KR830000023B1 - Method for preparing fluoroacyl resorcin - Google Patents

Abstract

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Description

Method for preparing fluoroacyl resorcin

The present invention relates to a process for the preparation of the novel substituted fluoroacyl resorcin of the following general formula (I) which is effective as pharmaceuticals, cosmetics and pesticides.

In the above general formula

R ₁ represents a perfluoroalkyl group or 2,2,3,3-tetrafluorocyclobutyl group having 1 to 8 carbon atoms

R ₃ and R ₅ are the same or different from each other, and have an alkyl group, halogen atom, nitro group or p-toluenesulfo group, cyclopentyl, cyclohexyl, cycloheptyl, cyclododecyl, methylcyclohexyl, dimethylcyclohexyl having 3 to 18 carbon atoms , Benzyl or methylthio group, or a group of the following general formula,

From here

F represents a -CH ₂ -or -S- group where G is an R ₅ group, or an R ₃ group when G is -CH ₂ -or -S-,

R ₁ is as defined above,

R ₃ also represents a hydroxy, methoxy, methyl or cyano group,

R ₅ also represents a methyl group.

However, 1) as defined above, except that one of the groups R ₃ and R ₅ is hydrogen,

2) The other one of R ₃ and R ₅ may represent a hydrogen atom or an ethyl group as defined above except that R ₁ is a trifluoromethyl group.

The compound of formula (1) is prepared by transposing the perfluoroacylsolecin of the following formula (II).

In the above general formula

R ₃ and R ₅ are as described above, and when E represents a -O-COR ₁ group, D represents a hydroxy group, or when E represents a hydroxy group, D represents an -O-COR ₁ group (-O -CO-R ₁ in substituent R ₁ are as described above).

The reaction is preferably carried out in the presence of Lewis acid as a catalyst, optionally in the presence of a solvent, at a temperature in the range of 0 to 150 ° C.

Examples of suitable Lewis acids are zinc anhydride, aluminum anhydride, zinc chloride in the presence of hydrochloric acid, ferric chloride, tin tin chloride. Examples of the solvent include aromatic hydrocarbons such as ether or chlorobenzene, nitrobenzene, toluene, dichlorobenzene or xylene and phosphorus oxychloride.

Starting compounds of formula (II) wherein D or E are —O—COR ₁ group are obtained according to known methods for esterifying the corresponding compound in which D or E represents a hydroxy group.

Formula (I) compounds are useful as pharmacological and / or pesticides. In particular, the compound is effective against bacteria, phytodermal pathogens, yeasts, fungi, and phytopathogenic fungi, and because the compound exhibits inhibitory effects on various major enzymes and cell cultures of carbohydrate metabolism, it promotes the inside or outside of the skin. Delay division. Therefore, these compounds are suitable for the treatment of acne, dandruff, bacterial skin infections, filamentous fungi, psoriasis, young skin, and excessive keratinization of the skin, and as a herbicide of weeds such as wild oats as well as diseases that rot due to moisture in plant cultivation. useful.

Several compounds of formula (I) also exhibit antiparasitic activity.

The following matrix and new compound were used to compare the inhibitory effect on bacteria and fungi, cell culture and enzyme action.

