JPS6233186A - Novel cephalosporin derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I[R<1> is (COOH-substituted) cyclic lower alkyl; R<2>-R<4> are H, OH, methoxy or acetoxy], its salt or its hydrolyzable ester. EXAMPLE:7-[(Z)-2-( 2-aminothiazol-4-yl )-2-cyclopentyloxyimino-acetamido[-3-(6,7-dihydroxy-2-methyl-1,2,3,4-t etrahydro-2-isoquinolinium)methyl-3-cephem-4-carbox ylate. USE:An antibacterial agent for the remedy and prevention of respiratory infection, urinary infection, obstetric infection, suppurative disease, surgical infection, etc. PREPARATION:The compound of formula IV can be produced by reacting the compound of formula II[R<5> is H or amino-protecting group; R<6> is H or COOH-protecting group; R<7> is (substituted) lower alkyl; X is halogen or eliminable group; Y is S or SO] with the amine of formula III(R<8>-R<10> are H, OH, etc.; R<11> is H or methyl). If necessary, the protecting groups are removed after methylation and/or reduction of the product.

Description

[Detailed description of the invention] Industrial use decomposition The present invention relates to novel cephalosporin derivatives.

β-lactam antibiotics are selectively toxic 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, the conductor is generally stable to penicillinase,
Its antibacterial spectrum is wide, and it is frequently used for the prevention and treatment of bacterial infections.

Prior Art Publicly disclosed techniques describing cephalosporin derivatives having a quaternary ammonium salt structure include, for example, JP-A-53
-53690, 55-59196, 58-17
No. 4387 and No. 58-198490, etc. are cited.

Currently, cefotaxime (Cerotaxime) antimicrobial agents and chemotherapeutics (Ant1microbial eight oents and
C to emo-therai) V, 14 749 (
Cephalosporin derivatives called third generation, such as 1978), exhibit excellent antibacterial activity against Durham-positive bacteria, Durham-negative bacteria, and especially against intestinal bacteria.

CeHazidime Antimicrobial Agent and Chemotherapy
8 antimicrobial 8 gcnts and
Chemotherat)y, 17 876 (19
80)) is Pseudomonas aeruginosa (Pseu
domonas aeruginosa) and Acinetobacter (Ac1netobacter),
It is the best cephalosporin derivative known to date.

Problems to be Solved by the Invention Cephalosporin derivatives can be used in resistant Staphylococcus or Pseudomonas aeruginosa that have various resistance mechanisms.

Sa), Acinetobacter calcoaceticus (8c
tnetobacter Ca1COaCetiCuS
), Serratia 9 marsetuscens (Serratia
It has low antibacterial activity against glucose-fermenting Durum-negative rods such as S. marcescens). Therefore, there is a need for novel cephalosporin derivatives with more potency and a broader spectrum for the treatment of refractory infections caused by these bacteria.

In addition, cephalosporin derivatives called third generation, such as the above-mentioned cefotaxime, exhibit excellent antibacterial activity against Durum-positive bacteria and Durham-negative bacteria, especially enterobacteria, but they are also effective against Pseudomonas and Acinetobacter (ACinOtObaCtQr). It is rare to find a substance that exhibits strong antibacterial activity. Therefore, there is a need for a highly potent and effective curing drug for the treatment of serious infections caused by these bacteria or mixed infections with these bacteria and other bacteria.

Means for Solving the Problem The present inventors have a 2-(2-aminothiazol-4-yl)-2-ffi-substituted oxyiminoacetyl group as a side chain at the 7-position, and a 2-methyl oxyiminoacetyl group at the 3-position. The present invention was completed by synthesizing a new cephem compound substituted with -1,2,3,4-tetrahydro-substituted isoquinolinium methyl and finding that this compound has a strong antibacterial spectrum over a wide range.

Effects of the present invention The present invention relates to the general formula (I) (wherein R1 is a cyclic lower alkyl group which may be substituted with a carboxyl group, R2, [3 and R1 may be the same or different, and each A compound represented by a hydrogen atom, a hydroxyl group, a methoxy group, or an arexy group, a salt thereof, or a physiologically hydrolyzable nisdel thereof.

In general, substitution of f3 on an oximino group can take the structure of E or Z geometric isomerism, but substitution of the oximino group contained in the acylamino moiety at the 7-position of the compound of formula (1) has the structure of Z. Examples of the cyclic lower alkyl group which may be substituted with a carboxyl group in the substituted WR' of the compound of formula (2) include a cyclopropyl group, a cyclobutyl group, a cyclopendel group, a cyclohexyl group, a 1-
Carboxy-1-cyclopropyl group, 1-carboxy-
Examples include a 1-cyclobutyl group, a 1-carboxy-1-cyclopentyl group, and a 1-carboxy-1-sifuhexyl group.

