JPH06104674B2 - New cefalosporin derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel cephalosporin derivative, a process for producing the same, and use thereof.

Problems to be Solved by the Prior Art and Invention β-lactam antibiotics show selective toxicity only to bacteria,
Since it does not affect animal cells, it plays an important role in the prevention and treatment of bacterial infections as an antibiotic with few side effects. In particular, cephalosporin derivatives are generally stable against penicillinase, have a broad antibacterial spectrum, and are frequently used for the prevention and treatment of bacterial infections. However, on the other hand, resistant staphylococci or resistant Pseudomonas
For the treatment of intractable infections caused by non-fermenting gram-negative bacterium of glucose such as Esginosa and Acinetobacter calcoaceticus, new cephalosporin derivatives having a stronger and broad spectrum are required.

Currently, cefotaxim [Antimicrobial Agent and Chemotherapy, vol. 14, p. 749 (1978
, Etc.) and other third-generation cephalosporin derivatives show excellent antibacterial activity against Gram-positive bacteria, Gram-negative bacteria, especially intestinal bacterial groups, but rarely show strong antibacterial activity against Pseudomonas and Acinetobacter. Is. Therefore,
A more potent and effective therapeutic agent is desired for the treatment of serious infectious diseases caused by these bacteria or a mixed infection of these bacteria with other bacteria. See also Ceftazidime [Anti-Microbial Agent and Chemotherapy, 17
Vol. 876 (1980)] is the best compound among existing cephalosporin compounds against Pseudomonas and Acinetobacter, but it is not always satisfactory because various resistant bacteria exist.

Cephalosporin derivatives having a quaternary ammonium salt structure are disclosed in, for example, JP-A-53-53690, JP-A-55-59196, and JP-A-58-1.
No. 74387, No. 58-198490, No. 59-219292, etc., the side chain at the 3-position of the cephem nucleus is 1,2,3,
No compound having a 4-tetrahydro-2-substituted isoquinolinium methyl group is disclosed at all, and the compound of the general formula [I] is a novel compound having a chemical structure different from those of the known derivatives.

MEANS FOR SOLVING THE PROBLEM The present inventors have developed 2-methyl- as a 3-side chain of the cephem nucleus.
As a result of synthesizing and investigating a novel cephem compound having a 1,2,3,4-tetrahydro-2-substituted isoquinolinium methyl group, it was found that the compound has a broad and potent antibacterial spectrum.

The present invention has the general formula (In the formula, R ¹ may be substituted by a carboxyl group, a linear or branched lower alkyl group, R ² is a hydrogen atom, a hydroxyl group or an acetoxy group, R ³ and R ⁴ are the same,
And a salt thereof or a physiologically hydrolysable ester thereof, a method for producing the same, and its use, which are bonded to adjacent carbon atoms and represent a hydroxyl group or an acetoxy group.

The compound of the general formula [I] is effective not only for Gram-positive bacteria but also for Gram-negative bacteria, especially glucose non-fermenting Pseudomonas aeruginosa, Acinetobacter calcoaceticus and the like, and has a broad antibacterial spectrum.

Generally, the substitution on the oximino group can take the geometrical isomeric structure of E or Z, but the substitution on the oximino group contained in the acylamino moiety at the 7-position of the compound of the general formula [I] is Z.
It has the structure of.

Next, various terms and symbols referred to in this specification will be described.

The lower alkyl group refers to an alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group,
Examples include isopropyl group and n-butyl group.

The linear or branched lower alkyl group, which may be substituted with a carboxyl group, represents an alkyl group having a carboxyl group at any substitutable position of the lower alkyl group, for example, a carboxymethyl group, 1 -Carboxy-1-methylethyl group and the like.

Examples of the amino protecting group include trityl group, formyl group, chloroacetyl group, trifluoroacetyl group, tert.
-Butoxycarbonyl group, trimethylsilyl group, tert-butyldimethylsilyl group and the like can be mentioned, and trityl group which can be easily removed by acid treatment is particularly preferable.

Examples of the carboxyl protecting group include the following groups. Lower alkyl group such as tert-butyl group; haloalkyl group such as 2,2,2-trichloroethyl group; alkanoyloxyalkyl group such as acetoxymethyl group, propionyloxymethyl group, pivaloyloxymethyl group, 2-acetoxyethyl group, 2 -Propionyloxyethyl group; alkanesulfonylalkyl group such as methanesulfonylmethyl group, 2-methanesulfonylethyl group; aralkyl group such as benzyl group, 4-methoxybenzyl group, 4-nitrobenzyl group, phenethyl group, trityl group, benzhydryl group, Bis (4-methoxyphenyl) methyl group, 3,4-dimethoxybenzyl group; alkylsilyl groups such as trimethylsilyl group, tert-butyldimethylsilyl group, and the like,
Benzhydryl group or t- which can be easily removed by acid treatment
A butyl group is particularly preferred.

The protective group for the hydroxyl group, 2-methoxyethoxymethyl group, methoxymethyl group, methylthiomethyl group, tetrahydropyranyl group, phenacyl group, isopropyl group, tert
Examples include -butyl group, benzyl group, 4-nitrobenzyl group, acetyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, acetonide, trimethylsilyl group and tert-butyldimethylsilyl group.

Examples of the halogen atom for X include chlorine, bromine, iodine and the like. Examples of the leaving group include an acetoxy group,
Examples thereof include a trifluoroacetoxy group, a methanesulfonyl group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a phenylsulfonyloxy group and a p-toluenesulfonyloxy group, and X is particularly preferably a bromine atom or an iodine atom.

X Examples of the anions include chlorine ion and bromine ion.
Halogen ion such as iodine and iodine ion, sulfate ion, sulfuric acid
Hydrogen ion, methyl sulfate ion, p-toluenesulfonic acid
Ion, methanesulfonate ion, trifluoroacetic acid
Anions such as on are listed.

R ² , R ³ and R ^{4 of} the general formula [I], and R ⁸ , R ⁹ and the general formula [III], the general formula [IV], the general formula [V] and the general formula [VII]
The substitution position of R ¹⁰ is not particularly limited as long as it is on the condensed benzene ring of the 1,2,3,4-tetrahydroisoquinoline skeleton.

The compound of the general formula [I] can be produced by any of the following Method A and Method B.

Method A general formula(In the formula, R^FiveIs a hydrogen atom or an amino protecting group, R⁶Is a hydrogen atom
Or carboxyl protecting group, R⁷Protected carboxyl
A linear or branched low chain which may be substituted by a group
Primary alkyl group, X is a halogen atom or a leaving group, Y is S or
Represents SO) or a salt thereof, and a compound of the general formula(In the formula, R⁸Is a hydrogen atom, an optionally protected hydroxyl group or
Is an acetoxy group, R⁹And R^TenAre the same and adjacent charcoal
An optionally protected hydroxyl group or an alkyl bonded to an elementary atom.
Setoxy group, R¹¹Represents a hydrogen atom or a methyl group)
Reaction with an amine(In the formula, R^Five, R⁶, R⁷, R⁸, R⁹, R^Ten, R¹¹And Y are as defined above
Have, x Represents an anion).
And, if necessary, after methylation and / or reduction,
Remove the guardian.

When the compound of the general formula [I] is produced by Method A, the compound of the general formula [II] and the general formula [II] are first prepared in a solvent.
I] compound is reacted. As the solvent, for example, a nonaqueous organic solvent such as methylene chloride, chloroform, diethyl ether, ethyl acetate, tetrahydrofuran, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide or the like or a mixture thereof is used. General formula [III]
The amount of the compound used is 1 to 5 mol, preferably 1.5 to 2.5 mol, relative to 1 mol of the compound of the general formula [II]. The reaction temperature is -35 to + 35 ° C, preferably -20 to + 5 ° C,
The reaction is completed in 0.2 to 10 hours.

When the compound of the general formula [III] in which the substituent R ¹¹ is a hydrogen atom is used, the product [IV] is reacted with methyl iodide in the above non-aqueous organic solvent, and R ¹¹ is a methyl group. Can be an ammonio compound [IV].

The reaction uses 1 to 30 moles, preferably 3 to 15 moles of methyl iodide to 1 mole of the product [IV], and the reaction temperature and the reaction time are -30 to + 35 ° C. and are completed in several hours to several days. .
The methylation reaction can also be performed by using an excess of methyl iodide instead of the organic solvent. The formed ammonio compound [IV] in which R ¹¹ is a methyl group can be isolated or used for the next reaction without isolation.

