DK162094B - 2- (2-TRITYLAMINO-4-THIAZOLYL) -2-VINYLOXYIMINOIC ACETIC ACID, SYN-ISOMER, USING AS AN INTERMEDIATE IN THE PREPARATION OF SYN-ISOMER OXIMELE MOSPHEREO-MOSHYL - Google Patents

Description

in

DK 162094 B

This invention relates to 2- (2-tritylamino-4-thiazolyl) -2-vinyloxyimino acetic acid, syn isomer, for use as an intermediate in the preparation of novel oxime derivatives of 7-aminothiazolylacetamidocephalosporanoic acid of the general formula of claim 1 and this intermediate is characterized by having the general formula 11 as set out in claim 1, in Danish Patent Application No. 236/77, novel oxime derivatives of 7-aminothiazolylacetamidocephalosporanoic acid 10 and their preparation and use as medicaments are disclosed *

This application describes the compounds of formula I

NH-R

15 WC (I)

C "" "" is ^ NH

II O --- S η LO CH 2 '°' [} “CH 3 CO? A 0 20 2 wherein R represents a hydrogen atom or an acid by hydrolysis or hydrogen lysis easily eliminable group, R * represents a hydrogen atom, an acid by hydrolysis or by hydrogenolysis readily eliminates and carries a group or a saturated or unsaturated alkyl group of 1-4 carbon atoms, A denotes either a hydrogen atom or an equivalent alkali metal, alkaline earth metal, magnesium or aminated organic base, the dash indicating that the group OR * may be in sight or anti-position, noting that when R7 represents an easily eliminable group by acid hydrolysis or by hydrogenolysis, then R represents an easily eliminable group by acid hydrolysis or by hydrogenolysis and when R1 represents a hydrogen atom, then R is also a hydrogen atom.

It will be appreciated that the above compounds of formula __ I may exist: - either in the form indicated by formula I - or in the form of compounds of formula 1%: 2

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R

in.

X

<> 5 shows <v V o ^^ · ° | οη3 where R, R * and A have the same meaning as above.

In Danish Patent Application No. 236/77, examples are described of compounds of the above general formula and methods for their preparation.

By means of the intermediate product 11 according to the invention, it is possible to prepare novel compounds of general formula I according to ans, 236/77, 15

In particular, the compounds include: - 3-aethoxymethyl-7- (2- (2-tritylamino-4-thiazolyl) -2-vinyloxyimino-acetamido) -ceph-3 “em-4-carboxylic acid” syn isomer, - the sodium salt of 3-aethoxymethyl-7- (2- (2-tritylamino-4-thiazolyl) -20-2-vinyloxyaminoacetamido) -ceph-3-em-4-carboxylic acid, syn isomer, 3-acetoxymethyl-7- (2- (2-Amino-4-thiazolyl) ~ 2-vinyloxyiminoacetamido) -ceph-3-em-4-carboxylic acid, syn isomer and its salts with alkali metals, alkaline earth metals, magnesium or aminated organic bases and especially: - 3-acetoxymethyl -7- (2- (2-amino-4-thiazolyl) -2-vinyloxyiminoacetamido) -ceph-3-em-4-carboxylic acid, syn-isomer and the sodium salt of 3-acetoxymethyl-7- (2- (2-amino-4-thiazolyl) -2-vinyloxyiminoacetamido) -ceph-3-em-4-oreboxylic acid, syn-isomer.

