FR2521146A1 - Erythromycin or its propionate salts with sulphur contg. acids - useful as antibacterials with low toxicity and giving high blood levels - Google Patents

Abstract

Erythromycin (I), or its propionate (II), salts with acetylcysteine (III), carboxymethylcysteine (IV), thiazolidin-4-carboxylic acid (V) or mercaptosuccinic acid (VI) are new. The salts are antibacterials for use in the same way as (I) or (II), but they have very low toxicity and give high blood levels. The salts have good mucolytic activity. The salts of (II) are absorbed orally at a rate similar to that of erythromycin estolate, but they have good mucolytic activity in contrast to the estolate. The salts of (I) are poorly absorbed orally.

Description

Thiol derivatives of erythromycin with therapeutic activity, process for their preparation, and pharmaceutical products in which they appear.

 The present invention relates to new thiol derivatives of erythromycin and the propionic ester of erythromycin, in particular salts of erythromycin with acids containing in their molecule a sulfur atom in the form of thioalcohol or thioether or thioester.

 The compounds of the present invention find a therapeutic application in cases where erythromycin or its propionyl ester is already used, and are generally characterized by very low toxicity and high blood concentration; these are very important aspects from a therapeutic point of view.

et X représente le radical de l'érythromycine ou du propionylester de l'érythromycine ayant pour formule:

où R1 représente H ou CH3 - CH2 - CO.The derivatives according to the present invention have the following general formula:
R - COO - X (1) where R represents the thEhoy1m-mercaptopropionylglycine radical

and X represents the radical of erythromycin or propionyl ester of erythromycin having the formula:

where R1 is H or CH3 - CH2 - CO.

 The compounds according to the present invention all appear as white, microcrystalline powders. In general, salts containing erythromycin monopropionyl ester are less soluble than corresponding salts containing erythromycin base; for all derivatives, in addition, the solubility increases in solvent mixtures, such as water-ethanol (1-5%), and water-glycol-ethylenic (1-5%).

 Their use is in any case provided for in all pharmaceutical forms: capsules, solutions, injections, aerosols, ointments, powders and suspensions, both for man and for veterinary applications. Particularly for the erythromycin base salts, pharmaceutical formulations of the injectable or aerosol-administrable type are provided, whereas for the propionyl erythromycin derivatives, particularly preferred oral dosage forms and suspensions are preferred. Almost all compounds are sensitive to sunlight, moisture and heat, and are real salts, chemically and physically well defined.The method of preparation of the thiol derivatives of erythromycin or erythromycin propionyl ester, according to the present according to the invention provides for reacting erythromycin base or propionic ester of erythromycin base with the acid, in a stoichiometric proportion or in the presence of a slight excess of the antibiotic nucleus and is characterized in that the reaction is carried out in an organic solvent, at a temperature between 20 and 400C and in the presence of water in an amount of not more than 20%.

 It has indeed been found, and this is surprising, that the presence of water, preferably in the order of 4 to 5% by volume relative to the reaction solvent, makes it possible to complete the reaction with excellent yields. On the other hand, the amounts of water greater than 20% carry the risk of a redissolution of the reaction product in the aqueous / organic mixture.

 The compounds of the present invention have been the subject of toxicological, pharmacological and pharmacodynamic tests for the purpose of verifying the toxicity (and therefore their potential for use in the therapeutic field) and the therapeutic properties.

In the results indicated below, the compounds of the invention have been referenced by the following symbols:
RV / 06 - erythromycin-thenoyl-mercaptopro-
pionylglycinate
RV / 16 - erythromycin propionate thenoyl-z-
mercaptopropionylglycinate.

A) Acute toxicity
Acute toxicity was determined in Swiss white mice by oral and intravenous route.

The LD50 were calculated by the Probit methods, based on the mortality recorded 10 days after the treatment.

