JPS59108792A - 7-(alpha-aminothiazolyl-alpha-imino)acetamidocephalosporin derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R1 and R2 are H or 1-3C lower alkyl; R3 is substituted vinyl, thiazolyl, or substituted carbamoyl of formula CONH-R4 (R4 is pyridyl, quinolyl, amino, ureido or oxamoylamino); the wavy line is anti or syn bond]. EXAMPLE:(Z)-7{alpha-(2-Amino-4-thiazolyl)-alpha-[(4-hydroxy-3-pyridylc arbamoyl)-methoxyimino ]acetamido }-3-[( 1-methyl-5-tetrazolyl )thiomethyl-3-caphem-4-carboxylic acid]. USE:Antibacterial agent effective to Gram-positive and Gram-negative bacteria. PROCESS:The objective compound is prepared e.g. by reacting the iminothiazole- acetic acid derivative of formula II (R4 is protected amino) with the 7-amino- cephalosporanic acid derivative of formula III (R5 is H or carboxy-protecting group), and eliminating the protecting group of the reaction product.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel 7-(α-aminothiazolyl-α-imino)acetamidocephalosporin derivative 1, represented by the following general formula.

In the formula, R8 and R2 are lower alkyl groups having 1 to 3 carbon atoms and differing in size by the same amount as hydrogen atoms.

R3 is a substituted vinyl group, a substituted or unsubstituted thiazolyl group, or a formula -coN■■-R, (in the formula.

R4 is a substituted carbamoyl group represented by a substituted or unsubstituted pyridyl group or a quinolyl group; an amino group: a ureido group or an oxamoylamino group;

The bond with the wavy line is an anti-type or a thin-type bond.
yn ) form of combination.

each meaning.

In the explanation of the general formula -F, examples of the lower alkyl group having 1 to 3 carbon atoms include a methyl group, an ethyl group, a propyl group, and an inpropyl group. Substituents for vinyl groups include, for example, halogen atoms (chlor atom, prohiro atom, iodine atom, fluoro atom), carboxy groups, etc., and substituents for thiazolyl groups include amine groups.

As a substituent for a pyridyl group or a quinolyl group, a lower algylamino group (for example, a methylamine group, ethylamino group, a dimethylamine group, etc.), etc., a hydroxyl group, a lower alkoxy group (for example, a methquine group, 'T-toxy group, etc.) etc.).

The salt of the compound represented by the general formula m is a salt with a pharmacologically acceptable non-toxic acid or base. Suitable salts include alkali metal salts such as sodium salts and potassium salts; calcium salts.

Alkaline earth metal salts such as magnesium salts; ammonium salts, trimethylamine salts, triethylamine salts, cyclohexylamine salts, /cyclohexfluamine salts, /ethanolamine salts.

Organic amine salts such as arginine salts and lysine salts; Mineral acid salts such as hydrochlorides, sulfates, and phosphates: acetates.

Organic acid salts such as lactate, tartrate, fumarate, maleate and the like can be mentioned.

The compound represented by the general formula (1) has an iminoether type oxytum or 2
- has an aminothiazole group, and these compounds have geometric isomers and tautomers. The present invention is based on a thin (
It includes all compounds in the form of syn), anti-geometric isomers and tautomers.

The compound reduced tobacco salt represented by the above general formula m provided by the present invention is Cephalospora R.

It is a new compound with a heavy chemical structure in that it has an imino needle structure represented by the formula -N to O-C-R at the 7-position side chain part of the acid skeleton, and it is effective against Durham-positive bacteria and Durham-negative bacteria. It is useful as an antibacterial agent because it has excellent antibacterial effects against bacteria.

The antibacterial activity of the compounds of the present invention was demonstrated using cefmetuxime (Cefm).
The following table shows the comparison with enoxime).

Next, a typical method for producing nine target compounds of the present invention will be explained.

(In the above formula, R,, R2 and R3 have the above-mentioned meanings, and R3 of the starting compound (II) is an amine group.

Alternatively, in the case of a group having a carboxy group, the amine group or carboxy group is protected.

), R6 means a protected amino group, and R5 means a hydrogen atom or a protecting group for a carboxyne group. ) The production method shown by the above reaction formula uses an iminothiazole acetic acid derivative shown by the general formula (■) or a reactive derivative thereof at the carboxy group.

This can be carried out by reacting with a 7-amino-cephalosporanic acid derivative represented by the general formula (III), 9 and then removing the protecting group of the 7-aminocarboxylic acid group of the amine M.

Here, examples of protecting groups for amine groups include triphenylmethyl group, polmyl group, tert-butoxycarbonyl group, etc., and examples of protecting groups for carboxyne group include trimethyl-7lyl group, :/ Suhi)
Protecting groups that can be easily removed under mild conditions, such as ryl ar β-methylsulfonylethyl group, enosyl group, p-gi/ben/ru group, tert-butyl group + p-nitrobe/fur group, etc. Can be mentioned.

The reaction is usually carried out in a solvent under cooling or at room temperature. There are no particular restrictions on the solvent as long as it does not participate in the reaction, but examples include those that are commonly used.

Dioxane, tetrahydrofuran, ether.

Acetone, methyl ethyl ketone, chloroporm.

Methylene chloride, ethylene chloride, methanol, ethanol, acetonitrile, ethyl acetate, ethyl formate,
Examples include organic solvents such as dimethylformamide and dimethylsulfoxide, and water. These solvents can also be used as a mixture as appropriate.

Compound jlJl kJ: In addition to being used in the form of free carboxylic acid, it is also subjected to reaction as a reactive derivative of carboxylic acid. Suitable ones are mixed acid anhydrides, acid...logenides,
These include active esters, active amides, acid anhydrides, acid azides, and the like. When compound (11) is used in the form of a free carboxylic acid, it is preferable to use a condensing agent such as N,N'-dinochlorohexylcarbodiimide or N,N'-diethylcarbodiimide.

Depending on the type of reactive derivative of carboxylic acid used, it may be preferable to carry out the reaction in the presence of a base in order to allow the two reactions to proceed smoothly. Such bases include inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, trimethylamine,
Organic bases such as triethylamine, dimethylaniline, pyridine and the like are preferred.

