FI71563B - (6R 7R) (4-HALOGEN-2 - / (Z) -METHOXIMINO / ACETAMIDO) -3 - (/ SUBST.-AS-TRIAZIN-3-YL) THIO / METHYL) -8-OXO-5-THIA-1 -AZABICYCLO / 4.2.0 / OKT-2-EN-2-CARBOXYLSYROR OR DERAS ESTRAR - Google Patents

Abstract

For the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE 1. A process for the manufacture of acyl derivatives of general formula I see diagramm : EP0030294,P12,F1 in which R represents hydrogen or a readily hydrolyzable ester group, as well as of salts of these compounds and hydrates of these compounds or of their salts by reating a halide of general formula II see diagramm : EP0030294,P12,F2 in which R has the significance given above and Y represents a halogen atom, or a salt of this compound with thiourea and, if desired, converting a compound of formula I obtained into a salt or hydrate or into a hydrate of this salt, characterized in that X signifies one of the groups see diagramm : EP0030294,P13,F3 in which R' represents hydrogen or a readily hydrolysable ether group.

Description

171563 (6R, 7R) ε-4-halo-2/7 (Z) -methoxyiminoacetamido] -3- (E) subst. (α-triazin-3-yl) thio] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.2] oct-2-ene-2-carboxylic acid and its esters 5 Separated by division of patent application 793 768 (pat. 67385)

The invention relates to (6R, 7R) - (4-halo-2 / T (Z) -methoxyimino) acetamido-3 - ((substituent-as-triazin-3-yl) thio) -10-methyl} -8-oxo- 5-thia-l-azabicyclo / ~ 4.2.07okt-2-ene-2-

carboxylic acids and their esters useful as intermediates in the preparation of therapeutically active cephalosporin derivatives of general formula II

15 H H

! YCH2— CO - C _ CONH -: - "\ ch3 ö ^ t '\ (^ _ CH2_S_X 11 20

COOR

wherein Y is a halogen atom and X is a group 25 H H7C \ H3C \ nN O 3 j or 30 (a) (b) R is a hydrogen atom or a readily hydrolysable ester or ether group and the group = N-OCH.j is in syn form, and their salts.

The novel cephalosporin derivatives 35 of the formula II can be used, for example, for the preparation of cephalosporin derivatives of the general formula 2 71563 h2nn /, s ^ s h y Π M! N - * - c — CONH —- T] II ^ 5 —CH2-5— *

OCH 2 I

COOR

Wherein X and R are as defined above and the group sN-OCH 2 is in syn form for the preparation of salts and hydrates of these compounds and for the preparation of hydrates of the salts. This process is characterized in that the cephalosporin derivative of the formula II or a salt of this compound is reacted with a thiourea and, if desired, the compound of the formula I obtained is converted into a salt or hydrate or a hydrate of the salt.

If R in group (b) is hydrogen, this group is in tautomeric equilibrium with group (a).

The readily hydrolyzed wool ester groups R of the compounds of the formula I mean the carboxyl-functional R groups in the form of a readily hydrolyzable ester group. Examples of suitable ester groups include lower alkanoyloxyalkyl, e.g. acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl; lower alkoxycarbonyloxyalkyl, e.g. methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and 1-isopropoxycarbonyloxyethyl; lactonyl residues, e.g. phthalidyl and thiophthalidyl; lower alkoxymethyl, e.g. methoxymethyl-30; and lower alkanoylaminomethyl, e.g. acetamidomethyl.

The readily hydrolysable ether groups R of the compounds of the formulas I and II mean the R groups in the enol function of the 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-a-triazin-3-yl group (b) which are easily in the form of a hydro-35 lysable ether group. Suitable ether groups are the same as those already mentioned above in connection with the 3,71563 easily hydrolyzable ester groups. Representative of such ethers are thus, for example, lower alkanoyloxyalkyl ethers, e.g. acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyether; Lower alkoxycarbonyloxyalkyl ethers, e.g. methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and 1-isopropoxycarbonyloxyethyl ether; lactonyl ethers, e.g. phthalidyl and thiophthalidyl ether; lower alkoxymethyl ethers, e.g. methoxymethyl ether? and lower alkanoylaminomethyl ethers, e.g. acetamidomethyl ether.