Instrument compound

2,4-dihydroxy-trifluoroacetophenone = A

5-ethyl-2,4-dihydroxy-trifluoroacetophenone = B

3-ethyl-2,4-dihydroxy-trifluoroacetophenone = C

2,4-dimethoxy-trifluoroacetophenone = D

New compounds

2,4-dihydroxy-5-n-hexyl-trifluoroacetophenone = E

2,4-dihydroxy-3-iso-butyl-trifluoroacetophenone = F

2,4-dihydroxy-5-iso-pentyl-trifluoroacetophenone = G

2,4-dihydroxy-3- (4'-methyl) -cyclohexyl-trifluoroacetophenone = H

2,4-dihydroxy-4- (3'-5'-dimethyl) -cyclohexyl-trifluoroacetophenone = I

2,4-dihydroxy-5-n-nonyl-trifluoroacetophenone = J

2,4-dihydroxy-3-iso-hexyl-trifluoroacetophenone = K

2,4-dihydroxy-3-cyclododecyl-trifluoroacetophenone = L

2,4-dihydroxy-3-isodecyl-trifluoroacetophenone = M

2,4-dihydroxy-3-cyclopentyl-trifluoroacetophenone = N

2,4-dihydroxy-3-cycloheptyl-trifluoroacetophenone = 0

2,4-dihydroxy-3-isopropyl-trifluoroacetophenone = P

Methylene-bis- (2,6-dihydroxy-3-isopropyl-5-trifluoroacetyl) -benzene = Q

Methylene-bis- (2,6-dihydroxy-3-ethyl-5-trifluoroacetyl) -benzene = R

Methylene-bis- (2,4-dihydroxy-3-methyl-5-trifluoroacetyl) -benzene = S

2,4-dihydroxy-3-methyl-trifluoroacetophenone = T

2,4-dihydroxy-5-chloro-trifluoroacetophenone = U

2,4-dihydroxy-3-methyl-pentafluoropropiophenone = V

2,4-dihydroxy-5-n-decyl-trifluoroacetophenone = W

2,4-dihydroxy-3-n-pentyl-trifluoroacetophenone = X

2,4-dihydroxy-3-n-propyl-trifluoroacetophenone = Y

Methylene-bis- (2,4-dihydroxy-3-isopropyl-5-trifluoroacetyl) -benzene = Z

Inhibitory effects on bacteria and fungi were tested by serial dilution test and Agar diffusion test (hole-test).

Bacteria used: Staphylococcusureus SG 511, Streptococcus Aronson, Streptococcus pyogenes ATCC 8668 (Streptococcuspyogenes ATCC 8668).

Fungi used: Candida albicans ATCC 10231, Trichophyton mentagrophytes ATCC 9129, and Aspergillus niger.

Continuous Dilution Test

Nutrition medium

1.Meat Extract Juicy: Staphylococcus aureus SG 511

100 ml of distilled water is added (pH 2 to 7.4)

Sterilization: 15 minutes at 120 ℃ in autoclave

2. Glucose Juicy: Streptococcus Aaronson and Streptococcus Piogenes

The composition is the same as the meat extract juice.

After sterilization, 1% by weight of glucose is added as a 50% sterile solution.

3. Savourad gravy: Candida albicans, Tritopython Mentagrophytes aspergillus niger

Sterilization: 5 to 10 minutes at 120 ° C. pH is not constant.

Normalization of the density of microorganisms

The first incubation period is 24 hours for bacteria and 14 days for fungi.

14mm, 필터 546nm)에 따른 광도계 및 1% 염화바륨용액 3.0ml를 1% 황산 97ml에 가하여 만든 황산바륨의 대조용 현탁액을 사용하여 수행한다. 표준화한후 박테리아는 염화나트륨 용액을 사용하여 1 : 1000의 농도로 더 희석하고, 진균류는 희석하지 않은 상태로 사용한다.Standardization of microbial suspensions is based on Eppendorf

14 mm, filter 546 nm) and a control suspension of barium sulfate prepared by adding 3.0 ml of 1% barium chloride solution to 97 ml of 1% sulfuric acid. After standardization, the bacteria are further diluted to 1: 1000 with sodium chloride solution, and the fungi are used undiluted.

Preparation of Compound Concentration

40 mg of compound is placed in a 10 ml mass flask, and the solvent (dilution ratio 1: 2500 = 4000 µg / ml) is filled to the graduation.

Dilution with distilled water or solvent further prepares the concentration of the compound as follows: 1000; 62.5 μg / ml.

Each test tube is filled with 4.9 ml of a compatible liquid nutrient medium, and then 0.1 ml of a dilution of the compound prepared above is placed in each test tube to the final concentration mentioned above. Finally, each test tube is inoculated with 0.1 ml of a standardized suspension of microorganisms. Control tests using solvent only are performed simultaneously.

culture

Bacteria are incubated at 37 ° C. for 18-20 hours and fungi at 27 ° C. for 7 days.

evaluation

The minimum inhibitory concentration (minimal bacteriostatic concentration) is determined by visual inspection.

Agar diffuaion test

Nutrition medium

Meat extraction agar: Staphylococcus aureus SG 511

Sterilization: 15 minutes at 120 ° C. in autoclave.

2. Clucose Agar: Streptococcus Aaronson and Streptococcus Piogenes

The composition is the same as meat extract agar. After sterilization 1% by weight of glucose is added as a 50% sterile solution.

3. Savourard Agar: Candida Almacans, Trichophyton Mentagrophytes, Aspergillus Niger

Sterilization: 5 to 10 minutes at 120 ℃, Ph is not constant.