Removal of the protecting group for the carboxyl group from the product thus i','r includes, for example, the benzhydryl group.

A tert-butyl group, a p-methoxypencyl group, etc. can be easily formed by contacting with an acid, and a 1-IJ methylsilyl group can be easily formed by contacting with water.

In fact, when an aralkyl group such as the above-mentioned trityl group or various acyl groups is used as a protecting group, removal of the protecting group of the amine group can be easily carried out by hydrolysis with an acid. The acid used in this case is phosphoric acid + h')
Fluoroacetic acid, hydrochloric acid, etc. are preferred.

Note that the removal of the protective group for the tunorboxy group and the removal of the protective group for the amine group can also be performed simultaneously.

The salt of the compound of the present invention represented by the general formula (1) can be prepared, for example, by using the salt of the starting compound in advance in the production method described above, or by using the free compound produced by the above production method. It can be produced by applying the salt-forming reaction used in the following.

For example, by first adding n-butanol solution of alkali 2-ethylhexanoate and then adding ethers with different solubility, ethyl acetate, etc., alkali metal salts can be prepared. ,/ethanolamine, arginine,
By adding and reacting an organic base such as lino or a basic amino acid in an equal amount to a slight excess, a salt with a child base or an amino acid surrounding the base can be produced, and by adding aqueous ammonia, an ammonium salt can be produced.

Isolation and purification of the compound (1) of the present invention and its salts are carried out according to the conventional method, which includes extraction with an organic solvent, crystallization, and separation and purification by column chromatography.

Antibacterial agents containing a compound represented by the general formula (Il) or a salt thereof as a main component can be prepared by any conventional method using any conventional pharmaceutical carrier or excipient. It may be administered orally as a tablet, capsule, or granule, or parenterally as an injection such as static pressure or intramuscular injection, or a suppository.The dosage depends on the symptoms and the age of the recipient. The dose is determined as appropriate depending on the individual/r, taking into consideration gender, etc., but the usual dosage is 250 to 3000 mg per day for adults.

Divide this into 2 to 4 times a day.

To further explain the present invention, the general formula fl
) Examples are given for the compounds in the table below that are included in the following. Note that the raw material compounds of the present invention represented by general formulas (11,) and (1,11) are new substances.

Its manufacturing method and physical properties are described in Reference Examples.

Example a) (Z)-α-(2-1-ditylamino-4-thiazolyl)-α-[(4-hydroxy-3-pyridylcarbamoyl)methoxyimino]acetic acid 1:30111 g,
7-amino-3-(1-methyl-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid benozhydryl ester 1141TIg, ]-hydroxybenozo) l) Dissolve 31 mg of azole in 2 m of DMF, Add 52 og of this 1 volume solution of KN,N-nocyclohexyl sulfonimide (Dec) and stir at room temperature for 4 hours. Add ice water to the reaction solution and extract with dichloromethane. The dichloromethano extract was washed with water, dried over anhydrous magnesium sulfate, and condensed. The residue was subjected to column chromatography, eluting first with chloroform and then with chloroform:methanol (100:2).
-7-(α-(2-1-ditylamino-4-thiazolyl)-α-[(4-hydroxy-3-pyridylcarbamoyl)methoxyimino]acetamide l-3-4(1-methyl-5-tetrazolyl)thiomethyl ]・-3-cephem-4-carponoic acid benozhydryl ester 130 m
get g.

N11) IIR (CD1j3) ■] Prefecture b) (Z)-7-1α-(2-tritylamino-4
-thiazolyl)-α-[(4-hydroquine-3-pyridylcarbamoyl)methoxyimino]acetamide 1-3
-[(1-methyl-5-tetrazolyl)thiomethyl-3
-Dissolve 1 g of Cefe 12-4-carboxylic acid benozhydryl ester in 74 ml of dichloromethane, add 0.8 ml of trifluoroacetic acid to 0.2 ml of anisole, and stir for 15 minutes. - to do.

The reaction solution is concentrated, 10 mt of π ether and 10 ml of petroleum ether are added to the residue, and the precipitated solid is filtered off and dried. 55% of this isomorph in 2 mt of chloric acid:water (1:1)
Stir for 15 minutes at ~60C. The reaction solution was concentrated, and the residue was dichloromethane), 73':15°. /, dissolves in, ,7.
=1b Add Ziac 12,7 little by little until the purple color does not disappear. After stirring for 2 hours in a 4 m room, it was condensed and the residue was subjected to column chromatography.
Elute with chloroform: nocnol: chloroform (100:10:0).
α-(2-Amino-4-thiazolyl-α-[(4-hydroxy-3-pyridylcarbamoyl)methoxyimino]acetamide-3-1: (1-methyl-5-tetrazolyl)thiomethyl-3-cephem-11-carphono Obtain 30n1g of acid benohydryl ester. Boil this with 72ml of dichloromethane and add 0.0ml of anisole under ice-cooling.
1 ml) Add 0.5 ml of refluoroacetic acid and stir for 15 minutes. Concentrate the reaction solution, add 10mt of ether,
One portion of the resulting precipitate was taken, and (Z)-7-1α-(2-amine-11-thiazolyl)-α-[(4-hydroxy-3
-pyridylcarbamoyl)nodoxiimino]acetamide 1-3-[(1-methyl-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid powder 14.81
11 g was obtained.

h]3 4.72 (2H, Nz')0
-CI(2-Co-...5.13(LH,p) 0ゝPrefecture m-go(6,35(1B, )6.86
(1″′・H2J91−) Note that two examples 1 a)
The raw material compound used in (Z)-α-(2-1-lytylamino-4-thiazolyl)-α-[(4-hydroxy-3-pyridylcarbamoyl)methoxyimino]acetic acid was obtained by the method of 2nd Reference Example 1. Manufactured by.

Reference example 1 (1) 5 g of io-1 acetic acid and 30 ml of dichloromethane
Add 752 g of jinenyldiazomec little by little, and stir at room temperature for 2 hours. The reaction solution was condensed, and the residue was subjected to column chromatography and eluted with n-hexano:benose 7 (]:1) to obtain 55 g of benohydryl iodoacetic acid ester.