When the compound of the general formula [II] in which the group Y is SO is used, the compound of the general formula [IV] is prepared by a known method, for example, Journal of Organic Chemistry, 35, 2430.
Page (1970), synthesis, page 58 (1979) or journal chemical research (S), page 341 (1979). For example, the compound of the general formula [IV] in which the group Y is SO is dissolved in an inert organic solvent such as acetone, methylene chloride, chloroform, tetrahydrofuran, ethyl acetate and the like, potassium iodide is added, and -40
It can be reduced by adding acetyl chloride dropwise at 0 ° C to 0 ° C and reacting at -20 to -10 ° C for 1 to 2 hours. The amount of potassium iodide used is 1 mol of the compound of the general formula [IV].
It is 5 to 15 mol, preferably 8 to 10 mol. The amount of acetyl chloride used is 1.5 to 5 mol. If necessary, a protecting group is removed from the compound thus obtained to obtain the compound of the general formula [I].

The protecting group can be removed by appropriately selecting a conventional method according to the type of the protecting group. Removal of the protecting group
For example, a method using an acid is preferable, and examples of the acid include inorganic acids such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, and organic acids, and trifluoroacetic acid is particularly preferable. When trifluoroacetic acid is used as the acid, the reaction is promoted by adding anisole. Further, this reaction is preferably carried out in an inert solvent, for example, an organic solvent such as methylene chloride, ethylene chloride, benzene or the like, or a mixed solvent thereof, particularly in methylene chloride. The reaction temperature is not particularly limited and may be appropriately selected depending on the chemical properties of the compound of the general formula [I] and the compound of the general formula [IV] in which the group Y is S, the kind of the protecting group, the removal method and the like. However, the reaction temperature is preferably under cooling or under mild conditions such as heating.

The compound of the general formula [III] is described in Journal of American Chemical Society, Volume 56, p. 1769 (1934).
), 60, 2101 (1938), Journal of
Organic Chemistry, Volume 30, p. 2247 (1965)
And 33, 494 (1968), etc., or according to the method.

The compound of the general formula [II] in which the group Y is S has the general formula (Wherein R ⁶ and X have the above-mentioned meanings, and Z represents a hydrogen atom or an acyl group), and a compound represented by the general formula [VI]
It can be obtained by acylation with a carboxylic acid or a reactive derivative thereof. In addition, the general formula [I in which the group Y is SO]
The compound [I] is obtained by oxidizing a compound of the general formula [II] in which the group Y is S with m-chloroperbenzoic acid in an organic solvent such as methylene chloride, ethylene chloride or chloroform that does not participate in the reaction. . The compound of the general formula [II] in which the substituent X is an iodine atom is a compound of the general formula [II] in which X is a chlorine atom.
It can be produced by reacting the compound (1) with sodium iodide.

The compound of general formula [V] is the compound of general formula [VIII] in which Z is an acyl group, and the compound of general formula [II] in which R ¹¹ is a methyl group.
It is obtained by reacting with the compound of [I] and then deacylating.

The compound of the general formula [VIII] has the general formula A compound represented by the formula (wherein R ⁶ and Z have the above-mentioned meanings) can be easily treated by a method described in, for example, JP-A Nos. 50-76089 and 56-86187. It can be manufactured.

Method B general formula(In the formula, R⁶, R⁸, R⁹, R^TenAnd X Has the above meaning)
A compound represented by, a salt thereof or a silyl compound thereof,
General formula(In the formula, R^FiveAnd R⁷Has the above meaning)
Acylation with carboxylic acid or its reactive derivative,
General formula(R in the formula^Five, R⁶, R⁷, R⁸, R⁹, R^TenAnd X Has the above meaning
Compound) and then protected as necessary
Remove the group.

When the compound of general formula [I] is produced by the method B, the compound of general formula [V] is acylated with a carboxylic acid of general formula [VI] or its reactive derivative to produce an ammonio compound [VII]. It is particularly preferable to use a reactive derivative. The reaction is carried out in an inert solvent such as water, acetone, dioxane, acetonitrile, tetrahydrofuran, methylene chloride, chloroform, benzene, ethyl acetate, N, N-dimethylformamide, etc. or a mixed solvent thereof, and the compound of the general formula [V] is used. 1 to 1.5 mol of the carboxylic acid of the general formula [VI] or its reactive derivative is used per 1 mol, and the reaction temperature is -40 to + 40 ° C, preferably -20 to +
30 ° C. When using the acid chloride of the compound of the general formula [VI], it is preferable to react in the presence of an alkali metal carbonate or an organic amine such as trimethylamine, triethylamine and N-methylmorpholine.

The production method from the compound of the general formula [VII] to the compound of the general formula [I] is the same as the above production method A.

As the reactive derivative of the compound of the general formula [VI], for example, halides, mixed acid anhydrides, active esters and the like are used. The acid halide of the compound of general formula [VI] can be obtained by reacting the compound of general formula [VI] with a halogenating agent. The reaction is carried out in an inert solvent such as methylene chloride,
It is carried out in chloroform, dichloroethane, benzene, toluene or the like or a mixed solvent thereof. Examples of the halogenating agent include thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, oxalyl chloride, phosgene and the like. The amount of halogenating agent used is represented by the general formula [VI]
1 to 10 mol, preferably 1 to 1.
At 5 mol, the reaction temperature is -40 to + 100 ° C, preferably -20 to
It is + 20 ° C.

The mixed acid anhydride of the compound of the general formula [VI] has the general formula [VI]
It can be obtained by reacting the compound (1) with an alkyl chlorocarbonate, an aliphatic carboxylic acid chloride or the like. The reaction is an inert solvent such as acetone, dioxane, acetonitrile,
It is carried out in tetrahydrofuran, methylene chloride, chloroform, benzene, ethyl acetate, N, N-dimethylformamide or the like or a mixed solvent thereof. The reaction is a tertiary amine,
For example, it is preferably carried out in the presence of triethylamine, N-methylmorpholine and the like, and the reaction temperature is -30 to + 20 ° C, preferably -15 to + 0 ° C.

The active ester of the compound of general formula [VI] has the general formula [VI]
It is obtainable by reacting the compound of 1) with preferably 1 to 1.2 mol of N-hydroxy compound or phenol compound. The reaction is carried out in an inert solvent such as acetone, dioxane,
Acetonitrile, tetrahydrofuran, methylene chloride,
It is carried out in chloroform, ethyl acetate, N, N-dimethylformamide or the like or a mixed solvent thereof. Examples of the N-hydroxy compound include N-hydroxysuccinimide,
Examples of phenol compounds such as N-hydroxyphthalimide and 1-hydroxybenzotriazole include 4-nitrophenol, 2,4-dinitrophenol, 2,4,5-trichlorophenol, pentachlorophenol and the like. The reaction is preferably carried out in the presence of a condensing agent such as N, N'-dicyclohexylcarbodiimide. The reaction temperature is -30 to + 40 ° C, preferably -10 to + 25 ° C, and the reaction time is
30 to 120 minutes.

The compound of general formula [I] can be converted into a salt or a physiologically hydrolyzable ester by a conventional method.

A conventional pharmaceutically acceptable salt of a compound of the general formula [I], for example, a salt with an alkali metal such as sodium or potassium; a salt with an alkaline earth metal such as calcium or magnesium; N, N'- Salts with organic amines such as dibenzylethylenediamine and procaine; Salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, hydrobromic acid; acetic acid,
Salts with organic acids such as lactic acid, propionic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, etc .; salts with organic sulfonic acids such as methanesulfonic acid, isethionic acid, p-toluenesulfonic acid; aspartic acid, Examples thereof include salts with amino acids such as glutamic acid. Examples of the physiologically hydrolyzable ester of the general formula [I] include alkanoyloxyalkyl esters such as acetoxymethyl ester and pivaloyloxymethyl, and alkoxycarbonyloxyalkyl esters such as 1- (ethoxycarbonyloxy) ethyl. (5-Substituted-2-oxo-1,3-dioxol-4-yl) methyl esters such as phthalidyl esters, (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl Etc. are preferred.

The minimum inhibitory concentration of the compound of the present invention against various bacteria (MIC: μg / ml) was measured by the agar plate dilution method using Sensitivity Disc Agar (Nissui) with cefotaxime and ceftazidime as comparative compounds (bacteria Number: 10 ⁶ CFU / ml). The results are shown in the table below.

