BE864505A - PROCESS FOR PREPARATION OF EPOXYSUCCINIC ACID DERIVATIVES, NEW PRODUCTS THUS OBTAINED AND THEIR USE IN PARTICULAR FOR THEIR ANTI-INFLAMMATORY ACTIVITY - Google Patents

Description

       

  "PROCESS FOR PREPARING EPOXYSUCCINIC ACID DERIVATIVES, NEW PRODUCTS THUS OBTAINED AND THEIR USE IN PARTICULAR

  
 <EMI ID = 1.1>

  
The present invention relates to acid derivatives

  
 <EMI ID = 2.1>

  
 <EMI ID = 3.1>

  
was known to be a compound of epoxysuccinic acid having thiolprotease inhibitory activity with anti-inflammatory activity.

  
 <EMI ID = 4.1>

  
However, this compound has a side effect, that is - &#65533; that is, acceleration of vascular permeability.

  
The novel epoxy succinic acid derivatives of the present invention are distinguished from the patented compound of the art

  
 <EMI ID = 5.1>

  
se and excellent anti-inflammatory activity and by the absence of acceleration of vascular permeability.

  
The present invention relates to novel derivatives of epoxysuccinic acid represented by the general formula:

  

 <EMI ID = 6.1>


  
 <EMI ID = 7.1>

  
 <EMI ID = 8.1>

  
 <EMI ID = 9.1>

  
 <EMI ID = 10.1>

  
thyles, or

  
 <EMI ID = 11.1>

  
 <EMI ID = 12.1>

  
 <EMI ID = 13.1>

  
 <EMI ID = 14.1> the general formula:

  
 <EMI ID = 15.1>

  
 <EMI ID = 16.1>

  
or this alylene group substituted with 1 to 3 hydroxy, methyl, thiol, methylthio, benzylthio, phenyl, substituted phenyl groups.

  
 <EMI ID = 17.1>

  
gene, an alkyl group containing 1 to 5 carbon atoms, benzyl

  
 <EMI ID = 18.1>

  
myle, alkoxycarbonyl, containing 2 to 5 carbon atoms, benzyloxy-

  
 <EMI ID = 19.1>

  
substituted with a nitro group, and R 9 is an amino group, or -OR 13

  
 <EMI ID = 20.1>

  
carbon, benzyl or an alkali metal cation, providing that

  
 <EMI ID = 21.1>

  
and their salts when R or R is hydroxy.

  
In this description and in the claims, unless otherwise indicated, the term "halogen" or "halo" refers to chlorine.

  
 <EMI ID = 22.1>

  
that are limited to trans isomers, i.e. the two carbonyl groups on the oxirane ring are in the trans configuration with respect to each other.

  
 <EMI ID = 23.1>

  
to 10 carbon atoms in R are cyclopropyl, ringbutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicycloheptyl, cyclooctyl, bicyclooctyl, adamantyl and the like. The substituent on the cycloalkyl group in R can be at any position and, when 2 or 3 substituents are present, they are the same or are different. Examples of cyclalkenyl group in

  
 <EMI ID = 24.1>

  
 <EMI ID = 25.1>

  
2-phenylethyloxy, 3-phenylpropyloxy, cinnamyloxy, styryloxy group and the like. Each substituent on the naphthyl and phenyl group in R6 can be independently at any position and, when 2 or 3 substituents are present, they are the same or are different. Examples of alkoxy group containing 1 to 12 atoms

  
of carbon in R are methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy and their isomeric forms.

  
 <EMI ID = 26.1>

  
at any position and, when 2 or 3 substituents are present, they are the same or are different. The placeholder on

  
the phenyl group attached to the alkylene group in A can be at any position and, when two or three substituents are present, they are the same or are different. Examples of alkali metal cations in R12 or R13 are independently potassium or sodium. Examples of the amino acid corresponding to the amino acid residue are glycine, α- or p-alanine, valine, leucine, serine, threonine, methionine, phenylalanine, tyrosi-

  
 <EMI ID = 27.1>

  
logues, and those with a suitable protection group.

  
 <EMI ID = 28.1>

  
are those with alkali metal cations, such as potassium and sodium.

  
In a preferred embodiment of the present invention, epoxysuccinic acid derivatives of the present invention can be prepared by the following sequence of reactions:

  

 <EMI ID = 29.1>
 

  
In this sequence of reactions, R 14 is a hydro-

  
 <EMI ID = 30.1>

  
notably hydrogen or an alkali metal cation, X is a halogen

  
 <EMI ID = 31.1>

  
where R 14 is halogen can be dissolved in an organic solvent, such as ethyl ether, benzene and cyclohexane. In the

  
 <EMI ID = 32.1>

  
organic, such as triethylamine, pyridine, and methylmorpholine, to give the epoxysuccinic acid diester (III). Also, in the starting material (II) where R14 is a hydroxy group, in the same organic solvent as that described above, R H

  
can be added in the presence of an acid catalyst, such as sulfuric acid, to give the epoxy succinic acid diester (III).

  
The epoxysuccinic acid diester (III) thus obtained

  
can be dissolved in an organic solvent or a mixture of the organic solvent and water. Examples of the organic solvent are

  
dioxane, acetone, tetrahydrofuran, dimethylformamide,

  
dimethylsulfoxide, and an alcohol such as ethanol, methanol,

  
 <EMI ID = 33.1>

  
that potash, soda and the like, in the same solvent as described above, or in water, can be added while cooling

  
 <EMI ID = 34.1>

  
culars of caustic alkali should be used in this reaction. The resulting mixture can be stirred for 5 to 120 minutes and, if necessary, followed by the addition of acetone, dioxane, ethyl ether or petroleum ether to give the compound.

  
 <EMI ID = 35.1>

  
R16 is an alkali metal cation, can be acidified with mineral acid such as sulfuric acid, hydrochloric acid,

  
or the like, and extracted with an organic solvent such as acetate

  
 <EMI ID = 36.1>

  
drogenous.

  
 <EMI ID = 37.1>

  
alkali metal, can be dissolved in an organic solvent such as

  
 <EMI ID = 38.1>

  
de, dichloromethane and the like, and then treated with a halogenating agent such as oxalyl chloride, to give the compound.

  
 <EMI ID = 39.1>

  
organic component, such as benzene, ethyl ether or dichlo-romethane, with an organic base such as triethylamine,

  
pyridine, methylmorpholine and the like, cooling

  
on ice or at room temperature, to give the compound
(VI).

  
In another method, the compound (IV), where R16 is hydrogen, can be dissolved in an organic solvent, such as ethyl ether, benzene, cyclohexane, dimethylformamide, dichloromethane, tetrahydrofurar.e and analog ?, and then set to

  
 <EMI ID = 40.1>

  
dicyclohexylcarbodiimide and / or in the presence of hydroxysuccinimide or

  
1-hydroxybenzothiazole to give compound (VI).

  
The compound (VI) thus obtained can be dissolved in

  
water, in an organic solvent, such as ethanol, benzyl alcohol, dioxane, ethyl ether and the like, and a mixture of water and the organic solvent. The resulting solution can be

  
reacted with the equimolar amount of a caustic alkali such as potash, soda, and the like, in the same solvent as described above, under ice-cooling or at room temperature. The resulting mixture can be stirred for 5 to

  
120 minutes and then, if necessary, followed by addition of ethanol, acetone, dioxane, ethyl ether or petroleum ether, to give the alkali metal salt of compound (VII). If desired, the protecting group attached to the carbonyl group in R of compounds (VI) or (VII) can be removed by the addition of an excess of the caustic alkali.

  
The obtained alkali metal salt can be collected by filtration and purified by washing or recrystallization. Salt can be acidified with a mineral acid, such as sulfuric acid,

  
and extracted with an organic solvent, such as ethyl acetate and benzene, to give the free acid.

  
If desired, the protecting groups attached to the amino or carboxyl group in R of compound (VI) or (VII) can be removed by catalytic reduction, using palladium-carbon or palladium black.

  
Starting material (II), where R14 is a hydroxy group, can be prepared by the process as described in Journal of Organic Chemistry, 24, 54 (1959), and starting material (II), where

  
R14 is halogen, can be prepared by the method as described in Journal of Medical Chemistry, 6, 233 (1963), or by the same

  
 <EMI ID = 41.1>

  
 <EMI ID = 42.1>

  
in large proportions, commercially available.

  
The compounds of the present invention effectively and specifically inhibit thiolproteases, such as papain, bromelains and certain genera of cathepsins in which certain sulfhydryl groups are essential for activity. On the other hand, the compounds of the present invention have no inhibitory activity.

  
 <EMI ID = 43.1>

  
trypsin, pepsin, the acid protease of Peacilomyces varioti with

  
 <EMI ID = 44.1>

  
esterolysis of benzoylarginine ethyl ester by kalliRein or against fibrinolysis by human plasmin.