NMR (CDCI,) δ (ppm); 3.71 (2H, I (Jj, , Co
-)6.82 (if(, -CI-1962)Monday(ii) (z)-α-(2-tritylamino-4-
thiazolyl)-α-hydroxyiminoacetic acid ethyl ester 6.92g, iodoacetic acid benozhydryl ester 55g
g, put 26g of potassium carbonate into 30mZ of acetonate, 40-50t? Stir for 5 hours. Pass through the reaction solution to remove insoluble matter, and concentrate the solution f.

After dissolving the residue in chloroform and washing with water, the chloroform layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to column chromatography, eluting with lt first benocetone, and then eluting with benose 7:ethyl acetate (20:1) at 1°C to give (Z)-α-(2-IJ thylamino-4-thiazolyl)- 45 g of α-(diphenylmethoxycarbonylmethoxyimino)acetic acid ethyl ester are obtained.

NMR (CDCI3) δ (ppm): 1.28 (3H, CH2CH-
z )4.33 (2H, -CI-]2CH3)4
．． 82 (2H,N-0-CH2Co-)6.92
(LH, -CH962) (ilD (Z)-α-(2-tritylamino-4-
thiazolyl)-α-(diphenylmethoxycarbonylmethoxyimino)acetic acid ethyl ester (45g) in dichloro7
Melt 2730mlK, cool at -20rK, add 2ml anisole. ) Add 8 ml of refluoroacetic acid. The reaction solution -
After stirring for 30 minutes with 10-OC, it was concentrated under water cooling, and the syrupy residue was mixed with 10 ml of ether and 200 ml of petroleum ether.
Wash with a mixture of 1 liter and subject the resulting candy-like substance to column chromatography.

Elution with chloroform:methanol (100:5) yielded (Z)-(21-ritylamino-4-thiazolyl)(
ethoxycarbonyl)methylenoaminooxy)acetic acid1.
Obtain 3g.

NMR (CDCI3) δ (ppm); 1.33 (3H, -CH2CH3)4
．． 34 (2H, CH2CH3)! (Dan (iV) CZ) -(2-Tritylamino-4-thiacyl)(ethoxycarbonyl)methylenoamino-oxyacetic acid 7601T1g, 3-amino-4-hydroxyviridi/326n1g, 1-hydroxybenozotriazole 200111g in dimethyl Formamide (DMF) 3
Dissolve mlK and add 334 n'g of K DCC under ice-cooling.

After stirring the reaction solution at room temperature for 2 days, ice water was added.

Extract with dichloromethane, dry the dichloromethane solution over anhydrous magnesium sulfate, and concentrate.

The residue was subjected to column chromatography, first eluted with chloroform, then sequentially chloroform:methanol (100
:]), chloroform:methanol (100:2)
Elute with (Z)-α-(2-dolythylamino-4-thiazolyl)-α-[(4-hydroxy-3-pyridylcarbamoyl)methoxyimino]acetic acid ethyl ester/+
Obtain 80n1g.

NMR (DMSO-tio) δ (ppm); 1.34 (3H, CH2CH3
)4.43 (2H, -CH2CH3)dandanOH ()(Z)-α-(2-1-ritylamino-4-thiazolyl-α-[(4-hydroxy-3-pyridylcarbamoyl)methoxyimino]acetic acid ethyl ester 60711
A solution prepared by dissolving 1 g of potassium hydroxide in 7 mtK of methanol is added with a solution of 112,111 g of potassium hydroxide dissolved in 2 ml of water, and stirred on an oil bath at 70 to 80 C for 1 hour and 50 minutes.

The reaction solution is concentrated, and the residue is dissolved in chloroform, washed with dilute hydrochloric acid and then with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was washed with ether and dried to give (Z)-α-
(2-tritylamino-4-thiazolyl)-α-[(4
170 mg of -hydroxy-3-pyridylcarbamoyl)methoxyimino]acetic acid are obtained.

NM, R(DMSOd6) and Example 2 a) (Z)-α-(2-tritylamino-4-thiazolyl)-α, -El-(4-hydroxy-3-pyridylcarbamoyl)-1-methylethoxy [imino]acetic acid and 7-amino-3-(1-methyl-5-tetrazolyl)
The procedure was repeated in the same manner as in Example 1 a) using thiomethyl-3-cephem-4-carphonoic acid benozhydryl ester as the antiphase.
thiazolyl)-α-[1-(4-hydroquino-3-pyridylcarbamoyl) l-methylethoxyimino]acetamide)-3-1: (1-methyl-5-tetrazolyl)thiomethyl]-3-cephemu 4-carboxylic acid Benzhydryl ester was obtained.

NMR (DMSOd6) Akira.

b) The compound obtained in Example 2 a) above was added to Example 1.
(Z)-7(α-(2-amino-4-thiazolyl)-α-El-(4-hydroxy-
A powder of 3-pyridylcarbamoyl)-1-methylethoxyiminoacetamide)-3-[(J-methyl-5-tetrazolyl)≠omethyl]-3-cephemu-4-carboxylic acid was obtained.

NMR (DMSO-d6) This is the raw material compound used in Example 2 a).
Z)-α-(2-tritylamino-4-thiazolyl)-
α-[]-(]4-Hydroxy-3-pyridylcarbamoyl-1-methylelky/imino]acetic acid was produced by the method of Reference Example 2 below.

Reference example 2 (i) (Z)-α-(2-1-ditylamino-4-
thiazolyl)-α-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetic acid ethyl ester 5
Dissolve g in dichlor 7271.0ml1K, anisole 5
ml of trifluoroacetic acid under ice-cooling], 5
Add rnl and stir for ] hours at room temperature. Concentrate the warped liquid under water cooling, and add 20 ml of ether and 2 ml of petroleum ether to the residue.
Add 0 ml and solidify. The solidified material is filtered and dried. This was subjected to column chromatography,
Elute with ethyl acetate, (Z)-2-C(2-1-dithylamino-4-thiazolyl)(ethquincarbonyl)
Methylene amino acid/]-2-notyl propionoic acid 2
．． Obtain 5 g.

