KR810000857B1 - Method for producing bis-penicillanoyloxy-alkanes - Google Patents

Abstract

Title compds. (I; R1, R2 = H, lower alkyl; C5-8 carbon cycle which is substituted with O or S; IV = C5-10 bicyclic system, C4-9bicyclic system which is substituted with O or S, C7-10 spiro cyclic system; R3 = H, lower alkyl, halogen-substituted lower alkyl, substituted aryl, aralkyl) were prepd. by reaction of II and III (Z = O, S). Thus, 1.90 g triethyl oxoniumtetrafluoroborate was added to 1.43 g 1-thioformylhexamethylenimine in 20 ml CH3Cl. The reatant was reacted with 2.22 g bis (6-aminopenicillanoyloxy)-methan and 1.80 g N, N-diisopropylethylamine to give I[IV = (hexahydro-lH-azepin-l-yl)-methyleneamino .

Description

Preparation of Bis-Penisilanoyloxy-Alkanes

The present invention relates to a process for the preparation of novel esters of the general formula (1) useful for human and animal treatment.

Wherein R ₁ and R ₂ are the same or different substituents respectively hydrogen or lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, secondary-butyl, tert-butyl, pentyl and hexyl,

기는 탄소원자 5-10개로 구성된 이환식계(bicyclie system) 예컨대 3-아자바이싸이클로(azabicyclo)[3,1,0] 헥실-3, 3-아자바이사이클로[3,2,0] 헵틸-3, 3-아자바이싸이클로[3,3,0] 옥틸-3, 3-아자비이싸이클로[3,2,2] 노닐-3, 8-아자바이싸이클로[4,3,0] 노닐-8, 4-아자바이싸이클로[5,4,0] 운데실-4 및 상응하는 이성체이거나, 또는 메틸렌기 대신에 산소나 황원자가 임의로 치환된 탄소원자 4-9개의 이환식계, 예컨대 3-옥사-9-아자-바이싸이클로[3,2,1] 옥틸-9 및 3-티아-8-아자바이싸이클로[4,3,0] 노닐-8 및 상응하는 이성체 및 유사환 환(環)계, 또는 탄소원자 7-10의 스피로 싸이클계, 예컨대 6-아자스피로[2,5] 옥틸-6, 8-아자스피로[4,5] 데실-8 및 3-아자스피로[5,5] 운데실-3 및 유사한 기이고,A is a carbon chain having 5 to 8 carbon atoms in which oxygen or a sulfur atom may be optionally substituted instead of a methylene group, or

The group is a bicyclie system consisting of 5-10 carbon atoms such as 3-azabicyclo [3,1,0] hexyl-3, 3-azabicyclo [3,2,0] heptyl-3, 3-azabicyclo [3,3,0] octyl-3,3-azabicyclo [3,2,2] nonyl-3,8-azabicyclo [4,3,0] nonyl-8,4-aza Bicyclo [5,4,0] undecyl-4 and the corresponding isomers, or 4-9 bicyclic systems, such as 3-oxa-9-aza-bi, having an optionally substituted oxygen or sulfur atom instead of a methylene group Cyclo [3,2,1] octyl-9 and 3-thia-8-azabicyclo [4,3,0] nonyl-8 and the corresponding isomers and pseudocyclic ring systems, or carbon atoms 7-10 Spiro cycle systems such as 6-azaspiro [2,5] octyl-6, 8-azaspiro [4,5] decyl-8 and 3-azaspiro [5,5] undecyl-3 and similar groups,

R ₃ is hydrogen or lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary-butyl, tert-butyl, pentyl, neopentyl and hexyl, and isomers and halogen-substituted lower alkyl such as Chloromethyl, trichloromethyl, trifluoromethyl, 2,2,2-trichloro ethyl and similar groups and aryl moieties are for example phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2 -Chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 2,4,6-trichlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxy phenyl, 2 -Methoxyphenyl, 3-methoxy phenyl, 4-methoxy phenyl, 4-ethoxy phenyl, 4-isopropyl oxyphenyl, 2-tolyl, 3-tolyl, 4-tolyl, 1-naphthyl, 2-naph Unsubstituted and substituted aryl with aralkyl.

