JPS5810585A - Alpha-substituted ureidobenzylpenicillanic acid - Google Patents

Abstract

NEW MATERIAL:A compound of formulaI[R<1> is H or OH; X is n-5C alkyl; Y is group of -(OR<2>)m (R<2> is H, 1-4C lower alkyl, 2-4C lower alkanoyl, etc; m is 1, 2 or 3), group -CN, -COOR<3> (R<3> is H or 1-4C lower alkyl), etc.; n is 2 when Y is -(OR<2>)m, and 1 when Y is another group]and a pharmacologically acceptable salt thereof. EXAMPLE:6-{D(-)-alpha-[3-(3,4-Dihydroxybenzoyl)-3-(3-hydroxypropyl)-1- ureido]- alpha-phenylacetamide}penicillanic acid. USE:An antimicrobial agent capable of exhibiting the activity in the living body particularly on some kinds of microorganisms belonging to the genus Pseudomonas. PROCESS:A novel compound of formula II (R<11> is H, OH, etc.; R<6> is OH, etc.) or a reactive derivative, e.g. pivalic acid or trichloroacetic acid, is reacted with a compound of formula III (R<7> is H or protecting group) or a reactive derivative thereof, and the protecting group is then removed to give the aimed compound of formulaI.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (I) (wherein B1 hydrogen atom or hydroxyl group is
, and Y is the substituent yl group or hydroxyl group of X, or the lower alkyl group of 02 to 4 substituted with a lower alkoxy group of A lower alkyl group, R4 is a hydrogen atom, a nitro group spanning OH~4 lower alkoxy group, BS is a hydroxyl group spanning group -000 (R13 is the same as above), Y is a group +OR ”) If it is s, put 2, if it is another group, put 1, and put 1, 1! or 3, 1
Kr1A is a compound represented by 0.1.2" (meaning 3) or a pharmaceutically acceptable salt thereof.

α-Leidobenzylpenicillin represented by the above general formula (1) is a new compound that has not been described in any literature, and exhibits strong antibacterial activity against Durham-positive bacteria and Gram odontoids.
In particular, it exhibits strong antibacterial activity against Shademonas bacteria and is superior in in vivo activity compared to conventionally known compounds. That is, the above general formula (
The compounds represented by 1) and their pharmaceutically acceptable salts are useful as antibacterial agents.

Thus, the object of the present invention is to provide an excellent antibacterial compound represented by the general formula (1) and a pharmaceutically acceptable salt thereof.

In the general formula (1), a lower alkyl group as meant by X, a lower alkyl group, a lower alkanoyl group, and a lower alkoxy group included in the definition of R2, a lower alkyl group as meant by R3, and a lower alkyl group as meant by R4. The lower alkoxy group is a bombarded hydrocarbon group which may be straight or branched.

The number of carbon atoms in the lower alkyl group represented by X is:
When the substituent Y means +0R2)%, it is selected from the range of 2 to 5, and when Y means a group other than +OR")m, that is, the group -ON, -000R", it is selected from the range of 1 to 5- selected from the range.

Substituent Y in the lower alkyl group represented by X
The position frjt may be in the range of 1 to 5 or 2 to 5 carbon atoms.

Since the α-substituted ureidobenzylpenicillins according to the present invention have a YK cacarxyl group at the 3-position and in some cases, they can form salts with various basic substances at the nuclear group, and among them are pharmaceutically acceptable. Salts with basic substances are important.

Examples of such salts include the bases of inorganic bases, such as alkali metal salts such as sodium and potassium, the salts of alkaline earth metals such as calcium, and the salts of organic bases, such as salts of tetraquine and dibenzylethylenediamine. It will be done.

These salts can be prepared by conventional methods, ie, by treating the carboxyl group with an equimolar amount of the above-mentioned crucible group.

Optical isomers exist in the compounds of the present invention due to the asymmetric carbon atom in the 6-acetamido group.

The DL-, D- and L-isomers, as well as optionally multiple diastereomers, are present and are all within the scope of this invention.

The compound represented by the general formula (1), α-substituted ureidobenzylpenicillins, can be produced by various methods.

For example, if the general formula (In (formula), B 11 represents a hydrogen atom, hydroxyl group or a protected hydroxyl group, R6 represents a hydroxyl group or a protected hydroxyl group,
YIFi is the same as Y in the above general formula (1), or when a hydroxyl group or carboxyl group is present in Y, it means that the group (C, etc.) is protected. X
Same as above. α-Substituted ureidophenylacetic acid represented by ) is a reactive derivative thereof, and 6-aminopenicillanic acid or with its reactive derivative and then R11,♂ nt or Yl
If the compound has a protecting group, this production method is characterized by removing it (and so on).

In general formula (II), Bll, RIG and Yl
As the protecting group for the hydroxyl group contained in , it is sufficient that the group is a mild group and can be easily removed, such as formyl group, acetyl group,
Acyl group such as propionyl group, butyryl group, chloroacetyl group, aralkyl group such as benzyl group, benzhydryl group, trityl group, substituted aralkyl group having a substituent such as methoxy, nitro, etc. on the allyl nucleus thereof, trimethylsilyl Protecting groups commonly used for hydroxyl groups such as triethylsilyl group, dimethylmethoxysilyl group, diethylmethoxysilyl group, trimethoxysilyl group, triethoxysilyl group, tetrahydropyranyl group, etc. chloromethyl group, 2.2.2-trichloroethyl group, 2,2.2-
) Substituted aralkyl groups having a halogenated lower alkyl group, benzyl group, benzhydryl group, aralkyl group such as trityl group, or a substituent such as methoxy group or nitro group on the allyl nucleus of the trifluoroethyl group. I can do it.

When the reactive derivative of the a-substituted ureidophenyl acetate represented by the general formula (1) is dissolved, the carboxyl group involved in the reaction is activated and it becomes a running conductor.

Examples include acid anhydrides, active esters, active amides, acid halides, and the like.

Specifically, for example, warm anhydrides with aliphatic carboxylic acids such as pivalic acid, trichloroacetic acid, and pentanoic acid; alkyl carbonic acid mixed anhydrides; phenylphosphoric acid mixed anhydrides; aromatic carboxylic acid mixed anhydrides; 1-hydroxy Benzotriazolyl ester, 4-dinitrophenyl ester, N-
Hydroxysuccinimidyl ester, N-hydroxyphthalimidyl ester, pentachlorophenyl ester, phenyl asophenyl ester, cyanomethyl ester, methoxymethyl ester; acid amides with imidazole, triazole, tetrazole, etc.