The use of the intermediates of Formula 11 ^ consists in the preparation of the compounds of Formula Ικ 30 µl 5 µ / °

Is 35 J -------------- • XCH = CH2 Xa 2 5 3 «3

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wherein A represents a hydrogen atom or equivalent of alkali metal, alkaline earth metal, magnesium or aminated organic base, and this preparation consists of reacting 7-aminocephalosporanoic acid of formula 5 H2NXnfX & S | With an acid of the formula 11 ^10 NH-C (C6H5> 3 Λ)

= VCO 2 H “S

15 I

O -CH = CH 2 or a functional derivative of this acid to give a compound of the formula 1 'NH-C (C, HL) 20/653 W

NTI ^. ^

J

0-CHrCl2 O2J-NVv ^^ CH2-OC-Cl3

CO 2 N O

which acid of formula II is optionally treated by conventional methods to obtain the corresponding salt of alkali metal, alkaline earth metal, magnesium or aminated organic base, which acid of formula 1 'or salt of this acid is optionally treated with an acid to give the compound of formula 1

NH

35 - c «3

O-CH = CH 2 CO 2 H

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4 which is optionally converted to salt by conventional methods of obtaining the salt corresponding to the acid X

The functional derivative of the acid of formula 11 is preferably the anhydride which is formed in situ by the action of cyclohexyl arbodiimide. The conversion to salt of the compounds of formula I'r or I'1 is preferably carried out by action on these o of an inorganic base, preferably sodium bicarbonate.

The acid which is preferably treated with the acid of formula 1 or a salt of this acid is formic acid.

The invention also relates to a process for the preparation of the intermediate of formula 11, and this process is property. according to the characterizing part of claim 2. Among the compounds of formula X-Cl 2 -CH 2 -X, the preferred product is that where X represents a bromine atom.

The base in which the compound X-CH2-CH2-X is reacted with the compound III forbind is preferably potassium carbonate in dimethylformamide. Potassium tert-butylate in dimethylformamide or tetrahydrofuran can also be used. Triethylamine can also be used. .

The strong base by which to treat the compound of the formula to obtain the compound of the formula is preferably potassium tert-butylate in dimethyl sulfoxide at room temperature.

The base in the presence of which the compounds of formula of the formula are converted to compounds of formula 11 is preferably potassium hydroxide in a mixture of dioxane and ethanol. Other bases such as sodium or barium hydroxide may also be used.

The acid used to isolate the acid of formula IIcj is preferably dilute hydrochloric acid, but acetic or formic acid can also be used.

The compounds 1, which can be prepared by the intermediate IIjj of the invention, like the compounds of 35 ans. 236/77 a very good antibiotic activity, partly on gram-positive bacteria such as staphylococci, streptococci and especially on penicillin-resistant staphylococci, and partly on gram-negative bacteria, especially on coliform bacteria, Klebsiella, Salmonella and Proteus.

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5

Disae properties make these compounds suitable for use in the treatment of sensitive germ disorders and in particular for staphylococci, such as staphylococcus septicemia, facial or skin malignant staphylococci, pyodermatitis, septic or suppurative ulcers, anthrax, phlegmone , erysipel, primitive or post-influenza acute staphylococci, bronchopneumonia and pulmonary suppurations.

These compounds can also be used as drugs in the treatment of colibacillosis and related infections, in infections with Proteus, Klebsiella and Salmonella and other disorders caused by gram-negative bacteria.

The present invention provides drugs of the compounds of formula I, and in particular: - 3-acetoxymethyl-7- (2- (2-amino-4-thiazolyl) -2-vinyloxyiminoacet-amide o) -ceph-3-em. 4-carboxylic acid, syn isomer, and the sodium salt of 3-acetoxymethyl-7- (2- (2-amino-4-thiazolyl) -2-vinyloxyiminoacetamide o) -ceph-3-em-4-carboxylic acid, syn. is omer.

The former compound of Application Example 3 below is immediately prior to the claims below compared to the following compound AA according to claim 236/77: s \ = i ΛΟΑIU Sv

TI ^ -! IN

30 Vh2ch3 ^ YJv /? Ac

s * n COjH

The compounds of formula III III which are used as starting products in the preparation can be prepared as follows:

Thiourea is reacted with a compound of formula A

6 DK 162094 B

Cl CHO-C-C-CO, alo

ON A

ί

OH

s to obtain a compound down the formula B

N «2 '{-}

»" "* '- ^ - * C02 alc B

OH

which compound is treated with an equivalent trityl chloride to give the expected compound of formula III

The compounds of formula B and IIIC are obtained where the group s = N-OH is in the position of vision when the effect of the thiourea on the compounds of formula A is carried out either in an aqueous insolvent such as aqueous acetone or aqueous ethanol or at room temperature. allowing a practically stoichiometric amount of thiourea to act for a sufficiently short time, namely, on the order of 1-3 hours, or finally when all the above conditions are combined.