Examples of the substituted isoquinoline ring of 2-methyl-1,2,3,4-tel to lahydro-substituted isoquinolinium methyl at the 3-position of cephem include unsubstituted isoquinoline, 6-hydroxyisoquinoline, 7-hydroxyisoquinoline, 6
-acetoxyisoquinoline, l-acetoxyisoquinoline, 6-methoxyisoquinoline, 7-m-1-xyinquinoline, 5.6-dihydroxyisoquinoline, 6.7-
Dihydroxyisoquinoline, 7.8-dihydroxyisoquinoline, 5.6-dihydroxyisoquinoline, G, 7
-Zia 1? ? -xyisoquinoline, 1.8-cya 廿1
-xyisoquinoline, 5,6-dimethoxyisoquinoline, 6.7-dimethoxyisoquinoline, 7.8-dimethoxyisoquinoline, 5,6.7-1-lihydroxyinquinoline, 5,6.8-trihydroxyinquinoline, 5
, 7.8-t-dihydroxyisoquinoline, 6,7.
8-trihydroxyisoquinoline, 5.6.7-triacetoxyisoquinoline, 5,6.8-1~ria is toxisoquinoline, 5.7.8-1~riace1-xyisoquinoline, 6. γ, 8-1-riat? I-xyisoquinoline, 5,6.7-trimethyl-1-xyisoquinoline, 5,6
．． 8-t-dimethoxyisoquinoline, 5.7.8-trimethoxyisoquinoline, 6,7.8-trimethoxyisoquinoline, 5.6-dihydroxy-7-methoxyisoquinoline, 5.6-dihydroxy-8- Methoxyisoquinoline, 6.7-cyhydroxy-5-methoxyisoquinoline, 6.7-cyhydroxy-8-methoxyisoquinoline, 7.8-dihydroxy-5-methoxyisoquinoline, 7.8-dihydroxy-6-methoxyisoquinoline, 5. 6-diacedoxy7-methoxyisoquinoline, 5.6-diacedoxy8-methoxyisoquinoline, 6.7-diacehxy5-methoxyisoquinoline, 6.7-diacedoxy-8-methoxyisoquinoline, 7.8 -Diacetoxy-5-methoxyisoquinoline, 7,8-diacetoxy-6-methoxyisoquinoline, and the like.

The compound of formula 1 can be produced by the following method.

General formula (in the formula, R5 is a hydrogen atom or an amine protecting group, R6 is a hydrogen atom or a carboxyl protecting group, R7 is a cyclic lower alkyl group that may be substituted with a protected carboxyl group, and X is a halogen atom or an elimination group, Y represents S or SQ) or a salt thereof, represented by the general formula (wherein R8, R9 and R1 may be the same or different,
hydrogen atom, optionally protected hydroxyl group, metal
~xy group or acetoxy group, R1+ represents a hydrogen atom or a methyl group. ＞<e indicates an anion
After methylating and/or reducing the compound as required, the protecting group is removed (
A method).

A compound represented by the general formula (wherein R6, -1R9, R1 and XO have the above-mentioned meanings), a salt thereof or a silyl compound thereof; Acylated with a reactive derivative of a carboxylic acid represented by the general formula C, R5,1<6, ]ze, 1<8, [9, A compound represented by is prepared, and then the protecting group is removed (Method 13).

Examples of the amine group 13 for the substituent 1<5 of the compound of formula (1) and the carboxylic acid of formula Vt include 1 to lydyl group, formyl group, chloroaretyl group, trifluoroacedel group, t-broxycarbonyl group , 1-rimedylsilyl group, t-butyldimethylsilyl group, and the like. A Heridel group is particularly preferred, since it can be easily removed by acid treatment.

Examples of carboxyl groups for the substituents R6 and R1 include the following cold-retaining groups. Lower alkyl groups such as t-butyl groups, haloalkyl groups such as 2,2,2-
Trichloroethyl group, alkanoyloxyalkyl group such as acetoxyethyl group, propionyloxymethyl group, pivaloyloxymethyl group, 2-acetoxyethyl group, 2-propionyloxymethyl group, alkanesulfonylalkyl group such as mesylethyl group, 2-mesylethyl group groups, aralkyl groups such as benzyl group, 4-methoxybenzyl group, 4-nitrobenzyl group, phenethyl group,
Alkylsilyl groups such as trityl group, benzhydryl group, bis(methoxyphenyl)methyl group, 3,4-thume-1-xybenzyl group, etc., such as trimethylsilyl group.

Particularly preferred are penthydryl or t-butyl groups, which can be easily removed by acid treatment. Substituent X of the compound of formula ■
Examples of the halogen atom include chlorine, bromine, iodine, etc., and examples of the J152 leaving group include acetoxy group, i~
Lifluoroacetoxy group, methanesulfonyloxy group,
Examples include trifluoromethanesulfonyloxy group, phenylsulfonyloxy group, p-tolylsulfonyloxy group, and the like. Bromine or iodine is particularly preferred.

As the reactive derivative of the carboxylic acid of formula Vl, for example, acid halides, mixed acid anhydrides, active esters, etc. are used. Acid halides of carboxylic acids of formula VI are obtained by reacting carbone M (VI ) with a halogenating agent. This acid halide forming reaction is carried out in an inert solvent such as methylene chloride, chloroform, dichloroethane, benzene, toluene, etc. and mixtures thereof.

Examples of halogenating agents include thionyl chloride, phosphorus trichloride,
Phosphorus oxychloride, phosphorus pentachloride, phosphorus tribromide, oxalyl chloride, phosgene, etc. are used. The amount of the halogenating agent used is 1 to 10 mol, preferably 1 to 1.5 mol, per 1 mol of carvone M (Vl). Reaction temperature is -40~
+100°C, preferably -20 to +20°C.