In addition, when R means a protecting group, especially a group capable of forming an ester, the amide bond forming reaction does not lead the substituted ureidophenylacetic acid to a reactive derivative, but converts the substituted ureidophenylacetic acid into an N,N'- dicyclohexylcarboside, N
, N'-diethylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N,N'-
The reaction can also be carried out efficiently by using carbodiimides such as diisopropylcarbodiimide as a condensing agent.

Furthermore, in general formula (1), R'', R' and f
When all of the hydroxyl groups and carboxyl groups contained in are protected, the α-substituted ureidophenylacetic acid can be subjected to the reaction in the form of a halide. In order to obtain an acid halide, a method using a commonly used halogenating agent such as oxalyl chloride or thionyl chloride,
Alternatively, a method may be used in which a Relsmeier reagent obtained by reacting dimethylformamide or N-methylformanilide with thionyl chloride, phosphorus oxychloride, trichloromethylchloroformate, phosgene, or the like is used.

When R7 of 6-aminopenicillanic acid represented by general formula (II) is a protecting group, # examples of the protecting group include salts of alkali metals, alkaline earth metals, triethylamine, N-methylpiperidine, pyridine, etc. Inorganic or organic bases that can be formed, halogenated lower alkyl groups such as the tetralomethyl group, 2.2.2-)lichloroethyl group, λ2,2-trifluoroethyl group, aralkyl groups such as the benzyl group, benzhydryl group, trityl group Substituted aralkyl group, trimethylsilyl group, triethylsilyl group, dimethylmethoxysilyl group, diethylmethoxysilyl group, trimethoxysilyl group, triphenylsilyl group having a substituent such as methoxy group or nitro group on the group or their allyl nucleus. Examples include silyl groups such as the like.

In addition, the reactive derivative of 6-amitubenicilanic acid is
It means a derivative in which the 6-amino group is activated. Activation is carried out, for example, by the introduction of a silyl group, such as a trimethylsilyl group.

The amide bond forming reaction is preferably carried out in a solvent,
As a solvent, acetone, tetrahydrofuran, dimethylformamide, pyridine, acetonitrile, dioxane, chloroform, dichloromethane, dichloroethane,
An inert cloth S solvent such as ethyl acetate is used. Among these, hydrophilic solvents can also be used in combination with water.

The reaction is usually carried out under cooling or at room temperature, but may also be carried out under heating. That is, the temperature is usually selected from the range of -30 to 30°C, but preferably 0 to 10°C when α-substituted ureidophenylacetic acid is used in the form of an active ester or active amide, and preferably 0 to 10°C when used in the form of an acid anhydride. is -1
5 to -5℃, when used in the form of a genide.
f-20 to -10°C.

Although it varies depending on the reaction time, reaction temperature, compound used in the reaction, solvent, etc., it is usually appropriately selected within the range of 0.5 to 48 hours, preferably 1 to 24 hours.

After carrying out the amide bond forming reaction, if the product has a protecting group, it is removed.

In the case of an acyl group, the protective group for the hydroxyl group contained in Bn, BIS and Yl can be removed by treatment with an inorganic or organic base. Examples of the inorganic base include sodium hydroxide, potassium hydroxide, etc. Alkali metal hydroxide, magnesium hydroxide.

Alkaline earth metal hydroxides such as calcium hydroxide, alkali metal carbonate salts such as sodium carbonate and potassium carbonate, all-alkaline earth carbonate salts such as magnesium carbonate and calcium carbonate, and sodium hydrogen carbonate.

Examples include alkali metal salts of carbonates such as potassium hydrogen carbonate, alkaline earth metal salts such as calcium phosphate, alkali metal salts of hydrogen phosphate such as disodium hydrogen phosphate and dipotassium hydrogen phosphate, ammonia, etc. Examples include alkali metal acetates, trialkylamines such as trimethylamine and triethylamine, and alcohol amines such as diethylaminoethanol and triethanolamine. Removal of acyl groups with these bases can be carried out using water or organic solvents containing alcoholic hydroxyl groups (eg, methanol, ethanol).

ethanolamine) or a mixture thereof. As a preferred example, methanolic ammonia I
) IJ Ethylamine-triethanolamine-dimethylformamide mixture may be mentioned.

When the protecting group is an aralkyl group or a substituted aralkyl group, it can be removed by catalytic reduction, for example using palladium-carbon. Furthermore, t-butyl groups, methoxymethyl groups, 7-enacyl groups, tetrahydropyranyl groups, etc. and silyl groups can be removed using an inorganic acid such as hydrochloric acid.

The protective group for the carboxyl group contained in Y1 and the protective group meant by R1 can be removed by reducing the aralkyl group and substituted In the case of aralkyl groups, catalytic reduction, e.g. using palladium on carbon, or beak, e.g. formic acid, trifluoroacetic acid, benzenesulfonic acid, p-)luenesulfonic acid, hydrochloric acid, cation exchange resins, This can be carried out using an inorganic acid or a Lewis acid such as aluminum chloride, and the silyl group can be removed by treatment with the above-mentioned acids or an alcohol such as methanol.
The salt-forming base of 7 can be removed by treatment with acid.

Isolation and purification of the target product from the reaction mixture can be easily carried out according to conventional methods. For example, dichloromethane, chloroform, tetrahydrofuran.

Extraction with organic solvents such as ethyl acetate, or various chromatography methods using activated carbon, silica gel, ion exchange resins, dextran crosslinked polymers, porous polymers of styrene-divinylbenzene or acrylic esters, etc. are applied. can be done.

The α-substituted ureidophenylacetic acid represented by the general formula (II) is a new compound. N-
A mold can be prepared from K by reacting a substituted alkylcarbamic acid halide and then removing a protecting group if necessary.

The protecting groups used here and their removal means are Ra
, Bll and Yl are as described above.

Another method for producing the compound represented by the general formula (1), α-substituted ureidobenzylpenicillins, is the general formula (P/) ¥- (wherein, Rs means a protected hydroxyl group).
K means a group corresponding to a hydroxyl group or a carboxyl group, if present, which is protected. ZkeI means a rogen atom. ) and the general formula (
V) Reacting with α-aminobenzylpenicillin represented by 11 (wherein R11 and R7 are the same as above) or a reactive derivative thereof, and then removing the protecting group present in the product. This is a method of using it as a sign.

In the general formula (FN), the protective groups contained in Ra and Y''K are the same as those described in t and f, respectively. It is a derivative in which an α-amino group is activated, and the activation is carried out by introducing a silyl group such as a trimethylsilyl group into the amino group.

The reaction is preferably carried out in a solvent, and examples of the solvent include acetone, tetrahydrofuran, acetonitrile, dimethylformamide, and pyridine.