20

An example of such a preparation is given below in the experimental section.

The following examples illustrate the invention.

25 30 35

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Preparation Example 3-Acetoxymethyl-7- (2- (2-tritylamino-4-thiazol, yl) -2-vinyloxyimino-acetamido) -ceph-5-em-4-carboxylic acid, sleep isomer.

Step A: Ethyl ester of 2- (2-bromethoxyimino) -2- (2-tritylamino-4-5-thiazolyl) -acetic acid syn syn isomer.

Under argon, a mixture of 4.94 g of hydrochloride of the ethyl ester of 2-hydroxyimino-2- (2-tritylamino-4-thiazolyl) -acetic acid, syn isomer, is added to 10 ml of dimethylformamide and introduced at room temperature over 3 minutes 4.14 g of potassium carbonate. The mixture is stirred for 20 minutes at 20 ° C and 8.65 ml of 1,2-dibromoethane are added. Stir for 30 hours and pour into an environment comprising 100 ml of distilled water and 20 ml of methylene chloride, then decant, re-extract with methylene chloride, wash with distilled water, re-extract, dry the organic solutions, suction, rinse and distils to dryness. The crude product is obtained which is chromatographed on silica gel eluting with benzene with 5% ether. A first fraction is collected which is recrystallized from methanol after dissolving at 50-60 ° C and suction at 0-5 ° C. 1.16 g of cream-white product are obtained with m.p. 117 ° 0th

A homogeneous fraction of 1.258 g is then obtained.

N.M.R. spectrum, ppm (CDG1):

Triplet - 3.55 J = 7 Hz 0H2Br triplet = 4.51 J = 6 Hz N-O-CHg singlet 6.55, proton in thiazole ring.

25

Step B: Ethyl ester of 2- (2-tritylamino-4-thiazolyl) -2-vinyloxy-amino-acetic acid synthesis isomer.

6.9 g of ethyl ester of 2- (bromethoxyamino) -2- - (2-tritylamino-4-thiazolyl) acetic acid, syn isomer, are prepared in step A in 35 ml of dimethyl sulfoxide. Then, at 20-25 ° C, 16 ml of 1 M solution of potassium tert-butylate in tetrahydrofuran is introduced over 5 minutes. Stir for 30 minutes and introduce at room temperature 3 ml of 1 M potassium tert.-butylate solution in tetrahydrofuran. Stir again for 30 minutes, again add 3 ml of the same potassium tert-butylate solution and after 30 minutes a third time 35 ml of the solution.

After the last introduction, stir for 30 minutes and pour into a mixture of 350 ml of water and ice and 90 ml of methylene chloride.

Acidify to a pH of 2 with 28 ml of 1 N hydrochloric acid, decant and re-extract with 3 times 50 ml of methylene chloride.

8 DK 162094 B

Wash with distilled water, dry, suction, rinse and distill to dryness to obtain a black resin which is purified by chromatography on silica gel column eluting with methylene chloride. Thus, there are obtained 3,227 g of the expected product, which is immediately used in the next step.

N. M. Spectrum, ppm (CDCl3):

Solid from 4.16 to 4.83 ppm = CHg solid from 6.66 to 7.33 ppm = CH singlet at 6.65, proton in thiazole ring.

After recrystallization of absolute ethanol, a product is obtained, mp 114 ° G.

Found: C # 69.54 W ° 5.21 H # 8.69 6.36 Found: 69.2 5.2 8.3 6.6 Step C: 2- (2 -tritylamino-4-thiazolyl) -2-vinyloxyiminoeddikesyre.

syn isomer.