Examples of salts of the compounds of Formula I include alkali metal salts such as the sodium and potassium salts; ammonium salt; alkaline earth metal salts such as calcium salt; Salts with organic bases, such as salts with amines, e.g. salts with N-ethylpiperidine, procaine, dibenzylamine, N, N'-dibenzylethylethylenediamine, alkylamines or dialkylamines, as well as salts with amino acids, e.g. salts with arginine or lysine with. The salts can be mono-salts or also di-salts. The salt may be formed with the hydroxy residue of the 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group.

The compounds of formula I also form addition salts with organic or inorganic acids. Examples of such salts are hydrohalides, for example hydrochlorides, hydrobromides, hydroiodides, as well as other salts of inorganic acids, such as sulphates, nitrates, phosphates and the like, alkyl and monoaryl sulphonates, such as ethanesulphonates, toluenesulphonates, toluenesulphonates, toluenes and other organic acid salts such as acetates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like.

The compounds of formula I (including their salts, readily hydrolysable esters and ethers) can be hydrated 4,71563. Hydration may occur during the manufacturing process or may occur gradually as a result of the initially hygroscopic properties of the anhydrous product.

Preferred compounds of formula I are (6R, 7R) -5- [2- (2-amino-4-thiazolyl) -2- (Z-methoxyimino) acetamide] -3 - [[(2,5-dihydro -6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio-7-methyl-N-oxo-5-thia-1-azabicyclo [2.07] oct-2-ene-2- carboxylic acid and its salts and the corresponding hydrates.

The halogenated cephalosporin derivatives of the formula II according to the invention can be prepared, for example, by a process characterized in that the primary amine of the general formula is

H H

15 f i / K.

Η2Ν jjj X -— CH2 — S *

20 COOR

wherein X and R are as defined above, is reacted with a halogenated carboxylic acid having the general formula

II

YCH "-C-C-COOH

25 2 H

N IV

XOCH3 wherein Y is a halogen atom, or the reactivity of this compound with a derivative. The halogenated carboxylic acid of formula IV is used either in free form with a condensing agent, e.g. an N, N'-disubstituted carbodiimide such as N, N'-dicyclohexylcarbodiimide, or with an azolide compound such as N, N'-carbonylide. in the presence of imidazole or N, N'-thionyldiimidazole or also in the form of an acid halide, such as acid chloride or bromide, in the form of an acid anhydride, such as an acid anhydride, formed with a carbonic acid monoester, e.g. monomethyl or monoisopropyl carbonate, in the form of an activated ester such as p-nitro-5-phenyl ester, 2,4-dinitrophenyl ester, N-hydroxysuccinimide ester or N-hydroxyphthalimide ester. The reaction generally takes place in an inert organic solvent, e.g. a halogenated hydrocarbon such as chloroform, dichloromethane, tetrachloromethane, ether, e.g.

10 in tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, water or mixtures thereof. The reaction temperature is preferably between about -50 and + 40 ° C, most preferably between about -10 and + 10 ° C.

The halogenated cephalosporin derivatives of formula II according to the invention can also be prepared by a process characterized by halogenating a compound of general formula

H H

20 CH —co — C-CO N H - 3 II e v v

N 2 -S-X

^ OCH3

COOR

25

wherein X and R are as defined above and the group = N-OCH 3 is in syn form. The starting material of formula V used in this case can in turn be prepared by a process characterized in that the primary amine of formula III as defined above is reacted with 3-oxo-2-methoxyiminoic acid or a reactive derivative of this compound. This reaction proceeds in substantially the same manner as the acylation of the primary amine described above with the halogenated carboxylic acid of formula IV or a reactive derivative thereof. Halogenation of the resulting acylation product of formula IV results in the reaction of formula II as defined above

6 71563 and takes place mainly by treatment with the corresponding halogen or thionyl halide, e.g. chlorine, bromine or sulfuryl chloride, preferably in an inert solvent such as halogenated hydrocarbon, e.g. dichloromethane, dichloroethane, chloroethane, chloroform, dichloroethylene, dichloroethylene, dichloroethylene, in acetic acid, an aromatic solvent such as benzene or toluene. The reaction temperature is generally about 0 to 60 ° C.