Inert organic solvents such as dioxane, chloroform, dichloromethane, dichloroethane, ethyl acetate are used. Among these, hydrophilic solvents can also be used in combination with water.

The reaction is usually carried out under cooling or heating, and the reaction time, which is preferably 0 to 30°C, is usually selected in the range of 1 to 48 hours, preferably 1 to IO hours.

Removal of protecting groups present in the product is performed by Bll, R6
The purification is carried out by the same means as described above for the removal of the protecting groups of R7 and Yl.

N-penzoylcarnocumic acid halides represented by the general formula (W) are new compounds, but when the corresponding benzamide or its derivative is mixed with phosgene, trichloromethylchloroform, etc. in an organic solvent such as dichloromethane, tetrahydrofuran, or ethyl acetate. It can be produced by reacting a carbonylating agent such as mate.

The production of an optical isomer, which is a type of α-substituted ureidobenzylpenicillins represented by the general formula (1), is carried out in the above production method using α-substituted ureidophenylacetic acid (general formula (H)) having the desired optical activity. , by using α-aminobenzylpenicillins (general formula (V)'), and N-benzoylcarbamic acid halides (general formula (IV)) having optical activity capable of forming a desired diastereomer. By using this, it can be carried out efficiently. The above-mentioned optically active substance can be obtained by applying ordinary optical resolution techniques.

The object compound of the present invention, that is, the compound represented by the general formula q) and its pharmaceutically acceptable salts, can be formulated into forms suitable for various administration methods, as in the case of other penicillin compounds.

Accordingly, embodiments of the invention include a variety of pharmaceutical compositions suitable for use in human or veterinary medicine. These compositions are provided in conventional manner using the necessary pharmaceutical carriers or excipients. That is, when provided as an injectable composition, it can take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle.

Suppositories may also be provided, using conventional suppository substrates such as cocoa milk fat or other glycerides.

These compositions may contain 0.1% or more, depending on the method of administration.
For example, it can contain from 5 to 99%, preferably from 10 to 60%, of talkative substances.

The dosage for humans is usually io for adults.

Selected in the range of ~3000■. For example, depending on the route of administration, frequency, weight, age, and symptoms, 500 to 200 mg/day
A dose of 000TIIg is a preferred example.

In order to demonstrate the pharmaceutical characteristics of the target compounds of the present invention, some of them were evaluated at the minimum inhibitory concentration (minimum inhibitory concentration) against various bacteria.
MIO, Q/d) and Pseudomonas sui infection treatment/experimental unity (gDso) in mice with 6-[D
(-)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)phenylacetamide]
Penicillanic acid (generic name Piveracillin) and 6-CD
(-)-α-(3-(3,4-dihydroxybenzoyl)-3-methyl-1-ureido)-α-phenylacetamide] penicillane lv (hereinafter also referred to as compound Z).

(described in West German Patent Publication 'm2921324).

1. MTO measurement results (1) Test method In vitro antibacterial activity was measured by the agar plate multiple dilution method described below. One platinum loop of the test strain, which had been cultured overnight in Note Infage Protein Pross and diluted 100 to 1000 times, was placed on Heart-in-7S-dicarbonate agar (HI agar) containing each of the compounds of interest. After inoculation and culturing at 37°C for 20 hours, MIO was measured.

(2) Results The symbol (A) indicating the test compound shown in Table-1.

B, ...) correspond to the symbols in the examples (the same applies below).

2. FiDso measurement results (1) Test method 5 ddY male mice, 5 weeks old and weighing 21 to 25 f.
They were used as one group. The test bacterial strain was cultured overnight at 37° C. on Plain Heart Inn 7Ag agar, suspended in 5% mucin, and intraperitoneally administered to mice.

Test compounds were prepared at various concentrations and injected subcutaneously into mice 1 and 3 hours after inoculation. After 5 days, BDsoM was calculated from the number of surviving mice at each dose.

B2) Test - The results in Section 4 and F show that the target compound of the present invention has excellent in vitro and in vivo activity.

EXAMPLES The method for producing the target compound of the present invention will be explained in detail with reference to Examples below.

Example 1゜(1) N-(3-hydroxypropyl)-3,4-dihydroxybenzamide5. 70 liters of dry dichloromethane containing Of and 12.99 kg of trimethylsilyl chloride
A solution of 40 cm of dry dichloromethane containing 11.5 f' of triethylamine was added dropwise to the candle solution under ice-ice cooling.

The mixture was heated in a nitrogen atmosphere for 40 minutes, then cooled at -10 to -5°C with trichloromethyl chloroformate λ8! ! Drip tl.

After gradually increasing the liquid temperature and stirring at 0 to 5°C for 2 hours,
Excess phosgene and solvent are distilled off under reduced pressure. 80 mj of cooled dry dichloromethane is added to the residue, insoluble materials are removed by gravity filtration, and the mixture is subjected to the reaction described below.

(2) Trimethylsilyl chloride 7.8f' was added dropwise to 100 td of a dry dichloromethane solution containing 8f of anhydrous ampicillin IO and 7.11% of triethylamine at 5 to 10°C. After stirring at the same temperature for 1 hour, the dichloromethane solution prepared in (1) above was added dropwise at 0 to 5° C. while stirring.

After stirring for 1 hour at 5-10°C, it was evaporated to dryness at room temperature under reduced pressure, and the residue was mixed with 300 d of ethyl acetate and cold 6N hydrochloric acid LO.
Add a mixture of O*l and separate the organic layer. The organic layer was washed with 300 WL of cold saturated brine, and then extracted twice with 300 d'''c of cold saturated aqueous sodium bicarbonate solution.The separated aqueous layer was washed with 100 gqe of ethyl acetate,
250 d of ethyl acetate is added thereto, and both values are brought to about 1.5 with cold 6N hydrochloric acid. After adding a sachet of food to saturate the aqueous layer, the organic layer is separated. The organic #100 in cold saturated saline solution
The washed fireflies were dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is subjected to column chromatography on activated carbon (chromatograph grade) and eluted with ethyl acetate. The eluate was collected and concentrated under reduced pressure until the volume was approximately 3011111, and then this was mixed with 300% of Sagi-hexane.
6-CD(-)-α-(3
-(3,4-dihydroxybenzoyl)-3-(3-hydroxypropyl)-1-ureido)-α-phenylacetamide] penicillanic acid (hereinafter also referred to as compound A) 5
．． Of is obtained as a white powder.

I RνKB'(m-1): 3700-2300.
1775゜aS 1675.1600.1515 N M R (DMSO-d6.60MHz) δ (IP)
:L41 (3H.

s), 1.55(3)(,s), 14-2.0(2H,
br).