기는 피페리딜-1 헥사하이드로-1H-아자핀-1-일 헥사하이드로-1(2H)-아조신-1-일, 옥타하이드로-1H-아조닌-1-일, 4-메틸피페리딜-1, 4-에틸피페리딜-1, 4-메틸-헥사하이드로-1H-아제핀-1-일, 2,2디메틸 피페리딜-1, 8-아자스피로[4,5] 데실-8, 시스-3-아자바이싸이클로[3,3,0] 옥틸-3, 시스-8-아자바이싸이클로[4,3,0] 노닐-8, 모르폴리닐-4, 티오모르폴리닐-4 및 1-티아-4-아자-싸이클로 헵틸이다.Especially,

Groups include piperidyl-1 hexahydro-1H-azin-1-yl hexahydro-1 (2H) -azosin-1-yl, octahydro-1H-azonin-1-yl, 4-methylpiperidyl -1, 4-ethylpiperidyl-1, 4-methyl-hexahydro-1H-azin-1-yl, 2,2dimethyl piperidyl-1, 8-azaspiro [4,5] decyl-8 Cis-3-azabicyclo [3,3,0] octyl-3, cis-8-azabicyclo [4,3,0] nonyl-8, morpholinyl-4, thiomorpholinyl-4 and 1-thia-4-aza-cycloheptyl.

기는 1-피페리딜, 헥사하이드로-1H-아제핀-1일, 헥사하이드로-1(2H)-아조신-1-일, 또는 옥타하이드로-1H-아조닌-1-일이다.In particular R ₃ is hydrogen, methyl, ethyl or phenyl,

The group is 1-piperidyl, hexahydro-1H-azin-1yl, hexahydro-1 (2H) -azosin-1-yl, or octahydro-1H-azonin-1-yl.

The term "lower" above and below denotes an organic group having 1-6 carbon atoms.

The present invention also provides pharmaceutically acceptable non-toxic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, P-toluenesulfonic acid, methanesulfonic acid, formic acid, acetic acid, propionic acid, citric acid, tartaric acid and maleic acid and general formula (1). Salts with esters of) and therapeutically effective acids, such as salts with other penicillins, cephalosporins and fusidic acids, are also within the scope of the present invention.

It is known that certain 6-amidino phenylsilanes and their salts are useful antibiotics despite insufficient absorption from the gastrointestinal tract. Hydrolyzable esters of certain 6-amidinophenicsilane acids, such as acyloxymethyl esters, are well absorbed but are somewhat toxic when administered parenterally.

The esters prepared according to the present invention are effectively absorbed upon oral administration and are not toxic upon parenteral administration. After absorption the ester is converted to the corresponding peniclanic acid by enzymatic hydrolysis. Moreover, these esters are chemically more stable than the corresponding free acids.

The process of the present invention is desired by reacting 1,1-bis (6-amino penicillanoyloxy) -alkanol of the following general formula (4) with 2 moles of a reactive derivative of amide or thioamide of the general formula (5) It consists of manufacturing the compound of the said General formula (1).

Wherein R ₁ , R ₂ , A and R ₃ are as described above and Z is oxygen or a sulfur atom.

Examples of the reactive derivative of the compound of formula (5) are as follows, but not limited to this form.

In formula, R <_1> , R <_2> and A are as above-mentioned.

The reaction with the reactive derivatives is well known to those skilled in the art of preparing amidino phenylsilane acid derivatives (see, for example, British Patent No. 1,293,590, which describes in detail the meaning of the reactive derivatives of the compound of formula (5)). ).

The starting materials of formulas (4) and (5) can be prepared by methods analogous to those known or used to prepare known compounds.

The reaction product of formula (1) may be purified or separated by conventional methods, and may also be obtained in free state or in the form of a salt.

The compounds prepared by the present invention are intended for use as pharmaceutical compositions useful for the treatment of infectious diseases in humans or animals.

Such compositions contain, as an active ingredient, at least one selected from the group consisting of a compound of formula (1) and salts thereof, with a solid carrier or a liquid carrier and / or diluent.

In the composition, the ratio of the therapeutically effective substance to the carrier substance is in the range of 1-95% by weight. The compositions may be formulated in various pharmaceutical forms, such as tablets, pills, dragees, suppositories, capsules, sustained-release tablets, suspensions, etc., containing a compound of plain stone (1) mixed with a carrier and / or diluent, or a nontoxic salt thereof. It can be prepared by.

