CS219308B2 - Method of making the new pleuromutilines - Google Patents

Abstract

The subject of the invention is a production method acylated derivatives of pleuromutilins which are obtained by introducing pleuromutilins in reaction with an acylating agent and obtained the derivatives are optionally converted into addition derivatives salts with acids or quaternary salts. The novel pleuromutilins of the invention are antibacterial agents useful in particular against. Mycoplasmas, both directly in the form of medicaments, as well as disinfectants means, optionally also as a drinking additive water

Description

The invention relates to a process for the preparation of the novel pleuromutilins of the general formula I,

 clay)

R 1 is ethyl or vinyl and R 2 is acyloxyalkyl of 2 to 5 carbon atoms in the acyloxy group and 1 to 4 carbon atoms in the alkyl group or benzoyloxy-alkyl of up to 4 carbon atoms in the alkyl moiety, and acid addition salts thereof; and quaternary salts, characterized in that the compound of the formula Ia,

 íui kde

R1 is as defined above and

R < ^{21 &} gt ^; is C1 -C4 hydroxyalkyl, reacted with an acylating agent of formula III;

R4-C-B

II o

(III), where

B is an alkoxy group having from 1 to 4 carbon atoms, a bromine atom, a chlorine atom, or an -O-C-R4 group; and

II o

R 4 is C 1 -C 4 alkyl or phenyl, and the resulting pleuromutilins of formula (I) are optionally converted to their acid addition salts or quaternary salts.

The process can be carried out, for example, by reacting a compound of formula (Ia) in a solvent with an acid derivative of formula (III) for some time. Preferably, the acid derivative may be used alone as a solvent or in admixture with an inert solvent such as a chlorinated hydrocarbon such as dichloromethane. The reaction product can be isolated from the reaction mixture by known methods and optionally purified.

The compounds of formula I may be converted into their acid addition salts and vice versa.

The corresponding quaternary salts can be obtained from the compounds of the formula I by known methods.

The hydroxyoxyalkyl group R < ^{21 &} gt ^; preferably has from 1 to 4, in particular 2, carbon atoms. The low acyloxy group R @ 2 preferably has from 1 to 4 carbon atoms, and in particular denotes an acetyl group. Low alkyl groups in the meaning of acyloxyalkyl or benzoyloxyalkyl groups of R2 preferably have 1 to 4, and in particular 2, carbon atoms. The number n preferably denotes two or three.

The compounds of formula I and their pharmacologically acceptable acid addition salts and quaternary salts have, at low toxicity, interesting biological and especially antirnicrobic properties and can therefore be used as medicaments. They exert a inhibiting effect on bacterial growth, as evidenced by in vitro examination or agar plate assay or in vivo experiments in mice using different strains of bacteria. This braking effect was detected starting at a concentration of about 0.002 to 5 µg / ml, in particular, a braking effect against myc-oplasms, which appeared starting from a concentration of 0.08 to 2.5 µg / ml, was found, therefore compounds produced by according to the invention as antibacterially active antibiotics.

The compounds of formula I and optionally their water-soluble, physiologically acceptable salts can be administered as medicaments in appropriate pharmaceutical forms together with inorganic or organic pharmacologically acceptable excipients. For example, these compounds are used as ingredients in capsules, injectable or drip formulations, which contain an amount of active ingredients sufficient to achieve an optimal blood level, i.e., about 10 to 500 milligrams per capsule.

Mycoplasma inhibitory activity was tested in vitro on the following organisms:

1. M. hominis II,

2. M. bovigenitalium,

3. M. gallisepticum

4. M. sp. ISRí,

5. M. laidlawii,

6. M. hominis I

7. M. hyorhinis.

The results obtained using compounds corresponding to formula I are shown in Table I below.