3.36 (2H, t, J=6Hz), 3.75C2H
,br).

4.20 (IH, s), 5.3-5.8 (3H
, S), 6.7-7.5 (8H, m), 9.2 (2
H,br)UV λBt0HssD): 209(
3, lX10'), 295 (sa! 6.3X10'), 225 (shoulder), 271 (6, lX1
03) Ferric chloride color reaction: positive (dark green) (a) In Example 1 (1), in place of N-(3-hydroxypropyl)-kame 4-dihydroxybenzamide 5, O2, N-(5 -Hydroxypentyl)-↓Using 5.0 f of 4-dihydroxybenzamide and following the same treatment, 6-CD(-)-α-(3-(3,4-
dihydroxybenzoyl)-3-(5-hydroxypentyl)-1-ureido)-α-7enylacetamide]
Beny7lanic acid (hereinafter also referred to as compound C) 5.2 f is obtained as a white powder.

I RyKB'(i'): 3700-2200.1
770°ga*tLM 1675.1600.1515 N M R (DM80-d6.60MHz) δ(P)
: 1.3 (6H.

brs)el, 41(3H*s) +1.55(3)
T + s) + 3.1~3.9 (4H, chicken) = 4.21
(IH,s), 5.3-5.8 (3H9嘱), 6.7
〜7-5(8H,戟), 9.14(LH.

dIJ-7Hz) -9,24(IH-d*
J-7Hz) UV λBt0Hss(g): 20
7 (2,2X10'), 225 (1az shoulder), 272 (4,0X10''), 293 (4,3
X103) Ferric chloride color reaction: positive (dark green) (b) In Example 1 (1), N-(2- (2-Hydroxyethoxy)ethyl)-'&4-dihyde V-xybenzamide5. Using Of and processing in the same way below, we get 6- CD (-)-α-(3-
(3,4-dihydroxybenzoyl)-3-(2-(2
-hydroxyethoxy)ethyl)-1-ureido]-α
-phenylacetamide] penicillane (hereinafter also referred to as compound ri) 5.2f is obtained as a white powder.

I RyKBr(i'): 3700-2200.1
775° inert aS 1675.1600, 1515.105ON M R,
(T)M2O-d6,60MHz)δ(11111)
: 1.41 (3H.

s), 1.55 (3Hes), 3.3-4.1 (8
H, m).

4.20 (IH, s), 5.3-5.8 (3H
, appalled), 6.7-7.6 (8H, @), 9.08 (1
1 (,d, J-7Hz).

9.20 (IH, d, J=7Hz)UV λ”
0H*m(g): 207(2,8X10'),
224η1S cloud (shoulder), 270 (4,6X10”), 295 (4,6X
lO') Ferric chloride color reaction: positive (dark green) (c) In Example 1 (1), N-(3-hydroxy 7
'o-bil)-14-dihydroxybenzamide 5, Of
N-(2-methoxyethyl)-3,4-q hydroxybenzamide instead of 5. of trimethylsilyl chloride at 9.7 f.

Using triethylamine 8.62 and the same procedure (C treatment, 6-CD (-)-α-(3-(3,4-dihydroxybenzoyl)-3-(2-methoxyethyl)-
1-Ure(l-α-phenylacetamido)penicillanic acid (hereinafter also referred to as compound E) 7. OS' is obtained as a white powder.

I RνKB'(ci'): 3700-2300.1
775° as 1675.1600,1515,1055N M R(
DMSO-d6.60MHz) δ(P)1.41(3)
(.

s) +1.56 (3H, s), 3.18 (3H, s).

3.40(2f(,br), 3.85(21(,br)
), saw i strawberry wholesale - hesitation i4.20 (IH, s), 5
．． 3-5.8 (3H, s), 6.7-7.6 (8) (,
%), 9.11 (IH.

d, J=7Hz), 9.15(IH,d, J=7
Hz) U V2”OHss (g): 208 (2,8X
10'), 2240F.

aW 272 (5,9X103), 295 (5,9X10'
) Ferric chloride color reaction: positive (dark green) (d) N-(3-hydroxypropyl')-3,4-dihydroxybenzamide in Example 1 (1)5.
N-(2-cyanoethyl)-3,4-dihydroxybenzamide instead of Ol4. Of, one trimethylsilyl chloride 7.9f,) ethylamine 7.
．． 12 and the same treatment thereafter, 6-CD (-
)-α-(3-(3,4-dihydroxybenzoyl)-
3-(2-cyanoethyl)-1-ureido)-α-7enylacetamide]penicillanic acid (hereinafter also referred to as compound F)4. Of is obtained as a white powder.

IR,yKB'(ffi'): 3700-230
0.2200゜15m 1770.1685,1600,151ON M R(
DMSO-d6, 60MHz) δ(P): 1.41(3
H.

s), L55(31-1,s), 2.78(2H,
br), 3.98 (2H, br), 4.20 (IH, s
), 5.3-5.8 (3H1 sacrifice), 6.7-7.5
(8H, %), 9.09 (IH, 4J-7Hz)
, 9.14 (IH, d, J-7Hz) tOH U V2 sm(f): 207 (18
X10), 225 (shoulder) - 11&8m 276 (5,1X1G"), 295 (5,5X1G")
Ferric chloride color reaction: positive (dark green) (e) N-(3-hydroxypropyl)-14-dihydroxybenzamide in Example 1 (1), and
Using 5.9P of trimethylsilyl chloride and 5.32P of triethylamine, and following the same treatment, 6-
(D (-)-α-(3-(3,4-dihydroxybenzoyl)-3-ethoxycarbonylmethyl-1-ureido)-α-phenylacetamide] penicillane beak (hereinafter also referred to as compound G) 4. Of is white Obtained as a powder.

IRνKBr(cR-”): 3700-2200,
1770.

π-1z 1730.1685,1600,1515N M R(
DMSO-d6.60MHz)δ(-): LO~
1.4 (3H.

inertia), 1.40(3T(,s), 1.55(3H,
s), 3.8-4.6 (4H, s), 4.20 (LH
, s), 5.3-5.9 (3H2 whisper), 6.7-7.
6 (8H, inertia), 9.22 (IH.

d, J=7Hz), 9.47(IH, d, J-7
Hz)UVλ"0Hss(')=208(15X10'
), 226 (Shoulder x 11m 258 (4,8X10"), 294 (4,8X10")
) Acclimatized ferric color reaction: @-type (dark green)
5. Instead of N-benzyl-4-dihydroxybenzamide. By using Of, 8.4f of 1) methylsilyl chloride, and 7.5f of ethylamine, 6-CD (-)-α-(3-(
3,4-dihydroxypensoyl)-3-benzyl-1
-Ure()')-α-phenylacetamide]penicillanic acid (hereinafter also referred to as compound H)4. Of is obtained as a white powder.