The above reaction of a halide of formula II or a salt thereof with a thiourea is preferably carried out in an inert solvent such as e.g. lower alkanol, e.g. ethanol, lower ketone such as acetone, ether such as tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, water or their . The reaction temperature is generally about 0 to 60 ° C, preferably room temperature. As the halide of the formula II, chloride, bromide, fluoride or iodide can be used, preferably chloride or bromide. The free acid of formula II can be used, but alternatively also a salt thereof, in which case the same salts as the salts of the compounds of formula I described above can be used.

Salts and hydrates of the compounds of formula I or hydrates of these salts may be prepared in a known manner, e.g. by reacting a carboxylic acid of formula I with an equivalent amount of the desired base, suitably in a solvent such as water or an organic solvent such as ethanol, methanol, acetone and other solvents. When two 30 equivalents of salt are used with the base, the formation of the tautomeric enol form (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group X), if any, occurs to give the di-salt. When forming a salt, temperature is not critical. It is usually at room temperature-35, but may also be slightly higher or lower, in the range of 0-50 ° C.

7 71563

Hydrates are usually prepared automatically during the manufacturing process or as a result of the initially hygroscopic properties of the anhydrous product. To prepare the hydrate, the intentionally completely or partially anhydrous product (carboxylic acid of formula I or an ester, ether or salt thereof) may be kept in a humid atmosphere at a temperature of, for example, about 10 to 40 ° C.

The compounds of the formula I, as well as the corresponding salts or hydrates of these products, have an antibiotic, antibacterial effect. They have a broad spectrum of activity against gram-negative microorganisms, including β-lactamase-forming staphylococci and various β-lactamase-forming gram-negative bacteria, such as Pseudomonas aeruginosa, Haemophilus influenzae, Escherichia coli, Serratia marcescens, Proteus and Klebsiella species.

Example 1 37.1 g of (7R) -7-amino-3-deacetoxy-3-02,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio7-cephalosporal The nitric acid is suspended in 800 ml of ethyl acetate and 100 ml of N, O-bis- (trimethylsilyl) acetamide are added. The mixture is stirred under protection from moisture for 30 minutes at 25 ° C to give a pale yellow solution. To this solution cooled to -10 ° C, a solution of (Z) -4-bromo-2-methoxyimino-3-oxobutyric acid chloride prepared in 22 is added dropwise over 30 minutes at -10 to 0 ° C. 4 g of (Z) -4-bromo-2-methoxyimino-3-oxobutyric acid in 300 ml of non-alcoholic and anhydrous dichloromethane and 20.8 g of phosphorus pentachloride at 8-10 ° C. The reaction mixture is stirred for 30 minutes at 0-5 ° C for 30 hours and for 25 hours at 25 ° C. Add 1 L of ethyl acetate and 500 mL of water with stirring. The aqueous phase and the resinous interlayer are discarded. The organic phase is washed six times with 500 ml portions of water, dried over sodium sulfate and evaporated in vacuo at 40 ° C to a volume of 200 ml. This orange concentrate is added dropwise with stirring to 1.8 liters of ether, whereupon the reaction product precipitates amorphous. This is filtered off, washed successively with one liter of ether and 1 liter of low-boiling petroleum ether and dried overnight in vacuo at 35 ° C. 37.2 g (64.4% of theory) of (6R, 7R) -7- [4-bromo-2 - [(Z) -methoxyimino) acetoacetamido] -3-? dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio-5-methyld- [8-oxo-5-thia-1-azabicyclo [4.2.07] oct-2-ene- 2-carboxylic acid as a beige, amorphous product with = -223.1 ° (c = 1 in methanol) 1 H-NMR spectrum in DMSO-d 6 (</ - values in ppm, s = singlet, d = doublet, q = quartet, b = broad, J = coupling constants in Hz; number of protons-10 in parentheses): 3.60 (N-CH 2) (s) (3), 3.63 (2-CH-)

(AB-q / centering value; Jgem = 18 Hz) (2), 4.07 3, (Z) J

(s) (3), 4.25 (3-CHO-S) (AB-q / centering value; J = 13 Hz) (2), 4.62 (Br-CH2-) (s) (2), 5 , 15 (H-6) (d, JR_6 H_? = 5 Hz) (1), 5.78 (H-7) (q = JR_7 / NH = 8 Hz, JH_7 # H_6 = 5 Hz) (1), 15.47 (NH) (d, JKTI1 „= δ'Ηζ); 11.12 (-COOH and -OH) (b) (2).

