CS195681B2 - Process for preparing derivatives of 7-/substituted phenylglycinamido/-3-substituted-3-cephem-4-carboxylic acid - Google Patents

Description

The present invention relates to a process for the preparation of cephalosporic acid derivatives according to the novel cephalosporanic acid derivatives of the present invention which can be represented by the general formula I selins having antibacterial activity. '-

where

R 1 represents a C 1 -C 6 alkanesulfonamido group,

R 3 is a thiazolylthio or thiadiazolylthio group optionally substituted with a C 1 -C 6 alkyl group and

M represents a hydrogen atom or a non-toxic pharmaceutically acceptable cation.

The term "C1-C6 alkanesulfonamido" in the meaning of R 1 means mesylamino-, ethanesulfonamido-, propanesulfonamido, isopropanesulfonamido-, butarisulfonamido-. isobutanesulfonamido-, tert-butanesulfonamido-, pentanesulfonamido-, hexanesulfonamido and the like.

The thiazolylthio- or thiadiazolylthio group is optionally substituted with a C 1 -C 6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl,

195881 isobutyl-, tert-butyl-, pentyl-, hexyl- and the like

The term "non-toxic, pharmaceutically acceptable cation" in the meaning of M means an alkali metal cation such as sodium, potassium and the like.

The cephalosporanic acid derivatives of the formula I can be prepared according to the invention in that the 7-substituted phenylglycinamido-3-alkanoyloxymethyl-3-cephem-4-carboxylic acid of the formula Π, .....

where.,

R 5 is C 2 -C 7 alkanoyl,

X is an amino group, or an amino group which is protected, for example, by benzyloxycarbonyl, alkoxycarbonyl, trityl, or alkylidene, and is reacted with a thiol of formula III.

R3-Η (III) where

R 5 is as defined above, or with an alkali metal salt thereof, optionally removing the amino protecting group from the reaction product.

The term "protected amino" in the meaning of X means an amino protected with a conventional amino protecting group. Such a protecting group is, for example, benzyloxycarbonyl-, substituted benzyloxycarbonyl-, alkoxycarbonyl-,

Substituted alkoxycarbonyl-, aralkoxycarbonyl-, adamantyloxyfrarbonyl-, trityl-, substituted nynylthio-, substituted aralkylidene-, substituted alkylldene, substituted cycloalkylidene, and the like.

The term Ca-Cz alkanoyl group "represented by R3 ¹ in formula II with means acetyl, propionyl, butyryl and the like.

The alkali metal and thiol salts of formula III may be sodium, potassium, and the like.

The reaction of 7-substituted phenylglycinamido-3-alkanoyloxymethyl-3-cephem-4-carboxylic acid II with thiol ΙΙΪ or an alkali metal salt thereof can be carried out in a solvent such as water, acetone, chloroform, nitrobenzene, dimethylformamide, methanol, dimethylsulfoxide or any other organic solvent which is inert to the reaction, preferably in a strongly polar solvent. Hydrophilic solvents may be used in admixture with water. The reaction is preferably carried out in an approximately neutral environment. When the compound of formula (II) or the thiol of formula (HI) is used in free form, the reaction is preferably carried out in the presence of a base such as an alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, trialkylamine and the like. at room temperature or with heating. The reaction product can be isolated from the reaction mixture by conventional means.

Some of the protected amino protecting groups represented by X in the 7-substituted phenylglycines of formula (II) may be cleaved off during the reaction or with sufficient treatment to directly produce compounds of formula (I). containing in the meaning of X a free amino group.

If the reaction product contains a protected amino group, the protecting group from the product may optionally be cleaved. Suitable cleavage reactions are given below. This process is also within the scope of the invention.

Reactions in which the amino protecting group is cleaved can be carried out by conventional methods. Such reactions include, for example, acid decomposition, catalytic reduction, and the like. The appropriate reaction is selected according to the type of amino protecting group. Acidic decomposition is one of the most preferred methods and can be used to cleave substituents such as benzyloxycarbonyl, substituted benzyloxycarbonyl, alkoxycarbonyl, substituted alkoxycarbonyl, aralkoxycarbonyl, adamantyloxycarbonyl; ; ,. trityl-, substituted phenylthio-, substituted aralkylidene ¹ , substituted alkylidene-, substituted cycloalyliderio and the like.

The acid is selected in the above reaction depending on the type of amino protecting group. Suitable acids are formic acid, trifluoroacetic acid and the like which readily evaporate under reduced pressure. When acid decomposition is carried out in a solvent, hydrophilic organic solvents, water or mixtures thereof are sometimes used. Catalytic reductions can be used to cleave amino protecting groups, such as benzyloxycarbonyl, substituted benzyloxycarbonyl-1-, 2-pyridylmethoxycarbonyl, and the like; is palladium, but other catalysts commonly used for catalytic reduction may also be used. The trifluoroacetyl group may be cleaved by treatment with water on the reaction product and halosubstituted; 8-quinolyloxycarbonyl. It can be cleaved by the action of a common metal such as copper, zinc and the like on the reaction product.

Reaction at. Some are. The amino protecting group can be carried out without isolation of the reaction product from the reaction medium and without purification. .

All of the reactants used in the various processes within the scope of the invention are commercially available or can be prepared by conventional methods well known in the art, or by methods analogous to known methods of making such compounds.

The precipitate formed during the reaction of the invention is separated from the reaction mixture by methods conventionally used for this purpose, and the resulting reaction product can be subjected to conventional purification, for example, recrystallization from a suitable solvent or a mixture of these solvents.

