H, s), 3.82 
C, 68.01; 
2960, (3H, s), 3.88(2H, t, J=6.8Hz), 5.54 
H, 8.30; 
1712, (1H, s), 7.37(2H, s), 7.45(1H, t, J= 
N, 7.21; 
1688, 2.6Hz). C, 68.01; 
1636. H, 8.30; 
N, 7.21. 
Ia-8 168.about. 
(KBr) (CDCl.sub.3) 1.30(3H, t, J=7.2Hz), 1.47 
(C.sub.22 H.sub.32 N.sub.2 O.sub.4) 
169 3598, (18H, s), 3.12(2H, d, t, J=2.6, 
C, 68.01; 
2960, 7.1Hz), 3.74(2H, q, J=7.2Hz), 3.98 
H, 8.30; 
1670, (2H, t, J=7.1Hz), 5.58(1H, s), 7.37 
N, 7.21; 
1625. (2H, s), 7.48(1H, t, J=2.6Hz), 9.62 
C, 67.73; 
(1H, s). H, 8.14; 
N, 7.13. 
Ia-9 179.about. 
(KBr) (CDCl.sub.3) 1.30(6H, d, J=6.6Hz), 1.47 
(C.sub.23 H.sub.34 N.sub.2 O.sub.4) 
180 3590, (18H, s), 3.11(2H, d.t, J=2.6, 7.0 
C, 68.63; 
3430, Hz), 3.97(2H, t, J=7.4Hz), 4.56(1H 
H, 8.51; 
1676, sept., J=6.6Hz), 5.56(1H, s), 7.37 
N, 6.96; 
1661, (2H, s), 7.45(1H, t, J=2.6Hz), 9.30 
C, 68.46; 
1625, (1H, s). H, 8.69; 
1592. N, 6.83. 
Ib-1 181.about. 
(KBr) (CDCl.sub.3) 1.48(18H, s), 5.00(2H, s), 
(C.sub.19 H.sub.26 N.sub.2 O.sub.3 S) 
185 3614, 5.42(b.s, NH), 5.56(s, OH), 7.42 
C, 62.95; 
3356, (2H, s), 7.57(1H, s), 8.66(b.s, 
H, 7.23; 
3188, NH). N, 7.73; 
1719, S, 8.85; 
1679. C, 62.91; 
H, 7.15; 
N, 7.80; 
S, 8.69. 
Ib-2 192.about. 
(KBr) (CDCl.sub.3) 1.47(18H, s), 4.98(2H, s), 
(C.sub.19 H.sub.26 N.sub.2 O.sub.4 S) 
197 3612, 5.57(1H, s), 7.40(2H, s), 7.56(1H, 
C, 60.29; 
3342, s). H, 6.92; 
3226, N, 7.40; 
1691, S, 8.47; 
1590. C, 60.01; 
H, 6.85; 
N, 7.29; 
S, 8.08. 
Ib-3 145.about. 
(KBr) (CDCl.sub.3) 1.48(18H, s), 3.37(3H, s), 
(C.sub.20 H.sub.28 N.sub.2 O.sub.4 S) 
147 3618, 5.00(2H, s), 5.57(1H, s), 7.26(2H, 
C, 61.20; 
3350, s), 7.58(1H, s), 9.11(1H, s), 
H, 7.19; 
1681, N, 7.14; 
1600. S, 8.17; 
C, 60,85; 
H, 7.36; 
N, 7.09; 
S, 8.06. 
Ic-1 173.about. 
(KBr) (CDCl.sub.3) 1.46(18H, s), 5.26(1H, b. 
(C.sub.19 H.sub.26 N.sub.2 O.sub.4) 
176 3614, s), 5.46(1H, s), 5.75(2H, s), 6.41 
C, 65.87; 
3378, (s, 1H), 7.55(2H, s), 8.02(1H, b. 
H, 7.57; 
3208, s). N, 8.09; 
1743, C, 65.61; 
1698, H, 7.94; 
1664. N, 7.47. 
Ic-2 203.5.about. 