NMR (CDCl2) δ (ppm); 1.29 (3H, -CH2CH3)
4.29 (2[-1,-CH2CH3)jp, I
((ii) (z) -2-[(2-tritylamino-
54 g of 4-thiazolyl)(ethquincarbonyl)methylenoaminooxy]-2-methyl-propio7ic acid are dissolved in 5 ml of dichloromethane, cooled to -10 UK, and 101111 g of triethylamine are added. At the same temperature, 1 ml of a dichloromethane solution containing 127 cm of oxalyl chloride was added dropwise. After dropping, the mixture was cooled with water and stirred for 30 minutes. To this solution was added 3ml/K of a methane solution prepared by dissolving 110μ of 3-amino-4-hydroxypyridine and 202μ+g of triethylamine under water cooling. After stirring the reaction solution at room temperature for 1 hour, water was added and extracted with chloroform:methanol (10:1). The extract was dried over anhydrous magnesium sulfate, made into cotton, and the residue was subjected to tunorum chromatography, first eluting with ethyl acetate and chloroform:methanol (100:5), and (Z)
-α-(2-tritylamino-4-thiazolyl)-α-
(], -(]4-Hydroxy-3-pyrinyl rubbermoyl-1-methylethoxyimino) Nishi'1 ethyl ester NMR (DMSO-d,) δ (ppm): 1.20 (3H, -CH
2 Cjj-3)4.17 (2H, -CH2CH3
)(iii) Dissolve 581 ml of potassium hydroxide in a mixture of 5 ml of methanol and 1 ml of water, then (
Z)-α-(2-tritylamino-4-thiazolyl)-
Add 330,111 g of α-[1-(4-hydroxy/-3-pyridylcal]cumoyl)-1-notylethoxyimino]acetic acid ethyl ester and let it flow for 2 hours. Add another 30+11 g of potassium hydroxide and reflux for 1 hour.

The reaction solution was concentrated, water was added, and the mixture was extracted with 2 chloroform.

The chloroporum extract was washed with water, dried (anhydrous magnesium sulfate), and the residue of concentration 1-2 was washed with a needle and dried (Z
)-α-(2-tritylamino-4-cyanolyl)-
α-[]-(]4-hydroxy-3-pyridylcarbamoyl-], -menalethoxoimino]acetic acid 240
14) mg.

NMR (DMSO-d, ) Example 3 a) (Z)--α-(tritylamino-4-thiazolyl-α-C(4-hydroxy-3-quinolylcarbamoyl)methocinoimino) with vinegar and 7-amino- 3-(1
-Methyl-5-tetrazolythiomethyl-3-cephem-4-carboxylic acid Hen's hydryl ester was used as the raw material, and the same procedure as in Example 1 a) was carried out at °C., (Z) -7-
1:α-(2-tritylamino-4-thiazoIJJS)-α-[(4-hydroxy-3-quinolinylcal]cumoylmethokifimino]acetamido]-C(1-methyl-5-tetrazolyl)thiomethyl ]-3-Cephem-
A 4-carboxylic acid ester was obtained.

NMR (CDCl2) 1)) 6,80 (], I(, -CH 02 )
The compound obtained in Example 3 a) above was combined with Example 1 b)
(Z)-7-1:α-(2-amino-
4-thiazolyl)-α-[(4-hydroquine-3-quinolinylcarbamoyl)methoxyimino]acetamide-
A powder of 3-['(1-methyl-5-tetrazolyl)thiomethyl]-3-cephemu-4-carboxylic acid was obtained.

NMR (DMSOd6) Tsune・ Note that the raw material compound used in Example 3 a).

(Z)-α-(tritylamino-4-thiazolyl)-α
-[(4-hydroxy-3-quinolylcarbamoyl)methoxyimino]acetic acid was produced by the method of Reference Example 3 below.

Reference Example 3 i) (Z)-(2-1Ritylamino-4-thiazolyl)(ethoxycarbonyl)methylenoaminooxyacetic acid 900TI 1g and 1-hydroxy-benozotriazole 236n1g were dissolved in DMF 5m/, and the solution K DCC394'' g and stirred at room temperature for 30 minutes.

]-Hydroxybe/citriazo-
After adding 236 mg of K and 1 g of DCC and stirring for 30 minutes, 344111 g of 3-amino-4-hydroxyginori/hydrochloride and 176 n1 g of triethylamino were added and stirred at room temperature for 2 hours and 1 hour.

Sieve off the insoluble matter from the reaction solution, and pour the solution into ice water.

Extract with chloroform. Wash the chloroform extract with water,
Dry (anhydrous magnesium sulfate/lamb) 2a shrink.

The residue was subjected to column chromatography, first eluting with benzene:ethyl acetate (10:1) and then with benzene:ethyl acetate (1:1) at °C.
-1-lytylamino-4-thiazolyl)-α-[(4-
0.8 g of hydroxy-3-quinolinylcarbamoyl)methoxyimino]acetic acid ethyl ester is obtained.

NMR (DMSO-do) δ (ppm); 1.1.5 (3H, -CH2CH
3) 4.1.0 (2H, CH2CH3) 472 (2
To H9N. -6H2oo-)6.98 (LH・-
H is) q 2) ii) (Z)-α-(2-1-
lytylamino-1-thiazolyl)-α-[(4-hydroxy/-;3-quinolylcarbamoyl)methoxyimino]
08 g of acetic acid ethyl ester and 6 ml of methanol
Suspend in 74 ml of 4-dioxa. Aqueous solution 3 in which 162,111 g of potassium hydroxide was dissolved in this solution
After adding ml, the solution is stirred at 70-80 C for 1 hour.

Concentrate the reaction solution, add dilute hydrochloric acid to the residue, and chloroform:
Extract with methanol (10:1).

The extract was dried over anhydrous magnesium sulfate and condensed. The residue was dissolved in 2 m of chloroform, 10 m of ether was added, and the precipitate was collected using PI3.

(2) -α-(tritylamino-4-thiazolyl)-α
0.52 g of -[(4-hydroxy-3-quinolylcarbamoyl)methoxyimino]acetic acid is obtained.