  
The papain inhibitory activity of the compounds of the present invention was evaluated as follows: A 0.5 ml of a solution

  
 <EMI ID = 45.1>

  
 <EMI ID = 46.1>

  
 <EMI ID = 47.1>

  
 <EMI ID = 48.1>

  
33 mM phosphate (pH 6.8) with or without inhibitor. After incubation at

  
 <EMI ID = 49.1>

  
3'a 1% milk casein solution, in the same buffer as that described above, and further incubated at 40 [deg.] C for 10 minutes. Then the mixture was added to 5 ml of a tri- acid solution.

  
 <EMI ID = 50.1>

  
Toyo filter n [deg.] 4. The extinction of the filtrate was read at 280 nm. The percent inhibition was calculated from the formula

  
LOO x (B - A) / B; where B represents the absorption capacity without inhibition

  
 <EMI ID = 51.1>

  
shown in Table I. The compound numbers in Table I are as defined in the Examples, as described below.

  
 <EMI ID = 52.1>

TABLE I

  

 <EMI ID = 53.1>
 

  
i TABLE I (Continued)
 <EMI ID = 54.1>
  <EMI ID = 55.1>

  

 <EMI ID = 56.1>


  
The compounds of the present invention also exhibit marked anti-inflammatory activity, as measured by their ability to inhibit adjuvant-induced polyarthritis in rats. The effect of the compounds of the present invention on the development

  
 <EMI ID = 57.1>

  
assessed as follows: adjuvant arthritis is produced by a single intracutaneous injection of 0.1 ml of the adjuvant mixture

  
 <EMI ID = 58.1>

  
known as Aoyama B, suspended in 0.6% liquid paraffin in the middle part of the distal tail of so-called Sprague Dawley rats (8 weeks old). The compounds suspended in a 0.5% solution. of carboxymethylcellulose protect the animal against the development of lesions due to arthritis caused by the adjuvant during oral daily administration, starting on the day of the adjuvant injection and continuing for 24 days afterwards. The activity is presented by the mean percentage inhibition for the increase in the volume of the hind leg of 8 rats per group, on days n [deg.] 17 and 23 when the legs were inflamed and reached maximum volumes. The result is shown in Table II.

   The compound numbers in Table II are as defined in the Examples, as described below.

TABLE II

  

 <EMI ID = 59.1>


  
 <EMI ID = 60.1>

  
oral, parenteral and rectal diet, for example tablets,

  
powder packets, cachets, dragees, capsules, solutions, suspensions, sterile injectable forms, suppositories, candles and the like. The support employed can be, for example, a solid or a liquid. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar-agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, water and the like. Likewise, the carrier or diluent can include a time-delayed release material well known in the art, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.

  
The compounds of the present invention can be used in the form of anti-inflammatory agents, at doses of 10 - 700 mg / kg, preferably 20 - 100 mg / kg in oral or injectable preparations as described above. , to protect mammals against the development of arthritis.

  
The compounds of the present invention have extremely low toxicity. Thus, they hardly show any acute oral toxicity in mice, at a dose of less than 2 g / kg of body weight. In addition, no side effects were observed after administration of 1 g / kg / day orally for 30 days in laboratory animals.

  
The following examples are an illustration of the present invention, without any limitation.

  
EXAMPLE 1

  
To a solution of 3.0 g (0.026 mole) of cyclohexanol and 2.1 g (0.026 mole) of pyridine dissolved in 50 ml of ethyl ether

  
 <EMI ID = 61.1>

  
Nyl dissolved in 5 ml of ethyl ether was added dropwise, while stirring and cooling to 0 to -5 [deg.] C. After the mixture was stirred for 30-60 minutes, the precipitated salt consisting of pyridyne hydrochloride was filtered off. The ethyl ether layer thus obtained was washed with water, dried over anhydrous sodium sulfate and distilled to dryness. The resulting residue was chromatographed on silica gel using n-hexane-acetone,
(10: 1) as a mixture of solvents, to give dicyclohexyl epoxysuccinate (EP-1) as an oil. Yield: 3.3 g (75%), boiling point 225 - 227 [deg.] C (6 mm Hg).

  
EXAMPLE 2
(a) In a solution of 2.5 g (0.0085 mol) of dicyclohexyl epoxysuccinate dissolved in 40 ml of cyclohexanol, a solution of 0.4 g of potassium hydroxide dissolved in 3 ml of methanol was added dropwise , at room temperature. After mixing

  
was stirred for 2 hours, thereto 300 ml of ethyl ether was added. Then the mixture was allowed to stand overnight, at about about 5 [deg.] C. The precipitate thus formed was filtered and recrystallized from an ethanol-ether mixture to give potassium cyclohexyl epoxysuccinate (EP-2) in the form of colorless needles; Yield: 1.2 a (48%), m.p. 187 - 189 [deg.] C.

  
 <EMI ID = 62.1> te of dicyclohexyl dissolved in 30 ml of dimethylformamide, we have

  
 <EMI ID = 63.1>

  
 <EMI ID = 64.1> mixture has been filtered. Then, in the solution, 400 ml of acetone was added and the mixture was allowed to stand for a while.

  
 <EMI ID = 65.1>

  
ne to give cyclohexyl potassium epoxysuccinate
(EP-2) in the form of colorless sharpeners. Yield: 0.74 g (74%), m.p. 188 - 190 [deg.] C.

  
EXAMPLE 3

  
In a solution of 3.0 g (0.026 mole) of 2-cis-methylcyclohexanol and 2.1 g (0.026 mole) of pyridine dissolved in

  
 <EMI ID = 66.1>

  
2.52 g (0.015 mole) of epoxy succinyl chloride dissolved in

  
5 ml of ethyl ether, while stirring and cooling between

  
0 and -5 [deg.] C. After the mixture has been stirred for 30-60 minutes,

  
the precipitated salt formed from pyridine hydrochloride was filtered off. The ethyl ether layer thus obtained was washed with water, dried.

  
over anhydrous sodium sulfate and dry distilled. The resulting residue was chromatographed on silica gel using n-hexane-acetone (10: 1) as solvent, to give di-2'-cis-methylcyclohexyl epoxysuccinate (EP-3) as d. 'oil. Yield: 3.3 g (77%).

  
 <EMI ID = 67.1>

  
s), 5.00 (2H, b.s.).

  
The following compounds were obtained from the materials

  
 <EMI ID = 68.1>

  
di-2'-trans-chlorocyclohexyl epoxysuccinate (EP-7),

  
 <EMI ID = 69.1>

  
 <EMI ID = 70.1>

  
(EP-13)

  
EXAMPLE 4

  
 <EMI ID = 71.1>

  
 <EMI ID = 72.1>

  
 <EMI ID = 73.1>

  
 <EMI ID = 74.1> ge was stirred for 10 to 15 minutes, thereto was added 1000 ml of acetone. The crystals formed were filtered off and recrystallized.

  
 <EMI ID = 75.1>

  
cyclohexyl and potassium (EP-4) as colorless crystals. Yield: 0.6 g (15%), m.p. > 300 [deg.] C (decomposition).

  
 <EMI ID = 76.1>

  
J = 2Hz), 4.95 (1H, m).

  
The following compounds were obtained from the corresponding materials by a process similar to that described in Example 4:

  
2'-trans-methylcyclohexyl potassium epoxysuccinate (EP-6)

  
2'-trans-chlorocyclohexyl potassium epoxysuccinate (EP-8)

  
3'-cis-bromocyclohexyl potassium epoxysuccinate (EP-10 /

  
 <EMI ID = 77.1>

  
hexyl and potassium (EP-12)

  
2 ', 6'-trans-dimethylcyclohexyl and potassium epoxysuccinate (EP-14).

EXAMPLE 5

  
In a solution of 3.0 g (0.026 mole) of 4-transmethylcyclohexanol and 2.1 g (0.026 mole) of pyridine dissolved in 50 ml of ethyl ether, a solution of 2.52 g (0.015 mole) of chloride of epoxysuccinyl dissolved in 5 ml of ethyl ether was added dropwise, while being stirred and cooled

  
 <EMI ID = 78.1>

  
minutes, the precipitated salt formed from pyridine hydrochloride was filtered off. The ethyl ether layer thus obtained was washed with

  
 <EMI ID = 79.1>

  
to give di-4'-trans-methylcyclohexyl epoxysuccinate
(EP-15) in the form of an oil. Yield: 3.8 g (88%).

  
 <EMI ID = 80.1>

  
4.69 (2H, b.s.).