The mixed acid anhydride of the carboxylic acid of formula I is a carboxylic acid (V
It can be obtained by reacting 1) with alkyl chlorocarbonate, aliphatic carboxylic acid chloride, etc. The reaction is carried out in an inert solvent such as aretone, dioxane, acetonitrile, tetrahydrofuran, methylene chloride, chloroform, bempine, ethyl acetate, dimethylformamide, etc. or mixtures thereof. This reaction is preferably carried out in the presence of a tertiary amine such as triethylamine or N-methylmorpholine. The reaction temperature is -30 to +20°C, preferably -15 to 0°C.

The active Nisder of the carboxylic acid of formula Vl is the carboxylic acid (V
l) preferably with 1 to 1.2 mol of an N-hydroxy compound or a phenolic compound. The reaction is carried out in an inert solvent such as acetone, dioxane, atit-nitrile, tetrahydrofuran, methylene chloride, chloroform, ethyl acetate, dimethylformamide, etc. or mixtures thereof. Examples of N-hydroxy compounds include N-hydroxysuccinimide, N-hydroxy
-Hydroxyphthalimide, 1-hydroxybenztriazole, etc., and as the phenol compound, for example, 4-nitrophenol, 2,4-dinitrophenol, trichlorophenol, pentachlorophenol, etc. are used. This 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,
Reaction time is 30-120 minutes.

The compound of formula (1), which is a group Y ffi S, is obtained by reacting a compound represented by the general formula (wherein R6 and X have the above-mentioned meanings and Z represents a hydrogen atom or an acyl group) with a carboxylic acid of formula Vl It can be obtained by acylation using a chemical derivative. Further, a compound of the formula (2) in which the group Y is SO can be obtained by oxidizing a compound of the formula (2) in which the group Y is S. The compound of the formula (2) in which the substituent X is iodine is preferably prepared by reacting the compound of the formula (1) in which the substituent X is chlorine with sodium iodide.

The compound of formula V is a compound of formula (1) in which Z is an acyl group.
After reacting with amine 2, where Te1 is a methyl group,
1 is produced by deacylation.

The compound of formula (2) can be easily produced from a compound represented by the general formula (wherein Rs and 2 have the meanings given above).

When producing the compound of formula 1 by method A, first the compound of formula (1) is reacted with the free amine or amine salt of (2) in a solvent. When using hydrochloride, hydrobromide, WtM salt, acetate, etc. as the amine salt, 3 of the neutralization amount
The reaction is carried out in the presence of a class amine such as triethylamine.

Examples of solvents include methylene chloride, chloroform, ether, ethyl acetate, butyl acetate, tetrahydrofuran,
A non-aqueous organic solvent such as acetate nitrile, dimethylformamide, dimethyl sulfoxide or a mixture thereof is used. The amine of formula (1) can also be used after being silylated with a silylating agent such as N,O-bistrimethylsilylacetamide in the above-mentioned solvent. The amount of the amine of formula (1) to be used is 1 to 2 moles per 1 mole of the compound of formula (2). The reaction temperature is 0 to 35°C, and the reaction is completed in 0.5 to 5 hours.

When using a secondary amine of the formula (2) in which the substituent RI+ is a hydrogen atom, the product (IV) may be left in the reaction solution without isolation, or the product may be produced.

Compound (IV') is separated and purified and reacted with methyl iodide to obtain ammonio compound (IV). When this methylation reaction is carried out in the above-mentioned non-aqueous organic solvent, the amount of methyl iodide used is 1 to 30 mol, preferably 3 to 15 mol, per 1 mol of product (IV), and the reaction temperature is -30 mol. ~+35°C, the reaction is complete in a few hours to a few days. Alternatively, in the absence of a solvent, excess methyl iodide was added to the product (IV) at 10 to 35°C.
Ammonio compound (IV') can also be obtained by reacting for 5 to 20 hours.

When using a compound of formula (■) in which the group Y is >S-O,
Ammonio (IV) can be prepared by known methods such as Journal of Organic Chemistry (Journal of Organic Chemistry).
or' Organic Chemistry)35
Volume 2430 (1970), Synthesis
esis) 58 (1979) or Journal of Chemical Research (Journal or Che.
micat Research) 341 (1979
) etc. For example, the product (IV
) in an inert organic solvent such as acetone, methylene chloride,
Dissolve in chloroform, tetrahydrofuran, ethyl acetate, etc., add potassium iodide or sodium iodide, and -40
Add acetyl chloride dropwise at ~0°C, -20~-10
Reduction can be achieved by reacting at ℃ for 1 to 5 hours. The amount of iodide used is 3.5 to 1 mole of product (IV).
10 mol, the amount of acetyl chloride used is 1.5-5
It is a mole. Removal of the protecting group from the compound thus obtained gives the compound of formula I.

The protecting group can be removed by appropriately selecting a commonly used method depending on the type of the protecting group.

A method using an acid is preferred, and examples of the acid include inorganic or organic acids such as dinic acid, trifluoroacetic acid, benzenesulfonic acid, p-1-luenesulfonic acid, and hydrochloric acid.
Trifluoroacetic acid is preferred. When trifluoroacetic acid is used as 13Fm, the reaction is accelerated by adding anisole. This reaction can also be carried out in an inert solvent, for example, an organic solvent such as methylene chloride, ethylene chloride, benzene, or a mixed solvent thereof, preferably in methylene chloride. The reaction time is not particularly limited, and is appropriately selected depending on the chemical properties of the raw material compound and reaction product, the type of protecting group, the removal method, etc.
It is preferable to carry out under mild conditions such as cooling or heating.