I RyKB' (m-1): 3700-2200.1
770゜a1 1680.1600.151O NMR (DM 80-d@, 60MHz) δ
(IF): 1.42 (3) (.

s), 1.55 (3H, s), 4.21 (LH, s),
4.8-5.1 (2H, brs), 5.3-5.8 (
3H, m), 6.7-7.6 (13H, m), 9.
16 (IH, d, J-7Hz).

9.24 (IH, d, J=7Hz) TJ V λ”OH8m (#): 208 (3,2
X10'), 272 (4,7'lI&8g1 Hydroxy 7
'ohik) -3,4-dihydroquibenzamide 05, using 2.7 f of N-cyanomethyl-&4-dihydroxybenzamide instead of Of, using 5.8 f of trimethylsilyl chloride, and 5.29 f of triethylamine. , and following busy processing, 6-CD(-)-
α-(3-(3,4-dihydroxybenzoyl)-3-
cytenomethyl-1-ureido)-α-quenylacetamide] penicillanic acid (hereinafter also referred to as compound I) 2.
Of force (obtained as a white powder).

I RWKB'(m'): 3700-2300
．． 1770°ag 1700.1600.1515 NMR (DMSO-ds, 60MHz) δ(!!
II): 1.41(3)(.

s) , 1-56 (3H, s) , 4.20 (IH, s
), 4.6 (2H, brs), 5.3=, 5.8
(3H, m), 6.8-7.6 (8H=s)
-9,21(2H#d*J!7Hz)U
V 2 ” 0Hs91L(') ' 207 (3
,3×10') $ 226 (IF) -S 278 (6,9X103), 296 (7,4X103)
Ferric chloride color reaction: positive (dark green) (h) KN-furfuryl-3,4-dihydroxy instead of N-(3-hydroxypropyl)-14-dihydroxybenzamide 5,Of in Example 1 (1) Benzamide 5. By using Of, trimethylsilyl chloride at 9.21F, ) IJ ethylamine at 8.2F, and the same treatment, 6-CD(-)-α-(3-(
3,4-dihydroxybenzoyl)-3-furfuryl-
1-ureido)-a-7enylacetamide] penicillansaki (hereinafter referred to as compound J) 5.5 f is obtained as a white powder.

IRW-,,Co5t): 3700-2200
．． 1770.

1680.1600.151O NMR (DM80-d6, 60MHz)' (lpl)
: L41 (3H,5)-1,55(3H,s)
, 4.20 (IH, s) , 4.8-5.1 (2H, b
rs), 5. '3~5.8 (3Hts), K
l ~ 7.6 (11H, s), 9.18 (2H, d, J
=7Hz) UVλ,. , sm (g): 20g (1
4X 10'), 272 (5,3XIO"), 29
4(5,8X103) Ferric chloride color reaction: Positive (dark green) (S) N-(3-hydroxypropyl)-3,4-dihydroxybenzamide 5.02 in Example 1 (1)
0 instead of N-(3-acetoxypropyl)-3,4-
Dihydroxybenzamide5. Using Of and trimethylsilyl chloride at 8.1? , using triethylamine in 7.2 and following the same treatment, 6-CD
(-)-α-(3-(3,4-dihydroxybenzoyl)-3-(3-acetoxypropyl)-1-ureido J
-α-phenylacetamide] penicillane (hereinafter referred to as compound 4) 1st is obtained as a white powder.

I R&1. , (m): 3700-23G0.177
5゜1730.1680,1600,1510゜N M
R (DM80-d@, 60MHz) J(P): 141(
3H,s).

15-2.1 (2H, br) tl, 55 (3Hes)
tl, 8g (3H, s), 16~tl (4H, s),
4.21 (IH.

* ) * 5.3~5.8 (3Hsm) #6.
8~7.6 (8Hes) *9.1741H, d, J
=7Hz), 9.30 (IH, d.

J-7Hz) UV 2”OHm5 (g): 205 (2,
8X10'), 223 (Jlf).

%a# 272 (4,0X103), 293 (4,4X103)
Ferric chloride color reaction: Positive (dark green) Example 2 (1) N-(2-hydroxyethyl)-3,4-dihydroxybenzamide5. Of and trimethylsilyl chloride 3.8 f are suspended in a mixed solvent of 30 d of dry dichloromethane and 30 d of tetrahydrochloride, and 30 d of dry dichloromethane containing 12.39 d of triethylamine is added dropwise to this under ice-water cooling. . The mixed solution was heated in a nitrogen atmosphere for 40 minutes, then cooled to -1O to -5
3.0° C. of trichloromethyl chloroformate is added dropwise. After gradually raising the liquid temperature and stirring at 0 to 5°C for 2 hours, the excess phosgene and the solvent are distilled off under reduced pressure. 80 d of dry dichloromethane is added to the residue, and the insoluble matter is naturally purified. It is removed by filtration and subjected to the reaction described below.

(2) 8.4 f of trimethylsilyl chloride is added dropwise to 110*/dry dichloromethane solution containing 11.6 f of anhydrous ampicillin and 7.6 f of triethylamine at 5 to 10°C. After stirring for 1 hour at the same temperature, the dichloromethane solution obtained in (1) above is added dropwise with stirring at 0 to 5°C. After stirring at 5-10°C for 1 hour, cooled saturated saline solution
Add 0*/ and separate the organic layer. The organic layer was washed with 300ml of cold saturated brine, and then extracted in two portions with 300trrl of cold anastomated aqueous sodium bicarbonate solution.The separated aqueous layer was washed with 100ml of ethyl acetate, and this ((ethyl acetate) 250- was added, and the value was adjusted to about 1.5 and 17 with cold 6N hydrochloric acid.After adding 11 salt to the - to hydrate the aqueous layer, the organic layer was separated.The organic layer was cooled and saturated. After washing with 100w7 brine, drying over anhydrous magnesium sulfate, and distilling off the solvent under reduced pressure.The residue was washed with 8ephadex L H-20.
(trade name of dextran cross-linked polymer manufactured by FINE CHI! 1Ml0ALs) was subjected to column chromatography, eluted with acetone, concentrated under reduced pressure until the liquid volume was about 30%, and diluted with diethyl ether 300wt1.
When treated with 6-CD (-)-α-(3-(3,4
-dihydroxybenzoyl)-3-(2-hydroxyethyl)-1-ureido)-α-phenylacetamide]
Penicillanic acid (hereinafter also referred to as compound B) 3. Of is obtained as a white powder.