Standardization of Microbial Density

14mm, 필터 546nm)에 다른 광도계를 사용하며 대조 현탁액으로 1%황산 97ml에 1%염화바륨용액 3.0ml를 가하여 만든 황산 바륨을 사용한다.The first incubation period is 24 hours for bacteria and only 14 days for fungi. Standardization of microbial suspensions is based on Eppendorf

14mm, filter 546nm) using a different photometer and use barium sulfate prepared by adding 3.0ml of 1% barium chloride solution to 97ml of 1% sulfuric acid as a control suspension.

After normalization, the Staphylococcus aureus SG 511 is diluted 1: 100 with sodium chloride. Fungi should be used undiluted.

Preparation of Compound Concentration

40 mg of compound is placed in a 10 ml mass flask and filled to the scale with a solvent (dilution ratio 1: 25 = 4000 µg / ml). Dilution of the concentrate used in the test is carried out with distilled water or each solvent.

Trial operation

19 ml of nutrient medium is placed in a sterile petri dish of 8 cm diameter and dried. Then add 4 ml of spawn agar to the agar plate. Since 100 ml of spawn agar contains 1.25 ml of the suspension of microorganisms, the agar plate contains 0.05 ml of the suspension of microorganisms. After solidifying the agar, a 5 mm diameter hole is made in the plate and filled with 0.05 ml of a solution of concentrated compound.

Control tests using only solvents are performed simultaneously.

culture

Bacteria are incubated at 37 ° C. for 18-20 hours and fungi at 27 ° C. for 7 days.

evaluation

Subtract the diameter of the hole and measure the diameter of the suppression area in mm. Measurements are shown in parentheses for the areas where the growth was significantly reduced instead of the areas where there was no growth at all.

Serial dilution test for Corynebacterium acnes and Pityrosporum ovale

Nutrition medium

Coryne Bacteria Acne: Thioglycolate Juicy

Fitirosporum Obare: Litman Juicy

5ml per test tube

Density of microorganisms

A suspension of microorganisms in 0.9% sodium chloride solution, standardized by different photometers in Eppendorf using a control suspension consisting of barium sulfate, was diluted 1: 100 for Coryne bacteria acne and not for Pytyrosporum obare. 0.1 ml each of the suspension was added to the test tube. Dimethyl sulfoxide is used as a solvent for this compound. A suspension of Coryne bacteria acne is incubated for 48 hours at 37 ° C., and a suspension of Pytirosforum obare is incubated at 20 ° C. for 7 days. Observe the microbial growth visually and measure the minimum inhibitory concentration.

Agar Diffusion Test for Phytirosporum Obare CBS 1878

Nutrition medium

Litman Baby: 23 ml per Patridish with a diameter of 100 mm

Density of microorganisms

A suspension of microorganisms in 0.9% sodium chloride solution, standardized using a photometer according to Eppendorf using a control suspension of barium sulfate, was used at 0.05 ml per agar plate. Test substance is dissolved in dimethyl sulfoxide. Incubation time is 7 days at 27 ° C. and the inhibition area (mm) is measured. A 0.05 ml solution of the test substance is filled into each hole 6 mm in diameter. The results of these tests are reported in Tables 1 and 2 below.

TABLE 1

The numbers in parentheses mean that the growth is reduced at this concentration.

nt: not tested, MIC: minimum inhibitory concentration, A.D.T. : Agar diffusion test, S.D.T. : Continuous dilution test

Determination of Glucose-6-Phosphate Hydrogenase: Equilibrium was observed.

Glucose-6-phosphate + NADP ⁺ + G6P-DH → gluconic acid-6-phosphate + H ⁺ (HADP = nicotinamide-adenine-dinucleotide-phosphate, G6P-DH = gluconic acid-6-phosphate-dehydrogenase )

The rate of formation of NADPH is measured for enzyme activity: this can be measured by an increase in absorbance at 340 or 366 nm per hour.

Way

Distilled water is added to 0.25 ml of Glucose-6-Phosphate-Dehydrogenase (Charringer Mannheim) and filled with 10 ml (Solution I).

10 mg of nicotinamide-adenine dinucleotide-phosphate is dissolved in 13 ml of distilled water (solution II).

47.2 mg of glucosepo-6-sulfate are dissolved in 10 ml of distilled water (solution III). At the same time buffer (solution IV) is prepared as follows: 0.28 g of trimethanol amine-hydrochloride and 1.46 g of ethylenediaminotetraacetic acid-disodium salt are dissolved in 1 L of distilled water and adjusted to 7.6 (pH) with sodium hydroxide solution. do. Test compound is dissolved in dimethylformamide or ethanol (solution V). Concentration used in the test: 50; 25; 12.5; 6.25; 3; 125; 1.56 and 0.78 μg / ml.