.TABLE I

Substance Minimum inhibitory concentration in µg / ml organisms

1 2 3 4 5 6 7

14-Mutilyl-3-morpholinopropyl- amino-N, N-acetate 14-de'9oxy-14 - [(3-morpholino- pr opylamino Jacetoxy] - 15.6 3,125 mutilin 14-Desoxy-14 - [(2-diethylamino- 62.5 5 ethylthio-acetoxy] mutilin 14-desoix-14 - [(2-dimethyl- aminoethylthio) acetoxy] - 0.312 0.625 mutilin 14-desoxy-14 - [(2-diethylaminoethylamino) acetoxy] - 1,561 0.31 mutilin 14-desoxy-14 - [(2-piperidino- 15,625 5 ethylthio) acetoxy] mutilin 14-desoxy-14 - [(2-morpholino- 1,25 0.39 ethylthio) acetoxy] mutilin - - The following table II shows: summarized you- in vivo test results for infections

0,078 12.5 250 7.81 15.6 1,25 31.25 500 12.5 25 0,039 3,125 15.6 0.195 0.78 0.019 3,125 15,625 <0.97 - 2.5 31.25 500 3,125 12.5 0.156 6.25 15.6 1.9 - 0.97 7.81 - 0.97 7.81 of the items listed in these tables with DE95

expressed in mg / kig weight.

Substance

TABLE II

Strept infection. haem.

DE95 in mg / kg per os subcutaneously

Strept infection. aronson

DE95 in mg / kg per os subcutaneously

Staph infection. aureus

DE95 in mg / kig per os subcutaneously

14-desoxy-1,4-[(2-diethyl- aminoethylthio) acetoxy] mutilin 52.2 37.0 14-desoxy-14 - [(2-t-trimethylammonioethylthio) acetoxy] mutilin iodide 8.1 14-Dimethyl-14 - [(2-diethylaminoethylthio) acetoxy] dihydromutilin 78.5 87.1 Acute toxicity

Acute toxicity of the compound

113 134 92.9 23.8 101 229 1112 • 42.4 I are DL50 was detected in mice. The results are shown in Table III and are given for some compounds.

Substance

TABLE III

DL 50 in mg / kg per os subcutaneously

14-desoxy-14 - [(2-diethylaminoethylthio) acetoxy] mutilin 14-desoxy-14 - [(2-trimethylammonioethylthio) acetoxy] mutilin

14-desoxy-14 - [(2-diethylaminoethylthlo) acetoixes], dihydromutilin

In addition, the pleuromutilins derivatives according to the invention are excellent additives for animal feed compositions. They can thus be added to the feed for reasons of prophylactic 479 197.5

727.6 10.62

620.6 256.0 ticks at concentrations between 0.05 and 5 ppm. The compounds according to the invention can also be used as additives in drinking water. Compounds of formula (Ia)

where

R 1 and R ² are as defined above, and can be obtained by

R1 is as defined above and

R 5 is an alkyl or aryl group, reacted with a compound of formula V,

HS- (CH ₂ ) ₂ -θ-R *

An acid addition salt of formula V, for example a hydrohalide or a free base, is dissolved in an alcohol such as ethanol, to which a solution of a compound of formula IV in an inert solvent, for example an aliphatic ketone, such as dimethylketone, is added. The reaction is preferably carried out at room temperature up to the boiling point of the reaction mixture, in particular at 25 to 50 ° C, and lasts between 2 and 12 hours.

In the following examples, which explain the invention in more detail, the temperatures are in degrees Celsius.

Example 1

14-Desoxy-14 {[2- (4-acetoxyethyl) piperazino] ethylmercaptoacetoxyjmutilin a} (4-Hydroxyethylpiperazino) ethanethanol

4-Hydroxyethylpiperazine was heated to 100 ° with a solution of ethylene sulfide in benzene in a 3: 1 molar ratio in an autoclave for 17 hours. After cooling the reaction mixture, the polymeric material was filtered off, washed with benzene, the solvent was evaporated and the product was distilled through a Vigreux column. Boiling point of the title compound 97.5 ° / 13.33 Pa.