<Tb>

<SEP> COMPOUND <SEP> SEP <SEP> ADMINISTRATION <SEP><SEP> LIMIT <SEP> CONFIDENCE
<tb><SEP> LD50 <SEP> mg / kg <SEP> (lf)
<tb> Erythromycin <SEP> Pathway <SEP> oral <SEP>><SEP> 3000
<tb> Hydrochloride
<tb> Erythromycin <SEP> Intravenous <SEP><SEP> 376.58 <SEP> (478.78-296.20)
<tb> Rv <SEP> 06 <SEP> Path <SEP> oral <SEP>><SEP> 3000
<tb> Kv <SEP> 06 <SEP> Intravenous <SEP><SEP> 426.43 <SEP> (526.55-455.34)
<tb> Rv <SEP> 16 <SEP> Path <SEP> Oral <SEP> 3000
<Tb>
B) In vitro anti-bacterial activity
The anti-bacterial activity of the compounds according to the invention was evaluated by comparing the different minimum inhibition concentrations (MIC) with those of erythromycin base and erythromycin estolate on gram-positive and gram strains. -negatives grown on Brain Heart Infusion (Difco).

 The examined samples of erythromycin estolate RV 06 were subjected to preventive hydrolysis as described in USP. (American Pharmacopoeia), 20th Edition, page 1347.

The MIC / ml corresponding to the lowest concentration likely to cause a complete inhibition of bacterial growth are shown in Table I below.

<tb><SEP> Erythro- <SEP> Erythro
<tb><SEP> STRAIN <SEP> mycine <SEP> mycine <SEP> RV <SEP> 06 <SEP> RV <SEP> 16
<tb><SEP> estolate
<tb><SEP> 1) <SEP> Staph.albus <SE> SS <SEP> 03 <SEP> 0.05 <SEP> 0.05 <SEP> 0.5 <SEP> 0.05
<tb><SEP> 2) <SE> SS <SEP> 04 <SEP> 0.05 <SEP> 0.05 <SEP> 0.025 <SEP> 0.05
<tb><SEP> 3) <SEP> Staph-aureus <SEP> SS <SEP> 07 <SEP> 0.025 <SEP> 0.205 <SEP> 0.025 <SEP> 0.025
<tb><SEP> 4) <SE> SS <SEP> 08 <SEP> 0.025 <SEP> 0.025 <SEP> 0.025 <SEP> 0.025
<tb><SEP> 5) <SE> SS <SEP> 09 <SEP> 0.1 <SEP> 0.05 <SEP> 0.1 <SEP> 0.1
<tb><SEP> 6) <SE> SS <SEP> 10 <SEP> 0.1 <SEP> 0.2 <SEP> 0.1 <SEP> 0.05
<tb><SEP> 7) <SEP> Strept.
<tb><SEP> haemolyticus <SEP> SS <SEP> 17 <SEP> 3 <SEP> 3 <SEP> 3 <SEP> 1.5
<tb><SEP> 8) <SE> SS <SEP> 18 <SEP> 1.5 <SEP> 3 <SEP> 1.5 <SEP> 1.5
<tb><SEP> 9) <SEP> Strep.
<tb><SEP> faecalis <SE> SS <SEP> 19 <SEP> 0.1 <SEP> 0.1 <SEP> 0.1 <SEP> 0.1
<tb> 10) <SEP> S.lutea <SEP> ATCC <SEP> 9341 <SEP> 0.01 <SEP> 0.01 <SEP> 0.01 <SEP> 0.01
<tb> 11) <SEP> B.subtilis <SEP> ATCC <SEP> 6633 <SEP> 0.025 <SEP> 0.01 <SEP> 0.01 <SEP> 0.01
<tb> 12) <SE> SS <SEP> 127 <SEP> 0.05 <SEP> 0.025 <SEP> 0.025 <SEP> 0.025
<tb> 13) <SEP> B.cereus <SEP> ATCC <SEP> 11778 <SEP> 0.4 <SEP> 0.8 <SEP> 0.4 <SEP> 0.4
<tb> 14) <SEP> B.anthranis <SEP> SS <SEP> 08 <SEP> 0.4 <SEP> 0.4 <SEP> 0.4 <SEP> 0.4
<tb> 14bis) <SE> SS <SEP> 09 <SEP> 0.4 <SEP> 0.4 <SEP> 0.4 <SEP> 0.4
<tb> 15) <SEP> Br.melitensis <SEP> SS <SEP> 19 <SEP> 3 <SEP> 3 <SEP> 3 <SEP> 3
<tb> 16) <SEP> Br.abortus <SEP> SS <SEP> 7 <SEP> 12 <SEP> 6 <SEP> 6 <SEP> 12
<tb> 17) <SEP> Citrobacter <SEP> SS <SEP> 05 <SEP>> 200 <SEP>> 200 <SEP>> 200 <SEP>> 200
<tb> 18) <SEP> - <SE> SS <SEP> 09 <SEP>> 200 <SEP>> 200 <SEP>> 200 <SEP>> 200
<tb> 19) <SEP> S.infantis <SE> SS <SEP> 08 <SEP> 100 <SEP> 100 <SEP> 100 <SEP> 100
<tb> 20) <SEQ> S.heidelberg <SEP> SS <SEP> 18 <SEP> 100 <SEP> 100 <SEP> 100 <SEP> 100
<tb> 21) <SEP> E.cloacae <SEP> SS <SEP> 07 <SEP>> 200 <SEP>> 200 <SEP>> 200 <SEP>> 200
<Tb>

