CS203168B2 - Method of preparing amino-acetamido-oxadethiacephalosporins substituted in the position 7 - Google Patents

Description

The invention relates to a process for the preparation of aminoacetamidooxadethiationphalosporins substituted in the 7-position.

Certain oxadethiationphalosporins are already known in the art. Japanese Published Patent Application No. 133,593 / 1974 relates to oxadethiacephalosporins, but the compounds disclosed herein are different from the oxadethiacephalosporins of the present invention with respect to the 7-position substituent and with respect to activity against resistant bacterial species.

The present invention relates to a process for the preparation of aminoacetamidooxadethiationphalosporins substituted in the 7-position of the general formula I y

RCONH CH CONH-i Ar (I) ^coz wherein R is OO

AA

-N N-R * w

wherein R ³ is hydrogen or C 1 -C 5 alkyl; group formula

XR ⁵

II / —NCN

I \

R ⁴ R ⁶ wherein X is oxygen or sulfur, and R ⁴ , R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen and alkyl groups containing 1 to 5 carbon atoms;

group formula

X

II

-NCN203168 wherein X is oxygen or sulfur and ^R7 is hydrogen or a mesyl group; --NCO - R ⁹

R ⁸ wherein R ⁸ is hydrogen or C 1 -C 5 alkyl, and R ⁹ is phenyl (C 1-5) alkenyl; phenyl substituted with one or two hydroxy or acetoxy groups; oxothiopyranyl; or 8- (C 1-5) alkyl-3- (C 1-5) alkoxy-5-oxo-5,8-dihydropyrido [1,2,3-e] pyridazinyl;

Ar is a phenyl group optionally substituted by one or two groups selected from the group consisting of hydroxy, carbamoyloxy and acetoxy;

Y is hydrogen or methoxy;

Het is l- (Ci_5) alkyltetrazole-5-yl, l, 3,4-thiadiazol-5-yl or 2- (Ci_5) alkyl-l, 3,4-t hiadiazol ^L-5-yl group, and

Z is a sodium oxy group or a potassium oxy group, the method comprising reacting a compound of formula II

RCONHCHCONH i

Al ·

O ^N V ^ CHSHct (I /)

COOH wherein R, Ar, Y and Het are the same substituents as. as mentioned above, with the sodium or potassium salt of a lower alkanecarboxylic acid in a solvent.

The lower alkanecarboxylic acid may be, for example, acetic acid, propionic acid, 2-ethylhexanoic acid, lactic acid and the like. An example of said solvent may be an alcohol (such as methanol, ethanol, propanol), a ketone (such as acetone, methyl ethyl ketone), an ether (such as ether, tetrahydrofuran, dioxane], an ester (such as ethyl acetate), etc.

For example, the above reaction may be accomplished by adding a solution of a suitable lower alkanoic acid salt in a suitable solvent to a solution of the free acid of Formula II, and then adding ethyl acetate to precipitate or crystallize the desired salt.

The oxadethiationphalosporins of the present invention may be used as highly active antibacterial agents against Gram-negative species and species resistant to other cephalosporins and penicillins; the compounds of the present invention are used in the form of sodium salts, which are prepared by dissolving the free acids in an aqueous solution of sodium bicarbonate.

The antibacterial activity of several selected typical compounds of formula (I) which are dissolved in aqueous sodium bicarbonate is shown in Table I, which follows.

Table I

Tested bacteria

Minimum inhibitory concentration Og / ml]

AND (B) C Staphylococcus aureus C-14 1.6 3.1 1.6 Escherichia coli NIHJ JC-2 0.2 0.01 0.1 Escherichia coli 0.4 12.5 25 Klěbsiella pneumoniae 0.01 0.01 0.05 Klehsiella ep. 363 0.1 12.5 100 ALIGN! Proteus mirabilis PR-4 0.4 0.4 1.6 Proteus vulgaris CN-329 0.2 0.2 0.8 Enterobacter cloacae 233 0.8 0.1 0.8 Serratia marcescens 0.8 0.05 0.8 Pseudomonas aeruginosa 25619 3.1 0.8 0.8 Pseudomonas aeruginosa Denken 12.5 6.3 6.3 Pseudomonas aeruginosa 24 25 3.1 6.3 Note: the use of solid carrier materials for external Test compounds (sodium salts), and internal administration is can mention lacquer- toose, sucrose, starch, dextrin, hydrogen- A = 7of-methoxy-7β- [D-α-phenyl-N-] sodium carbonate powder of liquorice, talc, - (4-Ethyl-2,3-dioxo-1-piperazinyl- kaolin, bentonite, calcium carbonate, paraffin carbonyl (glycylamino) -3- (1-methyl-1- etc. (1H-Tetrazol-5-ylthiomethyl) -1-oxa- As a gel or liquid carrier

dethia-3-cephem-4-carboxylic acid,

B = 7- [D-α- (p-hydroxyphenyl) -N- (4-ethyl-2,3-dioxo-1-piperazinylcarbonyl) glycylamino) -3- (1-methyl-1H-tetrazole-5) acid -ylthiomethyl) -1-oxadethia-3-cephem-4-carboxylic acid,

C = 7- [D-α- (p-hydroxyphenyl) -N- (4-ethyl-2,3-dioxo-1-piperazinylcarbonyl) glycylamino] -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) acid ) -3cephem-4-carboxylic acid control.