(KBr) (CDCl.sub.3) 1.45(18H, s), 5.48(1H, s), 
(C.sub.19 H.sub.26 N.sub.2 O.sub.5) 
205 3624, 5.75(2H, s), 6.42(1H, s), 6.58(1H, 
C, 62.96; 
3326, b.s), 7.54(2H, s), 10.29(1H, s). 
H, 7.23; 
3268, N, 7.73; 
1728, C, 62.81; 
1674. H, 7.36; 
N, 7.56. 
Ic-3 (CHCl.sub.3) 
(CDCl.sub.3) 1.46(18H, s), 3.31(3H, s), 
3624, 5.47(1H, s), 5.78(2H, s), 6.44(1H, 
3300(b), 
s), 7.55(2H, s), 9.39(1H, s). 
1700, 
1592. 
__________________________________________________________________________ 
Experimental Examples are set forth to show that the compounds of the 
present invention are useful for anti-inflammatory agent. 
EXPERIMENTAL EXAMPLE 1 
Inhibitory Activity on PGE.sub.2 Production from Rat Synovia Cells 
LEW/Crj rats (male, 300-350 g weight) were subjected to synovectomy. The 
isolated synovia cells were subcultivated under a certain condition up to 
a well amount of cells for the experiment. The cells were dispensed to 
each well of a 96-well microtiter plate at a concentration of 
4.times.10.sup.3 /160 .mu.l/well and then cultivated for 72 hours in a 
CO.sub.2 incubator. Serial dilutions (20 .mu.l each) of a test compound 
and human IL-1 .beta.(final concentration: 30 U/ml) were added to the 
wells and incubated for 15 hours in a Co.sub.2 incubator. After the 
incubation, the supernatant was collected from each well and stored at 
-80.degree. C. until PGE.sub.2 assay. After thawed, PGE.sub.2 in each 
supernatant was determined by RIA using .sup.125 I--PGE.sub.2. The results 
are shown on Table 2. 
EXPERIMENTAL EXAMPLE 2 
Inhibitory Activity on LTB.sub.4 Production from Rat Peritoneal Cells 
To each male Jcl-SD rat (300-350 g weight) was intraperitoneally 
administered 10 ml of Hanks' solution containing 0.1% bovine serum albumin 
(hereinafter referred to as BSA) and 25 U/ml of heparin. Then the ascites 
were collected and centrifuged (1500 rpm.times.5 min., at 4.degree. C.). 
The resulting cell fraction (precipitation) was suspended and adjusted at 
1.times.10.sup.5 cells/ml with Hanks' solution containing 0.1% BSA. The 
thus obtained suspension (800 .mu.l, 8.times.10.sup.5 cells) was dispensed 
into polypropylene tubes and incubated at 37.degree. C. 10 min, and 
successively for 10 min. after addition of serial dilutions (100 .mu.l 
each) of a test sample. Next, 100 .mu.l of Ca-ionophore A23187 (final 
concentration: 1 .mu.M) was added to the resulting suspension and allowed 
to stand for 15 min, then the mixture was ice-cooled to terminate the 
reaction. The reaction mixtures were centrifuged (3000 rpm.times.5 min., 
at 4.degree. C.) to give supernatants, which were collected and stored at 
-80.degree. C. until LTB.sub.4 assay. After thawed, the LTB.sub.4 assay 
was performed by RIA using .sup.3 H--LTB.sub.4. The results are shown on 
Table 2. 
EXPERIMENTAL EXAMPLE 3 
Inhibitory Activity on IL-1 Production caused by The Stimulation of LPS in 
THP-1 Cells 
A suspension of THP-1 cells in RPMI 1640 solution (5.times.10.sup.5 
cells/ml) was dispensed to each well of a 24-well microtiter plate at 800 
.mu.l/well. Serial dilutions (100 .mu.l each) of a test compound and LPS 
(final concentration: 10 .mu.g/ml) were further added to each well and the 
plate was kept at 37.degree. C. for 24 hours. Then, the supernatant was 
collected from each well and centrifuged (3000 rpm.times.10 min.). The 
IL-1 assay was performed by RIA using .sup.125 I--IL-1 .beta.. The results 
are shown on Table 2. 