<tb><SEP> STRAIN <SEP> erythro- <SEP> erythro
<tb><SEP> mycine <SEP> mycine <SEP> Kv <SEP> 06 <SEP> RV <SEP> 16
<tb><SEP> estolate
<tb> 22) <SEQ> E.aerogenes <SEP> SS <SEP> 011 <SEP> 100 <SEP> 50 <SEP> 50 <SEP> 100
<tb> 23) <SEP> Ps.aeruginosa <SEP> SS <SEP> 10 <SEP> 100 <SEP> 100 <SEP> 200 <SEP> 100
<tb> 24) <SEP> SS <SEP> 12 <SEP>> 200 <SEP> 200 <SEP> 200 <SEP> 200
<tb> 25) <SEP> E.coli <SEP> SS <SEP> 04 <SEP> 100 <SEP> 100 <SEP> 50 <SEP> 50
<tb> 26) <SE> SS <SEP> 05 <SEP> 50 <SEP> 100 <SEP> 100 <SEP> 100
<tb> 27) <SE> SS <SEP> 06 <SEP> 100 <SEP> 50 <SEP> 100 <SEP> 25
<tb> 28) <SEP> SS <SEP> 07 <SEP> 50 <SEP> 50 <SEP> 50 <SEP> 50
<tb> 29) <SEP> Pr.mirabilis <SEP> SS <SEP> 09 <SEP>> 200 <SEP>> 200 <SEP>> 200 <SEP>> 200
<tb> 30) <SEP> Pr.vugaris <SEP> SS <SEP> 10 <SEP>> 200 <SEP>> 200 <SEP>> 200 <SEP>> 200
<tb> 31) <SEP> Kl.aerogenes <SEP> SS <SEP> 71 <SEP> 50 <SEP> 100 <SEP> 100 <SEP> 100
<tb> 32) <SEP> R1.pneumoniae <SEP> SS <SEP> 04 <SEP> 100 <SEP> 100 <SEP> 100 <SEP> 100
<tb> 33) <SEP> Sr.marcescens <SE> SS <SEP> 03 <SEP> 200 <SEP>> 200 <SEP> 200 <SEP>> 200
<tb> 34) <SEP> C.diphteriae <SEP> SS <SEP> 19 <SEP> 0.01 <SEP> 0.025 <SEP> 0.02 <SEP> 0.02
<tb> 35) <SEP> D.pneumoniae <SEP> SS <SEP> 23 <SEP> 0.05 <SEP> 0.05 <SEP> 0.05 <SEP> 0.05
<tb> 36) <SEP> N.gonorreae <SEP> SS <SEP> 27 <SEP> 0.8 <SEP> 0.8 <SEP> 0.8 <SEP> 0.8
<tb> 37) <SEP> N.meningitidis <SE> SS <SEP> 04 <SEP> 0.8 <SEP> 1.5 <SEP> 0.8 <SEP> 0.8
<tb> 38) <SEP> H.influentiae <SEP> SS <SEP> 02 <SEP> 1.5 <SEP> 1.5 <SEP> 0.8 <SEP> 1.5
<tb> 39) <SEP> R.pertussis <SE> SS <SEP> 03 <SEP> 0.4 <SEP> 0.4 <SEP> 0.4 <SEP> 0.2
<tb> 40) <SEP> R.Tubercolosis <SE> SS <SEP> 03 <SEP> 50 <SEP> 50 <SEP> 50 <SEP> 50
<tb> 41) <SEP> C.albicans <SEP> SS <SEP> 04 <SEP> 100 <SEP> 200 <SEQ> 100 <SEP> 200
<tb> 42) <SEP> C <tetani <SEP> SS <SEP> 17 <SEP> 0.4 <SEP> 0.2 <SEP> 0.2 <SEP> 0.8
<Tb>