The compounds of the present invention showed strong antibacterial activity against sensitive and resistant Gram-positive and Gram-negative bacteria, especially resistant Pseudomonas aeruginosa Pseudomonas cepacia Acinetobacter calcoaceticus. For example, for Pseudomonas aeruginosa AK109, the compounds of Example 7, Example 8-F and Example 9 are 125 to 125% of cefotaxime.
The antibacterial activity was 250 times and 31 to 62 times that of ceftazidime. Example 7 against Pseudomonas cepacia 23,
The compounds of Example 8-F and Example 9 were cefotaxime 125
It exhibited ~ 250 times the antibacterial activity. Also, Acinetobacter
The compounds of Example 1-E, Example 2-C, Example 5, Example 7 and Example 8-F for chalcoceticus were 64-250 times that of cefotaxime, and 16-63 times that of ceftazidime. Showed antibacterial activity.

In addition, using the compound of Example 9 as a representative compound, in accordance with "GLP standard and toxicity test method guideline commentary" (supervised by the Ministry of Health and Welfare Pharmaceutical Affairs Bureau Examination Division; Yakuji Nipposha), 4-week-old ICR
Female mice (n = 3) were treated as a group with distilled water for injection containing a neutralizing amount of sodium hydrogen carbonate and the concentration of the drug solution was 1000 mg.
It was diluted so that it became / ml, and a single tail vein administration was performed at a dosing rate of 1 ml / min. As a result, Example 9 was added to the mouse.
The compound was administered at 1.5 g / kg, but no death of mice was observed for 3 days including the administration day.

Therefore, the compound of the present invention can be used as an antibacterial agent containing the compound of the general formula [I], a salt thereof or a physiologically hydrolyzable ester thereof as an active ingredient.

The compound of the present invention can be used in the form of a pharmaceutical preparation suitable for oral administration, parenteral administration or external administration by mixing with a carrier of a solid or liquid excipient. Examples of the pharmaceutical preparation include liquid preparations such as injections, syrups and emulsions, solid preparations such as tablets, capsules and granules, and external preparations such as ointments and suppositories.

The above-mentioned agents may contain commonly used additives such as auxiliaries, stabilizers, wetting agents and emulsifiers. For example, the injection may contain additives such as distilled water for injection, physiological saline, a solution such as Ringer's solution, a preservative such as methyl paraoxybenzoate and propyl paraoxybenzoate. Liquids such as syrups and emulsions include sorbitol syrup, methyl cellulose, glucose, sucrose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, edible oil, tonsil oil, coconut oil, oily ester, sorbitan monooleate, In addition to propylene glycol, glycerin, ethyl alcohol, water and the like, emulsifiers such as gum arabic, gelatin and lecithin, and surfactants such as tween and span may be contained. As the solid agent, lactose, sucrose, corn starch, calcium phosphate, magnesium stearate, talc, silicic acid, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, polyethylene glycol, sodium lauryl sulfate and the like are used. As a base for ointments and suppositories, for example, cocoa butter, glycerides, polyethylene glycols, white petrolatum and the like are used. You may contain a surfactant and an absorption promoter as needed.

The compound [I] of the present invention can be used for the treatment and prevention of bacterial infections such as respiratory infections, urinary tract infections, obstetrics and gynecologic infections, purulent diseases, and surgical infections. The dose varies depending on the age and condition of the patient, but it is usually used in the range of 1 to 100 mg / kg per day, 5 to 30 mg / kg per day
It is preferable to administer in 2 to 4 divided doses.

Hereinafter, the present invention will be described in more detail with reference to Reference Examples and Examples, but the present invention is not limited thereto.

Reference Example 1 (A) Benzhydryl 7-[(Z) -2-methoxyimino-
2- (2-Tritylaminothiazol-4-yl) acetamido] -3-[(2-methyl-1,2,3,4-tetrahydro-2-isoquinolinio) methyl] -3-cephem-4-carboxylate ・Iodo salt: Benzhydryl 7-[(Z) -2-methoxyimino-2- (2-
Tritylaminothiazol-4-yl) acetamide]-
3-iodomethyl-3-cephem-4-carboxylate 3g
(3.21 mmol) was suspended in 320 ml of diethyl ether,
2-Methyl-1,2,3,4-tetrahydroisoquinoline 94 at room temperature
0 mg (6.38 mmol) was added. After stirring for 15 minutes, the precipitate was collected by filtration. To the filtrate was added 2-methyl-1,2,3,4-tetrahydroisoquinoline (500 mg, 3.4 mmol), the solution was stirred for 40 minutes and the precipitate was collected. The precipitates were combined, dried and a mixture of Δ ² and Δ ³ isomers of the title compound.
I got 1.1g.

(B) 7-[(Z) -2- (2-aminothiazol-4-yl)
-2-Methoxyimisoacetamide] -3-[(2-methyl-
1,2,3,4-Tetrahydro-2-isoquinolinio) methyl]-
3-Cephem-4-carboxylate: 1.1 g of the mixture of Δ ² and Δ ³ isomers obtained in (A) was dissolved in 10 ml of methylene chloride and 1.1 ml of anisole, and 10 ml of trifluoroacetic acid was added dropwise under ice cooling. After stirring at 15 ° C for 3 hours, the reaction solution was concentrated under reduced pressure, and 30 ml of ethyl acetate and 20 ml of water were added.
Was added. After adsorbing the aqueous layer on HP-20 (30 ml), elution with 50% methanol collected the fractions containing the target compound, concentrated under reduced pressure, and lyophilized to obtain 50 mg of the target compound (2.9% absorption). . Melting point 163 ° C (decomposition).

IR (KBr): 1765, 1660, 1610, 1530, 1345, 1035 cm ^-1 NMR (D ₂ O) δ: 2.80-3.40 (6H, m), 4.03 (3H, s), 5.
40 (1H, d, J = 5.4Hz), 5.87 (1H, d, J = 5.4Hz), 7.00 (1
H, s), 7.30 to 7.45 (4H, m) Reference Example 2 (A) Benzhydryl 7-[(Z) -2-methoxyimino-
2- (2-Tritylaminothiazol-4-yl) acetamido] -3-chloromethyl-3-cephem-4-carboxylate 1-oxide: benzhydryl 7-[(Z) -2-methoxyimino-2- (2 -
Tritylaminothiazol-4-yl) acetamide]-
2.5 g of 3-chloromethyl-3-cephem-4-carboxylate
Dissolve (2.97 mmol) in 25 ml of benzene, and cool under ice cooling to 80
% Metachloroperbenzoic acid 640 mg (3.27 mmol) was added. After stirring for 1 hour at room temperature, the reaction solution was poured into ice water,
It was extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium sulfite solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give an oily product of the title compound.

(B) Benzhydryl 7-[(Z) -2-methoxyimino-
2- (2-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate 1-oxide: The oil obtained in (A) was dissolved in 50 ml of acetone to give sodium iodide. 670 mg (4.47 mmol) was added. After stirring at room temperature for 30 minutes, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium thiosulfate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as an oil.

(C) Benzhydryl 7-[(Z) -2-methoxyimino-
2- (2-Tritylaminothiazol-4-yl) acetamido] -3-[(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-2-isoquinolinio) methyl] -3-cephem -
4-Carboxylate 1-oxide / iodo salt: The oil obtained in (B) was dissolved in 20 ml of N, N-dimethylformamide to give 6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro. 1.23 g (5.93 mmol) of isoquinoline was added. After stirring at room temperature for 3 hours, the reaction solution was poured into ice water and extracted with methylene chloride. The organic layer was washed successively with water, 5% aqueous sodium sulfite solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The oily residue was treated with diethyl ether to obtain 2.6 g of powder (yield 75.7%).

(D) Benzhydryl 7-[(Z) -2-methoxyimino-
2- (2-Tritylaminothiazol-4-yl) acetamido] -3-[(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-2-isoquinolinio) methyl] -3-cephem -
4-carboxylate: 2.6 g (2.25 mmol) of the powder obtained in (C) was added to 40 ml of acetone.
Dissolved in water, 3.8 g (25.3 mmol) of sodium iodide was added to this solution, and then acetyl chloride 0.85 ml was added at -30 ° C.
(11.85 mmol) was added dropwise. After stirring at -30 to -20 ° C for 1 hour and at -20 to -10 ° C for 3 hours, the reaction solution was added to ice-cooled aqueous sodium metabisulfite solution, and the precipitate was collected by filtration and washed with water. The precipitate was dissolved in methylene chloride.
The solution was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the oily residue to solidify it, which was collected by filtration and dried to give 2.1 g of powder (yield
81.9%).