Pharmaceutically acceptable non-toxic, organic or inorganic solids or liquid carriers and / or diluents may be used to prepare compositions containing the compounds of the present invention. Suitable agents are all gelatin, lactose, starch, magnesium stearate, talc, plant and animal fats and oils, gums, polyalkylene glycols, buffers or other known carriers and / or diluents.

Moreover, the compositions may contain other pharmaceutically effective ingredients such as other antimicrobial agents which may be suitably administered with the compounds of the present invention in the treatment of infectious diseases.

The compound of formula (1) is dibasic and may be in the form of a monobasic salt as well as a dibasic. The compound of formula (1) is only slightly soluble in water. For injectable use, Formula (1) is preferably used as a salt of the compound, such as dihydrochloride.

As mentioned above, the compounds of the present invention may be prepared in a pharmaceutical form containing a suspending agent and a non-aqueous ointment and cream.

Pharmaceutical formulations for oral administration may be in the form of suspensions of one of the compounds of the invention, which formulation contains 10-100 mg per ml of non-aqueous carrier.

The compound of the present invention may be administered at this dose so that the desired action is achieved without side effects. In the treatment of humans, the compound of the present invention is conveniently administered in a dosage unit (adult) of 250-1000 mg, preferably containing 50 mg or more and 2500 mg (calculated by the compound of formula (1)).

In the form of dosage units, the compounds of the present invention may be administered once or more per day at appropriate intervals, but always in accordance with the condition of the patient and the physician's prescription.

Thus, the daily dose is preferably an amount of 0.25-5 g of the compound of formula (1) or a salt thereof, and is administered 2-4 times a day.

If it is desired to inject the composition, a sealed ampoule, glass bottle or similar container may be provided which contains an aqueous or oily injection solution or dispersion of a parenterally acceptable active substance as a dosage unit.

Parenteral preparations are particularly useful for the treatment of conditions in which a rapid response to treatment is desired. In the continuing treatment of patients suffering from infectious diseases, tablets or capsules are of suitable pharmaceutical form, particularly when given orally in the form of sustained release tablets.

In the treatment of infectious diseases, it may be useful for such tablets to contain penicillin or cephalosporin which show synergy with other active ingredients as described above, in particular with amidino peniclanic acid.

Hereinafter, the present invention will be described in detail with reference to Examples.

Example 1

Bis (6-[(hexahydro-1H-azin-1-yl) -methylene amino] -penicilanoyloxy) -methane, dihydro chloride

Triethyloxonium tetrafluoroborate (1.90 g) was added to a 1-thioformyl-hexamethyleneimine (1.43 g) ice-cold solution in anhydrous methylene chloride (20 ml), and the mixture was stirred at room temperature for 30 minutes and re-cooled in ice jade. . An ice-cold solution of bis (6-amino-penicilanoyloxy) -methane (2.22 g) and N, N-diisopropylethylamine (1.80 ml) in anhydrous methyl chloride (20 ml) was added and the reaction mixture was added. Concentration was slowly under vacuum at about 0 ° C. After 3 hours all catalysts were evaporated.

The residue was extracted with diethyl ether (3 x 100 ml) and the diethyl ether extract was dried and treated with charcoal.

Water (100 ml) was added and 4N hydrochloric acid was added to freeze-dry the aqueous phase with a pH adjusted to 2.5 to give an amorphous powder. This was determined from methanol / propanol-2 to give the product.

NMR-spectrum (D ₂ O) is δ = 1.58 (S), 1.64 (S), 1.5-2.1 (m), 3.5-3.9 (m), 4.78 (S), 5.56 (d, J = 4), 5.72 Signals were seen at (d, J = 4), 6.03 (bs) and 8.06 (bs) ppm.

Standard: 3-trimethylsilyl-propanesulfonic acid sodium salt was used as internal standard.

Example 2

Bis (6-[(hexahydro-1H-azin-1-yl) -methylene amino] -phenylsilanoyloxy) -methane, dihydro chloride

To a solution of bis (6-amino penicillanoyloxy) -methane (2.22 g) and triethylamine (3.2 ml) in anhydrous alcohol-free chloroform (10 ml), 1-chloromethylenehexa in anhydrous alcohol-free chloroform (10 ml) Methylene aluminum chloride (2.0 g) was added dropwise at about -20 占 폚, left at -20 占 폚 for 30 minutes, and the temperature was raised to 0 占 폚 within 15 minutes.