3.227 g of ethyl ester of 2- (2-tritylamino-4-thiazolyl) -2-vinyloxyimino acetic acid, syn isomer, are prepared in step B in 3.2 ml of dioxane. At room temperature 20 ml of 20.5 ml of potassium hydroxide in absolute ethanol and 12 ml of absolute ethanol are added. It is heated to 50 ° C with stirring and argon atmosphere and maintained for 1 hour. The potassium salt crystallizes out. Bring to 20 ° C, suction, rinse with ethanol and take up the product in a mixture of 50 ml of ethyl acetate and 50 ml of distilled water.

Acidify with 6 ml of 2 hydrochloric acid and stir until two homogeneous phases are obtained. Decant, wash with 3 times 20 ml of distilled water, re-extract with ethyl acetate, dry, suction and rinse with ethyl acetate. Evaporate to 15 ml and ice-cool at 0-5 ° C. Suction and rinse with ethyl acetate. 30 are dried and 2.53 g of the expected product are obtained. The product is used immediately in the next step.

After recrystallization, a purified sample is obtained with m.p.

150 ° 0th

35

Application Example 1.

3-acetoxymethyl-7- (2- (2-tritylamino-4-thiazolyl) -2-vinyloxyimino-acetamido) ceph-3-em-4-carboxylic acid. syn isomer.

2.53 g of 2- (2-tritylamino-4-thiazolyl) -2-vinyl oxyimino acetic acid, syn isomer, prepared in step C in 20 ml of methyl

9 DK 162094 B

chloride. It is cooled to 5 ° C and 0.632 g of di-cyclohexylcarbodiimide is introduced at one time. The room temperature can be reassessed. Stir under argon for 1 hour to obtain suspension A. Separately, under argon atmosphere, 0.718 g of 7-aminoeephalosporanic acid is introduced into 10 ml of methylene chloride. ♦ Cool to 10 ° C and 1.1 ml of triethylamine is added to obtain solution. B.

Suspension A is introduced over 10 minutes at 5-10 ° C in solution B. Stir, allowing to re-enter room temperature (over 35 minutes). Then stir for 3 hours at 20-25 ° C.

0.6 ml of acetic acid is then added, stirred for 10 minutes, and then the dicyclohexylurea compound formed is extracted. The organic solution is washed with water, dried and distilled under vacuum.

A yellow resin is obtained, which is taken up in ethyl acetate, filtering out some insoluble material. Evaporate to dry ice and give 3.475 g of the expected product.

The hydrochloride of the ethyl ester of 2-hydroxyimino-2- (2-triethylamino-4-thiazolyl) -acetic acid, syn isomer used as starting product in the Preparation Example is prepared as follows: 2- (2-amino-4-thiazolyl) -2-Hydroxyiroinoacetic acid, free ethyl ester, syn-isomer.

0.8 g of thiourea is dissolved in 2.4 ml of ethanol and 4.8 ml of water. The solution of 2 g of 4-chloro-2-hydroxyiminoacetylacetic acid ethyl ester is added over 5 minutes and stirred for 1 hour at room temperature. Most of the ethanol is evaporated under partial vacuum and neutralized to a pH of 6, adding solid sodium bicarbonate. One is cooled, suctioned, washed with water and dried under vacuum at 40 ° C. 1.32 g of the expected product is obtained. Mp. 232 ° C,

Analysis: C ^HgO ^ ^S

30 calculated: G & 39.06 H # 4.21 N & 19.52 Sfo 14.9 found: 38.9 4.4 19.7 14.6

The hydrochloride of 2- (2-tritylamino-4-thiazolyl) -2-hydroxyiminoacetic acid ethyl ester. syn isomer.

43.2 g of 2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetic acid ethyl ester, syn isomer, prepared above in 120 ml of dry dimethylformamide are introduced.