The results show that the compounds of the formula I according to the invention show a stronger antibacterial action, in particular against gram-negative bacterial species, than the corresponding thio compounds. The other compounds of the present invention exhibit similar antibacterial activity to that of the test compounds.

The compounds of formula (I) of the present invention, including certain esters and pharmaceutically acceptable salts thereof, are effective in preventing or treating various human and animal diseases caused by bacteria.

The compounds of formula I may be administered as such or in the form of mixtures. In addition, it should be noted that the compounds of the invention may be administered in combination with pharmaceutically acceptable carriers, diluents, adjuvants and other suitable drugs, if necessary.

The carriers are determined according to the chemical properties of the compound of formula I to be used in the present case, the objective to be attained and the route of administration. As an example, gelatin, water, ethanol, isopropanol, chloroform, glycerol and the like can be mentioned. Further, freon (trade name) may be used in conjunction with the present invention in the form of an aerosol in the form of an aerosol.

Practical examples of suitable pharmaceutical formulations of the compounds of formula I include tablets, capsules, pills, granules, powders and the like for oral administration and in the form of solutions for injection, ointments, aerosols, suppositories and the like for parenteral administration.

The pharmaceutical compositions of the present invention may contain the compound of formula I as active ingredient in an amount ranging from 0.01% to 99% by weight.

The compounds of formula (I) are generally administered to humans or animals at daily dosages ranging from about 250 milligrams to 5 grams, the amount of which may vary according to the objective to be achieved, the condition of the patient, the susceptibility of infectious bacteria and route and administration interval.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.

Example 1

The procedure is followed by adding to the solution of 7α-methoxy-7- / S- [D-of-phenyl-N- (4-ethyl-2,3-dioxol-1-piperazinylcarbonyl) glycylamino] -3 - (1-methyl-1H-tetrazol-5-yl-thiomethyl) -1-oxadethla-3-cephem-4-carboxylic acid (2 g) in ethyl acetate (40 ml), add sodium acetate solution (0), 4 grams in methanol in an amount

203188

4.35 milliliters. The mixture was stirred for 15 minutes, then allowed to stand at 0 ° C for 1 hour and finally filtered. The precipitate thus obtained, which is collected by filtration, is washed with a 1: 2 mixture of methanol and ethyl acetate, ethyl acetate and finally ether. Drying is then carried out to give 1.9 g of the starting compound sodium salt.

Yield: 95%.

IR .nu.max (KBr): 3200—2700, 1665 cm @ ¹ Examples 2-18

In these embodiments, the compound of formula II is converted to the compound of formula I of the invention under the conditions outlined in Table II. The antibacterial spectrum of each of the obtained products is shown in Table III.

RCONHCHCONH i

Ar

RCONHCHCONH i

Ar

OF

(AND)

Example #

Table II

Compound II

Ar Y

Solvent (mg) (ml)

2 CH3NHGONCH5— And what p-HO-Ph H 200 EA (4) 3 Ph— H 100 ALIGN! EA (1) 4 at Ph— H 58 EA (1)

Example # Reagent (mg) Reaction conditions Time (h) Compound I Yield Solvent (ml) Temperature (° C) (mg) (%) 2 AcONa (24) MeOH (0.5) 0 0.5 191 92 3 AcONa (11) MeOH (2) 0 0.25 84 81 4 AcONa (6) MeOH (2) 0 1/3 40 66

Example # R Compound II Ar Y Amount (mg) Solvent (ml) O 5 CH.SO.-N- ^ N- * * · 1_1 Ph— H 62 EA (1) O Λ 6 CH3SO2— N N— 1 1 p-HO — PH— H 100 ALIGN! EA (15) 7 PhCH = CHCONMe— Ph— H 158 MeOH (2) 8 MeNHCSNMe— Ph— H 98 EA (2) Example Reaction conditions Temperature Time Compound I C. Reagent Solvent (° C) (h) Yield (mg) (ml) (mg) (%) 5 1.0 M / L SEA - 25 1/6 42 65 in i-PrOH 0 1.5 (0,16) 6 AcNa (9) MeOH (2) 0 0.5 86 83 7 1.0 M / L SEH 25 1/6 115 70 in i-PrOH 0 1 (0.38) 8 AcONa (10) MeOH (2) 0 1/3 76 75 Example R Compound II Solvent C. Ar Y Amount (ml) (mg) O 9 M <zC> Ph— H 150 EA (3) '· * O O 10 -N 'w- p-HO — Ph— H 500 EA (10)

Example

Reaction conditions

Compound I

C. Reagent (mg) Solvent (ml) Temperature (° C) Time (h) Yield (mg) (%) 9 AcONa (15) MeOH (1) 0 0.5 123 80 10 AcONa (99) MeOH (0.1) 0 1 473 92

Example R

Compound II Ar Y

Solvent (mg) (ml)

C.