In preparing a compound of formula 1 by the process, a compound of formula V is first reacted with a reactive derivative of a carboxylic acid of formula Vl in a solvent. The reaction is carried out in an inert solvent such as water, acetone, dioxane, acetonitrile, tetrahydrofuran,
methylene chloride, chloroform, benvin, ethyl acetate,
Dimethylborumamide etc. or mixtures thereof. The amount of the reactive derivative of carboxylic acid (Vl) used is 1 to 1.5 mol per mol of the compound of formula V.

The reaction temperature is -40 to +40°C, preferably -20 to +30°C.
It is ℃. When using the acid chloride or mixed acid anhydride of carboxyl N (Vl), an alkali metal carbonate or an organic amine such as trimethylamine, triethylamine, N-
It is preferable to carry out the reaction in the presence of methylmorpholine or the like.

When the reaction is completed, the product (vl) is separated and the protecting group is removed in the same manner as in method A to obtain the compound of formula 1.

The compound of formula (1) can be converted into a salt or a physiologically hydrolyzable ester by conventional methods.

The salts of the compound of formula (2) include conventional medically acceptable salts, such as alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, N, N,
'-organic amines such as dibenzylethylenediamine, protylene, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, perchloric acid, hydrobromic acid, etc. (ff acids, acetic acid, lactic acid, propionic acid, maleic acid, fumaric acid, Organic acids such as malic acid, tartaric acid, citric acid, organic sulfonic acids such as methanesulfonic acid, isethionic acid, p-toluenesulfonic acid, aspartic acid,
Examples include salts of amino acids such as glutamic acid. Examples of physiologically hydrolyzable esters include acetoxyalkyl esters such as acetoxymethyl ester and pivaloyloxymethyl, alkoxycarbonyloxyalkyl esters such as 1-(ethoxycarbonyloxy)-1-ethyl, and 1- Phthalidyl ester, 5-methyl-
5-substituted-2-oxo-1,3-dioxo-4- such as 2-oxo-1,3-dioxo-4-ylmethyl
yl methyl esters and the like are preferred.

The minimum inhibitory concentration (H
IC: μg/ml) and cefotaxime (Cerota
xime) and Cefta Zidim
e) as a comparison compound, the sensitivity disc Agar to Tsui) (5sensitivity
It was measured by the agar plate dilution method using Disk Aoar (Nissui) (number of bacteria: 1 Q6CFU/d).

The results are shown in the table below.

The compounds of the invention can be used in sensitive and resistant Gram-positive and Gram-negative bacteria, especially in resistant Pseudomonas aeruginosa.

Sa), Seam-Tomonas cepacia (Pscudom
onascepacia), Acinetobacter ca.
It showed strong antibacterial activity against bacteria such as L. lcoacticus).

Therefore, the present invention is further useful as an antibacterial agent containing a compound of formula (1), a salt thereof, or a physiologically hydrolyzable ester thereof as an active ingredient.

The compounds of the invention can be mixed with solid or liquid excipient carriers and used in the form of pharmaceutical formulations suitable for oral, parenteral or external administration. Pharmaceutical preparations include injections, liquid preparations such as syrups and emulsions, solid preparations such as tablets, capsules, and granules, and external preparations such as ointments and suppositories.

The above formulations may contain commonly used additives such as auxiliaries, stabilizers, wetting agents, emulsifiers and the like. For example, the injection may contain additives such as distilled water for injection, physiological saline, a solution such as Ringer's solution, and a preservative such as methyl p-oxybenzoate and propyl p-oxybenzoate. Liquid preparations such as syrups and emulsions include syrup, methyl cellulose, glucose, sucrose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, edible oil, tonsil, coconut oil, oily ester, and sorbitan monomer. In addition to oleate, propylene glycol, glycerin, ethyl alcohol, water, etc., it may contain emulsifiers such as gum arabic, gelatin, lecithin, and surfactants such as Tween and Span. As solid agents, lactose, sucrose, corn starch, calcium phosphate, magnesium stearate, talc, silicic acid, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, polyethylene glycol, sodium lauryl sulfate, etc. are used.

As bases for ointments and suppositories, for example, cacao butter, glycerides, polyethylene glycols, white petrolatum, etc. are used. A surfactant or an absorption enhancer may be contained if necessary.

Compound (I) of the present invention can be used to treat bacterial infections, such as respiratory infections.
It can be used for the treatment and prevention of urinary tract infections, obstetric and gynecological infections, purulent diseases, surgical infections, etc. Dosage varies depending on patient's age and condition, usually 1 to 1 dose per day.
Used in the range of 00my/3y, 5-30r per day
It is preferable to administer in 2 to 4 doses at Rg/Kg.

Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto.

Examples Example 1 (8) Benzhydryl 7- ((Z)-2-cyclopentyloxyimino-2-(2-tritylaminothiazol-4-yl)acetamide) -3-(6,7-cyhydroxy-1.2, 3.4-tetrahydroisoquinolin-2-yl)-3-cephem-4-carboxylate 1-oxide benzhydryl 3-iodomethyl-7-((Z)-2
-cyclopentyloxyimino-S'-(2-tritylaminothiazol-4-yl)acetamide] -3-
3.5 g (3.49 mmol) of cephem-4-carboxylate was dissolved in 15 d of dimethylformamide and 6.7
-cyhydroxy-1.2,3.4-tetrahydroisoquinoline hydrobromide 1.28 g (5.2 mmol)
and triethylamine 0.73 d (5.2 mmol)
was added at room temperature. After stirring the reaction solution for 1 hour, dimethylbormamide was distilled off under reduced pressure. Water and chloroform were added to the residue, and the organic layer was washed with saturated brine. After dehydration with anhydrous sodium sulfate, the residue obtained by concentrating under reduced pressure was subjected to silica gel column chromatography (2 to 5
% methanol/chloroform) to give 3 g of the title compound.
(yield 82.6%).