It is cooled to -35 ° C, introduced with 32 ml of triethylamine and then 60 g of trityl chloride in portions over 30 minutes. The temperature is raised, a complete solution is observed and

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then a heating to 30 ° C. After 1 hour, pour into 1.2 liters of ice-cold water containing 40 ml of 22 ° B hydrochloric acid.

Stir in an ice-water bath, suction, rinse with 1 ΪΤ hydrochloric acid and rinse with ether. 69.3 g of hydrochloride are obtained.

5

Application Example 2.

The sodium salt of 5-aethoxymethyl-7- (2- (2-tritylamino-4-thiazolyl) -2-vinyloxyiminoaoetamido) -oeph-3β-4-carboxylic acid, syn isomer.

At room temperature 2.628 g of product prepared 0 are dissolved in the preparation example in the form of a resin in 5.2 ml of acetone.

10.4 ml of 1 M solution of sodium bicarbonate in water are added at once. The sodium salt is extracted after 1 hour of contact at 20 ° C and rinsed twice with 2 ml of a mixture of water and acetone (1: 1) and with 2 ml of distilled water. Dry under vacuum at 40 ° C to obtain 1.612 g of the expected crude product.

Application Example 3.

5-Acetoxymethyl-7- (2- (2-amino-4-thiazolyl) -2-vinyloxyiminoacetamido) - ceph-3-em-4-carboxylic acid, syn isomer.

0,612 g of sodium salt of 3-acetoxymethyl-7- - (2- (2-tritylamino-4'-thiazolyl) -2-vinyloxyiminoacetamido) -ceph-3-em-4-carboxylic acid, syn-isomer, are prepared in Example Example 2 in 4 ml of 98 ^ formic acid. Immediately after 4 ml of distilled water is added. The mixture is stirred at 40 ° C for 15 minutes. The heterogeneous suspension is ground for 30 minutes at room temperature. Extract at 20 ° C and rinse twice with 1.6 ml of 5Ofi formic acid. It is distilled to dryness and taken up in 5 ml of distilled water. It is extracted at room temperature, rinsed with distilled water and then with ether.

Dry and obtain 300 mg of the expected product. The insoluble material is separated in the same way as above using 50 µm formic acid, thus 0.214 g of additional acid is obtained.

Analysis: Ο- ^ γΗ ^^ ΟγϊΤ ^ δ calculated: C # 43.68 Hi 3.66 M # 14.98 S # 13.72 Found: 44.2 3.9 15.1 13.0 55 IT, M, R, Spectrum, ppm (DMSO): 6.91 (proton in thiazole ring) 7.28 (free amine Mg)

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Application example 4.

the sodium salt of 3- acetoxymethyl-7- (2- (2-amino-4-thiazolyl) -2-vinyl, yl-oxyiminoaoetamido) -ceph-3-ene-4-carboxylic acid.

To 5.08 g of 3-acetoxymethyl-7- (2- (2-amino-4-thiazolyl) -2-5-vinyloxyiminoacetamido) -ceph-3-em-4-carboxylic acid, syn isomer, prepared according to Example 3, 5 ml of ethanol and then stirred in ice-water bath 10 ml of 1 M aqueous solution of sodium bicarbonate. After dissolving, add 15 ml of ethanol, then evaporate to 30 ° C under vacuum, take up in ethanol and dry to constant weight. the expected product.

Pharmacological examination of the products prepared by using the intermediate according to the invention.

In vitro activity.

15

Method with dilutions in liquid environment.

A number of glasses are produced in which the same amount of sterile nutrient environment is distributed. In each glass, growing amounts of the product to be examined are distributed, and then each erlas is seeded with a bacterial strain, 20

After incubation for 24 or 48 hours in a refrigerator at 37 ° G, growth inhibition is assessed by illumination, which allows the minimum inhibitory concentration (MIC) to be expressed in μg / ml to be determined.