The (Z) -4-bromo-2-methoxyimino-3-oxobutyric acid used as starting material can be prepared as follows: 592.1 g of acetic acid tert-butyl ester are dissolved in 560 ml of glacial acetic acid. A solution of 290.6 g of sodium nitrite in 655 ml of water is added dropwise to this solution at 5-10 ° C over a period of 20 1/2 hours. The resulting yellow suspension is stirred for 30 minutes at 20 ° C, 940 ml of water are added and the mixture is stirred for a further two hours. 900 ml of water and 900 g of ice are added to the mixture and the mixture is extracted three times with 25 liters of ethyl acetate in a mixing vessel. The combined ethyl acetate extracts are washed three times with one liter of water, then 5 l of water are added and the pH is adjusted to 6.8 with sodium hydrogen carbonate. After separation of the aqueous phase, it is washed once more with water.

The ethyl acetate solution is then dried over sodium sulfate and evaporated to dryness in vacuo at 40 ° C. (Z) -2-Hydroxyimino-3-oxo-butyric acid tert-butyl ester is obtained in the form of a yellow oil which is dried for a further nine hours under high vacuum at 40 ° C. Yield 626.65 g (89.2% of theory).

626.65 g of (Z) -2-hydroxyimino-3-oxo-butyric acid tert-35-butyl ester are dissolved in 2.86 liters of acetone. The solution is cooled to 5 ° C and 703.5 g of potassium carbonate are added portionwise. 9,71563 are then added dropwise to the yellow suspension without cooling by dropwise addition over a period of 322 ml of dimethyl sulphate, so that the temperature of the mixture does not rise above 25 ° C.

The light beige suspension is stirred for about 5 to 4 hours at 20-25 ° C until no starting material is detected by thin layer chromatography. The mixture is then poured into seven liters of water and extracted three times with one liter of ethyl acetate. The combined ethyl acetate extracts are washed three times with one liter of water, dried over sodium sulfate and evaporated to dryness in vacuo at 40 ° C. The residual yellow oil is dried for a further six hours under high vacuum at 40 ° C and then distilled. 577 g of (Z) -2-methoxyimino-3-oxo-butyric acid tert-butyl ester (85.6% of theory) are obtained in the form of a yellow oil, b.p. 57 ° C under a vacuum of 0.02 mmHg. . 1 H-NMR spectrum in CDCl 3 (λ values in ppm, s = singlet; number of protons in parentheses): 1.55 ZT-C (CH 3) δ 7 (s) (9), 2.36 (CH 3 -CO) (s) (3), 4.01 / _ = N "0CH3, (Z) _7 (s) (3).

86 g of (Z) -2-methoxyimino-3-oxo-butyric acid tert-butyl-20-ester are dissolved in 400 ml of trifluoroacetic acid. The solution is allowed to stand for one hour at 25 ° C, then evaporated to dryness in vacuo at 35 ° C. the oily residue is crystallized from an ether / petroleum ether mixture. 50 g (80.6% of theory) of yellowish, water-soluble (Z) -2-methoxy-25-imino-3-oxobutyric acid are obtained, m.p. is 80-85 ° C. 1 H-NMR spectrum in CDCl 3 (d values in ppm, s = singlet, number of protons in parentheses): 2.43 (CH3-CO) (3), 4.14 7 = N'OCH3, (Z) I7 (s) (3), 10.47 (OH) (s) (1).

145 g of (Z) -2-methoxyimino-3-oxobutyric acid are dissolved in 30,000 ml of non-alcoholic and anhydrous dichloromethane.

To this solution is added 10 ml of 30% hydrobromic acid-glacial acetic acid solution. A solution of 37.5 ml of bromine in 112.5 ml of dichloromethane is then added dropwise over a period of about two hours, keeping the temperature of the reaction mixture at a slight cooling of 20-25 ° C. To remove HBr from the reaction mixture, a strong stream of nitrogen is then blown through it. Then 250 g of ice, 250 ml of 10 71 563 water and 2 l of ether are added successively. The aqueous phase is separated and discarded. The organic phase is washed with 250 ml of water and 250 ml of saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness in vacuo. 170 g of rus-5 boiling oil remain, which is crystallized from tetrachloromethane. 100 g (44.6% of theory) of practically colorless (Z) -4-bromo-2-methoxyimino-3-oxobutyric acid are obtained. 1 H-NMR spectrum in CDCl 3 (ε values in ppm, s = singlet, number of protons in parentheses): 4.24 / = N 2 CH 3, (Z) J, (s), 4.41 (-CH 2 - ) (s) (2) 10 (2), 11.0 (OH), (s) (1).