I RνKBr(ffi”): 3700-2200
,1770゜W cloud 1675.1600,151O NMR (DMSO-da, 60MHz) δ(
P): 1.41 (3H.

s), 1.56 (3H, s), 3.3-4.1 (4
H,s).

4.21 (IH, s), 5.3-5.8 (3H,
ri, 6.7-7.6 (8H, m), 9.21 (IH
, d, J-7Hz).

9.33 (IH, d, J=7Hz) UV λ”OHnmcl): 204 (3,3X
1 (1'), 221 (Shoulder ατ shoulder), 266 (5,4X103), 295 (5,6X
103) Ferric chloride color reaction: Positive (dark green) Example 3 N, 0-bis(
Trimethylsilyl)acetamide 119f1fr: Add and stir until homogeneous, and the dichloromethane solution prepared in Example 1 (1) is added dropwise to this at 5-10°C. After stirring for 1 hour in the same temperature bath and evaporating to dryness under reduced pressure at room temperature, the residue was mixed with ethyl acetate 250%, 11% tetrahydrofuran, 50%.
A mixed solution of 100 ml of cold IN-hydrochloric acid is added, and the organic layer is separated. The organic layer was washed with 300 ml of cold saturated saline, and then cooled with 300 ml of IJum aqueous solution.
Extract the target substance in two steps. Add to this 250 WtI of ethyl acetate and 50 WtI of tetrahydrofuran! After adding a mixed solvent with and bringing the value to about 1.5 with cold 6N hydrochloric acid, the aqueous layer was saturated by adding common salt, and the organic i@ was fractionated. After washing the separated organic layer with 100ml of cold saturated saline,
Dry over anhydrous magnesium sulfate and remove the solvent under reduced pressure. The residue is subjected to column chromatography on activated carbon (for chromatography) and eluted with acetone. The eluate was collected and concentrated under reduced pressure until the liquid volume was about 30 mm, and then added to 300 ml of ethyl ether with stirring to give 6-CD (-)-α-(3-(3,4
-dihydroxybenzoyl)-3-(3-hydroxypropyl)-1-ureido)-α-(4-hydroxyphenyl)acetamide]penicillanic acid (hereinafter also referred to as compound Ri) 4.5f is obtained as a white powder.

TR, vK8'(il): 3700-2300,
1770゜η1az 1680.1610.1515 NMR (DMSO-do, 60MHz) δ(F
): 1.42 (3H, s).

1.56 (3H, s), 1.3 to 1.9 (2H, br
), 3.1-4.0 (4H, s), 4.20 (IH
, m), 5.3-5.7 (3H, m), 6.
5-7.3 (7H, w), 9.0 (2H.

br) UVλP! to)] Cod (ε): 206 (2,8X10'
), 224 (2,2 inert4z XIO'), 276 (6,6X103), 283 (6,
4X103), 295(5,4X10) Ferric chloride color reaction: Positive (dark green) Example 4゜(1) Dry dichloromethane containing 4.72 of D(-)-phenylglycine and 7.81 of trimethylsilyl chloride Add 7°11 of triethylamine to a 100-ml suspension.
0 then N,O-bis(trimethylsilyl)acetamide INII! added dropwise at ~10°C! was added dropwise at the same temperature, and after stirring at room temperature for 1 hour, the dichloromethane solution prepared in Example 1 (1) was added dropwise while stirring at 5 to 10°C. After stirring at the same temperature for 1 hour and then evaporating to dryness under reduced pressure at room temperature, the residue was mixed with 300M of ethyl acetate and 100M of cold IN-hydrochloric acid.
Add mJ of the mixture and separate the organic layer. Nuclear #! Layer in cold saturated saline solution 300WLl! After washing with water, extract the target product in two portions with 300 Wdl of a cold saturated aqueous sodium bicarbonate solution.
was added, the value was brought to about 1.5 with cold 6N hydrochloric acid, and after adding common salt to the aqueous layer to saturate the aqueous layer, the organic layer was separated.

After washing the separated organic layer with cold saturated saline solution 100+y/
Dry over anhydrous magnesium sulfate and remove the solvent under reduced pressure. 5. The residue was diluted with (3-hydroxypropyl)-1-r:yvit)phenylacetic acid with acetone-chloroform.
5f was obtained as white crystals.

Melting point 139-141℃ (decomposition) Elemental analysis 0111H2 (lN207 'H20 as 0 HN Calculated value (to) 56.16 5.46 6.89
Actual value (to) 56.30 5.40 6.87I
RyKB'(611-"): 3540.3500.1
690° inertia 4x 1670.1595. 152O NMR (DM807ds, 60MHz) δ(P)
: 1.3 to 2, 0 (2H.

inertia), 3.35 (2H, t, J=6Hz), 3.73
(2H.

t, J-6,5Hri, 5.22(IH, deJ-7
Hz).

6.7-7.5 (8H, inertia), 9.19 (1) (, d
, J-7Hz) Ferric chloride color reaction: @ character (dark green) (2) Phenyl acetic acid obtained in (1) above 4. IIJF containing Of and trimethylsilyl chloride 4.92%
After dropping 4.21 g of triethylamine into a suspension trap of 50 d of dichloromethane at 5 to 10° C., the mixture was stirred at 15 to 20° C. for 1 hour to obtain the trimethylsilylation solution of phenylacetic acid, which was used in the reaction described below.

(3) Trichloromethyl chloroformate) To 30 d of dry dichloromethane solution containing 1.2 F, 0.8 f of dimethylformamide was added at -20°C, stirred at 0 to 5°C for 1 hour, and then heated to -300° C. as described in (2) above. Add the prepared dichloromethane clear solution and stir at -10°C to -15°C for 1.5 hours. This was then added with 2.9 f? of 6-amitubenicilanic acid.
A suspension of dry dichloromethane containing 50+1/N, 0-
A solution prepared by adding and dissolving 5.5 f of bistrimethylsilylacetamide is added dropwise at -10 to -15°C, and the mixture is stirred at the same temperature for 1 hour.

Hereinafter, the same extraction operation and molding as in Example 1 (2) were performed to obtain compound A4. Get Of. This product was identical to that obtained by the method of Example 1 in IR, NMR and UV.