EXPERIMENTAL EXAMPLE 4 
Inhibitory Activity on Carrageenin-Induced Paw-Edema of Rat 
This test was performed by partially modifying the Winter et al's method 
(Winter, C. A. et al., Proc. Soc. Exp. Biol. Med., 111, P54, 1962). 
Namely, male LEW/Crj rats (6-week-old, 140-170 g weight) fasted for 24 
hours were used (7 to 8 rats per group). 
A solution (0.1 ml) containing 1% .lambda.-carrageenin (PICININ-A, 
Zushikagaku) was injected into the subplantar tissue of the right hind paw 
of each rat orally administered a test compound before 1 hour, to induce 
edema. The paw volume was calculated plethysmographically before and after 
the injection at an interval of 1 hour until 5 hours later. The inhibitory 
rate of the drug-administered group was calculated, with the vehicle group 
as the reference, to determine the efficacy of the test compounds by 
Dunnett-t assay. The anti-edema activity was indicated as ED.sub.30 
calculated, by regression analysis method, based on the inhibitory rate 
shown 3 or 4 hours later after the administration of carrageenin. The 
results are shown on Table 2. 
(Reference compound: 
N-methoxy-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-pyrrolidone 
(described in Kokai 61-257967)) 
TABLE 2 
__________________________________________________________________________ 
ED.sub.30 (mg/Kg) 
IC.sub.50 (.mu.M) Inhibitory Activities to 
Compound 
Rat SVC 
Rat PEC 
THP-1 Carrageenin-Induced Paw 
No. PGE.sub.2 
LTB.sub.4 
IL-1 Edema of Rat 
__________________________________________________________________________ 
Ia-1 0.4 4 20 18 
Ia-4 0.2 3 25 16 
Ia-6 0.009 3 34 9 
Reference 
0.005 6 &gt;100 3 
Compound 
__________________________________________________________________________ 
Experimental Example 5 
Inducing Activities on Injury at Tunica Mucosa of Rat 
Sixs LEW/Crj male rats (six week old, 140-160 g weight) were used per one 
group. A drug was orally administered to each rat fasted for 24 hours, 
then six hours later each rat were bled to death under anesthesia of 
ether. From each rat was taken out the stomach, in which about 6 ml of 
physiological saline was filled, then the stomach was steeped in 1% 
formalin solution for 15 min. The stomach was incised along with curvatura 
ventriculi major and observed with an actual-microscope to see the injured 
condition thereof, then the number of rats injuried at stomach and the 
length of hemorrhage macula were determined. The degree of the injury was 
shown as Lesion index (mm) which was the cumulative value of the length of 
hemorrhage macula in each administered group. The results are shown on 
Table 3. (Reference Compound: 
N-methoxy-3-(3,5-ditert-butyl-4-hydroxybenzyliden)-2-pyrrolidone 
(described in Kokai 61-257967)) 
TABLE 3 
______________________________________ 
Injury at Tunica Mucosa Ventriculi 
Comd. Dosage Number Degree of Injury 
No. mg/kg Occurrence/Sample 
(mm) 
______________________________________ 
Ia-1 10 0/6 0 .+-. 0 
100 0/6 0 .+-. 0 
200 0/6 0 .+-. 0 
Ia-4 100 0/8 0 .+-. 0 
200 0/8 0 .+-. 0 
400 3/8 0.2 .+-. 0.1 
Ia-6 10 0/6 0 .+-. 0 
30 3/6 0.6 .+-. 0.5 
100 3/6 1.0 .+-. 0.5 
Ref. 3 6/6 4.5 .+-. 1.3 
Comd. 10 6/6 7.2 .+-. 1.2 
30 6/6 11.2 .+-. 2.2 
______________________________________ 
As revealed from the above experimental results, the compounds of the 
present invention may be applied to an advantage anti-inflammatory agent 
which hardly causes stomach disease which has been the representative side 
effect caused by prior anti-inflammatory agents.