Example 2 28.8 g of (6R, 7R) -7- {4-bromo-2 - [- (Z) -methoxyimino] -acetoacetamido] -3- [2,5-dihydro-6-hydroxy-2- Methyl-5-oxo-as-triazin-3-yl) thiomethyl / methyl-8-oxo-5-thia-1-azabicyclo-15,4,2,10a-octa-2-ene-2-carboxylic acid is dissolved in 400 any absolute ethanol . 7.6 g of thiourea are added to the solution.

After stirring for 15-20 minutes at 25 ° C, the reaction product begins to crystallize from the orange solution as hydrobromide. After stirring for 1 1/2 hours, the substance is filtered off, washed successively with 200 ml of alcohol and 200 ml of low-boiling petroleum ether and dried under high vacuum at 35-40 ° C overnight. 22 g of practically colorless hydrobromide are obtained. This is dissolved together with 15.7 g of sodium 25 acetate trihydrate in a mixture of 110 ml of water and 110 ml of acetone. To this solution add 140 ml of acetone until the solution is slightly cloudy. Shortly thereafter, the reaction product begins to crystallize. The mixture is stirred for 30 minutes, after which 180 ml of acetone are added dropwise over the next 30 minutes, whereby complete crystallization takes place. The reaction product is filtered off, washed successively with 250 ml of 85% aqueous acetone solution, 250 ml of acetone and 250 ml of low-boiling petroleum ether and finally dried in vacuo at 25 ° C. 19.6 g of 35 (59.3% of theory) of practically colorless (6R, 7R) -7H-2- (2-amino-4-thiazolyl) -2- (Z-methoxyimino) -acetamido-7- 3- [2- (2,5-Dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-one 71563 yl) thio] methyl] -8-oxo-5-thia-1-azabicyclo [74 , 2.07 oct-2-ene-2-carboxylic acid disodium salt, which is recrystallized from a water-acetone mixture. 17.3 g (52.3% of theory) of pure material are obtained, with = -150.8 ° (c = 1 in water). 1 H-NMR spectrum in DMSO-d 6 (S values in ppm, s = Singlet, d = doublet, q = quartet, b = broad; J = coupling constants in Hz; percentage in parentheses): 3.47 (N-CH 2) (s) (3), 3.49 (2-CH 2) (AB-q / centering value; Jgem = 18 Hz) (2), 3.85 Z = N "OCH 3, (Z) -7 (s) (3), 4.37 (3-CH2-S) (AB-q / centering value; 10 Jgem = 12.5 Hz) (2) '5.04 (H' 6) (d 'JH-6 , H-7 = 4.5 Hz) (1) '5.59 (H-7) (q, JH_7fNH = 8 Hz), JH_7 / H_6 = 4.5 Hz) (1), 6.75 (thiazolyl- H) (s) (1), 7.29 (-NH 2) (b) (2), 9.52 (-CO-NH-) 1d 'JNH, H-7-8 H 2 |

Claims (3)

10. H. , ·· S. YCH CO —C - CONHt -------- y N N I 1 xoch3 · s ~ x 11 15 COOR where Y is a halogen atom and X is a group, „H H-C \. N PR R 3 is a hydrogen atom or a readily hydrolysable ester or ether group and the group = N-OCH 3 is in syn form, and their salts. Compounds according to Claim 1, characterized in that Y is a bromine atom. A compound according to claim 1 or 2, which is (6R, 7R) {N, N-bromo-2-E (Z) -methoxyiminoazetoacetamido] -3- (Z-(2,5-dihydro-6-hydroxy-2) -methyl-5-oxo-as-triazin-3-yl) thio] methyl} -8-oxo-5-thia-1-azabicyclo [4.2.2] oct-2-35 ene-2-carboxylic acid and its salts.