The solution was evaporated in vacuo to stir the residue with diethyl ether (150 ml), the undissolved triethylamine hardochloride was filtered off, then water (50 ml) was added and 4N hydrochloric acid was added and the pH value was adjusted to 2.5. . Freezing-drying the aqueous phase gave an amorphous powder, which was determined from methanol / propanol-2 to give the product. NMR-spectrum was the same as described in Example 1.

Example 3-24

The compound of Table 1 was obtained according to the preparation method of Example 1 (method B) or Example 2 (method C).

TABLE 1

Preparation of the starting materials of Examples 1-24 (preparations were numbered according to the examples in which they were used).

[Manufacture 1B]

1-thioformyl-hexamethyleneimine

A solution of hexamethyleneimine (9.92 g) in diethyl ether (100 ml) was cooled in ice jade, ethylthioformate (10 ml) was added slowly and the mixture was stirred at rt for 18 h. Diethyl ether was evaporated and the residue was distilled under vacuum. Boiling point: 89-90 ° C., 0.1 mmHg.

The compound of Table 2 was obtained by the method of manufacture 1B.

TABLE 2

¹⁾ Obtained by evaporation of the reaction mixture.

Pure enough to be used for the next step without further purification.

[Manufacture 2B]

1-chloromethylenehexamethyleneimide chloride

1-formyl hexamethyleneimine (12.7 g) was dissolved in anhydrous diethyl ether (250 ml), oxalyl chloride (8.5 ml) in anhydrous diethyl ether (50 ml) was added dropwise while stirring and cooling, and the mixture was stirred at room temperature. Stirring overnight.

The precipitated iminium chloride was separated and washed with anhydrous diethyl ether and left in a desiccator.

Starting material 1-formylhexamethyleneimine was prepared from hexamethyleneimine and clotal (see, eg, British Patent 1,293,590).

The following compounds were prepared according to the method of Preparation 2B.

1-chloromethylenepiperidinium chloride

1-chloromethylene-2-methyl-piperidinium chloride

1-chloromethylene-3-methyl-piperidinium chloride

1-chloromethylene-4-methyl-piperidinium chloride

1-chloromethylene-2,6-dimethyl-piperidinium chloride

1-chloromethylene-hexahydro-1 (2H) -azosinium chloride

1-chloromethylene-octahydro-1H-azoninium chloride

4-chloromethylene-morpholinium chloride

3-chloromethylene-3-azabicyclo [3,3,2] nonanium chloride

[Manufacture 18C]

Cis-8-Azabai Cyclo [4,3,0] Nonan

To a slurry of lithium aluminum hydride (17.1 g) in anhydrous diethyl ether (375 ml), cis-hexahydrophthalimide (23.0 g) in anhydrous tetrahydrofuran (300 ml) was added for 2 hours under a nitrogen stream. After addition, the mixture was refluxed for 2.5 hours, cooled and treated very slowly with excess water. The precipitate was filtered off and the filtrate was evaporated to give cis-8-azabicyclo [4,3,0] nonane as a viscous oil which was used in the next step without purification.

Example 25

Bis (6-[(hexahydro-1H-azin-1-yl) -methylene amino] -phenyranoyloxy) -methane, dihydrochloride

N-formylhexamethyleneiminedimethyl in a solution of bis (6-amino penicilanoyloxy) -methane (2.22 g) and N, N-diisopropylethylamine (1.7 ml) in anhydrous chloroform (35 ml) at 0 ° C. Sulfate complex (2.5 g) was added and stirred at room temperature for 20 hours.

The solution was evaporated and the residue was taken up in ether (200 ml), and the precipitate was filtered off. Then, water (100 ml) was added, and 4N hydrochloric acid was added to adjust the pH to 2.5. Separation and freeze-drying of the aqueous phase gave an amorphous powder, which was determined from methanol / propanol-2 to give the same product as described in Example 1.