IR (Br): 1810.1730.1660
．． 1620.1530cm-INHrl(0830-d
6') δ: 1.4-1.9 (811, m).

2.3-3.4 (1011, m), 4.65 (1
11, m).

5.07 (Ill, d, J=4.511Z), 5
．． 85 (111, dd.

J-4, 5 and 711z), 6.31 (111,
s).

6.42 (111,s), 6.77 (11
1,s).

6.97(ill,s), 7.15-7.5
(2511°brs), 8.4~8.8(31
1,m) CB) Penthydryl 7- ((Z)-2-
cyclopentyloxyimino-2-(2-tritylaminothiazol-4-yl)acetamide) -3-(6
,7-cyhydroxy-2-methyl-1,2,3,4-tetrahydro-2-isoquinolinium)methyl-3-cephem-4-carboxylate 3 g of the compound obtained with 1-oxide iodo salt (8) (2,3 mmol) to methyl iodide 20 ad! (321 mmol) and stirred at air temperature for 19 hours. The reaction solution was concentrated under reduced pressure, and ether was added to the dissolved residue to remove 2.5 g (yield: 73.3%) of the title compound as a powder.

NHR(DH3O-66)δ: 1.4-1.9(8
11, m).

2.6-4.4 (1311, m), 4.63 (
III, m).

5.13 (Ill, m), 5.93 (ill, m
).

6.43 (Ill, S), 6.60 (III, S
).

6.18 (III, S), γ, 12 (Ill,
S).

7.3-7.5 (2511, brs), 8.8
0(211,m) (C) Penthydryl? −((Z)
-2-cyclopentyloxyimino-2-(2-tritylaminethiazol-4-yl)acetamide) -3
-(6,7-cyhydroxy-2-methyl-1,2,3,
4-tetrahydro-2-isoquinolinium)methyl-3
- 2.5 g (2.1 mmol) of the compound obtained from cephem-4-carboxylate iodo salt (B) was added to 50 ml of acetone.
3.5 g (21 mmol) of potassium iodide dissolved in
After adding 0.75 acetyl chloride at -20℃
d (10.5 mmol) was added dropwise. The reaction solution was stirred at -10°C for 5 hours. The reaction solution was poured into a 2% aqueous sodium metabisulfite solution, and the precipitate was collected by filtration. The precipitate was dissolved in chloroform and washed with saturated brine, and then the organic layer was dehydrated over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2.2 g (89%) of the title compound.

IR (KBr): 1800, 1730, 168
0,1620,1530°1450.1360 Rho 1 NHR (DH3O-d6) 6: 1.2-2.0
(811, m).

5.43 (III, m), 5.90 (11t,
m), 6.50 (ill, S), 8.63
(111,S), 6.77(111,S)
.

6.95 (111,s), 7.0~7.7 (2
5tl,brs).

9.55 (111, m) (D) 7- ((z)-2-(2-aminothiazol-4-yl)-2-cyclopentyloxyiminoacetamide) -3-(6,7-cyhydroxy-2-methyl 2.1 g (1.8 mmol) of the compound dissolved in ``-1,2,3,4-tetrahydro-2-isoquinolinium) methyl-3-cephem-4-carboxylate (C) were dissolved in 10 d of methylene chloride and 2 d of anisole. After dissolving and adding trifluoroic acid M16me dropwise under cooling, the mixture was stirred at the same temperature for 2 hours.The reaction solution was concentrated under reduced pressure, and ether was added to the residue to collect the precipitate.

Water 2007 was added to this precipitate to remove insoluble matter, and the heavy liquid was subjected to reverse phase column chromatography (Waters).
PrePack 500/C-18: 15-40% methanol/water) to collect fractions containing the target compound and lyophilize to obtain the title compound 220rIT! (Yield 19.5%
) was obtained.

Melting point = 178℃ (decomposition) IR (Br): 1780, 1670.1B2
0,1540,1390°1360cm-1 NHR(DH3O-d6')δ: 1.3-1.9(
811, m).

2.90(311,brs), 3.0~4.8(
1011, m).

4.65 (Ill, m), 5.17 (111, d
, J-4,511Z).

5.65 (Ill, dd, J=4.5 and 911z)
.

6.51(Ill,s), 6.62(111,s
).

6.68 (ill, S) Example 2 (8) Penthydryl 7- ((z)-2-(1-t
ar-butoxycarbonyl-2-(2-tritylaminothiazol-4-yl)acetamido)-3-iodomethyl-3-cephem-
4-carboxylate 1-oxide penthydryl 7- ((Z)-2-(1-ter-
Butoxycarbonyl-1-cycloproximino)-2
14.2 g (14.7 mmol) of -(2-tritylaminothiazol-4-yl)acetamide]-3-chloromethyl-3-cephem-4-carboxylate was dissolved in 280 d of methylene chloride and dissolved in methachloroperbenzoic acid under water cooling. 2.98 g (14.7 mmol) of acid was added and stirred for 10 minutes. Add 10% sodium thiosulfate aqueous solution 6 to the reaction solution.
After adding 0d, this solution was poured into a 5% aqueous sodium bicarbonate solution, extracted with methylene chloride, and dehydrated with anhydrous sodium sulfate.