  
The following compounds were obtained from the corresponding materials, by a process similar to that described in Example 5:

  
di-4'-cis-methylcyclohexyl epoxysuccinate (EP-17) di-4'-trans-chlorocyclohexyl epoxysuccinate (EP-19)

  
 <EMI ID = 81.1>

  
hexyl (EP-21)

  
di-3,5'-trans-dichlorocyclohexyl epoxysuccinate
(EP-23).

EXAMPLE 6

  
 <EMI ID = 82.1>

  
of di-4'-trans-methylcyclohexyl dissolved in 50 ml of dimethylformamide, 5.14 ml of aqueous solution was added dropwise

  
 <EMI ID = 83.1>

  
that the mixture was stirred for 10 to 15 minutes, to this was added
1,000 ml of acetone. The crystals formed were filtered and recrystallized from acetone-water to give 4'-transmethylcyclohexyl potassium epoxysuccinate (EP-16) as crystals.

  
 <EMI ID = 84.1>

  
 <EMI ID = 85.1>

  
J = 2Hz), 4.76 (1H, m).

  
The following compounds were obtained from the corresponding materials, by the process similar to that described in Example 6:

  
4'-cis-methylcyclohexyl potassium epoxysuccinate (EP-18)

  
4'-trans-chlorocyclohexyl potassium epoxysuccinate (EP-20)

  
3'-cis-chloro-4'-trans-bromocyclohexyl potassium epoxysuccinate (EP-22)

  
3 ', 5'-trans - dichlorocyclohexyl epoxysuccinate and

  
 <EMI ID = 86.1>

  
EXAMPLE 7

  
 <EMI ID = 87.1>

  
and 2.1 g (0.026 mol) of pyridine dissolved in 50 ml of ether

  
 <EMI ID = 88.1>

  
cooling between 0 and -5 [deg.] C, a solution of 2.52 g (0.015 mol) of epoxy succinyl chloride dissolved in 5 ml of ethyl ether.

  
 <EMI ID = 89.1>

  
Precipitated salt, formed from pyridine hydrochloride, was filtered off. The ethyl ether layer thus obtained was washed with water, dried over anhydrous sodium sulfate and distilled to dryness. The resulting residue was chromatographed on silica gel using a mixture of n-hexane- acetone (10: 1) as a solvent to give dicyclopentyl epoxysuccinate (EP-25) as an oil Yield: 3.6 g (77%), boiling point 221 - 223 [deg.] C ( 6 mm Hg).

  
The following compound was obtained from the corresponding material by the method similar to that described in Example 7:

  
 <EMI ID = 90.1>

  
EXAMPLE 8
(a) When the procedure similar to that described in Example 2 (a) was carried out using dicyclopentyl epoxysuccinate (2.5 g) and cyclopentanol (40 ml), instead of epoxysuccinate dicyclohexyl and cyclohexanol, respectively, was obtained as crystals of cyclopentyl and potassium epoxysuccinate (EP-26). Yield: 1.2 g (48%), p. f. 157 - 160'C
(recrystallized from water-acetone).
(b) When the procedure similar to that described in <EMI ID = 91.1>

  
cyclopentyl potassium epoxysuccinate (EP-26) was obtained in the form of crystals. Yield: 0.68 g (68%), m.p.
157-160 [deg.] C (recrystallized from water-acetone).

  
The following compound was obtained from the corresponding material by a process similar to that described in Example 8 (b):

  
 <EMI ID = 92.1>

  
EXAMPLE 9

  
In a solution of 3.0 g (0.026 mole) of 3-cis-chlorocyclopentanol and 2.1 g (0.026 mole) of pyridine dissolved in

  
50 ml of ethyl ether, a solution of 2.52 g (0.015 mole) of epoxysuccinyl chloride dissolved in 5 ml of ethyl ether was added dropwise while stirring and cooling between

  
0 and -5 [deg.] C. Then, when the procedure similar to that of Example 7 has been carried out, the epoxysuccinate of di-3'-cis-chlorocy-

  
1 clopentyl (EP-29) was obtained in the form of an oil.

  
 <EMI ID = 93.1>

  
The following compounds were obtained from the corresponding materials, by a process similar to that described in Example 9:

  
di-3'-trans-methylcyclopentyl epoxysuccinate (EP-31) di-2'-trans-bromocyclopentyl epoxysuccinate (EP-33).

EXAMPLE 10

  
When the procedure similar to that described in

  
 <EMI ID = 94.1>

  
cis-chlorocyclopentyl (1.0 g), instead of dicyclopentyl epoxysuccinate, 3'-cis-chlorocyclopentyl potassium epoxysuccinate (EP-30) was obtained as crystals. Yield: 0.52 g

  
 <EMI ID = 95.1>

  
The following compounds were obtained from the corresponding materials by the process similar to that described in Example 10:

  
 <EMI ID = 96.1>

  
After the mixture was stirred for 30-60 minutes, the formed precipitated salt of pyridine hydrochloride was filtered off. The ethyl ether layer thus obtained was washed with water, dried over anhydrous sodium sulfate and distilled to dryness. The resulting residue was chromatographed on silica gel using n-hexane-acetone (10: 1) as a mixture of solvents to give dicyclooctyl epoxysuccinate (EP-35) as an oil. . Yield: 3.4 g (88%).

  
 <EMI ID = 97.1> EXAMPLE 12

  
 <EMI ID = 98.1>

  
of dicyclooctyl dissolved in 50 ml of dimethylformamide, 5.14 ml of 3N aqueous potassium hydroxide solution was added dropwise, while stirring and cooling to C [deg.] C. After the mixture was stirred for 10 to 15 minutes, 1000 ml of acetone was added thereto. The crystals formed were filtered off and recrystallized from

  
 <EMI ID = 99.1>

  
4.79 (1H, m).

EXAMPLE 13

  
To a solution of 3.0 g (0.02 mole) of 2-adamantanol and 1.6 g (0.02 mole) of pyridine dissolved in 50 ml of ethyl ether was added dropwise a solution of 2.0 g

  
 <EMI ID = 100.1>

  
ethyl, while stirring and cooling between 0 and -5 [deg.] C. After the mixture was stirred for 30-60 minutes, the formed precipitated salt of pyridine hydrochloride was filtered off. Layer

  
 <EMI ID = 101.1>

  
mixture of n-hexane-acetone (10: 1) as a solvent to give di-2-adamantyl epoxysuccinate (EP-37) in the form of colorless crystals. Yield: 3.1 g (79%), m.p. 152-154 [deg.] C (recrystallized from n-hexane-acetone).

  
EXAMPLE 14

  
In a solution of 5.0 g (0.016 mol) of di-2-adamantyl epoxysuccinate dissolved in 50 ml of dimethylformamide, one

  
 <EMI ID = 102.1>

  
 <EMI ID = 103.1>

  
 <EMI ID = 104.1>

  
in Example 12, 2-adamantyl potassium epoxysuccinate (EP-38) was obtained as colorless crystals.

  
 <EMI ID = 105.1> EXAMPLE 15

  
In a solution of 0.8 g (0.011 mol) of cyclopropane-

  
 <EMI ID = 106.1>

  
of ethyl ether, a solution of 1.0 g (0.0006 mole) of epoxy succinyl chloride dissolved in 3 ml of ethyl ether, was added dropwise, while stirring and cooling to 0 to -5 [deg.] C. After the mixture was stirred for 30-50 minutes, the formed precipitated salt of pyridine hydrochloride was filtered off. The ethyl ether layer thus obtained was washed with water, dried over

  
sodium sulfate anhydrous and dry distilled. The resulting residue was chromatographed on silica gel using n-hexane-acetone (10: 1) as a mixture of solvents to give

  
 <EMI ID = 107.1>

  
Mass: m / e 240 (M).

  
 <EMI ID = 108.1>

  
Hz)

  
EXAMPLE 16

  
 <EMI ID = 109.1>

  
was stirred for 10 to 15 minutes, 500 ml of acetone was added. The crystals formed were filtered ;; and recrystallized from acetone

  
 <EMI ID = 110.1>

  
methyl (EP-40) in the form of colorless crystals. Yield: 0.15 g
(26%), m.p. > 300 [deg.] C (decomposition).

  
 <EMI ID = 111.1>

  
EXAMPLE 17

  
In a solution of 3.0 g (0.026 mol) of cyclohexane-

  
 <EMI ID = 112.1>

  
of ethyl ether, a solution of 2.52 g (0.015 mole) of epoxy succinyl chloride dissolved in 5 ml of ethyl ether was added

  
 <EMI ID = 113.1>

  
After the mixture was stirred for 30-60 minutes, the formed precipitated salt of pyridine hydrochloride was filtered off. The thus obtained chyl ether layer was washed with water, dried over anhydrous sodium sulfate and distilled to dryness. The resulting residue was chromatographed on silica gel using n-hexane-.