(E) 7-[(Z) -2- (2-aminothiazol-4-yl)
-2-Methoxyiminoacetamido] -3-[(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-2-isoquinolinio) methyl] -3-cephem-4-carboxylate: (D 2.1 g (1.84 mmol) of the powder obtained in) was added to methylene chloride.
It was dissolved in 15 ml and 2 ml (18.4 mmol) of anisole, and 15 ml of trifluoroacetic acid was added dropwise under ice cooling. After stirring at the same temperature for 3 hours, the reaction solution was concentrated under reduced pressure and 30 ml of ethyl acetate was added.
And 20 ml of water were added. The aqueous layer was separated, washed twice with ethyl acetate, adsorbed on HP-20 (50 ml), and eluted with 50% methanol. Fractions containing the desired product are collected, concentrated under reduced pressure,
Lyophilization gave 70 mg of the desired compound (6.3% yield). Melting point 146 ° C (decomposition).

IR (KBr): 1765, 1655, 1600, 1510, 1340 cm ^-1 NMR (D ₂ O) δ: 3.05 to 3.45 (6H, m), 3.94 (6H, s), 4.
10 (3H, s), 5.48 (1H, d, J = 5.5Hz), 5.97 (1H, d, J = 5.5
Hz), 6.90 (1H, s), 7.02 (1H, s), 7.07 (1H, s) Reference Example 3 (A) Benzhydryl 7-[(Z) -2-ethoxyimino-
2- (2-Tritylaminothiazol-4-yl) acetamido] -3-chloromethyl-3-cephem-4-carboxylate 1-oxide: benzhydryl 7-[(Z) -2-ethoxyimino-2- (2 -
Tritylaminothiazol-4-yl) acetamide]-
3-chloromethyl-3-cephem-4-carboxylate 4.0g
Dissolve (4.7 mmol) in 40 ml of benzene, and cool with ice to 80
% Metachloroperbenzoic acid 1.0 g (5.8 mmol) was added. After stirring at room temperature for 40 minutes, the reaction solution was poured into ice water,
It was extracted with ethyl acetate. The organic layer was washed with a 5% aqueous sodium sulfite solution and saturated saline, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. N-Hexane was added to the oily residue to solidify it and dried to give 3.8 g of the title compound powder.
(Yield 93%) was obtained.

IR (KBr): 1800, 1720, 1680, 1040, 700 cm ^-1 NMR (DMSO-d ₆ ) δ: 1.0 to 1.40 (3H, m), 3.30 (2H, s),
3.70 to 4.20 (4H, m), 4.30 to 4.70 (2H, m), 5.05 (1H,
m), 5.90 (1H, m), 6.80 (1H, s), 7.00 (1H, s), 7.10 ~
7.70 (25H, m), 8.75 (1H, m) (B) Benzhydryl 7-[(Z) -2-ethoxyimino-
2- (2-Tritylaminothiazol-4-yl) acetamido] -3-[(2-methyl-1,2,3,4-tetrahydro-2-isoquinolinio) methyl] -3-cephem-4-carboxylate 1 -Oxide / iodo salt: 1.44 g (9.6 mmol) of sodium iodide was added to 60 ml of acetone, and the solution was stirred under ice cooling for 10 minutes. To this solution was added 3.8 g (4.4 mmol) of the powder obtained in (A). After stirring for 15 minutes, the reaction solution was concentrated under reduced pressure. Ice water and ethyl acetate were added, the organic layer was separated, washed successively with a 5% aqueous sodium sulfite solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give an oily 3-iodomethyl derivative. To this 3-iodomethyl form, 15 ml of N, N-dimethylformamide and 1.1 g (7.5 mmol) of 2-methyl-1,2,3,4-tetrahydroisoquinoline were added. After stirring for 40 minutes at room temperature, the reaction solution was poured into ice water and extracted with methylene chloride. The organic layer was washed successively with water, 5% aqueous sodium sulfite solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The oily residue was treated with diethyl ether to give 4 g of a powder. This powder was subjected to flash silica gel column chromatography (methylene chloride: methanol = 2
Purification by 0: 1) gave 1.6 g (33.5% yield) of a powder of diastereomeric mixture of the title compound.

IR (KBr): 1800,1720,1670,1220,1030,750,700cm ^-1 NMR (DMSO-d ₆ ) δ: 1.0 to 1.35 (3H, m), 4.13 (2H, q, J
= 6Hz), 5.17 (1H, m), 6.06 (1H, m), 6.78 (1H, s), 6.9
2 (1H, s), 7.00 to 7.70 (29H, m), 8.70 (1H, s), 8.95 (1
(H, d, J = 7.5Hz) (C) Benzhydryl 7-[(Z) -2-ethoxyimino-
2- (2-Tritylaminothiazol-4-yl) acetamido] -3-[(2-methyl-1,2,3,4-tetrahydro-2-isoquinolinio) methyl] -3-cephem-4-carboxylate ・Iodine salt: 1.6 g (1.46 mmol) of the powder obtained in (B) was added to 40 ml of acetone.
2.4 g (14.4 mmol) of potassium iodide was added thereto, and then 0.55 ml (7.7 mmol) of acetyl chloride was added dropwise at -30 ° C. -30 to -20 ° C for 30 minutes, then -10
After stirring at ℃ for 2.5 hours, the reaction solution was added to an ice-cooled sodium metabisulfite aqueous solution, and the precipitate was collected by filtration and washed with water. This precipitate was dissolved in methylene chloride, the solution was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the oily residue to solidify it, 1.4 g of a diastereomeric mixture of the title compound (yield 8
8.7%) powder was obtained.

IR (KBr): 1780,1720,1670,1220,1030,750,700 cm ^-1 NMR (DMSO-d ₆ ) δ: 1.0-1.40 (3H, m), 4.0-4.90 (8
H, m), 5.43 (1H, m), 5.93 (1H, m), 6.80 (1H, s), 6.93
(1H, s), 7.0 ~ 7.70 (29H, m), 9.60 (1H, m) (D) 7-[(Z) -2- (2-aminothiazol-4-yl)
-2-Methoxyiminoacetamide] -3-[(2-methyl-
1,2,3,4-Tetrahydro-2-isoquinolinio) methyl]-
3-Cephem-4-carboxylate: 1.37 g (1.27 mmol) of the powder obtained in (C) was dissolved in 10 ml of methylene chloride and 1.3 ml of anisole, and 9 ml of trifluoroacetic acid was added dropwise under ice cooling. After stirring at the same temperature for 2 hours,
The reaction solution was concentrated under reduced pressure, 10 ml of ethyl acetate and 100 ml of ice water.
Was added. Separate the aqueous layer, wash with ethyl acetate, and then
It was adsorbed on -20 (150 ml) and washed until the eluate became neutral. Then, pass 50% methanol, collect the fractions containing the target compound, concentrate under reduced pressure, and freeze-dry to obtain 340 mg of the target product.
(Yield 50.4%) was obtained. Melting point 159 ° C (decomposition).

IR (KBr): 1770,1610,1530,1030cm ^-1 NMR (DCI-D ₂ O) δ: 1.30 (3H, t, J = 7.0Hz), 2.95-3.
50 (7H, m), 4.30 (2H, q, J = 7.0Hz), 5.35 (1H, d, J = 4.5
Hz), 5.80 (1H, m), 7.05 (1H, s), 7.10 to 7.40 (4H, m) Reference Example 4 (A) Benzhydryl 7-[(Z) -2- (1-t-butoxycarbonyl-1) -Methylethoxyimino) -2- (2-tritylaminothiazol-4-yl) acetamido] -3-chloromethyl-3-cephem-4-carboxylate 1-oxide: benzhydryl 7-[(Z) -2- ( 1-t-Butoxycarbonyl-1-methylethoxyimino) -2- (2-tritylaminothiazol-4-yl) acetamido] -3-chloromethyl-3-cephem-4-carboxylate 10 g (10.3 mmol) chloride The mixture was dissolved in 200 ml of methylene, and 1.78 g (10.3 mmol) of 80% metachloroperbenzoic acid was added over 10 minutes under ice cooling, and the solution was stirred for 20 minutes. 40 ml of 10% sodium thiosulfate aqueous solution was added to the reaction solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a powder.