NMR (DMSO-a, ) Example 4 a) (Z)-α-(2-tritylamino-4-thiazolyl)-α-(semi-rubatide 530 n1 g of 1-hydroxybenozo 3.321 ng of triazole was dissolved in DMF4mtK, dichloromethano6mZ was added to this solution, and then DCC219m
g and stirred at room temperature for 30 minutes. The resulting precipitate was filtered, 3 to 4 CKi of liquid C was removed, and 7-amino-3-(1-methyl-5-tetrazolyl)thiomethyl-
Add 480 mg of 3-cephem-4-carboxylic acid be/zhydryl ester. The reaction solution was stirred for 2 hours under water cooling, poured into ice water, and extracted with chloroform. The chloroform extract was washed with water, dried over anhydrous magnesium sulfate,
Concentrate.

The residue was subjected to column chromatography, first eluted with chloroform and then sequentially chloroform:methanol (100:
2), chloroform:methanol (100:3)
, chloroform:methanol (100:4), chloroform:methanol (100:6), (Z
)-7-4α-(2-tritylamino-4-thiazolyl)-α-(semi-rubatide-ruponylmethoxyimino)
acetamido]-3-[(1-methyl-5-tetrazolyl)thiomethyl]-3-cephemu 4-carbo7 acid base/
720 ml of hydryl ester was obtained.

NM, R(DMSO-do) Crystal 3 6.80, 6.84 (each [4゜y month H) I 11 b) (Z) -7-[α obtained in Example 4 a) above
-(2-tritylamino-4-theanolyl)-α-(semicarbatidecarbonylmethoxyimino)acetamide 1-3-[(J,-methyl-5-tetrazolyl)thiomethyl] = 3-cephemu 4-carboxylic acid benoz 700,111 g of hydryl ester was dissolved in 5 ml of dichloromethane, 0.8 ml of anisole was added while cooling with water, and 3 ml of trifluoric acid M was added at °C, followed by stirring for 30 minutes.

The reaction solution was concentrated, and 30 ml of ether was added to the residue to solidify it. The solid material is filtered once and dried.

Dissolve this in 6 ml of trifluoroacetic acid (F) under water cooling, and add 2.5 ml of water to the solution.
After stirring at ~22 U for 1 hour and 10 minutes, concentrate. 5 m of ethanol and 10 m of ether were added to the residue, the resulting precipitate was filtered, and (Z)-7-[α-(2-amine-4-
thiazolyl)-α-(semi-rubatide-rubonylmethoxyimino)acetamide l]-3-4(1-methyl-5
-Tetrazolyl)thiomethylio3-cephem-4-carboxylic acid powder 290"g are obtained.

NMR (DMSOda) 4.56 (2[(-N to.CH2C0)■■ ~ Note that this is the raw material compound used in Example 4 a)
(Z)-α-(2-tritylamino-4-thiazolyl)
-α-(semi-rubatide-luponylmethoxyimino)acetic acid was produced by the method of Reference Example 4 below.

i) (z)-(2-tritylamine-4-thiazolyl)(ethoxycarbonyl)methylenoaminooxyacetic acid], 03 g, 1-hydroxybenzotriazole 5
40 mg, was dissolved in DMF8m7, and this solution K DC
After adding C990n, stir at room temperature for 1 hour. The precipitated insoluble matter was filtered once, and 808 l11 g of lX'I'olK triethylamine and 221 g of semicarbatite hydrochloride were obtained.
, mg and 2 mt of water are added and stirred at room temperature for 18 hours. Pour the reaction solution into ice water and extract with chloroporm. The extract is washed with brine, dried (anhydrous magnesium sulfate), and condensed. The residue was subjected to column chromatography, first eluting with chloroform, then chloroform:methanol (100:5) at °C to give (Z)-α-(2-tritylamino-4-thiazolyl)-α. -(sicirbatidecarponylmethoxyimino)acetic acid ethyl ester 580
I got ■.

NMR (CDCl2) δ (pPm); 1.32 (3H, -CH2CQ
3)4.36 (2H, CI(2CH:1
)4・74(2■”・ゝ～o-CH2oo-)i
i) (z)-α-(2-1-lythylamino-4-thiazoryl)-α-(semirubatidecarbonylmethoxyimino)ilIi'l: acid ethyl ester 570111
Dissolve g in 7 ml of methanol. To this solution, add 1 g of sulfur and lithium hydroxide to 7 ml of methanol and 0 ml of water.
．． After adding the dissolved solution to the mixture with 5 ml, 45 ~
Stir on a 50 C oil bath for 2 hours. After adding 10 ml of reaction liquid pressure ether to the resulting precipitate, it was filtered once.

The precipitate was dissolved in 20 ml of water, adjusted to pi-11-2 with IN-hydrochloric acid solution, and diluted with chloroform:methanol (]0
: Extract at 1°. The extract was dried over anhydrous magnesium sulfate and concentrated to give (Z)-α-(2-tritylamino-4
0.38 g of -thiazolyl)-α-(semical)butidecarbonylmethoxyimino)acetic acid was obtained.

NMR (DMSO-do) δ (ppm): 450 (2H,L,.cat2co
)6.82 (IH,1N2z) HN μM Example 5 a) (Z)-α-(2-tritylamino-4-thiazolyl)-α-(tert-b).・Xiimino)acetic acid 0.56g.

1-hydroxybenzotriazole 1.25 rng 1
゜4- Dioxa 710ml1K dissolved, DCC20
Add 9111 g and stir at room temperature for 1 hour. The precipitated insoluble matter is filtered, the P solution is cooled to 3 to 40, and the δj solution is added to the 7)
-amino-3-(1-methyl-5-tetrazolyl)
Thiomethyl-3-cephe1. -4-Carboxylic acid benozhydryl ester 4591TIg is added. The reaction solution was stirred at room temperature for 2 hours and 30 minutes, and then concentrated.

The residue was subjected to column chromatography. First, benzene was eluted, followed by benoceno:ethyl acetate (100
: 5), benzene:ethyl acetate (100:IO)
, benzeno:ethyl acetate (1,00: 1.5)
.

Benzene: *[i Elute with ethyl (1:1).

(Z) -7-[α-(2-tritylamino-4-thiazolyl)-α-(tert-butquinecarbonylhydrazinocarponylmethoxyimino)acetamide']-3
-((1-methyl-5-tetrazolyl)thiomethyldi-
400 ml of 3-cephem-4-carboxylic acid benozhydryl ester was obtained.