  
 <EMI ID = 114.1>

  
dicyclohexanemethyl cinate (EP-41) in the form of an oil. Yield:
3.6 g (84%), boiling point 238-240 [deg.] C (6 mm Hg).

  
The following compounds were obtained from the corresponding materials by a process similar to that described in Example 17:

  
dicyclopentanemethyl epoxysuccinate (EP-41)

  
 <EMI ID = 115.1>

  
dibornyl epoxysuccinate (EP-53)

  
dinorbornyl epoxysuccinate (EP-55)

  
dinorbor-5-en-2-yl epoxysuccinate (EP-57).

EXAMPLE 18

  
In a solution of 5.0 g (0.015 mole) of epoxysuccinate

  
of dicyclohexanemethyl dissolved in 50 ml of dimethylformamide, 5.14 ml of 3N aqueous potassium hydroxide solution was added dropwise, dropwise, while stirring and cooling to 0 [deg.] C. After the mixture was stirred for 10 to 15 minutes, 1000 ml of acetone was added thereto. The crystals formed were filtered off and recrystallized from acetone-water to give potassium cyclohexanemethyl epoxysuccinate (EP-42) as colorless crystals. Yield:

  
 <EMI ID = 116.1>

  
 <EMI ID = 117.1>

  
4.85 (1H, m).

  
The compounds were obtained from the corresponding materials by the process similar to that described in Example 18:

  
 <EMI ID = 118.1>

  
(EP-44)

  
potassium 1-cyclopentaneethyl epoxysuccinate
(EP-46)

  
potassium and &#65533; -adamantanemethyl epoxysuccinate

  
 <EMI ID = 119.1>

  
 <EMI ID = 120.1>

  
(EP-52)

  
bornyl potassium epoxysuccinate (EP-54) norbornyl potassium epoxysuccinate (EP-56) norbor-5-en-2-yl potassium epoxysuccinate
(EP-58).

  
EXAMPLE 19

  
In a solution of 3.0 g (0.026 mole) of 2-cyclopentaneethanol and 2.1 g (0.026 mole) of pyridine dissolved in 50 ml of ethyl ether, a solution of 2.52 g was added dropwise.
(0.015 mol) of epoxysuccinyl chloride dissolved in 5 ml of ethyl ether, while stirring and cooling to 0 to -5 [deg.] C. After the mixture was stirred for 30-60 minutes, the formed precipitated salt of pyridine hydrochloride was filtered off. The ethyl ether layer thus obtained was washed with water, dried over anhydrous sodium sulfate and distilled to dryness. The resulting residue

  
was chromatographed on silica gel using a mixture of n-hexane-acetone (10: 1) as a solvent to give di-2-cyclopentaneethyl epoxysuccinate (EP-59) as an oil. Yield: 3.2 g (74%).

  
 <EMI ID = 121.1>

  
J = 6.7Hz).

  
The following compound was obtained from the corresponding material by a process similar to that described in Example 19:

  
di-2-cyclohexaneethyl epoxysuccinate (EP-61).

  
EXAMPLE 20

  
In a solution of 5.0 g (0.015 mole) of epoxysuccinate

  
of di-2-cyclopentaneethyl dissolved in 50 ml of dimethylformamide, 5.14 ml of aqueous solution of 3N potassium hydroxide was added dropwise, while stirring and cooling to 0 [deg.] C. After the mixture was stirred for 10 to 15 minutes, 1000 ml of acetone was added thereto. The crystals formed were filtered and recrystallized from acetone-water to give 2-cyclopentane-ethyl potassium epoxysuccinate (EP-60) as colorless crystals.

  
 <EMI ID = 122.1> Yield: 1.1 g (27%), m.p.> 300 [deg.] C (decomposition).

  
 <EMI ID = 123.1>

  
4.18 (2H, t, J = 6.7Hz).

  
The following compound was obtained from the corresponding material by a process similar to - ^ described in Example 20:

  
 <EMI ID = 124.1>

  
(EP-62).

  
-EXAMPLE 21

  
In a solution of 3.0 g (0.023 mole) of 3-cyclopentanepropanol and 1.82 g (0.023 mole) of pyridine dissolved in 50 ml of ethyl ether, a solution of 2.0 g (0.012 mole) of chloride

  
 <EMI ID = 125.1>

  
dropwise, while being stirred and cooled to 0 to -5 [deg.] C. After the mixture was stirred for 30-60 minutes, the formed precipitated salt of pyridine hydrochloride was filtered off. The ethyl ether layer thus obtained was washed with water, dried.

  
over anhydrous sodium sulfate and dry distilled. The resulting residue was chromatographed on silica gel using the mixture of n-hexane-acetone (10: 1) as a solvent to give di-3-cyclopentanepropyl epoxysuccinate (EP-63) as a. 'oil. Yield: 3.8 g (83%).

  
 <EMI ID = 126.1>

  
ple 21:

  
di-3-cyclohexanepropyl epoxysuccinate (EP-65) di-4-cyclohexanebutyl epoxysuccinate (EP-67).

EXAMPLE 22

  
 <EMI ID = 127.1>

  
was stirred for 10 to 15 minutes, thereto was added 1000 ml of acetone. The crystals formed were filtered and recrystallized from acetone-water to give 3-cyclopentanepropyl potassium epoxysuccinate (EP-64) as colorless crystals.

  
 <EMI ID = 128.1> Yield: 0.5 g (13%), m.p. > 300 [deg.] C (decomposition).

  
 <EMI ID = 129.1>

  
4.15 (2H, t, J = 6.7Hz).

  
The following compounds were obtained from the corresponding materials by a process similar to that described in Example 22:

  
3-cyclohexanepropyl potassium epoxysuccinate
(EP-66),

  
4-cyclohexanebutyl potassium epoxysuccinate
(EP-68).

  
EXAMPLE 23

  
In a solution of 3.0 g (0.027 mole) of 3-cyclohexenemethanol and 2.1 g (0.027 mole) of pyridine dissolved in 50 ml of ethyl ether, a solution of 2.52 g was added dropwise.
(0.015 mol) of epoxysuccinyl chloride dissolved in 5 ml of ethyl ether, while stirring and cooling to 0 to -5 [deg.] C. After the mixture was stirred for 30-60 minutes, the formed precipitated salt of pyridine hydrochloride was filtered off. The ethyl ether layer thus obtained was washed with water, dried over anhydrous sodium sulfate and distilled to dryness. The resulting residue

  
was chromatographed on silica gel using a mixture of n-hexane-acetone (10: 1) as a solvent to give di-3-cyclohexenemethyl epoxysuccinate (EP-69) as an oil. Yield: 3, 5 g (81%).

  
 <EMI ID = 130.1>

  
7.2Hz), 5.64 (4H, s).

  
The following compounds were obtained from the corresponding materials by a process similar to that described in Example 23:

  
di-2-cyclopentenemethyl epoxysuccinate (EP-71)

  
 <EMI ID = 131.1>

  
EXAMPLE 2

  
In a solution of 5.0 g (0.016 mol) of epoxysuccinate

  
of di-3-cyclohexenemethyl dissolved in 50 ml of dimethylformamide, 5.14 ml of 3N aqueous solution of potassium hydroxide was added dropwise, while stirring and cooling to 0.degree. After the mixture

  
&#65533; &#65533;

  
ge was stirred for 10 to 15 minutes, to this was added 1000 ml

  
 <EMI ID = 132.1>

  
4.07 (2H, d, J = 6Hz), 5.66 (2H, s).

  
The following compounds were obtained from the corresponding materials by a process similar to that described in Example 24:

  
 <EMI ID = 133.1>

  
(EP-72)

  
4-cyclooctenemethyl potassium epoxysuccinate
(EP-74).

EXAMPLE 25

  
In a solution of 3.0 g (0.029 mole) of tetrahydrofurfuryl alcohol (tetrahydro-2-furanemethanol) and 2.3 g (0.029 mole) of pyridine dissolved in 50 ml of ethyl ether, was added dropwise

  
 <EMI ID = 134.1>

  
filtered. The ethyl ether layer thus obtained was washed with water, dried over anhydrous sodium sulfate and distilled to dryness. The resulting residue was chromatographed on silica gel using n-hexane-acetone (10: 1) as a mixture of solvents to provide

  
 <EMI ID = 135.1>

  
of oil. Yield: 3.2 g (73%), boiling point 221 - 224 [deg.] C

  
(6 mm Hg).

  
The following compound was obtained from the corresponding material by a process similar to that described in Example 25:

  
di-2-furanemethyl epoxysuccinate (EP-77).