C) In vitro anti-bacterial activity
Experimental infection with Staph.aureus and
D. pneumoniae
20 g Swiss white mice infected by parenteral introduction with a quantity of pathogenic Staph genes were used. aureus SS 07 and
D. pneumoniae SS 23 in lethal amount.

 The protective activity expressed by ED50 (mg / kg) of erythromycin base, erythromycin estolate, RV 06, RV16 orally and erythromycin ethylsuccinate, RV 06 by the skin.

 Antibiotics were administered at the time of injection of the infecting germ and after 6 to 24 hours. On the basis of survival after 7 days, the ED50s, indicated in the following Tables II and III, where the reliability limits are shown in parentheses, were determined.

Table II
Experimental infection with Staph. aureus
SS 07 (ED50) mg / kg erythromycin

<tb><SEP> COMPOUND <SEP> SEP <SEP> ADMINISTRATION <SEP> LIMIT <SEP><SEP> CONFIDENCE
<tb><SEP> ED50 <SEP> mg / kg
<tb> Etylsuccinate
<tb> Erythromycin <SEP> Subcutaneous <SEP> 1.03 <SEP> (1.34-0.79)
<tb> RV <SEP> 06 <SEP> Subcutaneous <SEP> 1.13 <SEP> (1.53-0.83)
<tb> Erythromycin <SEP> Oral <SEP> 2.09 <SEP> (2.36-1.86)
<tb> Estolate
<tb> erythromycin <SEP> Oral <SEP> 2.20 <SEP> (2.44-1.99)
<tb> RV <SEP> 06 <SEP> Oral <SEP> 2.02 <SEP> (2.32-1.75)
<tb> RV <SEP> 16 <SEP> Oral <SEP> 2.29 <SEP> (2.58-2.04)
<Tb>
Table III
Experimental infection with D-pneumoniae
SS 23 (EDsn) mg / kg erythromycin

<tb><SEP> CHANNEL <SEP> SEP <SEP> ADMINISTRATION <SEP><SEP> LIMIT <SEP> CONFIDENCE
<tb><SEP> ED50 <SEP> m <SEP> g / kg
<tb> Etylsuccinating
<tb> erythromycin <SEP> Subcutaneous <SEP> 54.23 <SEP> (69,76-42,16)
<tb> RV <SEP> 06 <SEP> Subcutaneous <SEP> @ <SEP><SEP> 59.65 <SEP> (75.02-47.43)
<tb> Erythromycin <SEP> Oral <SEP> 113.53 <SEP> (147,33-87,48)
<tb> Estolate
<tb> Erytrhomycin <SEP> Oral <SEP> 127.89 <SEP> (156,42-104,57)
<tb> RV <SEP> 06 <SEP> Oral <SEP> 121.65 <SEP> (150.91-98.06)
<tb> KV <SEP> 16 <SEP> Oral <SEP> 113.88 <SEP> (144.73-89.60)
<Tb>
D) Pharmacodynamics
a) In the rat
Oral absorption of different salts of erythromycin is studied in male rats
Sprague-Dawley, administered in batch of 6 fasting animals for 12 hours, erythromycin, erythromycin estolate, RV 06, RV 16 at a dose of 100 mg / kg (expressed as erythromycin ) orally (gastric sounding).