NMR (DMSO-a,, ) constant b) (z)-7-Cα-(2-tritylamino-4-thiazolyl)-α-(tert-butoxy7carbonylhydrazinocarbonylmethoxyimide/)acetamide]-3
-C(1-methyl-5-tetrazolyl)thiomethyl]-
40011 tg of 3-cephemu 4-carbo/acid benozhydryl ester was dissolved in 0.75 ml K of anisole, and after adding 5 ml of trifluoroacetic acid at -20C, the solution was stirred for 20 minutes under water cooling, and then 18-20 C
After stirring for 20 minutes, concentrate.

Add 30 ml of ether to the residue to solidify it.

The solid material is filtered once and dried. Dissolve this solid in 5 ml of trifluoroacetic acid under water cooling, and add 1 ml of water to the solution.
．． Add 5 ml. The solution is stirred at 20-22C for 1 hour and then concentrated. Add 0.5 ml of ethanol to the residue
, 10 ml of ether was added and the resulting precipitate was filtered,
Dry to give (Z) -7-Cα-(2-amino-4-thiazolyl)-α-(hydrazinocarbonylmethoxyimino)acetamide]-3-C(1-methyl-5-tetrazolyl)thiomethyl]-3- 400" g of cephemu 4-carboxyl trifluoroacetate powder is obtained.

NMR (DMSOdo) 3.93 (7 for 3H,I) Crystal 3 467 (2s' ・N~o-cH,,co-) However, the above Example 5 a) used (・ta(Z)- α−(2
-tritylamino-4-thiazolyl)-α-(tert
-Butoxycarbonylhydrazinocarbonylmethokifimino)acetic acid was produced by the method of Reference Example 5 below.

Reference Example 5 +) (z) -(2-)Ritylamino-4-thiryozolyl)(ethoxycarbonyl)methylenoaminooxyacetic acid and tert-butoxycarbonylhydrazine were treated in the same manner as in Reference Example 41) as raw materials to obtain ( Z) −α−(
2-tritylamino-4-thiazole 1)-α-(t
Ethyl acetate was obtained.

NMR (DMSO-do) δ (ppm); 1.12 (3H, -ch1□C
l-13) 4.01 (2H, CH2CH3) 4.52 (2H, N, o-c,, c) 6.95 (
IH, -J7'4) IH and... 11) The compound obtained in Reference Example 51) was treated in the same manner as in Reference Example 411) to obtain (Z)-α-(2-1-dithylamino-4-thiazolyl). )-α-(tert-butoxycarbonylhyFlannocarponylmethoxyimino)acetic acid was obtained.

7 -amino-3-(
In the same manner as in Example 5a) using 1-methyl-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid henohydryl ester as a raw material, (Z)-7-(
α-(2-tritylamino-4-thiazolyl)-α-[
(2oxamoylhydrazino)carbonylnodoximino]acetamide)-3-[(1-methyl-5-tetrazolyl)thiomethyl2-3-cephem-4-carbonylbenozhydryl ester was obtained.

NMR (DMSO-d6) constant 1 μ Tj I (b) The compound obtained in Example 6 a) above was carried out in 911
4 b) to obtain (Z)-7-(α-(2-
Amino-4-thiazolyl)-α-[(2-oxamoylhydrazino)carbonylmethoxyimino5-tetrazolyl)thiomethyl]-3-cephem-4-
A carboxylic acid powder was obtained.

NMR (DMSO-d6) Constant - (Z)-α-(2-tritylamino-4-thiazolyl)-α-[(2-oxamoylhydrazino)carbonylnodoquinimino] used in Example 6 a) Acetic acid was produced by the method of Reference Example 6 below.

Reference Example 6 1) Proceed in the same manner as Reference Example 4 i) using Ogisami and Kuhydranod. (Z)-α-(2-1-ditylamino-4
-thiazolyl)-α-[(2-oxamoylhydrazino)carbonylmethoxyimino]ethyl acetate was obtained.

NMR(DMSOdo) δ(ppm);]13(3H,-CH,,CI(3
)3.99 (2H,-CH2CH3)J]''1 11) Reference Example 61) The compound obtained in Reference Example 411)
In the same manner as above, (Z)-α-(2-tritylamino-4-thiazolyl)-α-[(2-oxamoylhydrazino)carbonylmethoxyimino]butyric acid was obtained.

NMR (DMSOd6) + (T (Example 7 a) (Zl-α-<2-1-ricalamino-4-
thiazolyl)-α-[(2-bromo-2-propenyl)
Oximino]acetic acid and 7-amino-3-(1-methyl-
5-7”l-razolyl)thiomethyl-3-cephem-4
- Carboxylic acid benzhydryl ester was used as a raw material in the same manner as in Example 5 a), and (ZL-7-1α-(2
-tritylamino-4-thiazolyl)-α-[(2-bromo-2-flobenyl)oquinimino]acetamide 1
-3-[(1-methyl-5-tetrazolyl)thiomethylcou-3-cephembene-carboxylic acid benzhydryl ester was obtained.

b) The compound obtained in Example 7 a) was treated in the same manner as in Example 4 b) to obtain (Z)-7-1α-(2-
amino-4-thiazolyl)-α-[(2-bromo-2-
propenyl)oxinimino]acetamide)-3-[(
A powder of 1-methyl-5-tetrazolyl)thiomethyl]-3-cephemu-4-carboxylic acid was obtained.

NMR (DMSO-d6) Note that tz, which is the raw material compound used in Example 7 a),
+-α-(2-tritylamino-4-thiazolyl)-α
-[(2-Bromo-2-propenyl)oxyimino]acetic acid was produced by the method of Reference Example 7 below.

Reference Example 7 1) (Z)-α-(2-trinalamino-4-thiazolyl)-α-(hydroxyimino)acetic acid ethyl ester.
Dissolve 2.4 g of hydrochloride in 8 ml of DMSO.

To this solution was added 19 g of 1,2,3-)ribromopropane.

Add 166 g of potassium carbonate and stir at room temperature for 2 days.

The reaction solution was poured into ice water, and the precipitated solid matter was filtered off.