  
EXAMPLE 26

  
In a solution of 5.0 g (0.016 mol) of epoxysuccinate

  
of di-tetrahydro-2-furanemethyl dissolved in 50 ml of dimethylformamide, 5.14 ml of an aqueous solution was added dropwise <EMI ID = 136.1>

  
that the mixture was stirred for 10 to 15 minutes, to this was added
1,000 ml of acetone. The crystals formed were filtered and recrystallized from acetone-water to give tetra-epoxysuccinate.

  
 <EMI ID = 137.1>

  
colorless.

  
Yield: 0.6 g (16%), m.p. > 300 [deg.] C (decomposition).

  
 <EMI ID = 138.1>

  
4.20 (2H, t, J = 6Hz).

  
The following compound was obtained from the corresponding material by a process similar to that described in Example 26:

  
2-furanemethyl potassium epoxysuccinate (EP-78).

EXAMPLE 27

  
In a solution of 3.0 g (0.029 mole) of 2-thienyl alcohol (2-thiofuranemethanol) and 2.3 g (0.029 mole) of pyridine

  
 <EMI ID = 139.1>

  
in 5 ml of ethyl ether, while stirring and cooling to 0 to -5 [deg.] C. Then, when the procedure similar to that

  
 <EMI ID = 140.1>

  
(82%), m.p. > 300 [deg.] C (decomposition).

  
Mass: m / e 324 (M)

  
 <EMI ID = 141.1>

  
EXAMPLE 28

  
When the procedure as described in Example 26

  
was performed using di-2-thenyl epoxysuccinate (1.9 g) instead of di-tetrahydro-2-furanethyl epoxysuccinate, 2'-thenyl potassium epoxysuccinate (EP -80) in the form

  
colorless crystals recrystallized from water-acetone (yield:

  
 <EMI ID = 142.1>

  
7.35 (2H, m), 7.35 - 7.60 (1H, m).

  
EXAMPLE 29

  
 <EMI ID = 143.1> and 2.0 g (0.025 mole) of pyridine dissolved in 50 ml of ethyl ether, a solution of 2.35 g (0.014 mole) of epoxy succinyl chloride dissolved in 5 ml of ether ethyl was added dropwise while being stirred and cooled to 0 to -5 [deg.] C. Then, when the procedure as described in Example 23

  
was carried out, the di-naphthylmethyl epoxysuccinate was obtained

  
 <EMI ID = 144.1>

  
m.p. 105-107 [deg.] C (in n-hexane-acetone).

  
The following compounds were obtained from the corresponding materials by a process similar to that described in Example 29:

  
 <EMI ID = 145.1>

  
di-4 ', 5' -dimethyl-1 '-naphthylmethyl epoxysuccinate
(EP-87).

EXAMPLE 30

  
When a procedure similar to that described in the example

  
 <EMI ID = 146.1>

  
corresponding by a process similar to that described in Example 30.

  
 <EMI ID = 147.1>

EXAMPLE 31

  
In a solution of 3.0 g (0.025 mole) of p-methylbenzyl alcohol and 2.0 g (0.025 mole) of pyridine dissolved in

  
 <EMI ID = 148.1>

  
Epoxy succinyl ride dissolved in 5 ml of ethyl ether was added dropwise, while stirring and cooling to 0 to -5 [deg.] C. After the mixture was stirred for 30-60 minutes, the formed precipitated salt of pyridine hydrochloride was filtered off. The ethyl ether layer thus obtained was washed with water, dried over anhydrous sodium sulfate and distilled for 2 sec. The resulting residue was chromatographed on silica gel using a mixture of n-hexane-acetone (10: 1) as a solvent to give di-p-methylbenzyl epoxysuccinate (EP-89) as colorless crystals. . Yield: 3.5 g (84%), m.p.

  
 <EMI ID = 149.1>

  
The following compounds were obtained from the corresponding materials by a process similar to that described in Example 31:

  
 <EMI ID = 150.1>

  
added dropwise 2.0 ml of an aqueous solution of potassium hydroxide

  
 <EMI ID = 151.1>

  
was stirred for 10 to 15 minutes, to which was added 200 ml of acetone.

  
 <EMI ID = 152.1>

  
 <EMI ID = 153.1>

  
corresponding by a method similar to that described in Example 32:

  
o-methylbenzyl potassium epoxysuccinate (EP-92)

  
 <EMI ID = 154.1>

  
sium (EP-96)

  
2'-bromo-3'-methylbenzyl potassium epoxysuccinate (EP-98)

  
 <EMI ID = 155.1>

  
tassium (EP-100).

EXAMPLE 33

  
In a solution of 3.0 g (0.022 mol) of p-methoxy-benzyl alcohol and 1.74 g (0.022 doctor blade) of pyridine dissolved in

  
50 ml of ethyl ether, a solution of 1.85 g (0.011 mole)

  
of epoxy succinyl chloride dissolved in 5 ml of ethyl ether was added dropwise, while being stirred and cooled

  
 <EMI ID = 156.1>

  
minutes, the precipitated salt formed from pyridine hydrochloride was filtered off. The ethyl ether layer thus obtained was washed with water, dried over anhydrous sodium sulfate and distilled at

  
dry. The resulting residue was chromatographed on silica gel using a mixture of n-hexane-acetone (10: 1) as a solvent to give di-p-methoxybenzyl epoxysuccinate (EP-101) in the form of needles. colorless. Yield: 3.1 g (78%), m.p. 82 -
84 [deg.] C (in n-hexane-acetone).

  
The following compound was obtained from the material

  
 <EMI ID = 157.1>

  
EXAMPLE 34

  
In a solution of 1.9 g (0.0051 mole) of epoxysuccinate

  
of di-p-methoxybenzyl dissolved in 19 ml of dimethylformamide,

  
2.0 ml of a 3N aqueous potassium hydroxide solution was added dropwise while stirring and cooling to 0 [deg.] C. After the mixture was stirred for 10 to 15 minutes, 200 ml of acetone was added thereto. The crystals formed were filtered and recrystallized from wateracetone to give potassium p-methoxybenzylec epoxysuccinate (EP-102) in the form of colorless needles. Yield: 0.95 g
(47%), m.p. 189 - 193 [deg.] C (decomposition).

  
The following compound was obtained from the corresponding material by a process similar to that described in Example 34:

  
 <EMI ID = 158.1>

  
benzyl (EP-104).

  
EXAMPLE 35

  
In a solution of 3.0 g (0.013 mole) of o-iodobenzyl alcohol and 1.0 g (0.013 mole) of pyridine dissolved in 50

  
ml of ethyl ether, a solution of 1.2 g (0.007 mol) of epoxysuccinyl chloride dissolved in 5 m2 of ethyl ether was

  
 <EMI ID = 159.1>

  
and -5 [deg.] C. After the mixture was stirred for 30-60 minutes, the formed precipitated salt of pyridine hydrochloride was filtered off.

  
The ethyl ether layer thus obtained was washed with water, dried over anhydrous sodium sulfate and distilled to dryness. The resulting residue was chromatographed on silica gel using a mixture of n-hexane-acetone (10: 1), as a solvent, to give di-o-iodobenzyl epoxysuccinate (EP-105) under form

  
 <EMI ID = 160.1>

  
The following compounds were obtained from the corresponding materials by a process similar to that described in Example 35:

  
 <EMI ID = 161.1>

  
di-p-iodobenzyl epoxysuccinate (EP-111) di-p-bromobenzyl epoxysuccinate (EP-113) di-p-chlorobenzyl epoxysuccinate (EP-115)

  
 <EMI ID = 162.1>

  
di-2'-bromo-4'-iodobenzyl epoxysuccinate (EP-119).

  
 <EMI ID = 163.1>

  
In a solution of 4.5 g (0.008 mol) of epoxysuccinate

  
 <EMI ID = 164.1>

  
 <EMI ID = 165.1>

  
while being stirred and cooled to 0 [deg.] C. After the mixture was stirred for 10 to 15 minutes, 500 ml of acetone was added thereto. The crystals formed were filtered and recrystallized from water-acetone, to give o-iodobenzyl potassium epoxysuccinate
(EP-106) as a colorless amorphous solid. Yield: 0.9 g

  
 <EMI ID = 166.1>

  
 <EMI ID = 167.1>

  
(4H, m).

  
The following compounds were obtained from the corresponding materials by a process similar to that described in Example 36:

  
 <EMI ID = 168.1> p-bromobenzyl potassium epoxysuccinate (EP-114) p-chlorobenzyl potassium epoxysuccinate (EP-116) 2 ', 4'-dichlorobenzyl and potassium epoxysuccinate
(EP-118)

  
2'-bromo-4'-iodobenzyl potassium epoxysuccinate
(EP-120).