Example 26

1,1-bis (6 [(hexahydro-1H-azin-1-yl) -methyleneamino] -penicilanoyloxy) -ethane

To an ice-cold solution of 1-thioformyl-hexamethyleneimine (1.43 g) in anhydrous methylene chloride (20 ml) was added triethyloxonium tetra fluoroborate (1.90 g). The solution was stirred for 30 minutes at room temperature and then recooled on an ice-bath. After adding an ice-cold solution of 1,1-bis (6-amino penicillanoyloxy) -ethane (2.29 g) and N, N-diisopropylethylamine (180 ml) dissolved in anhydrous methylene chloride (20 ml) The reaction mixture was slowly concentrated under vacuum at about 0 ° C. After about 3 hours all solvents were evaporated off.

The residue was extracted with diethyl ether (3 x 100 ml), the ether extract was dried, treated with charcoal and evaporated in vacuo to afford a yellow oil.

NMR-spectrum (CDCl ₃ ) shows δ = 1.67 (S); 1.58 (S); 1.58 (d, J = 6); 1.3-2.0 (m); 3.1-3.6 (m); 4.35 (S); 5.80 (bd, J = 4); 5.45 (m); 6.90 (q, J = 6); A signal appeared at 7.60 (S) ppm.

TMS was used as internal standard.

Example 27-44

In the process of Example 26, the compound of Table 3 was obtained using the corresponding 1,1-bis (6-amino penicilanoyloxy) -alkane as starting material.

TABLE 3

Preparation of the starting materials of Examples 26-44 (preparations were numbered according to the examples in which they were used).

[Manufacture 26B]

1,1-bis (6-aminophenylsilanoyloxy) -ethane

Quinoline (1.46 g) was added to a stirring solution of phosphorus pentachloride (1.28 g) in anhydrous alcohol-free chloroform (30 ml).

The mixture was cooled to −10 ° C., 1,1-bis (6-phenylacetamido-penicilanoyloxy) -ethane (1.38 g) was added, followed by stirring at −10 ° C. for 15 minutes, propane-1 (6.6 ml) was added and then maintained at −10 ° C. for 15 minutes before the mixture was poured into water (50 ml) and petroleum ether (110 ml) was added.

The aqueous phase was separated and the pH was adjusted to 7.5 by addition of sodium bicarbonate and the mixture was extracted with ethyl acetate (3 x 25 ml).

The organic phase was collected and evaporated to dryness in vacuo to give a mixture of the desired compound and quillin. The residue was extracted with petroleum ether (3 x 20 ml) and quillin was removed to give the desired compound as a yellow oil. This was determined with chloroform / hexanes.

NMR-spectrum (CDCl ₃ ) was determined by δ = 1.57 (S), 1.60 (S, J = 7), 1.67 (S), 1.85 (S), 4.38 (S), 4.60 (d, J = 4), 5.52 ( m). The signal appeared at 6.93 (q, J = 7) ppm.

TMS was used as internal standard.

According to the preparation process of Preparation 26B, the following compound was obtained from the corresponding 1,1-bis (6-phenylacetamido-phenylananoyloxy) -alkane.

27B 1,1-bis (6-aminophenylsilanoyloxy) -propane

28B 1,1-bis (6-aminophenylsilanoyloxy) -butane

29B 1,1-bis (6-aminophenylsilanoyloxy) -2-methylpropane

30B 1,1-bis (6-aminophenylsilanoyloxy) -pentane

31B 1,1-bis (6-aminophenylsilanoyloxy) -3-methylbutane

32B 1,1-bis (6-aminophenylsilanoyloxy) -2-methylbutane

33B 1,1-bis (6-aminophenylsilanoyloxy) -2,2-dimethylpropane

34B 1,1-bis (6-aminophenylsilanoyloxy) -3,3-dimethylbutane

35B 1,1-Bis (6-aminophenylsilanoyloxy) -heptane

36B α, α-bis (6-aminophenylsilanoyloxy) -toluene

37B α, α-bis (6-aminophenylsilanoyloxy) -3-fluoro-toluene

38B α, α-bis (6-aminophenylsilanoyloxy) -2-chloro-toluene

39B α, α-bis (6-aminophenylsilanoyloxy) -4-chloro-toluene

40B α, α-bis (6-aminophenylsilanoyloxy) -2,6-dichloro-toluene

41B α, α-bis (6-aminophenylsilanoyloxy) -2,4,6-trichloro-toluene

42B 2- (bis (6-aminophenylsilanoyloxy) -methyl) -naphthalene

43B α, α-bis (6-aminophenylsilanoyloxy) -2-hydroxy-toluene

44B α, α-bis (6-aminophenylsilanoyloxy) -4-methoxy-toluene

[Manufacture 26C]