After washing with water, this solid was dissolved in chloroform and subjected to column chromatography, eluted with chloroform, and (Z
)-α-(2-tritylamino-4-theagryl)-α
-0.61 g of ethyl [(2-bromo-2-flobenyl)oximino]acetate is obtained.

NMR (DB, 4S 0-d6) δ (ppm): 1.13 (3H, -CH2CH,
>4.00 (2H, -CH,,CH3)11) (Zl-α-(2-tritylamino-
Dissolve 05 g of ethyl 4-thiazolyl)-α-[(2-bromo-2-propenyl)oxyimino)[ in 4 ml of 1,4-dioxane. (Hydroxylate in this solution) IJ
Add 0.5 ml of an aqueous solution containing 50 μm of
Stir at 0-80"C for 1 hour. Add 0.5 ml of an aqueous solution containing 50,111 g of sodium hydroxide to the reaction solution, and stir further at 700-8°C for 1 hour and 305 minutes. Concentrate the reaction solution. , add ice water and chloroform to the leftovers,
Prepare pr-i1-2 with IN-hydrochloric acid solution. The chloroform layer was separated, washed with water, dried over anhydrous magnesium sulfate, and condensed to give (Z)-α-(2-tritylamino-1
04 g of 1-thiazolyl)-α-[(2-bromo-2-propenyl)oximino]acetic acid is obtained.

NMR (DMSO-d6) HJ (Prefecture and Example 8a) (Z)-α-(2-tritylamino-4-thiazolyl)-α-[(2-tert-butoxycarbonyl-2=propenyl)oximino]acetic acid and 7-amino-
3-(1-methyl-5-tetrazolyl)thiomethyl-3
-Cephem-4-carboxylic acid henzhydryl ester
was carried out in the same manner as in Example 5a) using Zl-7- as the raw material.
(α-(2-1-cutylamino-4-thiazolyl-α-
[(2-tert-phthoxycarbonyl-2-propenyl)oginimino]acetamide)-3-[(1-methyl-5-tetrazolyl)thiomethyl]-3-cephemu 4-carboxylic acid benzhydryl ester was obtained.

NMR (DMSO-d6) Wataru H3 3.86 (3H/SN lecture) CH3 and 5.16 (11 (, 0fJ7) 1, N゛～',), 76 (IH,. Masu) 6.74 ( LH,, □, ri t) 6.84 (IH-CHφ2) b) The compound obtained in Example 8 a) above was treated in the same manner as in Example 5b) to obtain (Z)-7-+α-( 2-amino-4-thiazolyl)-α-[(2-carboxy-2-
propenyl)oximino]acetamide 1-3-[(
A powder of 1-methyl-5-tetrazolyl)thiomethyl]-3-cephemu-4-carboxylic acid was obtained.

NMR (DMSO-dQ) 2π δ (ppm); 368 (2H, ~) 4.76
(2I(,u0CH2-C=) ~ [几5.78 (IH,,.o) Note that the raw material compound used in Example 8 a) (Z+
-α-(2-tritylamino-4-thiazo1-nor)-α
-C (2tert -)
Bonyl-2-propenyl)oxy/imi/]acetic acid was produced by the method of reference fl18 below.

Reference Example 8 1)ㅅ)-α-(2-tritylamino-4-thiazolyl)-α-hydroxyiminoacetic acid bebenhydryl ester], l, 9g, 2-bromomethyl-acrylic acid tert
-Add 442 mg of butyl ester and 332 ml of potassium carbonate to 7 ml of acetone. After stirring this solution at room temperature for 2 hours, 2-bromomethylacrylic acid tert-j
Tyl ester 500111g.

Add 4001T1 g of potassium carbonate and stir at room temperature for 16 hours. Insoluble matter from the reaction solution was filtered, the P solution was concentrated, and the residue was subjected to column chromatography.

First benzene, then benzene:ethyl acetate (10
0:2), benzene:ethyl acetate (100:4), (Z)-α-(2-tritylamino-4-thiazolyl)-α-(: (2-tert-butoxycarbonyl-
10 g of 2-propenyl)oxyimino]acetic acid benzhydryl ester are obtained.

NMR (DMSO-d.) Sieve 3 NC- 6,66 (IH, -HN sieve A, ) 6.81
(LH-CHφ2) 11) tz+-α-(2-tritylamino-4-thiazolyl)-α-C(2tert-butoxycarbonyl-2
-Propenyl)oxy/imino]acetic acid benzhydryl ester 1.0 g Tibutaromethane 6mZ), cooled to -40°C, anisole 05mt,
Then add 4 ml of l.lifluoroacetic acid. This solution was stirred at -15°C to -10°C for 15 minutes, concentrated under water cooling, and the residue was dissolved in 8 ml of dichloromethane and heated at -40°C.
After adding 3mZ of triethylamine and 1.1g of ) liphenylchloromethane to this solution,
Stir for 5 minutes. Concentrate the reaction solution, dissolve the residue in chloroform, add the chloroform solution to water, IN-hydrochloric acid solution,
After sequentially washing with water, drying with anhydrous magnesium sulfate.
Concentrate. The residue was subjected to column chromatography.

First, it was eluted with chloroform, then with chloroform:methanol (100:5), and (Z)-α-(2-
tritylamino-4-thiazolyl)-α-[(2-te
560 mg of rt-butoxycarbonyl-2-propenyl)oximino]acetic acid are obtained.

δ(ppm); ]43<9Iq, -cc
)October 3 1 100d IH Example 9 a) (2)) -α-(2-Tritylamino-4-thiazolyl)-α-[I (2-1-cutylamino-4-thiazolyl) 500 mg of methoxyimino]acetic acid was suspended in 6 ml of mono/chloromethane and cooled to 3°-4°C.

Add 1 g of phosphorus pentachloride 133II and stir at 3° to 4° C. for 15 minutes. -force, 7-amino-3-(1-methyl-5-
Tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl Nisder 3161T (1 g) was dissolved in 6 ml of dichloromethane, cooled to -35°C, and 500 mg of pynodine was added to the solution. drip.

After the dropwise addition, the mixture was stirred at -20° to -30°C for 15 minutes, then 20 mt of ice water was added to the reaction solution, and the pH was adjusted to 1 with IN hydrochloric acid solution.
~2 and separate the dichloromethane layer.