  
EXAMPLE 37

  
To a solution of 3.0 g (0.024 mole) of mfluorobenzyl alcohol and 1.9 g (0.024 mole) of pyridine dissolved in 50 ml of ethyl ether, a solution of 2.0 g was added dropwise. (0.012 mole) of epoxy succinyl chloride dissolved in 5 ml of ethyl ether, while stirring and cooling to 0 to -5 [deg.] C. After the mixture was stirred for 30-60 minutes, the formed precipitated salt of pyridine hydrochloride was filtered off. The ethyl ether layer thus obtained was washed with water, dried over anhydrous sodium sulfate and distilled to dryness. The resulting residue was chromatographed on silica gel using a mixture of n-hexane-acetone (10: 1), as a solvent, to give di-m-fluorobenzyl epoxysuccinate.
(EP-121) in the form of an oil. Yield: 3.1 g (75%).

  
 <EMI ID = 169.1>

  
The following compounds were obtained from the corresponding materials by a process similar to that described in Example 37:

  
di-o-fluorobenzyl epoxysuccinate (EP-123)

  
 <EMI ID = 170.1>

  
of di-m-fluorobenzyl dissolved in 35 ml of dimethylformamide, 4.8 ml of 3N aqueous solution of potassium hydroxide were added dropwise,

  
 <EMI ID = 171.1>

  
was stirred for 10 to 15 minutes, thereto was added 500 ml of acetone. The crystals formed were filtered off and recrystallized from water-acetone to give m-fluorobenzyl potassium epoxysuccinate (EP-122), as a colorless amorphous solid. Yield: 1.1 g (25%).

  
^ 0> <EMI ID = 172.1>

  
7.52 (4H, m).

  
The following compounds were obtained from the corresponding materials by a process similar to that described in Example 38:

  
o-fluorobenzyl potassium epoxysuccinate (EP-124) 3'-chloro-4'-bromobenzyl potassium epoxysuccinate (EP-126)

  
2 ', 5'-dichlorobenzyl potassium epoxysuccinate
(EP-128).

  
EXAMPLE 39

  
In a solution of 3.0 g (0.025 mole) of 2-phenylethanol and 2.0 g (0.025 mole) of pyridine dissolved in 50 ml of ethyl ether, a solution of 2.35 g (0.014 mole) of chloride of epoxysuccinyl dissolved in 5 ml of ethyl ether was added dropwise, while being stirred and cooled to 0 to -5 [deg.] C. After the mixture was stirred for 30-60 minutes, the precipitated salt formed from pyridine hydrochloride was filtered off. The ethyl ether layer thus obtained was washed with water, dried over anhydrous sodium sulfate and distilled to dryness. The resulting residue was chromatographed on silica gel using a mixture of n-.

  
 <EMI ID = 173.1>

  
J = 6.7Hz), 7.17 (10H, s).

  
The following compound was obtained from the corresponding materials by a process similar to that described in Example 39:

  
 <EMI ID = 174.1>

  
EXAMPLE 40

  
In a solution of 3.3 g (0.01 mole) of epoxysuccinate

  
 <EMI ID = 175.1>

  
 <EMI ID = 176.1>

  
while being stirred and cooled to 0 [deg.] C. After the mixture was stirred for 10 to 15 minutes, 1000 ml of acetone was added thereto.

  
 <EMI ID = 177.1> The crystals formed were filtered off and recrystallized from acetone water to give 2'-phenylethyl potassium epoxysuccinate.

  
 <EMI ID = 178.1>

  
4.20 (2H, t, J = 6Hz).

  
The following compound was obtained from the corresponding material by a process similar to that described in Example 40:

  
3-phenylpropyl potassium epoxysuccinate (EP-
132).

EXAMPLE 41

  
In a solution of 3.0 g (0.025 mol) of 3-phenyl-2-pro

  
 <EMI ID = 179.1>

  
dissolved in 50 ml of ethyl ether, a solution of 2.35 g (0.014 mol) of epoxy succinyl chloride dissolved in 5 ml of ethyl ether was added dropwise, while stirring and cooling between 0 and - 5 [deg.] C. Then, when the procedure similar to that

  
 <EMI ID = 180.1>

  
n-hexane-acetone).

EXAMPLE 42

  
When the procedure similar to that described in the example

  
 <EMI ID = 181.1>

  
of potassium (EP-134) in crystal form. &#65533; colorless in water acetone. Yield: 0.98 g (48%), m.p. 153-155 [deg.] C.

EXAMPLE 43

  
To a solution of 2.4 g of dimethyl epoxysuccinate in 45 ml of methanol was added, while cooling with ice, a solution of 0.84 g of potassium hydroxide in 8.4 ml of methanol. The mixture was stirred for two hours and concentrated in vacuo. The residue was dissolved in 30 ml of water and acidified with concentrated sulfuric acid. The resulting solution was extracted 5

  
 <EMI ID = 182.1> were combined and concentrated to dryness. The recrystallization of the resin

  
 <EMI ID = 183.1>

  
of methyl (EP-135) in the form of white plaques. Yield:

  
 <EMI ID = 184.1>

  
 <EMI ID = 185.1>

  
The following composa was obtained from the corresponding material by a process similar to that described in Example 43:

  
phenyl acid epoxysuccinate (EP-136).

  
EXAMPLE 44

  
 <EMI ID = 186.1>

  
2 hours, and the deposited solid was collected by filtration and

  
 <EMI ID = 187.1>

  
(2H, q, J = 7Hz).

  
 <EMI ID = 188.1>

  
corresponding res by a process similar to that described in Example 44:

  
n-propyl potassium epoxysuccinate (EP-138)

  
 <EMI ID = 189.1>

  
propargyl potassium epoxysuccinate (EP-141) n-butyl potassium epoxysuccinate (EP-142)

  
 <EMI ID = 190.1>

EXAMPLE 45

  
In a solution of 8.16 g of di-n-amyl epoxysuccinate in 3 ml of n-amyl alcohol, a solution of 1.68 g of potassium hydroxide in 12 ml of amyl alcohol was added while cooling by

  
ice. The mixture was stirred for 4C minutes and added to

  
 <EMI ID = 191.1>

  
thus obtained was combined and washed with petroleum ether to give 2.6 g of n-amyl potassium epoxysuccinate (EP-144).

  
 <EMI ID = 192.1>

  
 <EMI ID = 193.1>

  
d.d., J = 2Hz), 4.19 (2H, t, J = 6Hz).

  
The following compound was obtained from the corresponding material by a process similar to that described in Example 45:

  
n-dodecyl potassium epoxysuccinate (EP-145).

  
EXAMPLE 46

  
In a solution of 1.98 g of ethyl epoxy succinate and

  
of potassium (i.e. ethylpotassium 2,3-dicarboxylate oxirane) in 50ml of ethyl ether, a solution of 1.4g of oxalyl chloride in 30ml of ethyl ether was added dropwise, while being stirred and ice-cooled for 30 minutes. After the mixture has been stirred, further, to

  
at room temperature for 2 hours, the precipitate formed

  
been filtered. The filtrate was evaporated under actual pressure to give epoxysuccinic acid monoethyl ester chloride as an oil. Then the acid chloride was dissolved in

  
30 ml of ethyl ether and the resulting solution was added

  
 <EMI ID = 194.1>

  
that, all er. stirring and cooling with ice for

  
 <EMI ID = 195.1>

  
At room temperature for 3 hours, the precipitate formed was filtered off. The filtrate was evaporated under reduced pressure to give an oil. The oil thus obtained was further purified by chromatography on a silica gel column, using a mixture of chloroform-

  
 <EMI ID = 196.1>

  
carbonyloxirane-2-carbonyl) -L-leucine (EP-146) as an oil

  
 <EMI ID = 197.1>

  
(3H, t, J = 7Hz), 1.64 (3H, m), 3.42 (O, 5H, d, J = 2Hz), 3.51 (0.5H,

  
 <EMI ID = 198.1>

  
 <EMI ID = 199.1>

  
 <EMI ID = 200.1>

  
When 0.65 g of epoxysuccinic acid monoallyl ester chloride, which was prepared from 1.0 g of epoxysuccina- <EMI ID = 201.1> <EMI ID = 202.1>

  
potassium oxirane) by treatment with oxalyl chloride, in a manner similar to that described in Example 46, was reacted with the benzyl ester of L-tyrosine in dichloro-

  
 <EMI ID = 203.1>

  
 <EMI ID = 204.1>

  
carbonyl) -L-tyrosine (EP-147) as a colorless oil.

  
 <EMI ID = 205.1>

  
Mass: m / e 425 (M +).

  
 <EMI ID = 206.1>

  
 <EMI ID = 207.1>

  
4.5 - 6.2 (6H, m), 5.08 (2H; d, J = 3Hz), 6.25 - 7.0 (4H, m), 7.25 (5H, s).