IR (KBr): 1795,1720,1680,1500,1365,1300,1250,1170,
1140,1050 cm ^-1 NMR (DMSO-d ₆ ) δ: 1.36 (9H, s), 1.45 (6H, s), 3.9
(2H, m), 4.55 (2H, m), 5.1 (1H, d, J = 5Hz), 6.0 (1H, d
d, J = 5,9Hz), 6.8 (1H, s), 7.0 (1H, s), 7.3 (25H, br
s), 8.15 (1H, d, J = 9Hz), 8.7 (1H, s) (B) Benzhydryl 7-[(Z) -2- (1-t-butoxycarbonyl-1-methylethoxyimino) -2- (2-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate 1-oxide: The compound obtained in (A) was dissolved in 200 ml of acetone and 3.38 g of sodium iodide ( 22.5 mmol) was added and the solution was stirred at room temperature for 30 minutes. To the reaction solution were added cold ethyl acetate (600 ml) and 10% cold sodium thiosulfate solution (200 ml), the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was flash column chromatographed (ethyl acetate-n-hexane 1: 2). Separated and purified in. Fractions containing the desired product were collected and concentrated. Diisopropyl ether was added to the residue, and 7.0 g (yield 63.0%) of the title compound in powder form was collected by filtration.

IR (KBr): 1795,1720,1680,1500,1370,1300,1250,1170,
1140,1050 cm ^-1 NMR (DMSO-d ₆ ) δ: 1.35 (9H, s), 1.45 (6H, s), 3.95
(2H, m), 4.45 (2H, m), 5.1 (1H, d, J = 5Hz), 6.0 (1H, d
d, J = 5.9Hz), 6.8 (1H, s), 7.0 (1H, s), 7.3 (25H, br
s), 8.15 (1H, d, J = 9Hz), 8.7 (1H, s) (C) Benzhydryl 7-[(Z) -2- (1-t-butoxycarbonyl-1-methylethoxyimino) -2- (2-Tritylaminothiazol-4-yl) acetamido] -3-[(2-
Methyl-1,2,3,4-tetrahydro-2-isoquinolinio) methyl] -3-cephem-4-carboxylate 1-oxide
Iodo salt: 50 g of the compound obtained in (B) (1.86 mmol) in ethyl acetate 50
It was dissolved in ml and 300 mg (2.04 mmol) of 2-methyl-1,2,3,4-tetrahydroisoquinoline was added. After stirring at room temperature for 6 hours, the reaction solution was concentrated under reduced pressure, the residue was separated and purified by silica gel flash column chromatography (2-3% methanol-methylene chloride), and the fractions containing the target compound were collected and concentrated to give a powder. Form of the title compound 1.20 g (yield 52.8
%) Was obtained.

(D) Benzhydryl 7-[(Z) -2- (1-t-butoxycarbonyl-1-methylethoxyimino) -2- (2-tritylaminothiazol-4-yl) acetamido] -3-[(2-
Methyl-1,2,3,4-tetrahydro-2-isoquinolinio) methyl] -3-cephem-4-carboxylate iodo salt: 1.20 g (0.98 mmol) of the compound obtained in (C) and 810 mg of potassium iodide ( 4.88 mmol) to 30 ml of acetone,
Then 0.17 ml (2.39 mmol) of acetyl chloride was added dropwise at -20 ° C. The reaction solution was stirred at -20 to -10 ℃ for 2 hours, then potassium iodide 810mg and acetyl chloride 0.17m
l was added, and the mixture was further stirred at the same temperature for 1.5 hours. After the reaction, 100 ml of methylene chloride and 100 ml of 1% aqueous solution of sodium metabisulfite-saturated saline (1: 1) were added, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound as a powder.

IR (KBr): 1785,1720,1360,1250,1220,1140cm ^-1 (E) 7-[(Z) -2- (2-aminothiazol-4-yl)
-2- (Carboxy-methylethoxyimino) acetamido] -3-[(2-methyl-1,2,3,4-tetrahydro-2-isoquinolinio) methyl] -3-cephem-4-carboxylate: (D) The compound obtained in 1. was dissolved in 12 ml of methylene chloride, 1.2 ml of anisole was added, and 12 m of cold trifluoroacetic acid was added under ice cooling.
l was added. After stirring the reaction solution at the same temperature for 6 hours, the solvent was distilled off under reduced pressure. 20 ml of ethyl was added to the residual liquid and concentrated under reduced pressure (this operation was repeated twice). Ethyl acetate (150 ml) and water (100 ml) were added to the residue and the layers were separated. Further, 100 ml of water was added to the organic layer for liquid separation. The aqueous layers were combined and washed with 50 ml of ethyl acetate. After removing the dissolved organic solvent under reduced pressure, the solution was subjected to reverse phase chromatography (Waters Pre Pack
Separation and purification (200 ml of H ₂ and 400 ml of 4% tetrahydrofuran aqueous solution) were carried out with 500 / C-18, 40 ml). Fractions containing the target compound were concentrated under reduced pressure and freeze-dried to obtain diastereomers A and B of the title compound.

Compound A 42 mg (yield 7.0%) Melting point: 138 ° C (decomposition) IR (KBr): 1775,1660,1610,1530,1350,1190,, 1160cm ^-1 NMR (DMSO-d ₆ ) δ: 1.45 (6H, br s), 2.95 (3H, br
s), 5.2 (1H, d, J = 5Hz), 5.75 (1H, dd, J = 5,9Hz), 7.3
(4H, br s), 9.5 (1H, d, J = 9Hz) Compound B 78mg (yield 12.9%) Melting point: 140 ° C (decomposition) IR (KBr): 1775,1660,1610,1530,1340,1185, 1155 cm ^-1 NMR (DMSO-d ₆ ) δ: 1.45 (6H, br s), 2.95 (3H, br
s), 5.2 (1H, d, J = 5Hz), 5.75 (1H, dd, J = 5,9Hz), 7.3
(4H, br s), 9.45 (1H, d, J = 9Hz) High Performance Liquid Chromatography Column: Develosil ODS-5 (10 × 250mm) Mobile phase: 15% aqueous tetrahydrofuran solution Flow rate: 2ml / min Detection: UV 254nm retention Time Compound A: 5.5 minutes Compound B: 6.5 minutes In the same manner as in Reference Example 2, compounds of Reference Examples 5 and 6 were obtained.

Reference Example 5 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [6-acetoxy-2-methyl-1,2,3,4-tetrahydro 2-isoquinolinio) methyl] -3-cephem-4-carboxylate (diastereomer A, B mixture): mp: 154 ° C. (decomposition) IR (KBr): 1780,1670,1620,1540,1380,1220cm ^{- 1} NMR (DMSO-d ₆ ) δ: 2.25 (3H, s), 2.8 to 4.7 (13H, m),
3.83 (3H, s), 5.15 (1H, d, J = 5Hz), 5.67 (1H, dd, J = 5,
7Hz), 6.73 (1H, s), 7.0 to 7.3 (5H, m), 9.50 (1H, d, J =
7 Hz) Reference Example 6 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [6-hydroxy-2-methyl-1,2,3,4 -Tetrahydro-2-isoquinolinio) methyl] -3-cephem-4-carboxylate (mixture of diastereomers A and B): Melting point: 175 ° C (decomposition) IR (KBr): 1780,1680,1620,1540cm ^-1 NMR (DMSO-d ₆ ) δ: 2.8 to 4.6 (16H, m), 5.15 (1H, d, J
= 5Hz), 5.67 (1H, dd, J = 5,9Hz), 6.63 (1H, s), 6.70
(1H, s), 7.20 (2H, br s), 9.53 (1H, d, J = 9Hz) Example 1 (A) Benzhydryl 7-[(Z) -2-methoxyimino-
2- (2-Tritylaminothiazol-4-yl) acetamido] -3-chloromethyl-3-cephem-4-carboxylate 1-oxide: benzhydryl 7-[(Z) -2-methoxyimino-2- (2 -
Tritylaminothiazol-4-yl) acetamide]-
3-chloromethyl-3-cephem-4-carboxylate 6g
Dissolve (7.14 mmol) in 60 ml of benzene, and cool to 80
% Metachloroperbenzoic acid 1.54 g (8.92 mmol) was added. After stirring for 1 hour at room temperature, the reaction solution was poured into ice water,
It was extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium sulfite solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give an oil.

(B) Benzhydryl 7-[(Z) -2-methoxyimino-
2- (2-Tritylaminothiazol-4-yl) acetamido] -3-iodomethyl-3-cephem-4-carboxylate 1-oxide: The oil obtained in (A) was dissolved in 120 ml of acetone to give sodium iodide. 1.6 g (10.7 mmol) was added. After stirring at room temperature for 30 minutes, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium thiosulfate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give an oil.