The residue obtained by concentration under reduced pressure was dissolved in 300 d of acetone, and 4.4 g (29°, 4 mmol) of sodium iodide was added at 0°C, followed by stirring at room temperature for 15 minutes. After washing the reaction solution with an aqueous sodium thiosulfate solution and saturated brine, the organic solvent layer was dehydrated with anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was subjected to silica gel flash column chromatography (ethyl acetate di-hexane = 1:2) to obtain 9.52 g (yield 60%) of the title compound.

(B) Penthydryl 7- ((z)-2-(1-t
er-7 Toxycarbonyl-1-cyclopropoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamide)-3-(6,7-cyhydroxy-1.
3.0 g (2.8 mmol) of the compound obtained from 2,3.4-tetrahydroisoquinolin-2-yl)methyl-3-cephem-4-carboxylate 1-oxide (A) was added to 30% dimethylformamide. Dissolve and add 0.85 g (3.3 mmol) of 6,1-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide and 0.93 d (6.6 mmol) of triethylamine; Stirred at room temperature for 2 hours. It was concentrated under reduced pressure, and the residue was subjected to silica gel flash column chromatography (ethyl acetate di-hexane-3:1) to obtain the amorphous title compound 3.8.
8 g (containing dimethylformamide) was obtained.

Ml(R(D)180-d6)δ: 1.40(13
11, m), 5.08 (11i, d, J-4hZ)
, 5.90 (IN, Q, J-4, 8).

6.32 (III, brs), 6.42 (II
I, brs).

6.84 (IH, S), 6.97 (IH, 5)
(C) Penthydryl 7- ((z)-2-(1-t
ar-butoxycarbonyl-1-cyclopropoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamide)-3-(6,7-cyhydroxy-2
-Methyl-1,2,3,4-tetrahydro-2-isoquinolinium) methyl-3-cephem-4carboxylate 1-oxide iodo salt CB) Compound 3.88 (j is methyl iodide 3h
te (610 mmol) and left at room temperature for 12 hours. After distilling off excess methyl iodide under reduced pressure,
The residue was purified by silica gel column chromatography (5% methanol/methylene chloride) to obtain 3.2 g of the amorphous title compound (yield 73% from the CB step).

NHR(DH3O-66)δ: 1.40(13+1
．． III), 2.80 (311, brs), 5
．． 18(ill,brd), 6.95(tll
, m), 6.43 (ill, brs), 6
．． 58 (111°brs), 6.85 (1!l
,s).

(0) Penthydryl 7- ((z)-2-(1-t
er-butoxycarbonyl-1-cyclopropoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamide)-3-(6,γ-dihydroxy-2
-Methyl-1.2,3.4-tetrahydro-2-isoquinolinium) 3.2 g (2.54 mmol) of the compound obtained from methyl-3-cephem-4-carboxylate iodo salt (C) was dissolved in 32 d of acetone. and potassium iodide 1.68g (1
0.1 mmol) was added thereto, and 0.36 d (5.07 mmol) of acetyl chloride was added dropwise at -5°C, followed by stirring for 1 hour. The reaction solution was poured into 170 mQ of 10% aqueous sodium metabisulfite solution, and then extracted with ethyl acetate. After dehydrating the extract over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a residue containing the title compound, which was used in the next reaction without purification.

(E) 7- ((z)-2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-cyclopropoxyimino)acetamide) -3-(6,7-cyhydroxy-2-methyl -1,2,3,4-tetrahydro-2-isoquinolinium)methyl-3-cephem-4
- The residue obtained from carboxylate (D) was mixed with methylene chloride 6d and anisole 6
After dissolving in d, trifluoroacetic acid 15rd at 0℃,
was added and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, ethyl acetate and water were added to the residue, the aqueous layer was separated, and the organic layer was extracted twice with water again. After combining and concentrating the aqueous layers, reverse phase column chromatography (ODS; LC-3o
rb) to obtain 131 mg of the title compound (mixture of diastereomers A and B, yield 8% from (D)).

Melting point: 156℃ (decomposition) IR (KBr): 3420.1780.1620
cm-1NHR(DH3O-d6)δ: 1.32(
411, m), 2.80 (311, brs)
, 4.95(Ill, m), 5.40(i
ll, m), 6.2-6.3 (III, m),
6.35 (III, s), 6.84 (lft,
s), 8.04 (lli, m) Example 3 (A) Benzhydryl 7- ((2) -2-(1-benzhydryloxycarbonyl-1-cyclopentyloxyimino) -2-(2-tritylamino) Thiazol-4-yl)acetamido)-3-chloromethyl-3-
Rofuemu 4-carboxylate (Z)-2-(1-benzhydryloxycarbonyl-
1-cyclopentyloxyimino)-2-(2-tridelaminothiazol-4-yl) vinegar 112.129(
3 mmol) and penthydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate 1.
24 g (3 mmol) was dissolved in 50 d of methylene chloride, and 1.2 m (9,6 ml) of N,N-dimethylaniline was dissolved under water cooling.
0.29 m of phosphorus oxychloride
(! (3.15 mmol) was added dropwise and stirred at the same temperature for 4 hours. To the reaction solution was added 30 d of chloroform and 30 d of water.
was added and the organic layer was washed with water and saturated brine, then dried over anhydrous sodium sulfate and concentrated to obtain the title compound residue.
This was used in the next reaction without purification.