EXAMPLE 48

  
 <EMI ID = 208.1>

  
ne-2-carbonyl) -L-tyrosine (EP-148). Yield: 61%.

  
 <EMI ID = 209.1>

  
J = 2Hz). 3.47 (0.5H, d, J = 2Hz), 3.60 (0.5H, d, J = 2Hz), 3.64 (0.5H,

  
 <EMI ID = 210.1>

  
(8H, m), 7.30 (SE, s).

  
The following compounds were obtained from the corresponding materials by a process similar to that described in Example 48:

  
N- (3-piperonyloxycarbonyloxirane-2carbonyl) -L-methionine methyl ester (EP-149),

  
N- (3-Ethoxycarbonyloxirane-2-carbo- ethyl ester <EMI ID = 211.1>

  
bonyl) -L-tryptophan (EP-151)

  
N- (3-ethoxycarbonyloxirane-2-carbonyl) -L-proline benzyl ester (EP-152)

  
N- (3-n-propyloxycarbonyloxirane2-carbonyl) -glycine benzyl ester (EP-153)

  
N- (3-ethoxycarbonyloxirane-2-carbonyl) -glycine benzyl ester (EP-154)

  
 <EMI ID = 212.1>

  
nyl) -L-methionine (EP-155)

  
N- (3-Ethoxycarbonyloxirane- acid dibenzyl ester

  
 <EMI ID = 213.1>

  
N- (3-ethoxycarbonyloxirane-2-carbonyl) -p-alanine benzyl cstcr (EP-157)

  
 <EMI ID = 214.1>

  
carbonyl) -L-valine (EP-158)

  
N- (3-Benzyloxycarbonyloxirane-2-carbonyl) -L-phenylalanine ethyl ester (EP-159)

  
N- (3-o-chlorobenzyloxycarbonyloxi- ethyl ester

  
 <EMI ID = 215.1>

  
N- (3-Anisyloxycarbonyloxirane-2-carbonyl) -L-proline benzyl ester (EP-161)

  
N- (3-p-Bromobenzyloxycarbonyloxirane-2-carbonyl) -L-valine benzyl ester (EP-162)

  
 <EMI ID = 216.1> <EMI ID = 217.1>

EXAMPLE 49

  
In a solution of 0.5 g of dissolved N- (3ethoxycarbonyloxirane-2-carbonyl) -L-leucine (EP-146) ethyl ester

  
in 2 ml of ethanol and 1 ml of water, a solution of 0.3 g of potassium hydroxide dissolved in 1 ml of water was added. After mixing

  
was stirred at room temperature for 2 hours, then

  
 <EMI ID = 218.1>

  
recrystallized from ethanol-water to give dipotassium salt of

  
 <EMI ID = 219.1>

  
colorless needles. Yield: 0.32 g (60%), m.p. 210 [deg.] C.

  
The following compounds were obtained by a process similar to that described in Example 49:

  
 <EMI ID = 220.1>

  
phenylalanine (EP-175)

  
N- (3-carboxyoxirane-2-carbonyl) -Ncarbobenzoxy-L-lysine dipotassium salt (EP-176).

EXAMPLE 50

  
After saponification of 0.15 g of N- ethyl ester

  
 <EMI ID = 221.1>

  
in an experiment analogous to Example 49, the reaction mixture was acidified with hydrochloric acid and extracted with ethyl ether. Evaporation of the solvent gave N- (3 "carbo-

  
 <EMI ID = 222.1>

  
EXAMPLE 51

  
In a solution of 5.1 g of benzyl ester ditosylate

  
 <EMI ID = 223.1>

  
zyl (i.e. henzyloxirane acid 2,3-transdicarboxylate),

  
1.6 g of methylmorpholine and 1.3 g of N-hydroxysuccinimide dissolved in 30 ml of dimethylformamide, was added dropwise, with stirring at -10 [deg.] C, a solution of 3.0 g of dicyclohexylcarbodiimide dissolved in 20 ml of dimethylformamide. The mixture was stirred for 1 hour at -10 [deg.] C and a further 1 hour at room temperature, then allowed to stand overnight. After filtration of the precipitate thus formed, the filtrate was diluted with

  
200 ml of ethyl acetate and washed with a solution saturated with sodium bicarbonate and saturated with sodium chloride, in turn. The organic layer was dried over magnesium sulfate and evaporated to dryness. Column chromatography on silica gel using

  
 <EMI ID = 224.1>

  
nine (EP-178) as colorless needles. Yield: 2.4 g
(61%), m.p. 141 - 142 [deg.] C.

  
The following compounds were obtained by a process similar to that described in Example 51:

  
 <EMI ID = 225.1>

  
carbonyl) -NG-nitro-L-arginine (EP-184)

  
N [deg.] - (3-ethoxycarbonyloxirane-2-carbonyl) -L-histidine methyl ester (EP-185)

  
Na- (3-ethoxycarbonyloxirane-2-carbonyl) -L-serine ethyl ester (EP-186)

  
 <EMI ID = 226.1>

  
N- (3-p-Chlorobenzyloxycarbonyloxirane-2-carbonyl) -y-aminobutyric acid ethyl ester (EP-189)

  
a N- {3-methoxycarbonyloxirane-2-carbonyl) -L-threonine ethyl ester (EP-190)

  
N- (3-benzyloxycarbonyloxirane-2- benzyl ester

  
 <EMI ID = 227.1>

  
EXAMPLE 52

  
 <EMI ID = 228.1>

  
 <EMI ID = 229.1>

  
10 ml of ethanol was added dropwise, while cooling with ice, a solution of 0.056 g of potassium hydroxide in 5 ml of ethanol. The precipitate thus formed was filtered and reprecipitated in waterethanol to give the potassium salt of Na- (3carboxyoxirane-2-carbonyl) -NN ethyl ester; -carbobenzoxy-L-lysine (EP-195)

  
 <EMI ID = 230.1>

  
148-149 [deg.] C.

  
The following compounds were obtained from the corresponding materials by a process similar to that described in Example 51:

  
Na- (3-carboxy-) benzyl ester potassium salt

  
 <EMI ID = 231.1>

  
EXAMPLE 53

  
A mixture of 0.4 g of N- (3-benzyloxy- methyl ester

  
 <EMI ID = 232.1>

  
in 25 ml of a mixture of methanol-acetic acid-water (8/2/1 v / v / v) was stirred in the presence of 0.1 g of a mixture

  
 <EMI ID = 233.1>

  
room temperature for 4 hours. After removing the catalyst by filtration, the filtrate was evaporated under reduced pressure to give an oil. This was dissolved in water and extracted

  
with ethyl acetate. The aqueous layer was evaporated under reduced pressure to give a solid. Further purification

  
of this solid by chromatography on a column on a product called Sephadex LH-20 (from the company known as Farmacia Co.), using a 5% aqueous solution of methanol as solvent, provided the methyl ester of N- (3-carboxyoxirane -2-carbonyl-L-arginine (EP-200) in the form of colorless glassy crystals. Yield: 0.21 g

  
(76%), m.p. 99-102 [deg.] C.

  
 <EMI ID = 234.1>

  
corresponding res by a process similar to that described in Example 53:

  
N- (3-ethoxycarbonyloxirane-2-carbonyl) -L-lysine (EP-201) N- (3-carboxyoxirane-2-carbonyl) -L-arginine (EP-202).

EXAMPLE 54

  
By substituting 1 g of L- ethyl ester hydrochloride

  
 <EMI ID = 235.1>

  
895 (epoxy).

  
NMR (CDCl) &: 0.95 (6H, d, J = 5Hz), 1.30 (3H, t, J = 7Hz), 0.8-2.1
(16H, m), 3.42 (0.5H, d, J = 2Hz), 3.53 (0.5H, d, J = 2Hz), 3.67 (1H,

  
 <EMI ID = 236.1>

  
(1H, m), 6.0 - 6.7 (1H, b.).

  
The following compounds were obtained from the material

  
 <EMI ID = 237.1>

  
carbonyl) -N -carbobenzoxy-L-lysine (EP-204)

  
N- (3-Cyclopentyloxycarbonylcxirane-2-carbonyl) -L-valine benzyl ester (EP-205)

  
N- [3- (1'-Cyclopentylethoxy) -carbo- benzyl ester

  
 <EMI ID = 238.1>

  
&#65533; ' <EMI ID = 239.1>

  
oxirane-2-carbonyl) -glycine (EP-207)

  
N- [3- (4'-cyclohexylbutoxy) -carbo- benzyl ester

  
 <EMI ID = 240.1>

  
carbonyloxirane-2-carbonyl] -L-tyrosine (EP-211).

EXAMPLE 55

  
 <EMI ID = 241.1>

  
4.5 - 5.0 (1H, m), 5.02 (1H, bs), 5.12 (1H, s), 6.2 - 6.5 (1H, bs), 6.8 - 7, 4 (5H, m).