(C) Benzhydryl 7-[(Z) -2-methoxyimino-
2- (2-Tritylaminothiazol-4-yl) acetamido] -3-[(6,7-dihydroxy-2-methyl-1,2,3,4-tetrahydro-2-isoquinolinio) methyl] -3-cephem -4-Carboxylate 1-oxide iodo salt: 1/2 amount of the oil obtained in (B) was dissolved in 30 ml of N, N-dimethylformamide to give 6,7-dihydroxy-2-methyl-1,2 , 3,
900 ml (5.03 mmol) of 4-tetrahydroisoquinoline was added, and the solution was stirred at room temperature for 5 hours and then placed in a refrigerator.
Left for days. The reaction solution was poured into ice water and extracted with methylene chloride. The organic layer was washed three times with water, washed successively with a 5% aqueous solution of acidic sodium sulfite and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The oily residue was treated with diethyl ether to obtain 2.1 g of powder (yield 52.2%).

(D) Benzhydryl 7-[(Z) -2-methoxyimino-
2- (2-Tritylaminothiazol-4-yl) acetamido] -3-[(6,7-dihydroxy-2-methyl-1,2,3,4-tetrahydro-2-isoquinolinio) methyl] -3-cephem -4-Carboxylate: 2.1 g (1.86 mmol) of the powder obtained in (C) was added to 40 ml of acetone.
The solution was added with 3.1 g (18.7 mmol) of potassium iodide, and 0.67 ml (9.42 mmol) of acetyl chloride was added dropwise at -30 ° C. After stirring at -20 to -10 ° C for 90 minutes, the reaction solution was added to an ice-cooled aqueous solution of metabisulfite, and the precipitate was collected by filtration and washed with water. The precipitate was dissolved in methylene chloride, this solution was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the oily residue to solidify it, which was collected by filtration and dried to give a powder (1.5 g).
(Yield 72.5%) was obtained.

(E) 7-[(Z) -2- (2-aminothiazol-4-yl)
Methoxyiminoacetamido] -3-[(6,7-dihydroxy-2-methyl-1,2,3,4-tetrahydro-2-isoquinolinio) methyl] -3-cephem-4-carboxylate: obtained with (D) 1.5 g (1.35 mmol) of powdered methylene chloride
Dissolved in 15 ml and anisole 1.5 ml (13.8 mmol),
Under ice-cooling, 15 ml of trifluoroacetic acid was added dropwise, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate (30 ml) and water (20 ml) were added, the aqueous layer was separated, washed twice with ethyl acetate, then passed through HP-20 (50 ml), and cold water (150 ml) was poured to obtain the desired product. The fractions containing was collected, concentrated under reduced pressure and freeze-dried to obtain 50 mg of the target compound (yield 6.4%). Melting point 127 ° C (decomposition).

IR (KBr): 1765, 1655, 1610, 1525, 1350, 1280, 1030 cm ^-1 NMR (D ₂ O) δ: 2.9 to 3.3 (6H, m), 5.40 (1H, d, J = 5.4)
Hz), 5.90 (1H, d, J = 5.4Hz), 6.72 (1H, s), 6.82 (1H,
s), 7.04 (1H, s) Example 2 (A) Benzhydryl 7-[(Z) -2-methoxyimino-
2- (2-Tritylaminothiazol-4-yl) acetamido] -3-[(6,7-diacetoxy-2-methyl-1,2,3,4-tetrahydro-2-isoquinolinio) methyl] -3-cephem -4-carboxylate 1, oxide / iodo salt: Benzhydryl 7-[(Z) -2-methoxyimino-2- (2-
Tritylaminothiazol-4-yl) acetamide]-
3-chloromethyl-3-cephem-4-carboxylate 4g
Benzhydryl 7-[(Z) -2-methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamide] -obtained by the same procedure as in Reference Example 2 and Example 1 from (4.76 mmol) Oil of 3-iodomethyl-3-cephem-4-carboxylate 1-oxide was dissolved in 20 ml of N, N-dimethylformamide to give 6,7-diacetoxy-2-methyl-1,
2.2 g (8.3 mmol) of 2,3,4-tetrahydroisoquinoline
Was added. After stirring at room temperature for 5 hours, the reaction solution was poured into ice water and extracted with methylene chloride. The organic layer is washed successively with water, 5% aqueous sodium sulfite solution and saturated saline,
It was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The oily residue was treated with diethyl ether to give powder 4.9 g (yield 8
4.0%).

(B) Benzhydryl 7-[(Z) -2-methoxyimino-
2- (2-Tritylaminothiazol-4-yl) acetamido] -3-[(6,7-diacetoxy-2-methyl-1,2,3,4-tetrahydro-2-isoquinolinio) methyl] -3-cephem -4-carboxylate / iodo salt: 4.9 g (4.0 mmol) of the powder obtained in (A) was added to 70 ml of acetone.
8.7 g (52.4 mmol) of potassium iodide was added to this solution, and then acetyl chloride 1.44 ml was added at -30 ° C.
(20 mmol) was added dropwise. -30 to -20 ℃ for 30 minutes,-
After stirring at 10 to -8 ° C for 75 minutes, the reaction solution was added to 320 ml of an aqueous solution containing 4.4 g of sodium metabisulfite, and the precipitate was collected by filtration and washed with water. The precipitate was dissolved in methylene chloride.
The solution was washed with water, an acidic sodium sulfite aqueous solution and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the oily residue, powder 3.95 g.
(Yield 62.7%) was obtained.

NMR (CDCl ₃ ) δ: 2.22 (9H, s), 2.0 to 2.3 (2H, m),
2.4 to 3.4 (4H, m), 3.98 (3H, s), 4.2 to 5.0 (4H, m), 5.7
2 (1H, bd), 6.20 (1H, m), 6.70 (1H, s), 6.98 (1H, s),
6.9 ~ 8.0 (28H, m) (C) 7-[(Z) -2- (2-aminothiazol-4-yl)
Methoxyiminoacetamido] -3-[(6,7-diacetoxy-2-methyl-1,2,3,4-tetrahydro-2-isoquinolinio) methyl] -3-cephem-4-carboxylate: (B) 3.95 g (3.26 mmol) of the powder was dissolved in a mixed solution of 20 ml of methylene chloride and 3.9 ml (35.9 mmol) of anisole, and 20 ml of trifluoroacetic acid was added dropwise under ice cooling.
After stirring at the same temperature for 2 hours, the reaction solution was concentrated under reduced pressure, and 30 ml of ethyl acetate and 30 ml of cold water were added. The aqueous layer was separated, washed twice with ethyl acetate, adsorbed on HP-20 (70 ml), and then eluted with 50% methanol. Fractions containing the desired product were collected, concentrated under reduced pressure and freeze-dried to obtain 180 mg of a crude powder. This crude powder was subjected to reverse phase column chromatography (Waters
Pre-pack 500 / C-18) and eluted with 5-33% methanol to obtain 18 mg of the target compound (yield 0.6%) and 50 mg of a mixture (1: 1) containing the target compound. Melting point 154 ° C (decomposition).

IR (KBr): 1760,1610,1520,1360,1210,1175,1090,1030c
m ^-1 NMR (D ₂ O) δ: 2.38 (6H, s), 2.9 to 3.5 (6H, m), 4.03
(3H, s), 5.40 (1H, d, J = 5.4Hz), 5.92 (1H, d, J = 5.4H)
z), 7.02 (1H, s), 7.16 (1H, s), 7.28 (1H, s) Example 3 (A) Benzhydryl 7-[(Z) -2-methoxyimino-
2- (2-Tritylaminothiazol-4-yl) acetamido] -3-[(6,7-diacetoxy-1,2,3,4-tetrahydro-2-isoquinolinin-2-yl) methyl] -3-cephem -
4-Carboxylate 1-oxide: 6,7-diacetoxy-1,2,3,4-tetrahydroisoquinoline hydrobromide 760 mg (2.24 mmol) 20 ml water and 20 ml methylene chloride were added. This solution was neutralized with sodium hydrogen carbonate powder, the organic layer was dried over anhydrous sodium sulfate,
A methylene chloride solution containing 6,7-diacetoxy-1,2,3,4-tetrahydroisoquinoline was prepared. Add benzhydryl 7-[(Z) -2-methoxyimino-2- (2-
Tritylaminothiazol-4-yl) acetamido-3-
1.12 g (1.18 mmol) iodomethyl-3-cephem-4-carboxylate 1-oxide was added and the solution was stirred at room temperature for 1 hour. After distilling off methylene chloride under reduced pressure,
The residue was subjected to silica gel column chromatography (methylene chloride → 2% methanol / methylene chloride) to obtain 836 mg (yield 98%) of amorphous powder.