The dichloromethane layer was washed with water, dried (anhydrous magnesium sulfate), concentrated, and the residue was subjected to column chromatography, first eluting with benzene.

Next, elute with benzene:ethyl acetate (5:]).

(Z+-7-(α-(2-1-cutylamino-4-thiazolyl)-α-IC2-tritylamino-4-thiazolyl)methoxyimino]acetamide)-3-1: (1-
Methyl-5-tetrazolyl)thiomethyl]-3-cephem-;4-carboxylic acid benzhydryl ester 51.0
11g is obtained.

NMR (DMSO-d,) Dan 5.14 (IH,.) And 5.78 (both IH and 6) 6.38.6.70 (each LH.

H b) fZl-7-(α-(2-tritylamino-4
-thiazolyl)-α-[(2-+-ritylamino-4-
thiazolyl)methoxyimino]acetamide+-3-1
:(1-methyl-5-tetrazolyl)thiomethyl]-3
-Cephem~4-carboxylic acid benzhydryl ester 5
Dissolve 10 Ing'q in 4 mt of dichloromethane, add 0.5 ml of anin')' and 4 ml of trifluoroacetic acid under water cooling, and stir for 20 minutes. Concentrate the reaction solution, add 30 ml of ether, and solidify. This solid was filtered once, dried, and then diluted with trifluoroacetic acid under water cooling.
ml and 3 ml of water. Add. Add this solution for 20~
After stirring at 23°C for 1 hour, the mixture was condensed, the residue was dissolved in 0.4 ml of ethanol, ether was added, and the resulting precipitate was filtered.

Wash with ether, dry and (z)-1α-(2-amino-
4-thiazolyl)-α-[(2-amino-4-thiazolyl)methoxyimino]acetamide 1-3-'Ccx-
200 mg of powder of methyl-5-tetrazo1-nor)thiomethylio-3-cephem-4-carboxylic acid is obtained.

NMR (DMSO-de) 5.12 (], H,. pheasant) 5.78 (LH・.亙) 6.74.6.81 (each IH.

Note that the raw material compound used in Example 9 a) (Z
l-α-(2-1-limethylminor 4-thiazol)
-α-((2-)lytylamino-4-thiazolyl)methquinimino]acetic acid was produced by the method of Reference Example 9 below.

Dissolve 25 g of H1,3-dichloro-2-propanone in 300 mZ of ethanol, add 14.95 g of thiourea,
Stir at room temperature for 2 hours. Concentrate the reaction solution.

Dissolve w4 in 300 ml of dichloromethane and explode. To this solution was added 398 g of triethylamine while cooling with water using chlortriphenylmethane, and the mixture was stirred at room temperature for 16 hours. Add ice water to the reaction solution.

The chloromethane layer was separated, dried over anhydrous magnesium sulfate, condensed, and the residue was subjected to column chromatography, first eluting with benzene, then benzene:ethyl acetate (
10:1) to obtain 15 g of 4-chloromethyl-2-tritylamino-thiazole.

NMR (DMS o-do) δ (ppm); 4.32 (2H, -CH
2-CI) 11) N-hydroxyphthalimide 1 1
．． 48 g is suspended in 150 ml of acetonitrile. 711 g of triethylamine is added to this suspension and dissolved.

Add 4-chloromethyl-2-tritylamino- to this solution.
Add a solution of 27.5 g of thiazole dissolved in 200 ml of dichloromethane, and stir on an oil bath at 80°C for 7 hours. Concentrate the reaction solution, dissolve the residue in ethyl acetate, wash with water, dry over anhydrous magnesium sulfate, and concentrate. The residue was subjected to column chromatography and eluted with chloroform to obtain 14.5 g of (2-tridelamino-4-thiazolyl)methoxyphthalimide.

NMR (DMSO-d,) δ("Pm)' 480 (2H, -CH,, -
)6, 68 (1.H, , Uketo CH,-)3,
5 iii) 62 g of (2-1-lytylamino-4-thiazolyl)methoxyphthalimide was dissolved in 80 g of ethanol.
ml) Kenn Shusase, Hydrazine Hydra-1-600m
Add g.

Reflux for 1 hour and 30 minutes. After the reaction solution was cooled with ice water, the precipitate was filtered off, and the P class was concentrated. Add 50n of ethyl acetate to the residue.
+l, pass through the precipitated insoluble matter and remove
Add 100 m/ml of ethanol to the residue obtained by concentrating the liquid to dissolve it. Add 478 g of 2-(2-tritylamino-4-thiazolyl)glyoxylic acid to this solution,
Additionally, 100 mt of methanol, 20 mt of chloromethane
Add 0m/:.

] Stir at room temperature for 1 hour. Concentrate this reaction solution by 1 hour,
After adding 50 mL of DMF and stirring for 30 minutes, 500 mL of chloroform and 300 mL of ice water were added.
Adjust the pH to 1-2 with IN hydrochloric acid solution. At this time, the precipitated material was allowed to pass through, soaked with water, washed with ether, and dried (Z).
-α-(2-tritylamino-4-thiazolyl)-α-
[(2-1-Ritylamino-4-thiazolyl)
57 g of methoxy/imino]acetic acid are obtained. On the other hand, the chloroform layer was washed with water, dried with anhydrous magnesium sulfate, concentrated, ether was added to the residue, and filtered through f5 to further remove the desired product.
51 g was obtained.

NMR (DMS O-d, ) δ (ppm); 474 (21(,-CH,) μy Applicant: Yamanouchi Pharmaceutical Co., Ltd. Agent Akira Sasaki -

Claims (1)

[Scope of Claims] A novel 7-(α-aminothiazolyl-α-imino)acetamidocephalosporin derivative represented by the following general formula or a salt thereof. In the formula, R1 and R2 are the same or different and represent a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms =Rslr1
．． ．． Substituted vinyl group, substituted or unsubstituted thiazolyl group, or formula -CONH-R4 (in the formula, R6 is substituted t, ζ is unsubstituted pyridyl group or ginolyl group; amino group; ureido group or oxamoylamine (means a substituted carbamoyl group). The wavy line joins the anti-shaped bone or the s
yn ) form of combination. each meaning.