(h) 14-Desoxy-14 - {[2- (4-acetoxyethyl) plperazino] ethylmercaptoacetoxyjmutilin

1.81 g of (4- ^, hydroxyethylpiperazino) ethanethanol are added under nitrogen to a solution of 0.35 g of sodium in 25 ml of anhydrous ethanol and after (V) where:

R ² is as defined above.

For example, the process can be carried out by dropwise adding a solution of 5.85 g of 14-desoxy-14-tosyloxyacetoxymutilin in 15 ml of ethyl methyl ketone in a solution of sodium in anhydrous low alcohol. After stirring at room temperature for four hours, the solvent was removed in vacuo and the residue was taken up in 50 ml of ethyl acetate, thereby partially over-esterifying. Separation of the acetylated product from the non-acetylated product is accomplished by column chromatography on silica gel eluting with 7: 1 chloroform-methanol. The quicker fraction was converted with ethereal hydrochloric acid into the hydrochloride, which softened at 137-140 °. M.p. 142-144 °, maleic acid (bis-maleate) acid salt.

Example 2

14-Desoxy-14-j [2- (4-acetoxyethyl) piperazino] ethylmercaptoacetoxyjmutilin

(a) 14-Desoxy-14 - {[2- (4-hydroxyethyl) piperazinoethylmercaptoacetoxyjmutilin

The procedure is as in Example 1b, but the residue is removed from the solvent after vacuum evaporation into 50 ml of methylene chloride, washed 5 times with water and dried over magnesium sulfate. The solution is mixed with 5 ml of a 5.8 N solution of hydrochloric acid in ether. Upon further addition of ether, the hydrochloride precipitates as a crystalline mass. T. softening 192-197 °.

b) 14-Desoxy-14 - {[2- (4-acetoxyethyl) piperazino] ethylmercaptoacetoxyjmutilin

To 4.0 g of 14-desoxy-14 - {[2- (4-hydroxyethylpiperazino] ethylmercaptoacetoxy} mutilin was added 10 ml of acetic anhydride under ice-cooling, and then stirred at room temperature for 5 hours, then poured into 150 ml of cold. The aqueous phase was basified with 10N aqueous sodium hydroxide solution under cooling, the resulting free base was taken up in ethyl acetate, dried over magnesium sulfate and the solvent was evaporated. Melting point bi3 (hydrogen maleate): 142-144 °.

Example 3

14-Desoxy-14 - {[2- (4-propionyloxyethyl) piperazino] ethylmercaptoacetoxyjmutilin

0.50 g of 14-desoxy-14 - {[2- (4-hydroxyethyl) -piperazinomethylmercaptoacetoxyjmutiline was refluxed for 2 hours in 5 ml of dichloromethane with 0.20 g of propionyl chloride. After cooling, crystalline dihydrochloride precipitates by addition of ethereal hydrochloric acid and dilution with anhydrous ether. The salt is filtered off with suction and washed with ether. Mp 182-187 °.

Example 4

14-Desoxy-14 - {[2- (4-plvaloyloxyethyl) piperazoylmethylmercaptoacetoxyjmutilin

0.50 g of 14-desoxy-14 - {[2- (4-hydroxyethyl) piperazino] ethylmercaptoacetoxyjmutiline was refluxed in 5 ml of dichloromethane with 0.15 g of pivaloyl chloride for 4 hours. After cooling by addition of ethereal hydrochloric acid and dilution with anhydrous ether, crystalline dihydrochloride precipitates. After aspiration, this was washed briefly with anhydrous ether and dried in vacuo. Substance in the presence of water very easily hydrolyzes to the base.

Example 5

14-Desoxy-14 - {[2- (4-benzoyloxyethyl) piperazino] ethylmercaptoacetoxyjmutilin

0.50 g of 14-desoxy-14 - {[2- (4-hydroxyethyl) piperazino] ethylmercaptoacetoxyjmutilin was reacted with 0.16 g of henzoyl chloride for 2 hours as described in Examples 3 and 4. The dihydrochloride is then precipitated as described. Softens at 132-135 °.