(B) Penthydryl 7- ((Z)-2-(1-benzhydryloxycarbonyl-1-cyclopentyloxyimino)-2-(2-tritylaminothiazole-
4-yl)acetamido)-3-chloromethyl-3-cepham-4-carboxylate The residue obtained in 1-oxide (A) was dissolved in 50 d of methylene chloride, and mixed with metachloroperbenzoic acid (purity 80%) under water cooling. 710Itg
(3.3 mmol) and stirred for 20 minutes. After adding 30 IILe of methylene chloride and 40 d of 5% aqueous sodium bicarbonate solution to the reaction solution, the organic layer was separated and washed with water and saturated brine. The organic layer was dehydrated over anhydrous sodium sulfate and then concentrated to obtain a residue of the title compound, which was used in the next reaction without purification.

(C) Penthydryl 7- ((Z)-2-(1-benzhydryloxycarbonyl-1-cyclopentyloxyimino) -2-(2-tritylaminothiazol-4-yl)acetamidocy 3-iodomethyl-3-
To cephem-4-carboxylene 1, dissolve the residue in 40d of acetone with 1-oxide (8), add iodine,
990 mg (6.6 mmol) of sodium chloride was added, and the mixture was stirred at room temperature for 30 minutes. To the reaction solution were added 120 d of ethyl acetate and 20 d of a 5% aqueous sodium dithioate solution to separate the layers. The organic layer was washed with water and saturated brine, then dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by silica gel flash column chromatography (ethyl acetate)
Fractions containing the target compound were collected in hexane (1:2), concentrated under reduced pressure, and isopropyl ether was added to the residue to obtain 2.92 g of the title compound in powder form (yield from A: 80.3
%) is 19.

? 4MR (DH3O-d6): 1.80 (41
1, m), 2.1 (411, m).

3.9 (2tl, m), 4.4 (211, m),
5.10 (11I, d, J=5tlz), 5
．． 95 (ill, dd, J=5 and 9Hz), 6.
77 (ltl, s), 6.80 (111, s),
7.35 (3511, m), 8.5 (Ill,
d.

J=9111), 8.8(ill, brs)(D
) Penthydryl 7- ((Z)-2-(1-benzhydryloxycarbonyl-1-cyclopentyloxyimino)-2-(2-tritylaminodeazole-4-
-3-(6゜7-hydroxy-1.2,3.4-tetrahydroisoquinolin-2-yl)methyl-3-cephem-4-carboxylate 1
Compound 39 (2,47 mmol) obtained from -oxide iodo salt (C) was dissolved in dimethylbormamide 307, and 913 mg of 6,7-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrogen bromide Fi salt ( 3.71 mmol) and triethylamine 17 (7.17 mmol) were added at room temperature. After stirring the reaction solution for 40 minutes, dimethylformamide was distilled off under reduced pressure. 80 d of methylene chloride and 40 7 d of water were added to the residue, and the V3 layer was dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was separated and purified by silica gel flash column chromatography (10-30% acetone/methylene chloride) to obtain 3 g of the title compound in powder form (containing some dimethylformamide).

IR (KBr): 1800, 1730, 167
0,1530.1500°1450, t390.12
80.1180cm-1゜(E) Penthydryl 7-
((Z)-2-(1-Benzhydryloxycarbonyl-ruoxiimino)-2-(2-tritylaminothiazol-4-yl)acetamide) -3-(6.

7-hydroxy-2-methyl-1.2,3.4-tetrahydro-2-isoquinolinium) methyl-3-cephem-4-carboxylate 1-oxide iodo salt (D)) Methyl 6-( 9
6. 3 mmol) and left overnight at room temperature. After concentrating the reaction solution under reduced pressure, chloroform was added to the residue.
Added 0d. After dissolution, the mixture was concentrated to obtain the title compound, which was used in the next reaction without purification.

(F) Penthydryl 7- ( (z)-2-(1-
Benzhydryloxycarbonyl-1-cyclopentyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamide)-3-(6.

The residue obtained from 1-dihydroxy-2-methyl-1.2,3.4-tetrahydro-2-isoquinolinium) methyl-3-cephem-4-carboxylate iodo salt (E) was mixed with acetone 667! 2.05 g (12.3 mmol) of potassium iodide was added to -
Acetyl chloride 0.44 d at 20°C (6.
19 mmol) was added dropwise, and the mixture was stirred at -10°C for 1 hour.

After reducing the temperature to -20℃ again, potassium iodide 2.05 (j
(12.3 mmol) and acetyl chloride 0.44
d was added and stirred at -10°C for 1 hour, and this operation was repeated twice. Chloroborum 240d and water 60- were added to the reaction solution, and the organic layer was washed with water, dehydrated with anhydrous sodium sulfate, and concentrated to dryness to obtain a residue of the title compound (used in the next reaction without purification). Using).