 Blood samples were taken 0.30 - 1 - 2 - 3 - 4 - 5 - 6 hours after absorption.

For the assay, the microbiological method was used and, as a test microorganism, B. subtilis. The experimental results are shown in the following Table IV:
Table IV
Levels in the rat
(Averages + ES)

<tb><SEP> Number <SEP> mcg / ml <SEP> after <SEP> ......... <SEP> hours
<tb><SEP> COMPOSE
<tb><SEP> Animals
<tb><SEP> 0.30 <SEP> 1 <SEP> 2 <SEP> 3 <SEP> 4 <SEP> 5 <SEP> 6
<tb> Erythromycin <SEP> 6 <SEP> 0.71 <SEP> 1.03 <SEP> 1.15 <SEP> 1.05 <SEP> 0.37 <SEP> 0.26 <SEP> 0.03
<tb><SEP> 0.19 <SEP> 0.23 <SEP> 0.24 <SEP> 0.22 <SEP> 0.10 <SEP> 0.08 <SEP><SEP> - <SEP>
<tb> Estolate <SEP> of
<tb> Rhythmomycin <SEP> 6 <SEP> 0.68 <SEP> 1.74 <SEP> 2.49 <SEP> 1.49 <SEP> 0.61 <SEP> 0.37 <SEP> 0.04
<tb><SEP> 0.07 <SEP> 0.14 <SEP> 0.35 <SEP> 0.22 <SEP> 0.10 <SEP> 0.05 <SEP> 0.01
<tb> RV <SEP> 06 <SEP> 6 <SEP> 0.37 <SEP> 0.80 <SEP> 1.23 <SEP> 0.80 <SEP> 0.60 <SEP> 0.33 <SEP > 0.07
<tb><SEP> 0.10 <SEP> 0.19 <SEP> 0.36 <SEP> 0.21 <SEP> 0.17 <SEP> 0.11 <SEP> 0.03
<tb> RV <SEP> 16 <SEP>. <SEP> 6 <SEP> 0.73 <SEP> 1.97 <SEP> 2.82 <SEP> 1.28 <SEP> 0.58 <SEP> 0.35 <SEP> 0.05
<tb><SEP> 0.09 <SEP> 0.09 <SEP> 0.14 <SEP> 0.11 <SEP> 0.08 <SEP> 0.05 <SEP> 0.01
<Tb>
b) In the healthy volunteer
In groups of 5 healthy volunteers fasting for 24 hours, erythromycin estolate, RV 16, was administered orally at a dose of 500 mg erythromycin.

 Blood samples were pre-treated 0.30 - 1 - 2 - 3 - 4 hours after absorption.

 For the assay, the microbiological method was applied using a B. subtilis strain.