(b) In Example 4 (1), KN-(2-hydroxyethyl)-3°4-dihydroxybenzamide was used instead of N-(3-hydroxypropyl)-3,4-dihydroxybenzamide, and the same treatment was carried out thereafter. and D(
-)-α-(3-(3,4-dihydroxybenzoyl)
-3-('2-hydroxyethyl)-1-ureido)
Compound B is obtained by synthesizing phenylacetic acid and subjecting this product to the same operation as in Example 4 (2). This product was obtained by the method of Example 2 and IR, NMR and U
It was agreed in V.

(b) In Example 4 (1), N-(5-hydroxy 4-ethyl)-3,4-dihydroxybenzamide was used instead of N-(3-hydroxypropyl)-3,4-dihydroxybenzamide, and the same procedure was followed. Process and D(
-)-α-(3-(3,4-dihydroxybenzoyl)
Compound C is obtained by synthesizing -3-(5-hydroxy-4-ethyl)-1-ureido)phenylacetic acid and subjecting this product to the same operation as in Example 4(2). This product has the same IR as that obtained by the method of Example 1 (a).

NMR and UVK results were consistent.

(c) In Example 4 (1), instead of N-(3-hydroxypropyl)-3,4-dihydroxybenzamide, N-(2-(2-hydroxyethoxy)ethyl) -
The same treatment was performed using 3,4-dihydroxybenzamide to obtain D (-)-α-[3-(3,4-dihydroxybenzoyl)-3-(2-(2-hydroxyethoxy)ethyl)-1- Synthesize ureido]phenylacetic acid,
This product is subjected to the same operation as in Example 4 (2) to obtain a compound. This product was identical to that obtained by the method of Example 1 (b) in IR, NMR and UV.

(d) In Example 4 (1), N-(2-methoxyethyl)-3,4-dihydroxybenzamide was used instead of N-(3-hydroxypropyl)-3,4-dihydroxybenzamide, and trimethylsilyl The amounts of chloride and triethylamine were reduced by 1 molar equivalent, and the same treatment was performed to obtain D(-)-α-(3-(
Compound E is obtained by synthesizing 3,4-dihydroxybenzoyl)-3-(2-methoxyethyl)-1-ureido)phenylacetic acid and performing the same operations as in Example 4(2). This product was identical to that obtained by the method of Example 1 (c) in IR, NMR and UV.

(E) In Example 4 (1), N-(2-cyanoethyl)-3,4-dihydroxybenzamide was used instead of N-(3-hydroxypropyl-3,4-dihydroxybenzamide), and trimethylsilyl chloride and Using the triethylamine garnish reduced by 1 molar equivalent, the same treatment was carried out to obtain D(-)-α-(3-(3
, 4-dihydroxybenzoyl)-3-(2-cyanoethyl)-1-ureido)phenylacetic acid, and then subjected to the same procedure as in Example 4(2) to obtain compound F. This product was identical to that obtained by the method of Example 1 (d) in IR, NMR and UV.

(f) Using N-ethoxycarbonylmethyl-kame 4-dihydroxybenzamide in place of N-(3-hydroxypropyl)-3,4-dihydroxybenzamide in Example 4 (1), and the amount of trimethylsilyl chloride and triethylamine. was reduced by 1 molar equivalent and treated in the same manner to obtain D(-)-α-(3-(
Compound G is obtained by synthesizing (4-dihydroxybenzoyl)-3-ethoxycarbonylmethyl-1-ureido)phenylacetic acid and subjecting this product to the same operation as in Example 4(2). This product was obtained by the method of Example 1 (e) and ITL.

Consistent in NMR and UV.

(G) In Example 4 (1), N-benzyl-3,4-dihydroxybenzamide was used instead of N-(3-hydroxyfuropi/l/)-3,4-dihydroxybenzamide, and q trimethylsilyl chloride The amount of triethylamine was reduced by 1 molar equivalent, and the same treatment was performed to obtain D(-)-α-(3-(3,4-dihydroxypensoyl)-3-benzyl-1-ureido)phenyl. Compound H is obtained by synthesizing acetic acid and performing the same operation as in Example 4 (2).

This product is the same as that obtained by the method of Example 1 (v).
Consistent in R, NMR and UV.

(H) Using N-cyanmethyl-3,4-dihydroxybenzamide in place of N-(3-hydroxypropyl)-3,4-dihydroxybenzamide in Example 4 (1), and the amount of trimethylsilyl chloride and triethylamine. is used by reducing it by 1 molar equivalent,
The same treatment was applied to D(-)-α-(3-(turtle 4-dihydroxybenzoyl)-3-!cyanoethyl-1
-Ureido J phenyl acetate was synthesized, and the same procedure as in Example 4 (2) was carried out to obtain compound (1). This product was obtained by the method of Example 1 (g) and I
They matched in R, NMR and UV.

(S) In Example 4 (1), N-furfuryl-3,4-dihydroxybenzamide was used instead of N-(3-hydroxypropyl)-3,4-dihydroxybenzamide, and the amounts of trimethylsilyl chloride and triethylamine were 1 Using the reduced molar equivalent, the same treatment was performed to synthesize D(-)-α-(3-(3,4-dihydroxybenzoyl)-3-furfuryl-1-ureido) phenyl acetate. Compound J is obtained by performing the same operation as in Example 4 (2).

This product is the same as that obtained by the method of Example 1 (h).
, NMR and UV.

,, (N) N-(3-hydroxyphenyl)-3,4-dihydroxybenzamide in Example 4(1).

Using N-(3-acetoxypropyl)-&4-dihydroxybenzamide instead of D, and reducing the amount of trimethylsilyl chloride and triethylamine by 1 molar equivalent, the same treatment was carried out to obtain D(-). −α
-(3-(3,4-dihydroxybenzoyl)-3-(
3-acetoxypropyl)-1-ureido)phenylacetic acid was synthesized and subjected to the same operation as in Example 4 (2) to obtain Compound K. This is Example 1 (
IR, obtained by the method of

Consistent in NMR and UV.

(l) In Example 4(1), D(-)-(4-hydroxyphenyl)glycine was used in place of D(-)-phenylglycine, and the same button treatment was carried out to give D(-)-
α-(3-(3,4-dihydroxybenzoyl)-3-
(3-hydroxypropyl)-1-ureido)-α-(
4-Hydroxyphenyl)acetic acid was synthesized, and the same procedure as in Example 4(2) was carried out to obtain a compound. This is the one obtained by the method of implementation @3 and IR
.

Consistent in NMR and UV.

Example 5゜(1) N-(3-hydroxypropyl)-3,4-di4
After adding f, add triethylamine 1 while stirring at room temperature.
Slowly drip 1.98 f. The mixture was heated under reflux for 60 minutes, then cooled to 10°C, then trichloromethylchloroformate L6d was added and stirred at 25°C for 3 hours.