NMR (CDCl ₃ ) δ: 2.23 (6H, s), 2.4-2.9 (4H, m),
3.12 (1H, d, J = 18Hz), 3.2 to 3.5 (4H, m), 4.04 (3H,
s), 4.05 (1H, d, J = 18Hz), 4.42 (1H, d, J = 5Hz), 6.08
(1H, dd, J = 5,11Hz), 6.68 (1H, s), 6.72 (1H, s), 6.85
(1H, s), 6.96 (1H, s), 7.1 to 7.8 (25H, m) (B) Benzhydryl 7-[(Z) -2-methoxyimino-
2- (2-Tritylaminothiazol-4-yl) acetamido] -3-[(6,7-diacetoxy-2-methyl-1,2,3,4-tetrahydro-2-isoquinolinio) methyl] -3-cephem -4-Carboxylate 1-oxide iodo salt: 817 mg (0.766 mmol) of the amorphous powder obtained in (A) was dissolved in 8.2 ml (132 mmol) of methyl iodide. After leaving at room temperature in the dark for 3 days, the reaction solution was subjected to silica gel column chromatography (methylene chloride → 2% methanol / methylene chloride → 4% methanol / methylene chloride) to give 470 mg of the title compound powder (yield 51%). ) Got. This product's NMR-
Spectra and thin layer chromatography are shown in Example 2 (A).
It was in agreement with the compound obtained in.

Example 4 7-[(Z) -2- (2-aminothiazol-4-yl) methoxyiminoacetamido] -3-[(6,7-dihydroxy-2-)
Methyl-1,2,3,4-tetrahydro-2-isoquinolinio) methyl] -3-cephem-4-carboxylate: 2.5 mg of the compound obtained in Example 2 (C) in 0.5% methanol
It was suspended in ml and 35 μl of concentrated aqueous ammonia was added. After left at room temperature for 1 hour, the reaction mixture was analyzed by HPLC [Develosil ODS-
5 (10 × 250 mm), THF-H ₂ O (15:85)]. As a result, the raw material peak (Rt = 9.6 minutes) disappeared and Example 1
The same peak as the compound obtained in (E) (Rt = 8.0 min)
Was recognized. This peak was collected and freeze-dried to obtain 1 mg of the title compound. This is a bio-autographer [TLC: Merck Silica Gel F ₂₅₄ , CH ₃ CN: C ₂ H ₅ OCOCH
₃ : H ₂ O (3: 1: 1), E. Coli NIHJ], a spot showing an antibacterial property was shown at Rf = 0.1, which coincided with the antibacterial spot of the compound of Example 1 (E). The antibacterial spot of the raw material is Rf
= 0.4. This product also showed the same antibacterial spectrum as the compound of Example 1 (E).

The compounds of Examples 5 to 9 were obtained in the same manner as in Reference Example 2.

Example 5 7-[(Z) -2- (2-aminothiazol-4-yl) methoxyiminoacetamido] -3-[(5,6-dihydroxy-2-
Methyl-1,2,3,4-tetrahydro-2-isoquinolinio) methyl] -3-cephem-4-carboxylate (mixture of diastereomers A and B): Melting point: 166 ° C (decomposition) IR (KBr): 1780 , 1680,1620,1200,1140,1050cm ^-1 NMR (DMSO-d ₆ ) δ: 2.96 (3H, br s), 3.2 to 4.9 (13H,
m), 5.29 (1H, d, J = 5Hz), 5.87 (1H, d, J = 5,9Hz), 6.45
(1H, m), 6.73 (1H, s), 6.9 to 7.3 (2H, m), 9.60 (1H, d,
J = 9 Hz) Example 6 7-[(Z) -2- (2-aminothiazol-4-yl) methoxyiminoacetamido] -3-[(2-methyl-1,2,3,4-tetrahydro-6 , 7,8-Trihydroxy-2-isoquinolinio) methyl] -3-cephem-4-carboxylate (mixture of diastereomers A and B): Melting point: 182 ° C (decomposition) IR (KBr): 1780,1670,1620 , 1540,1480cm ^-1 NMR (DMSO-d ₆ ) δ: 2.6 to 4.5 (16H, m), 5.17 (1H, m)
5.68 (1H, m), 6.20 (1H, s), 6.73 (1H, s), 7.20 (2H, br
s), 9.55 (1H, d, J = 9Hz) Example 7 7-[(Z) -2- (2-aminothiazol-4-yl) -2-isopropoxyiminoacetamide] -3-[(6, 7-Dihydroxy-2-methyl-1,2,3,4-tetrahydro-2-isoquinolinio) methyl] -3-cephem-4-carboxylate (mixture of diastereomers A and B): Melting point: 174 ° C (decomposition) IR (KBr): 1780,1620,1540,1390,1360cm ^-1 NMR (DMSO-d ₆ ) δ: 1.23 (6H, d, J = 6Hz), 2.90 (3H, br
s), 3.0 to 4.6 (11H, m), 5.17 (1H, d, J = 5Hz) 5.67 (1
H, dd, J = 5,9Hz), 6.51 (1H, s), 6.63 (1H, s), 6.70 (1
H, s), 7.20 (2H, br s), 9.45 (1H, d, J = 9Hz) Example 8 (A) Benzhydryl 7-[(Z) -2- (benzhydryloxycarbonylmethoxyimino) -2 -(2-Tritylaminothiazol-4-yl) acetamido] -3-chloromethyl-3-cephem-4-carboxylate 1-oxide: benzhydryl 7-[(Z) -2- (benzhydryloxycarbonylmethoxyimino) ) -2- (2-Tritylaminothiazol-4-yl) acetamido] -3-chloromethyl-
2-3.4 g (22.3 mmol) of 3-cephem-4-carboxylate was dissolved in 500 ml of methylene chloride, 4.8 g (22.3 mmol) of 80% metachloroperbenzoic acid was added over 10 minutes under ice cooling, and this solution was stirred for 20 minutes. did. To the reaction mixture was added 10% aqueous sodium thiosulfate solution (150 ml), the organic layer was washed with 5% aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a powder. This was used in the next reaction without purification.

IR (KBr): 1800,1730,1680,1520,1490,1450,1375,1250,
1180,1090,1060,1010,750,700cm ^-1 (B) Benzhydryl 7-[(Z) -2- (Benzhydryloxycarbonylmethoxyimino) -2- (2-tritylaminothiazol-4-yl) acetamide] -3-Iodomethyl-3-cephem-4-carboxylate 1-oxide: The compound obtained in (A) was dissolved in 380 ml of acetone, 7.4 g (49 mmol) of sodium iodide was added, and this solution was added at room temperature.
Stir for 30 minutes. To the reaction mixture were added 10% aqueous sodium thiosulfate solution (300 ml) and ethyl acetate (1150 ml), and the layers were separated. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel flash column chromatography (ethyl acetate / n-hexane = 1: 1) to obtain 22.4 g of the title compound in powder form (yield 86.7% from the previous step).

IR (KBr): 1795,1725,1685,1520,1495,1450,1370,1290,
1230,1180,1085,1060,750,700 cm ^-1 NMR (DMSO-d ₆ ) δ: 3.9 (2H, br s), 4.5 (2H, m), 4.9
(2H, br s), 5.08 (1H, d, J = 5Hz), 5.93 (1H, dd, J = 5,8
Hz), 6.87 (1H, s), 6.92 (1H, s), 7.0 (1H, s), 7.35 (3
6H, m), 8.85 (2H, m) (C) Benzhydryl 7-[(Z) -2- (benzhydryloxycarbonylmethoxyimino) -2- (2-tritylaminothiazol-4-yl) acetamide]- 3- [(6,7-
Dihydroxy-1,2,3,4-tetrahydroisoquinoline-2-
Iyl) methyl] -3-cephem-4-carboxylate 1-oxide: 4 g (3.4 mmol) of the compound obtained in (B) and 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrogen bromide 1.27 g (5.2 mmol) of acid salt as N, N-dimethylformamide
It was dissolved in 15 ml, and 0.71 ml (5.1 mmol) of triethylamine was added at room temperature. After stirring at the same temperature for 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% methanol / chloroform) to obtain 3.5 g of the title compound (yield 84%).