The following results are obtained as per: 25 30 35

12 DK 162094 B

Product of Application Example 3, Q + MIC in µβ / ιη1 _ Strain_ 24 h 48 h

Staphylococcus aureus ATCC 6 538 penicillin sensitive 1 1 5

Staphylococcus aureus UC 1 128 penicillin resistant 1 1

Staphylococcus aureus exp, no, 54 146 1 2

Streptococcus pyogenes A 561 <10 * 02 ^ 0.02

Streptococcus faecalis 5 432 3 5 10 Streptococcus faecalis 99 F 74 5 10

Bacillus subtilis ATCC 6 633 2 5

Escherichia coli tetracycline sensitive ATCC 9 637 0.5 0.5

Escherichia coli tetracycline resistant ATCC 11 303 0.05 0.05

Escherichia coli exp. TOggBg 0.2 0.2

Escherichia coli gentamicin resistant tobramycin B 0.5 123 D 0.5 0.5

Klebsiella pneumoniae exp, 52 145 ^ 0.02 ^ .0.02

Klebsiella pneumoniae 2,536 gentamycin resistant 1 2

Proteus mirabilis (indole-) A 235 -c 0.02. 0.02 7 \\ 7

Salmonella typhimurium 420 0.5 0.5

Enterobacter cloacae 681 3 ..... 5

Providencia Du 48 22 25 Serratia gentamicin resistant 2 532 1 2

COMPARATIVE

Following the same procedure as above, the compound of Application Example 3 above is compared with the compound AA mentioned in the preamble of Ans. No. 236/77. The following results, expressed as MIC in pg / ml after 24 hours are obtained: 35

13 DK 162094 B

Connection

according to application- Compound * Strain Ex. 3 AA

_ovenfor

Staphylococcus aureus ATCC 6 538 pen. "sensitive 1 2 5 Δ

Staphylococcus aureus UG 1 128 pen.

resistant 1.2

Staphylococcus aureus exp # 54 54 1 2

Streptococcus pyogenes A 561 / 0.02 0.02

Escherichia coli tetracycline sensitive 10 ATCC 9 657 0.5 1

Escherichia coli tetracycline resistant ATCC 11 303 0.05 0.2

Escherichia coli exp. T02gBg 0.2 0.4

Escherichia coli gentamicin resistant tobramycin R 55 123 D 0.5 0.6 15 f

Klebsiella pneumoniae exp. 52 145 0.02 0.02¾

Klebsiella pneumoniae 2,536 gentamycin resistant 1 2

Proteus mirabilis (indole) A 235 ^ 0.02 0.05

Salmonella typhimurium 420 0.5 1 20 Enterobacter cloacae 681 3 40

Providencia Du 48 2 c

D

Serratia gentamicin resistant 2,532 1 2 25 30 35

Claims (3)

0-CH = CH X 2 II 3 10 1 · LU 2 0 0 where A represents a hydrogen atom or an equivalent alkali metal, alkaline earth metal, magnesium or aminated organic base, characterized by formula IIj. NH-C (C6H5) 3 115 15 CO H S ~ Li '\ 0. CH - CH2 Process for the preparation of the intermediate according to claim 1, characterized in that in the presence of a base, a compound of the formula XC ^-C ^-X, wherein X represents a chlorine, bromine or iodine atom, is reacted with a compound of formula III_ b 25 I ™ - C (C6HS) 3. <RTI ID = 0.0> JV-CV1 </RTI> OH 30 where alc represents an alkyl group of 1-4 carbon atoms to give a compound of formula IV, NH -C (C, H-), 653 IV / \ \ I C02alc 0 -CH2-CH2X DK 162094 E which compound is treated with a strong base to give a compound of formula V, - NH-C (CH) - Λ 5 and then with an acid to give the expected compound of formula II, -. Process according to claim 2, characterized in that the strong base used to convert the compound of formula IV to the compound of formula Vc is potassium tert-butylate in dimethyl sulfoxide at room temperature. 20 25 30 35