(G) 7- ((Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-cyclopentyloxyimino)acetamide) -3-(6.7
The residue obtained from -cyhydroxy-2-methyl-1.2,3.4-tetrahydro-2-isoquinolinium)methyl-3-cephem-4-carboxylate (F) was dissolved in methylene chloride 15d and anisole 1.5- Later, under water cooling, trifluoro vinegar M
15 d was added dropwise. After stirring at the same temperature for 2 hours, the solvent was distilled off under reduced pressure. 80 d of ether was added to the residual liquid, and the precipitate was collected by filtration. This precipitate was added to 300 g of water and stirred for 30 minutes, and then insoluble matter was filtered off. The filtrate was subjected to reverse phase silica gel column chroma-1-graphy (ODS, 100m,
Separation and purification with 4% tetrahydrofuran-water) and lyophilization yielded the title compound 290 (diastereomers A, B).
A mixture of (17.4% yield from (D)) was obtained.

Melting point: 181℃ (decomposition) IR (Br): 1780, 1660, 162
0,1580,1400゜1360cm-1゜NMR (DH3O-d6+ TFA) δ: 1.75 (
4ft, brs).

2.1 (4H, brs), 3.0 (3H, brs)
, 2.9-4.8 (1011, m) , 5.4
(111, d, J-511z).

5.95 (111, dd, J-5 and 811Z),
6.4 (IH.

brs), 6.65 (111,s), 7.1
7(111,s) Example 4 7-((z)-
2-(2-aminothiazol-4-yl)-2-(1-
Carboxy-1-cyclobutoxyimino)acetamide)-3-(6,7-cyhydroxy-2-methyl-1,2
, 3,4-detrahydro-2-isoquinolinium)methyl-3-cephem-4-carboxylate was obtained.

Melting point: 182℃ (decomposition) IR (KBr): 1780, 1670, 162
0,1530,1390°1350,1280cm-1
°N) IR (0830-d6) δ: t, 90 (21-1
, m), 2.4 (4It, m), 2.95 (
311,brs), 3.3~5.2(1011
, m), 5.25 (111, d, J=51
1z), 5.8 (E, dd, J= 5 and allz
), 6.55 (111, brs) 6.65 (ill
, s) , 6.8(Ill, s) , 9.
7 (111, d, J-8112) Effects of the Invention The compounds of the present invention are effective against Gram-negative bacteria, particularly non-glucose-fermenting Synodmonas aeruginosa, Acinetobacter.
It is effective against Calcoaceticus and has a broad antibacterial spectrum.

Therefore, it is expected to be a therapeutic agent for these bacterial infections.

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R^1 is a cyclic lower alkyl group which may be substituted with a carboxyl group, R^2, R ^3 and R^4
may be the same or different and each represents a hydrogen atom, a hydroxyl group, a methoxy group, or an acetoxy group), a salt thereof, or a physiologically hydrolyzable ester thereof. 2. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, R^5 is a hydrogen atom or an amino protecting group, R^6 is a hydrogen atom or a carboxyl protecting group, and R^7 is a protected carboxyl a cyclic lower alkyl group which may be substituted with a group, X is a halogen atom or a leaving group, Y is S or S
A compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) (In the formula, R^8, R^9 and R^1^0 may be the same or different) (typically a hydrogen atom, an optionally protected hydroxyl group, a methoxy group, or an acetoxy group, and R^1^1 represents a hydrogen atom or a methyl group) to form a compound of the general formula ▲ mathematical formula, chemical formula, There are tables etc.▼(IV) (In the formula R^5, R^6, R^7, R^8, R^9, R^
1^0, R^1^1 and Y have the above meanings, X^■
represents an anion), which is methylated and/or reduced as necessary, and then the protective group is removed. There are general formulas, mathematical formulas, chemical formulas, tables, etc. ▼(I) (In the formula, R^1 is a cyclic lower alkyl group which may be substituted with a carboxyl group, R^2, R^3 and R^4
may be the same or different and each represents a hydrogen atom, a hydroxyl group, a methoxy group, or an acetoxy group), a salt thereof, or a method for producing a physiologically hydrolyzable ester thereof. 3. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (V) (In the formula, R^6 is a hydrogen atom or a carboxyl protecting group, R^
8, R^9 and R^1^1 may be the same or different,
A compound represented by a hydrogen atom, an optionally protected hydroxyl group, a methoxy group or an acetoxy group, a salt thereof or a silyl compound thereof, respectively, is represented by the general formula ▲ mathematical formula, chemical formula, table, etc. ▼(VI) (In the formula, R^5 is a hydrogen atom or an amino protecting group, and R^7 is a cyclic lower alkyl group optionally substituted with a protected carboxyl group.) Reaction of a carboxylic acid represented by the following formula: Acylated with a sexual derivative, the general formula ▲ has mathematical formulas, chemical formulas, tables, etc. ▼ (VI) (In the formula, R^5, R^6, R^7, R^8, R^9, R^
There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (I) (formula In the middle, R^1 is a cyclic lower alkyl group which may be substituted with a carboxyl group, R^2, R^3 and R^4
may be the same or different and each represents a hydrogen atom, a hydroxyl group, a methoxy group, or an acetoxy group), a salt thereof, or a method for producing a physiologically hydrolyzable ester thereof. 4. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R^1 is a cyclic lower alkyl group that may be substituted with a carboxyl group, R^2, R^3, and R^4
may be the same or different and each represents a hydrogen atom, a hydroxyl group, a methoxy group, or an acetoxy group), a salt thereof, or a physiologically hydrolyzable ester thereof, as an active ingredient.