IR (KBr): 1800, 1740, 1660, 1530 cm ^-1 NMR (DMSO-d ₆ ) δ: 2.3 to 2.7 (4H, m), 3.0 to 3.5 (6H,
m), 4.37 (1H, d, J = 6.0Hz), 4.87 (2H, br s), 6.03 (1
H, m), 6.30 (1H, s), 6.47 (1H, s), 6.70 (1H, s), 6.88
(1H, s), 6.95 (1H, s), 7.1-7.5 (35H, m) (D) Benzhydryl 7-[(Z) -2- (benzhydryloxycarbonylmethoxyimino) -2- (2-trityl) Aminothiazol-4-yl) acetamido] -3-[(6,7-
Dihydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolinio) methyl] -3-cephem-4-carboxylate
1-Oxide-iodo salt: 3.5 g of the compound obtained in (C) was dissolved in 20 ml (321 mmol) of methyl iodide. After stirring at room temperature for 15 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2-5% methanol / chloroform) to obtain 2.7 g of the title compound (yield 69%).

IR (KBr): 1800, 1690, 1640, 1620, 1530 cm ^-1 NMR (DMSO-d ₆ ) δ: 2.6 ~ 3.0 (3H, m), 3.0 ~ 3.7 (6H,
m), 3.9 to 4.5 (4H, m), 4.83 (2H, br s), 5.40 (1H, d, J
= 4.5Hz) 5.93 (1H, m), 6.47 (1H, s), 6.61 (1H, s), 6.
77 (1H, s), 6.88 (1H, s), 7.1-7.6 (35H, m) (E) Benzhydryl 7-[(Z) -2- (benzhydryloxycarbonylmethoxyimino) -2- (2- Tritylaminothiazol-4-yl) acetamido] -3-[(6,7-
Dihydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolinio) methyl] -3-cephem-4-carboxylate iodo salt: 2.7 g (2.0 mmol) of the compound obtained in (D) was added to acetone 50m
It was dissolved in 1 and 3.35 g (20.2 mmol) of potassium iodide was added, followed by 0.72 ml (10 mmol) of acetyl chloride at -20 ° C. After stirring at -20 ° C for 30 minutes and at -10 ° C for 3.5 hours, the reaction solution was poured into a 2% aqueous solution of sodium metabisulfite, and the precipitate was collected by filtration. The precipitate was dissolved in chloroform, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give the title compound 2.
3 g (yield 86%) was obtained.

NMR (DMSO-d ₆ ) δ: 2.6 to 2.9 (3H, m), 3.1 to 3.8 (6H,
m), 4.0 to 4.6 (4H, m), 5.17 (1H, m), 6.07 (1H, m), 6.4
3 (1H, s), 6.60 (1H, s), 6.85 (1H, s), 6.88 (1H, s),
7.1 to 7.6 (35H, m) (F) 7-[(Z) -2- (2-aminothiazol-4-yl)
-2-Carboxymethoxyiminoacetamide] -3-
[(6,7-Dihydroxy-2-methyl-1,2,3,4-tetrahydro-2-isoquinolinio) methyl] -3-cephem-4-carboxylate (mixture of diastereomers A and B): (E) 2.2 g (1.66 mmol) of the compound obtained in 1. was dissolved in 10 ml of methylene chloride and 2.2 ml of anisole, and 15 ml of trifluoroacetic acid was added dropwise under ice cooling. After stirring for 2 hours, the reaction solution was concentrated under reduced pressure, ethyl acetate and water were added to the residue, and the aqueous layer was subjected to reverse phase chromatography (Waters Pre Pack 500 / C-18: 2).
% Tetrahydrofuran / water) and the fractions containing the desired product are collected and freeze-dried to give 180 mg of the title compound (yield 17.5).
%) Was obtained.

Melting point: 179 ° C (decomposition) IR (KBr): 1780,1620,1540,1390,1360,1280cm ^-1 NMR (DMSO-d ₆ ) δ: 2.93 (3H, br s), 3.0 to 4.7 (10H,
m), 4.57 (2H, br s), 5.60 (2H, br s), 5.20 (1H, d, J =
5Hz) 5.53 (1H, s), 5.73 (1H, m), 6.63 (1H, s), 6.83
(1H, s), 7.23 (2H, br s), 9.80 (1H, d, J = 9Hz) Example 9 7-[(Z) -2- (2-aminothiazole-4) was prepared in the same manner as in Example 8. -Yl) -2- (1-carboxy-1-methylethoxyimino) acetamido] -3-[(6,7-dihydroxy-2-
Methyl-1,2,3,4-tetrahydro-2-isoquinolinio) methyl-3-cephem-4-carboxylate (mixture of diastereomers A, B) was obtained.

Melting point: 184 ℃ (decomposition) IR (KBr): 1780,1620,1540,1390,1360,1280,1200,1160c
m ^-1 NMR (DMSO-d ₆ ) δ: 1.50 (6H, s), 2.93 (3H, br s), 3.
0 to 4.7 (10H, m), 5.22 (1H, d, J = 5Hz), 5.75 (1H, dd, J
= 5,9Hz), 6.53 (1H, s), 6.65 (1H, s), 6.75 (1H, s),
9.55 (1H, d, J = 9Hz) Effect of the invention The compound of the present invention is a novel compound not described in the literature, and exhibits strong antibacterial activity against susceptible and resistant Gram-positive and Gram-negative bacteria and is useful as an antibacterial agent. Is.

 ─────────────────────────────────────────────────── --Continued from the front page (56) References JP-A-53-53690 (JP, A) JP-A-58-174387 (JP, A)

Claims (1)

[Claims] (1) General formula(In the formula, R¹May be substituted by a carboxyl group
A linear or branched lower alkyl group, R²Is hydrogen
Child, hydroxyl group or acetoxy group, R³And R^FourAre the same,
Hydroxyl or acetoxy group bonded to adjacent carbon atoms
A compound represented by
Its ester that is degradable. (2) General formula(In the formula, R^FiveIs a hydrogen atom or an amino protecting group, R⁶Is a hydrogen atom
Or carboxyl protecting group, R⁷Protected carboxyl
A linear or branched low chain which may be substituted by a group
Primary alkyl group, X is a halogen atom or a leaving group, Y is S or
Represents SO) and a salt of(In the formula, R⁸Is a hydrogen atom, an optionally protected hydroxyl group or
Is an acetoxy group, R⁹And R^TenAre the same and adjacent charcoal
An optionally protected hydroxyl group or an alkyl bonded to an elementary atom.
Setoxy group, R¹¹Represents a hydrogen atom or a methyl group)
Reaction with an amine(In the formula, R^Five, R⁶, R⁷, R⁸, R⁹, R^Ten, R¹¹And Y are as defined above
Have, x Represents an anion).
And, if necessary, after methylation and / or reduction,
General formula, characterized by removing protective groups(In the formula, R¹May be substituted by a carboxyl group
A linear or branched lower alkyl group, R²Is hydrogen
Child, hydroxyl group or acetoxy group, R³And R^FourAre the same,
Hydroxyl or acetoxy group bonded to adjacent carbon atoms
A compound represented by
A method for producing the decomposable ester. (3) General formula(In the formula, R⁶Is a hydrogen atom or a carboxyl protecting group, R⁸Is water
Elementary atom, optionally protected hydroxyl group or acetoxy
Base, R⁹And R^TenAre identical and bond to adjacent carbon atoms
, A hydroxyl group or acetoxy group which may be protected,
X Represents an anion), its salt or
Is the silyl compound of the general formula(In the formula, R^FiveIs a hydrogen atom or an amino protecting group, R⁷Is protected
Linear, optionally substituted by a carboxyl group
Or a branched lower alkyl group)
Acylation with boric acid or its reactive derivative
Expression(In the formula, R^Five, R⁶, R⁷, R⁸, R⁹, R^TenAnd X Has the above meaning
)) And then, if necessary,
General formula, characterized in that the protecting group is removed(In the formula, R¹May be substituted by a carboxyl group
A linear or branched lower alkyl group, R²Is hydrogen
Child, hydroxyl group or acetoxy group, R³And R^FourAre the same,
Hydroxyl or acetoxy group bonded to adjacent carbon atoms
A compound represented by
A method for producing the decomposable ester. (4) General formula(In the formula, R¹May be substituted by a carboxyl group
A linear or branched lower alkyl group, R²Is hydrogen
Child, hydroxyl group or acetoxy group, R³And R^FourAre the same,
Hydroxyl or acetoxy group bonded to adjacent carbon atoms
A compound represented by
Antibacterial containing the degradable ester as an active ingredient
Agent.