Example 6

14-De'soxy-14 - {[2- (4-acetoxyethyl) piperazino] ethylmercaptoacetoxy] dihydromutilin

a) 14-Desoxy-14-tosyloxyacetoxydihydromutilin

Way ":

To a solution of 8.86 g of dihydropleuromutilin in 30 ml of dry pyridine is added, at -15 °, with vigorous stirring, 6.10 g of p-toluenesulfochloride at once. Stir for 2 hours at -15 ° and then for an hour at 0 °. It is then poured into ice water and the product is taken up in methylene chloride. The organic phase is washed successively with ice water and then saturated sodium bicarbonate solution while cooling. Drying over sodium sulfate and evaporation gave a product which was uniform in thin layer chromatography and softened at 78-80 °.

Method / 3}:

0.53 g of 14-desoxy-14-tosyloxyacetoxymutililine in 10 ml of ethyl acetate is hydrogenated to 0.10 g of 10% palladium on carbon at atmospheric pressure and room temperature. The calculated amount of hydrogen is absorbed after about 1 hour. The catalyst was removed from the solution by filtration and evaporated in vacuo. The fabric has a softening point of 78-80 °.

b) 14-Desoxy-14 - {[2- (4-hydroxyethyl) piperazino] ethylmercaptoacetoxy} dihydromutilitic

14-Desoxy-14-tosyloxyacetoxydihydromutilin was reacted with analogy to Example 2 and reacted with 2- (4-hydroxyoxypropylazino) ethanethiol to give 14-desoxy-14 - {[2- (4-hydroxyethyl) piperazino] ethylmercaptoacetoxy] dihydroinutin. T. softening of dihydrochloride 135-140 °.

c) 14-Desoxy-14 - {[2- (4-acetoxyethyl) piperazino] ethylmercaptoacetoxy (dihydromuitilin

0.50 g of 14-desoxy-14 - {[2- (4-hydroxyethyl] piperazino] ethylmercaptoacetoxy] di-dromutilin is left to stand at room temperature for 2 hours with 1.5 ml of acetic anhydride and then diluted with 10 ml of water and stirred for 1 hour. The solution was extracted with ether (3.times.) and the dihydrochloride was precipitated with ethereal acetic acid as described in Example 4, m.p.

Claims (2)

SUBJECT INVENTION U Ri ethyl or vinyl group, and R2 is ^{1-acyloxyalkyl} o * 2-5 carbon atoms in the acyloxy portion and 1 to 4 carbon atoms in the alkyl group or benzoyloxyalkyl their addition salts with acids, and one quaternary salts thereof, wherein the compound of formula Ia . where R1 is as defined above and R &lt; ^{21 &} gt ^; is C1-C4 hydroxyalkyl, reacted with an acylating agent of formula III, R <—C — B II o (III), where B is C 1 -C 4 alkoxy, bromine, chlorine, or -O-C-R 4; and II o R4 is alkyl of 1 to 4 carbon atoms or phenyl, and the resulting pleuromutilins of formula I are optionally converted into their acid addition salts or quaternary salts. 2. A process for the preparation of the novel pleuromutilins of the formula I, wherein R1 is as defined in 1 and R2 is acyloxyalkyl of 2 to 5 carbon atoms in the acyloxy group and 1 to 4 carbon atoms in the alkyl group, and their acid addition salts and quaternary acids. a salt, characterized in that the compound of formula (Ia) wherein R 1 is as defined above and R ²¹ is C 1 -C 4 hydroxyalkyl is reacted with a compound of formula (III) wherein B is C 1 -C 4 alkoxy and R 4 is C 1 -C 4 alkyl and the pleuromutilins of formula I obtained are optionally converted to their acid addition salts or quaternary salts.