Immediate inhibition effect measurement

0.1 ml of solution I, 0.1 ml of solution II, 2.67 ml of solution IV, and 0.03 ml of solution V were mixed and left at 25 ° C. for 5 minutes, and then mixed with 0.1 ml of solution III and mixed for 3 minutes at 366 nm with a spectrophotometer. Measure

Measurement of inhibitory effect after culture

0.1 ml of solution I, 0.1 ml of solution II, 2.67 ml of solution IV, and 0.03 ml of solution V were mixed and left at 37 ° C. for 60 minutes, then mixed by adding 0.1 ml of solution III and changing the absorbance with a spectrophotometer at 366 nm for 3 minutes. Measure The inhibitory value is injected from the average value of the three measured values (change in absorbance per minute) compared to the control solution made of pure solvent as the inhibitory solution. ED ₅₀ is then the value calculated from the inhibition for various concentrations according to the method of Reed and Muenck.

The results are shown in the following table.

Measurement of Cell Culture Inhibition

Way

Hela-cell culture is treated with trypsin and adjusted to contain 150,000 cells per ml in fresh medium. The compound is dissolved in the same amount of dimethylsulfoxide and then further diluted with growth medium. 0.1 ml of diluted compound is added to each hole of the microtiter plates, followed by 0.2 ml of cell suspension (4 holes per dilution). Several growth controls are prepared containing 0.1 ml of growth medium instead of 0.1 mole of diluted compound. After careful mixing, incubate at 37 ° C. for 3 days under 5% atmospheric pressure of carbon dioxide. The results are measured by comparison with these controls. Results were measured as a percentage for reduction and alteration compared to the growth control. Minimum inhibitory concentrations were determined from these results and ED ₅₀ was calculated according to the Reed and Muenck method and expressed in μg of compound per ml of total medium.

The results are reported in the following table.

The compounds mentioned are chemically stable, exhibit good lipophilic action (distribution coefficient n-octanelong / mol> 1000) and can also be well incorporated into ointments, creams, tinctures, sprays, powders and the like suitable for topical use.

Excellent applicability to the skin (there is a cream containing 10% of compound E which does not irritate for more than 24 hours under closed conditions and low toxicity).

Acute toxicity was measured as a mouse.

LD _50, i.e. the amount of 50% lethal animal within 14 days, was calculated.

LD ₅₀ in mice

In general, pharmacological tests of compounds affecting major body functions, such as the heart / circulatory system or nervous system, showed no significant effect. Thus, no systemic side effects from local use occur.

However, only a small amount is reabsorbed, as shown in the analysis of excretion because it has a good lipophilic action when the polar groups of the compounds that are well penetrated into the skin are present simultaneously.

Adaptation and sensitivity tests on the skin with molar moth showed that the introduction of trifluoro acetyl groups eliminated some susceptibility to resorcin. In some cases, this is very beneficial because resorcin, such as hexylsolecin, causes allergies in humans.

Currently, effective treatment of acne is possible only with systemic treatments using strong antibiotics (tetracycline, erythromycin) and locally peeling agents such as vitamin-A-acid and benzoyl peroxide. The use of antibiotics in non-life-threatening diseases results in the formation of resistance, and the use of skin removers requires significant irritation of the skin.

In the treatment of acne using antibiotics, it is reduced in sebum due to a decrease in the content of free fatty acids in sebum separated from triglycerides by Gram-positive bacteria, the main pathogen for acne.

As shown in Table 1, the aforementioned compounds have potent activity against Corynebacteria acne.

In addition, it can be seen that after topical use, the content of free fatty acids can be significantly reduced. Therefore, local treatment is possible and comparable to the effect of oral administration of antibiotics.

The exact cause of hair dandruff is not known yet. However, keratosis is known as hair dandruff. For example, mitosis in the epidermis is promoted, resulting in additional keratinization. The yeast pyrrolosporum obare has been shown to produce hair dandruff.

[Reference: R.A.Gosse, R.W. Vander Wyck, J. Soc. Cosmet. Chem. 20, 603 (1969).

Table 2 shows that some of the compounds described above exhibit potent action against Pytyrosporum obare.

It can be seen from Tables 3 and 4 that these and other compounds can delay accelerated mitosis progression. Therefore, for the treatment of hair dandruff, it is possible to use compounds which exhibit excellent effects in Tables 2, 3 and 4.