1,1-bis (6-phenylacetamido-penicilanoyloxy) -ethane

After stirring a mixture of sodium iodide (6.0 g), 1,1-dichloroethane (4.3 ml) and N, N-dimethylformamido (30 ml) at 100 ° C. for 18 hours, the reaction mixture was cooled to 40 ° C. and Sodium benzyl penicillate (3.50 g) was added. After stirring for 44 h at 40 ° C., the mixture was diluted with ethyl acetate (100 ml) and extracted with water (2 × 25 ml), saturated aqueous sodium titanium (20 ml) and water (25 ml). The organic phase was evaporated to dryness in vacuo.

The residue was extracted with petroleum ether (3 × 50 ml) and the remaining black viscous oil was purified by drying column chromatography on silica gel (eluent: cyclohexane / ethyl acetate 1: 1) to obtain the desired compound as yellow. It was obtained in the form of bubbles. IR-spectrum (CHCl ₃ ) showed strong bands at 1780,1675 and 1495 cm ⁻¹ and NMR spectrum (CDCl ₃ ) was δ = 1.43 (S); Signals at 1.54 (d, J = 6), 3.63 (S), 4.34 (S), 5.55 (m), 6.17 (d, J = 8.5), 6.87 (q, J = 6), 7.30 (m) ppm appear.

TMS was used as internal standard.

[Manufacture 26D]

1,1-bis (6-phenylacetamido-phenylsilanoyloxy) -ethane

To a solution of 1-chloro-1-iodine-ethane (1.0 ml) in N, N-dimethylformamide (30 ml) was added sodium benzyl penicillinate (3.50 g) and the mixture was stirred at 40 ° C. for 48 hours. Ethyl acetate (100 ml) was added and extracted with water (2 × 25 ml), saturated aqueous sodium bicarbonate (20 ml) and water (2 × 25 ml). The black oil obtained by evaporation to dryness in vacuo of the organic phase was purified by dry column chromatography to give a yellow oil.

NMR-spectrum was the same as described in Preparation 26C.

[Manufacture 36C]

α, α-bis (6-phenylacetamido-penicilanoyloxy) -toluene

A mixture of sodium iodide (6.0 g), benzal chloride (6.35 ml) and N, N-dimethyl formamide (50 ml) was stirred at 40 ° C. for 18 hours, then sodium benzyl penicillinate (3.50 g) was added and 40 ° C. Stirred further for 22 hours. The mixture was diluted with ethyl acetate (200 ml) and extracted with water (2 × 50 ml), saturated aqueous sodium bicarbonate (50 ml) and water (50 ml). The organic phase was evaporated to dryness in vacuo and the residue was extracted with petroleum ether (3 x 50 ml) to remove the remaining black oil under silica column (eluent: cyclohexane / ethyl acetate 1: 1) under dry column chromatography. The compound of was obtained as yellow oil.

NMR-spectrum (CDCl ₃ ) is δ = 1.38 (S), 1.43 (S), 3.65 (S), 4.42 (S), 5.60 (m), 6.37 (d, J = 8), 7.40 (m), 7.72 A signal was seen at (S) ppm. TMS was used as internal standard.

[Manufacture 27C-44C]

The compound of Table 4 was obtained by the method of manufacture 26C, 26D, or 36C.

TABLE 4

Claims (1)

As detailed in the text, the 1,1-bis (6-aminophenylsilanoyloxy) -alkane of the following general formula (4) is reacted with 2 moles of a reactive derivative of amide or thioamide of the following general formula (5) Method for producing a compound of formula (1) characterized in that the following.

Wherein R ₁ and R ₁ each represent hydrogen or lower alkyl as the same or different substituents, and A represents a carbon chain of 5-8 carbon atoms in which an oxygen or sulfur atom may be optionally substituted instead of a methylene group. Display; or

The group represents a bicyclic system containing 5-10 carbon atoms, or a bicyclic system containing 4-9 carbon atoms optionally substituted with oxygen or a sulfur atom instead of a methylene group, or a 7-10 carbon atom Spiro cycle system containing dogs, R ₃ is hydrogen or lower alkyl; Halogen substituted lower alkyl and unsubstituted and substituted aryl and aralkyl, Z is oxygen or sulfur atom.