(2) 9.5f of anhydrous ampicillin was added to 100% of ethyl acetate.
After adding 6°52 of trimethylsilyl chloride, add triethylamine 6, while stirring under water cooling.
Slowly drip 1 f'i. After stirring at 5-10°C for 1 hour, the tetrahydrofuran solution prepared in (1) is added, and the mixture is stirred at about 20°C for 1-2 hours. After the reaction, 20 liters of water
Add 0+Itl and stir further.

After stirring thoroughly, stir and separate the organic layer. (organic layer)
Extract with IJum aqueous solution 2004. Wash the separated aqueous layer with ethyl acetate. Then add 200 ml of ethyl acetate to this.
4 was added, the value was brought to about 1 to 2 with cold 6N hydrochloric acid, and after further adding common salt to saturate the aqueous layer, the organic layer was separated.

After washing the cough organic rfiI three times with cold saturated saline 100-
It was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then added to 500 ml of hexane with stirring to obtain crude compound '#AA11.5f as a yellowish white powder.

This crude compound A7. Of and hydrogen carbonate) IJum0゜Qf'4 cold *30-! After dissolving it, it was subjected to column chromatography (350d) using Diaion HP-30 (trade name, manufactured by Mitsubishi Kasei Corporation), and dissolved with water and then aqueous acetone (acetone concentration = 10v/v%). let Add 200% of ethyl acetate to the collected eluate and cool for 60 minutes.
Adjust the volume to about 1.5 with N-hydrochloric acid, then add common salt to saturate the aqueous layer, and then separate the organic layer. After washing the obtained organic layer with 100 m/100 mL of chilled saline solution, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure until the liquid volume becomes about 30 aff. When this was added to 300% of 5-hexane under stirring, compound A5. Of is obtained as a white powder.

This product was obtained by the method of Example 1 and IR, NM
Matched in R and UV.

(B) In Example 5 (1), N-(2-hydroxyethyl)-3,4-dihydroxybenzamide was used instead of N-(3-hydroxypropyl)-3,4-dihydroxybenzamide, and the same procedure was followed. Work up to obtain compound B. This product was identical to that obtained by the method of Example 2 in IR, NMR and UV.

(b) To a suspension of 12.9 f of amoxicillin trihydrate in 70 d of ethyl acetate, 12.9 f of N,0-bis(trimethylsilyl)acetamide was added at 10 to 15°C and stirred until uniform. The tetrahydrofuran solution prepared in Example 4 (1) is added and stirred at about 20°C for 1 to 2 hours. Thereafter, the same treatment is performed to obtain compound L 4.7 f. What was obtained by the method of this example 3 and IR,
Consistent in NMR and UV.

Applicant: Chugai Pharmaceutical Co., Ltd. Agent Yasu @ Kensho Continuation of page 1 0 shots by Takao Noto 3-41-8 Takada, Toshima-ku, Tokyo Inside Chugai Pharmaceutical Co., Ltd. 0 shots clear person Toshiyuki Nehashi 3-41-8 Takada, Toshima-ku, Tokyo Inside Chugai Pharmaceutical Co., Ltd. 0 shots clear person Yusuke Harada 3-41-8 Takada, Toshima-ku, Tokyo Inside Chugai Pharmaceutical Co., Ltd. 0 shots clear by Hisao Endo 3-41-8 Takada, Toshima-ku, Tokyo Inside Chugai Pharmaceutical Co., Ltd. 0 shots clear person Takao Kimura 3-41-8 Takada, Toshima-ku, Tokyo Inside Chugai Pharmaceutical Co., Ltd. 0 shots clear person Kana Kojima 3-41-8 Takada, Toshima-ku, Tokyo Inside Chugai Pharmaceutical Co., Ltd. 0 shots clear person Masahiko Matsumoto 3-41-8 Takada, Toshima-ku, Tokyo Inside Chugai Pharmaceutical Co., Ltd. 0 shots clear person Okazaki dissolution 3-41-8 Takada, Toshima-ku, Tokyo Inside Chugai Pharmaceutical Co., Ltd. 0 shots: Haruki Ogawa 3-41-8 Takada, Toshima-ku, Tokyo Inside Chugai Pharmaceutical Co., Ltd. 0 shots clear person Minoru Shindo 3-41-8 Takada, Toshima-ku, Tokyo Inside Chugai Pharmaceutical Co., Ltd.

Claims (1)

[Claims] 1) The following general formula (wherein BI Fi hydrogen atom or hydroxyl group, X is Os
- lower alkyl group of S, and Y is substituent 01 of X
4 lower alkyl group, 02-4 lower alkanoyl group,
or a 02-4 lower alkyl group substituted with a hydroxyl group or a lower alkoxy group of Ox~4, R3 is a hydrogen atom or a 01-4 lower alkyl group, R4 is a hydrogen atom,
A nitro group or a lower alkoxy group of 01 to 4, Rs means a hydroxyl group or a group -00OR"(R" is the same as above), and % is 2 when Y is a group +OR")s, For other groups, l is inertiaFi1.2 or 3
, means jl multiplied by 0.1.2 and multiplied by 3. ) or a pharmaceutically acceptable salt thereof. 2) In claim 1), X is a 02-5 lower alkyl group, Y is a group+OR")s, R" is a C7-4 lower alkanoyl group or a pharmaceutically acceptable group thereof, and KAMO is 1. A compound or a pharmaceutically acceptable salt thereof. 4) In claim 1), X#iC%~5 lower alkyl groups, and Y is a substituent of X, and the group -+0R2
)%. 02-4 lower alkyl group substituted with hydroxyl group or C1-4 lower alkoxy group, R3 is hydrogen atom or C1-4 lower alkyl group, R4 is hydrogen atom, nitro group or C1-4 lower alkyl group BS lower alkoxy group
is a hydroxyl group or a group -00OR'(R" is the same as above -)
, when 2-digit Y is the base +0♂)m, 2 is used, and when it is other groups, Fi1'III:, 1° 2-3, L is 0.1.2 or 3 or a pharmaceutically acceptable salt thereof. 5) In claim 1), X is a lower alkyl group of 02 to 3, Y group + OR'')s, R'' group,
A compound which is a lower alkyl group of 01-3 or "a lower alkyl group of 02-3 substituted with a water beak group" and whose formula is 1, or a pharmaceutically acceptable salt thereof. 6) The compound according to claim 5), wherein R2 is a hydrogen atom, or a pharmaceutically acceptable salt thereof. 7) An antibacterial agent containing at least one compound of claims 1) to 6) or a pharmaceutically acceptable salt thereof.