Distalol, tar and high activity adrenal cortex are used locally for the effective treatment of dryness and only antagonists such as methotrexate, corticosteroids and cell inhibitors are available for systemic treatment. Do. In addition to the combination of UV-light, X-ray physical therapy and psoriasis (systemic and local therapy) and UV-light. All these therapies are accompanied by minor or significant side effects. Therefore, simple local use is beneficial. Tables 3 and 4 show that some of the compounds described above can be used to treat psoriasis.

Diseases caused by filamentous fungi on the skin occur frequently. Sometimes, it is particularly beneficial to determine the type of microorganism that causes the stimulus.

Since the compounds described above in Tables 1 and 2 have shown potent activity against these microorganisms, it can be seen that they can be used to treat filamentous fungi and bacterial skin infections.

The following examples illustrate the invention.

Example 1

2,4-dihydroxy-5-n-hexyl-trifluoroacetophenone

2 g of 4-n-hexylesolecin-mono-trifluoroacetic acid ester are warmed at 120 ° C. for 30 minutes with 20 ml of nitrobenzene dissolved with 3 g of anhydrous aluminum chloride.

Pour 100 g of ice while stirring the reaction mixture and separate the organic layer. The aqueous layer was washed three times with 50 ml of ethylene chloride, washed and combined with organics, washed with 100 ml of water, dehydrated with calcium chloride and evaporated to recrystallize the residue from heptane and petroleum ether.

Melting Point: 90 ℃, Yield: 1.4g (47% of Theory)

1.1 g (38% of theory) are frozen when no solvent is used. The following compounds are prepared by the method of Example 1.

2,4-dihydroxy-3-methyl-trifluoroacetophenone melting point: 101 ° C

2,4-dihydroxy-3-isopropyl-trifluoroacetophenone melting point: 145 ° C

2,4-dihydroxy-3-isobutyl-trifluoroacetophenone melting point: 114 ° C

2,4-dihydroxy-3- (4-methyl) -cyclohexyl-trifluoroacetophenone melting point: 43 ° C.

2,4-dihydroxy-5-n-heptyl-trifluoroacetophenone melting point: 85 ° C

2,4-dihydroxy-3-isohexyl-trifluoroacetophenone melting point: 97 ° C

2,4-dihydroxy-3-n-pentyl-trifluoroacetophenone melting point: 105 ° C

2,4-dihydroxy-5-n-pentyl-trifluoroacetophenone melting point: 95 ° C

2,4-dihydroxy-3-n-propyl-trifluoroacetophenone melting point: 93 ° C

2,4-dihydroxy-5-n-propyl-trifluoroacetophenone melting point: 112 ° C

2,4-dihydroxy-5-n-octyl-trifluoroacetophenone melting point: 85 ° C

2,4-dihydroxy-5-n-nonyl-trifluoroacetophenone melting point: 86 ° C

2,4-dihydroxy-5-isopentyl-trifluoroacetophenone melting point: 101 ° C

2,4-dihydroxy-5-tert-butyl-trifluoroacetophenone melting point: 158 ° C

Example 2

2,4-dihydroxy-3-methyl-trifluoroacetophenone-monoacetate

4.4 g (0.02 mole) of 2,4-dihydroxy-3-methyl-trifluoroacetophenone was dissolved in 25 ml of benzene and 3.2 g (0.04 mole) of acetel chloride and 3.6 g (0.045 mole) of Pyripine is added with stirring. After stirring for 2 hours at room temperature, the mixture is poured into water and the benzene layer is separated. The solution is washed with 50 ml of water and dehydrated with sodium sulfate. The residue obtained by evaporation in a rotary concentrator is recrystallized in n-hexane. Melting point: 49 to 50 ° C, tndbf: 4.5g (86.5% of theory)

In a similar manner, the following compounds are prepared.

2,4-Dihydroxy-5-chloro-trifluoroacetophenone-monoacetate

Prepared from 2,4-dihydroxy-5-chloro-trifluoroacetophenone and acetylchloride.

Melting point; 80 to 83 ℃, yield: 71.5% of theory

2,4-dihydroxy-5-chloro-trifluoroacetophenone-monostearate

Prepared from 2,4-dihydroxy-5-chloro-trifluoroacetophenone and stearoyl chloride.