  
 <EMI ID = 242.1>

  
 <EMI ID = 243.1>

  
carbonyloxirane-2-carbonyl] -glycine (EP-213)

  
N- [3- (2'-trans-bromocyclopentyloxy) - benzyl ester

  
 <EMI ID = 244.1>

  
carbonyloxirane-2-carbonyl] -L-alanine (EP-215).

  
EXAMPLE 56

  
Substituting 1.14 g of thenyl acid epoxy succinate

  
and 2.7 g of L-glutamic acid dibenzyl ester tosylate

  
with benzyl acid epoxysuccinate and N -nitro-L-arginine benzyl ester ditosylate in Example 51, there was obtained, under

  
&#65533; &#65533; <EMI ID = 245.1>

  
 <EMI ID = 246.1>

  
 <EMI ID = 247.1>

  
The following compounds were obtained from the corresponding materials by methods similar to those described in Example 56:

  
 <EMI ID = 248.1>


    

Claims (1)

1 - Derivative of epoxysuccinic acid. characterized in that it is represented by the general formula: <EMI ID = 249.1> where <EMI ID = 250.1> cycloalkyl group being substituted by 1 to 3 halogens or methyl groups, or a cycloalkenyl group containing 5 to 8 carbon atoms, A is an alkylene group containing 2 or 3 carbon atoms, <EMI ID = 251.1> <EMI ID = 252.1> alkoxy containing 1 to 12 carbon atoms, allyloxy, propargyloxy. phenoxy or benzyloxy, and R is an amino acid residue represented by the general formula: -NH-A -COR <EMI ID = 253.1> or this alkylene group substituted by 1 to 3 hydroxy, methyl, thiol, methylthio, benzylthio, phenyl, phenyl groups substituted by a hydroxv or halogen, indazolyl, imidazolyl, -COR or <EMI ID = 254.1> group an alkyl group containing 1 to 5 carbon atoms, benzyl, or a ca- <EMI ID = 255.1> <EMI ID = 256.1> methoxybenzyloxycarbcnyl, tosyl, guanyl, or substituted guanyl <EMI ID = 257.1> <EMI ID = 258.1> <EMI ID = 259.1> hydroxy group, ni R 7 when R <2> is hydroxy group, and their salts when R <1> and R <2> is hydroxy group. 2 - A compound according to claim 1, characterized in that <EMI ID = 260.1> substituted by a methyl group, and R is a cycloalkyl group containing 3 to 10 carbon atoms, this cycloalkyl group being substituted by 1 to 3 halogens or methyl groups, or a cycloalkenyl group containing 5 to 8 carbon atoms. 3 - A compound according to claim 1, characterized in that <EMI ID = 261.1> containing 2 or 3 carbon atoms or alkenylene containing 2 or 3 carbon atoms, and R is phenyl. 4 - A compound according to claim 1, characterized in that <EMI ID = 262.1> rahydrofuryl, thienyl, naphthyl, naphthyl substituted with 1 or 2 halogens or methyl groups, or phenyl substituted with one to three halogens, methyl groups, methoxy, methylenedioxy or trifluoromethyls. 5 - A compound according to claim 1, characterized in that <EMI ID = 263.1> alkylene containing 0 to 4 carbon atoms or an alkylene group substituted by a methyl group, and R is a cycloalkyl group <EMI ID = 264.1> killed by one or three halogen or methyl groups, or a cycloalkenyl group containing 5 to 8 carbon atoms. 6 - A compound according to claim 1, characterized in that <EMI ID = 265.1> alkylene containing 2 or 3 carbon atoms or alkenylene containing 2 <EMI ID = 266.1> 7 - A compound according to claim 1, characterized in that <EMI ID = 267.1> furyl, tetrahydrofuryl, thienyl, naphthyl, naphthyl substituted with one or two halogens or methyl groups, or phenyl substituted with one to three halogens, methyl groups, methoxy, methylenedioxy or trifluoromethyls. 8 - A compound according to claim 1, characterized in that <EMI ID = 268.1> <EMI ID = 269.1> a methyl group, R 4 is a cycloalkyl group containing 3 to 10 carbon atoms, this cycloalkyl group substituted by 1 to 3 halogens or methyl groups, or a cycloalkenyl group containing 5 to 8 atoms <EMI ID = 270.1> general mule: -NH-A <3> -COR9 where A <3> is an alkylene group containing 1 to 5 carbon atoms or this alkylene group substituted by 1 to 3 hydroxy, methyl, thiol, methylthio, benzylthio, phenyl, phenyl groups substituted by <EMI ID = 271.1> an alkyl group containing 1 to 5 carbon atoms, benzyl, or a <EMI ID = 272.1> <EMI ID = 273.1> nyl, methoxybenzyloxycarbonyl, tosyl, guanyl, or guanyl substituted with a nitro group, and R 9 is an amino group, or -OR 13 where R <1> <3> is hydrogen, an alkyl group containing 1 to 5 atoms of carbon, benzyl or an alkali metal cation. 9 - A compound according to claim 1, characterized in that <EMI ID = 274.1> lene containing 2 or 3 carbon atoms, or alkenylene containing 2 or 3 carbon atoms, R is phenyl and R is an amino acid residue represented by the general formula: -NH-A <3> -COR9 <EMI ID = 275.1> or this alkylene group substituted by 1 to 3 hydroxy, methyl, thiol, methylthio, benzylthio, phenyl, phenyl groups substituted by <EMI ID = 276.1> an alkyl group containing 1 to 5 carbon atoms, benzyl, or a <EMI ID = 277.1> alkoxycarbonyl containing 2 to 5 carbon atoms, benzyloxycarbonyl, methoxybenzyloxycarbonyl, tosyl, guanyl, or guanyl substituted with a nitro group, and R is an amino group or -OR where R is hydrogen, an alkyl group containing 1 to 5 carbon atoms carbon, the benzyl group or an alkali metal cation. 10 - A compound according to claim 1, characterized in that i <EMI ID = 278.1> hydrofuryl, thienyl, naphthyl, naphthyl substituted with one or two halogens or methyl groups, or phenyl substituted with one to three ha- <EMI ID = 279.1> general: -NH-A <3> -COR9 where A <3> is an alkylene group containing 1 to 5 carbon atoms or this alkylene group substituted by 1 to 3 hydroxy, methyl, thiol, methylthio, benzylthio, phenyl, phenyl groups substituted by a <EMI ID = 280.1> an alkyl group containing 1 to 5 carbon atoms, benzyl or a <EMI ID = 281.1> alkoxycarbonyl, containing 2 to 5 carbon atoms, benzyloxycarbonyl, methoxybenzyloxycarbonyl, tosyl, guanyl or guanyl subs- <EMI ID = 282.1> is hydrogen, an alkyl group containing 1 to 5 carbon atoms, benzyl or an alkali metal cation. 11 - A compound according to claim 1, characterized in that <EMI ID = 283.1> 12 carbon atoms, allyloxy, p &#65533; opargyloxy, phenoxy or benzyloxy, <EMI ID = 284.1> <EMI ID = 285.1> where A <3> is an alkylene group containing 5 carbon atoms or this alkylene group substituted by 1 to 3 hydroxy, methyl, thiol, methylthio, benzylthio, phenyl, phenyl groups substituted by a group <EMI ID = 286.1> alkyl containing 1 to 5 carbon atoms, benzyl or a cation of <EMI ID = 287.1> bonyle containing 2 to 5 carbon atoms, benzyloxycarbonyl, methoxybenzyloxycarbonyl, tosyl, guanyl, or guanyl substituted by a nitro group, and R is an amino group or -OR where R <1> <3> is hydro- <EMI ID = 288.1> an alkali metal cation. 12 - A compound according to claim 1, characterized in that that R is a hydroxy group and R is a group R where R is an amino acid residue represented by the general formula: -NH-A <3> -COR9 where A is an alkylene group containing 1 to 5 carbon atoms, or this alkylene group substituted by 1 to 3 hydroxy, methyl, thiol, methylthio, benzylthio, phenyl, phenyl groups substituted by <EMI ID = 289.1> alkoxycarbonyl containing 2 to 5 carbon atoms, benzyloxycarbonyl, methoxybenzyloxycarbonyl, tosyl, guanyl, or guanyl substituted with a nitro group, and R 9 is an amino group or -OR 13 where R <1> <3> is hydrogen, a alkyl group containing 1 to 5 carbon atoms, benzyl or an alkali metal cation. 13 - Pharmaceutical compositions with inhibitory action of thiolprotease and with anti-inflammatory activity, characterized in that they contain, as active ingredient, at least one of the products indicated in claim 1.