The compounds of the present invention can be converted by methods customary for making salts from acids to their pharmaceutically acceptable, substantially non-toxic salts, for example by reaction with an alkali metal hydroxide, an alkali metal bicarbonate, an alkali metal carbonate, or an organic base. Sodium salts are preferred. Preferably. In preparing the salts, the acid is dissolved in a solvent in which the salt is insoluble and then a solution of a salt-forming compound or a base is added to the resulting solution.

The compounds of the invention have a high antibacterial effect and inhibit the growth of numerous microorganisms including gram positive and gram-negative bacteria. The minimum inhibitory concentration of some compounds of the invention in vitro against selected strains of microorganisms is illustrated by the following antibacterial activity test. Test. The culture of each of the test strains is harvested with trypticase incubated overnight (10 ⁸ viable cells / ml). The culture is plated on heart-agar (HI-agar) agar containing a graduated concentration of antibiotics. The minimum inhibitory concentration is determined after a 2 hour incubation at 37 ° C in (Ug / ml.

Compound number

Formula

195Β81 í * 7 8

Minimum inhibitory concentration (µg / ml)

Strain Compound number

2

Staph. Aureus 209-P JC-1

B. subtilis ATCC-6633

Staph. aureus 277

Staph. aureus 278

For therapeutic administration, the cephalosporin compounds of the invention are used in the form of pharmaceutical compositions comprising the compounds of the invention in admixture with pharmaceutically acceptable organic or inorganic solid or liquid excipients suitable for oral or parenteral administration. The pharmaceutical preparations may be in solid form, such as capsules, tablets or dragees in liquid form, such as solutions, suspensions or emulsions. If desired, adjuvants, stabilizing agents, wetting agents, emulsifying agents, can be added to the above compositions. pH buffers and other commonly used additives.

Although the dosage also depends on the age and condition of the patient, an average unit dose of between 100, 250 and 500 mg has been shown to be effective for treating diseases caused by bacterial infection. In general, amounts ranging from about 10 to about 1000 mg or more can be administered.

The following examples serve to illustrate the invention in more detail, but do not limit the scope of the invention in any way.

Example 1

1. Add sodium bicarbonate (0.86 g) to a stirred suspension of 7- [DN-tert-butoxycarbonyl-2- (3-mesylaminophenyl) glycinamido] cephalosporanic acid (3 gj in pH 6.4 phosphate buffer (130 ml). The solution was treated with 5-methyl-1,3,4-thiadiazole-2-thiol (0.68 g) and stirred at 60-65 ° C for 6 hours. C. The acetone was removed from the resulting mixture under reduced pressure, and the remaining aqueous layer was washed with ether, the pH of the aqueous solution was adjusted to 2 with dilute hydrochloric acid and then extracted with ethyl acetate. The residue was purified by silica gel column chromatography (eluent: chloroform) to give 7- [DN-tert-butoxycarbonyl-2- (3-mesylaminophenyl) glycinamido) -3- (5-methyll, 3,4). (thladiazo-2-yl) thiomethyl-2-cephem-4-carboxylic acid (1.8 g).

3.13. 1.56

0.78 0.39

6.25 '0.78

6.25 3.13

IC in (nujol) (cm ^-1 ):

3300, 1780, 1725, 1685, 1870.

2. The thus obtained 7- (N-tert-butoxycarbonyl-2- (3-methylaminophenyl) glycinamido) -3 (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid 23 g) was dissolved in formic acid (35 ml) and the mixture was stirred at 18-20 ° C for 4 hours, the resulting mixture was concentrated under reduced pressure, the product was powdered with ethyl acetate and then filtered. 7- [D-2- (3-mesylaminoíenyljglyciriatnido] -3- (5-methyl-3 _I 4-thiadiazol-2'-yl) thiomethyl-3-cephem-4-carboxylic acid (1.95 g). The product was added to acetone (30 mL) and the mixture was stirred at 15-20 ^° C for one hour, then allowed to stand and the supernatant solution was decanted, acetone (30 mL) was added to the residue, and the mixture was stirred for 3 hours. at 15-20 [deg.] C. The precipitate was filtered off, washed with acetone and then with ether to give a pale yellow powder which formed the product.

IR in (nujol) (cm ^-1 ): · 'A ·. <·; ··

1765, 1690, 1605. '

NMR '<< ·

D2O — DC1 - -7 · (PPm):

2.97 (3H, s), 3.01 (3H, s),

3.38, 3.78 (2H, ABq, 18Hz),

4.26, 4.47 (2H, ABq, J = 14 Hz),

5.12 (1H, d, J = 4Hz),

5.35 (1H, s),?

5.71 (1H, d, J 4Hz). ’/

Example 1 and d 2;

In an analogous manner to Example 1, 7- [D-2- (3-mesylaminophenyl) glycinamido] -3- (1H-1,2, B-triazol-5-yl) thiomethyl-3-cephem-4-carboxyl was prepared. acid, m.p. &gt; 175 DEG C. (decomposition).

1B

SUBJECT OF THE INVENTION

Claims (1)

A process for the preparation of 7- [substituted-cephem-4-carboxylic acid derivatives of phenyiglycinamido] -3-substituted-3- of formula I, wherein: R1 is C1-C6 alkanesulfonamido, R 3 is triazolylthio- or thiadiazolylthio, optionally substituted with C 1 -C 6 alkyl, and M is hydrogen or. A nontoxic pharmaceutically acceptable cation, characterized in that the 7-substituted phenyl-glycinamido-3-alkanoyloxymethyl-3-cephem-4-carboxylic acid of formula II, wherein: R5 is C2-C7 alkanoyloxy, X is an amino group, or an amino group which is protected, for example, by benzyloxycarbonyl, alkoxycarbonyl, trityl, or alkylidene, and R1 and M are as defined above, reacted with a thiol of formula III, R3 — Η (III) R 5 is as hereinbefore defined, or with an alkali metal salt thereof, optionally followed by reaction. product splits off