Melting point: 52 ° C, yield: 40% of theory

2,4-dihydroxy-3-methyl-trifluoroacetophenone-monoundecynate

Prepared from 2,4-dihydroxy-3-methyl-trifluoroacetophenone and 11-undecylene acid chloride and purified by compound distillation. Boiling point: 0.07 = 165 ° C, yield: 64% of theory

2,4-Dihydroxy-5-chloro-trifluoroacetophenone-monoundecynate

Prepared in 2,4-dihydroxy-5-chloro-trifluoroacetophenone and 11-undecylene acid chloride. The compound is purified by distillation. Boiling Point: _0.07 = 168 ° C, Yield: 65% of theory

2,4-Dihydroxy-5-hexyl-trifluoroacetophenone-monoacetate

Prepared from 2,4-dihydroxy-5-hexyl-trifluoroacetophenone and acetylchloride. Melting point: 30 ° C., yield: 83% of theory

2,4-Dihydroxy-5-hexyl-fluoroacetophenone-monostearate

Prepared from 2,4-dihydroxy-5-hexyl-fluoroacetophenone and stearoylchloride.

Yield: 77% of theory

2,4-dihydroxy-3-methyl-trifluoroacetophenone-di-phenylacetate

It is prepared from phenylacetelchloride and 2,4-dihydroxy-3-methyl-trifluoroacetophenone.

Melting Point: 65 ℃, Yield: 90% of Theoretical Value

Example 3

Mixtures of mono and dissalicylates of 2,4-dihydroxy-3-methyl-trifluoro-acetophenone

Dissolve in 20 g benzene of 32 g sodium salicylate and 2.2 g 2,4-dihydroxy-3-methyltrifluoroacetophenone and add 3.2 g phosphorus oxychloride, then reflux the mixture for 2 hours. . The mixture is poured into 150 ml of ice to decompose phosphorus oxychloride and the benzene layer is separated. The aqueous layer is extracted with 50 ml of benzene, the combined benzene solvents are washed with 100 ml of water, dehydrated with sodium sulfate and evaporated to recrystallize the residue from 75% ethanol. Melting Point: 94-98 ℃, Yield: 40% of Theoretical Value

It was found to be a mixture of mono- and disalicylates in the UV, IR and NMR spectra.

The compound of formula (I) may be mixed with conventional pharmaceutical preparations, namely, pop phase aerosols, powder-spraying agents, powders, throat sprays, shampoos, creams, ointments, tinctures, pastes or gels. The inert content has a volume of 0.05 to 1% by weight, preferably 0.1 to 0.8% by weight.

For use as plant protection agents the compounds according to the invention can be made into conventional preparations, in particular solutions or emulsion concentrates, powders, granules, powders for spraying, powders for seed treatment and solutions.

The active substance content in the powder and powder for spraying is 0.01 to about 3% by weight. Seed solutions (about 10 to 50% by weight) and seed treatment powders (about 20 to 90% by weight) as well as concentrates (up to about 95% by weight) contain higher concentrations of the active compound.

Seed preparations are sprayed (solution state) or mixed with seeds (powder state). This compound is used in particular to control genus Thieletia, Helmintosporum, Eustilag and Fusarium fungi.

Claims (1)

A process for the production of substituted fluoroacylsolecins of general formula (I), characterized in that the perfluoroacylsolsin of formula (II) is heated in the presence of Lewis acid as a catalyst at a temperature of 0 to 150 ° C.

In the above general formula R ₁ represents a perfluoroalkyl group or 2,2,3,3-tetrafluorocyclobutyl group having 1 to 8 carbon atoms R ₃ and R ₅ are the same or different from each other, and have 3 to 18 alkyl, halogen, nitro or P-toluene sulfonyl, cyclopentyl, cyclohexyl, cycloheptin, cyclododecyl, methylcyclohexyl, dimethylcyclohexyl , Benzyl or methylthio groups or represented by the following general formula

From here F represents a -CH ₂ -or -S- group when G is R ₅ , or represents a R ₃ group when G is -CH ₂ -or -S- R ₁ is as defined above, R ₃ also represents a hydroxy, methoxy, methyl or cyano group, R ₅ also represents a methyl group, However, 1) as defined above, except that one of the groups R ₃ and R ₅ is hydrogen 2) as defined above except that R ₁ is a trifluoromethyl group, or when E represents an —O—COR ₁ group, D represents a hydroxy group, or E represents a hydroxy group In the case, D represents an —O—COR ₁ group. (Substituent R ₁ in the -O-CO-R ₁ are as described above).