0 0 11 Pf Et-N n- p-HzNCOO— —Ph— H 300 EA (5) 0 0 12 V ^- (Et - N W \ __ Z p-AcO — Ph— H 600 EA (10) 13 0 0 y— Et-N N \ _ / p-HO — Ph— About me 500 EA (10) 14 0 0 Et-N Ή- p-HzNCOO— —Ph— About me 450 EA (10) 15 Dec 0 0 TO, Et-N N- Ph— H 500 EA (10) Example C. Reaction conditions Reacting Solvent Temperature Component (mg) (ml) (° C) Time (h) Compound I Yield (mg) (%)

11 AcONa (55) MeOH (0,1) 0 1 277 90 12 AcONa (99) MeOH (1,0) 0 0.5 585 95 13 AcONa (99) MeOH (1,0) 0 1 478 93 14 AcONa (99) MeOH (1,0) 0 1 416 90 15 Dec AcONa (99) MeOH (1,0) 0 1 494 96

Example C. R Compound II Amount Solvent (mg) Body (ml) Ar Y ¹⁶ MeNHCONMe Ph- H 26 THF (0.5) EA (0.5) o O 17 Ma-N N- O 0 Ma-N N ~ p-HO — Ph- H 520 EA (10) 18 p-HzNCOO — Ph— H 500 EA (10) Example Reacting Reaction conditions Time Compound I C. Component (mg) Solvent Temperature (h) Yield (ml) (° C) (mg) (%) 16 SEH (8) i -PrOH rt 0.2 40 90 (0.2) 17 AcONa (100) MeOH (1.0) 0 1 470 88 18 AcONa (100) MeOH (1.0) 0 1 465 90 Note: SEH = Sodium 2-ethylhexanoate THF = tetrahydrofuran

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E. coli EC-14 0.02 0.1 0.02 0.05 0.2 0.8 0.02 0.05

The test compounds listed in Table III, which are designated D to S, correspond to the products of Examples 2 to 9 and 11 to 18 according to the following table:

rconhchconh4 - ('θη coz

4-J

0)

2-2:

I \ $

1 = 7

Lz ^ -2:

? = 2. L · - *

2Γ1

XX x

XXX

E

2-Σ:

«Žřf ~ ί = ^ Γ *! X

CD

F-J> u τ β

rH m

> Ph

Ph ca β

• HH β

0)> u β

O

R 'H cn

Λ

Ph

Λ

Ph

Λ PU AND xí AND 1 PU Λ O | Ph O and 5 O O < 1 O E t and E AND and and

Ph

ř)

E

O.

CD 2 2 cn O E 2 03 / 2 O ώ /? •of and oíj oň 1? • H P bj Lu eo CTI rH n cn rH rH rH 2 2 2

O

O

Et-N

TP rH

Compound Example No. R Ar Y Het i-2> -> 2-X .S-X

AND

X

CM

AND

X a

I o

CM fil ft

in co rH rH and i co

203188

Claims (1)

Subject OF THE INVENTION A process for the preparation of aminoacetamidooxadethiationphalosporins substituted in the 7-position of the general formula I O O UJÍ \ _f where R ³ represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms; group formula XR ⁵ II of —NCN I \ R ⁴ R ⁶ X is oxygen or sulfur and R ⁷ is hydrogen or mesyl; --NCO - R ⁹ R ⁸ where R ⁸ is a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms and R ⁹ is phenyl (C 1-5) alkenyl; a phenyl group substituted with one or two hydroxy or acetoxy groups; oxo-thiopyranyl; or 8- (C 1-5) alkyl-3- (C 1-5) alkoxy-5-oxo-5,8-dihydropyrido [2,3-c] pyridazinyl; Ar is a phenyl group optionally substituted with one or two groups selected from the group consisting of hydroxy, carbamoyloxy and acetoxy, Y is hydrogen or methoxy; Het represents 1-C 1-6 -alkylthetrazol-S-yl, 1,3,4-th, iadiazol-5-yl or 2- (C 1-5) -alkyl-1,3,4-thiadiazol-5-yl ; and Z is a sodium oxy group or a potassium oxy group, characterized in that a compound of the general formula (II) is reacted in the reaction X is oxygen or sulfur and R ⁴ , R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen or C 1 -C 5 alkyl; group formula X ^{1 11} * -NCN-you RCONHCHCONH Al · 'η — Τ' Ί (ii) COOH in which R, Ar, Y and Het are as previously defined, with a sodium or potassium salt of a lower alkanecarboxylic acid in a solvent.