The results are shown in the following Table V:
Table V
Levels at the volunteer
healthy (average + ES)

<tb><SEP> COMPOUND <SEP> Number <SEP> mcg / ml <SEP> after <SEP> ........... <SEP> hours
<tb><SEP> subjects <SEP> 0.30
<tb><SEP> 1 <SEP> 2 <SEP> 3 <SEP> 4 <SEP> 5 <SEP> 6
<tb> Estolate <SEP> of
<tb> Rhythmomycin <SEP> 5 <SEP> 0.27 <SEP> 0.58 <SEP> 2.10 <SEP> 1.41 <SEP> 1.31 <SEP> - <SEP> - <SEP>
<tb><SEP> 0.05 <SEP> 0.09 <SEP> 0.17 <SEP> 0.07 <SEP> 0.08 <SEP> - <SEP> - <SEP>
<tb> RV <SEP> 16 <SEP> 5 <SEP> 1.23 <SEP> 1.51 <SEP> 2.26 <SEP> 1.66 <SEP> 1.24 <SEP> - <SEP> - <September>
<tb><SEP> 0.10 <SEP> 0.11 <SEP> 0.11 <SEP> 0.06 <SEP> 0.08 <SEP> - <SEP> - <SEP>
<Tb>
E) Mucolytic action
The method described by
Quevauviler and COM. (Therapy 22, 485, 196?) Which consists in causing a bronchial hypersecretion after exposure of the animal to a S02 aerosol session. This study was performed on Sprague male rats
Dawley.

 All rats were challenged daily with SO.sub.2 in a concentration of 0.03%. After 50 hours of inhalation, the animals were grouped in batches of 10 elements each.

One batch received no treatment (control animals), while the others received 2 hours daily for 15 consecutive days of SO2 inhalations and treated respectively with erythromycin estolate, RV 16 oral dose of 500 mg / kg and with erythromycin ethylsuccinate,
RV 06 intramuscularly at a dose of 250 mg / kg.

 The day after the last treatment, the anesthetized animals were sacrificed, the lungs were removed and prepared for microscopic and macroscopic examination. The results are shown in the following table.

Table VI
Qualitative and quantitative estimation of
obstruction of the bronchial tree
(% of incidence)

<tb><SEP> TREATMENT <SEP> PATH <SEP> OBSTRUC
<tb><SEP> OF ADMINIS- <SEP> TION
<tb><SEP> TRATION <SEP> Plug <SEP> Clusters <SEP> Clusters <SEP> PARTIAL
<tb><SEP> compact <SEP> nodular <SEP> bullous
<tb><SEP> S02 <SEP> (control) <SEP> ----- <SEP> 40 <SEP> 13.33 <SEQ> 6.66 <SEP> 26.66
<tb><SEP> S02 + estolate
<tb><SEP> of erythromycin
<tb><SEP> 500 <SEP> mg / kg <SEP> oral <SEP> 46.66 <SEP> 20 <SEP> 6.66 <SEP> 20
<tb> S02 + <SEP> RV <SEP> 16
<tb> 500 <SEP> mg / kg <SEP> oral <SEP> 26.66 <SEP> 6.66 <SEP> 6.66 <SEP> 6.66
<tb> S02 <SEP> + erythromy- <SEP> intra
<tb> cine <SEP> ethylsuc- <SEP> muscu- <SEP> 53.33 <SEP> 26.66 <SEP> 13.33 <SEP> 20
<tb> cinate <SEP> 250 <SEP> mg / kg <SEP>
<tb> S02 + <SEP> RV <SEP> 06
<tb> 250 <SEP> mg / kg <SEP> .. <SEP><SEP> 25.66 <SEP> 6.66 <SEP> 6.66 <SEP> 13.33
<Tb>
Histological examination was then performed on the control animals and the treated animals.

1) Control animals subject to inhalation
from 502
The macroscopic bronchial obstructions noted on histological examination correspond to a mass of mucus mixed with fibrin and infiltrated with polymorphonuclear elements. Hypersecretion also concerns peripheral bronchioles and alveoli. With regard to the bronchial epithelium, there is a proliferation of goblet cells. Hyperplasia of the main bronchus results in stratification of 7 to 8 layers, associated with bronchial hypertrophy.

2) Animals treated with erythromycin estolate
at a dose of 500 mg / kg orally and at
erythromycin ethylsuccinate at the dose of
250 mg / kg intramuscularly
From the histological examination, it appears that the bronchial obstruction is formed by an abundant mucus melted with fibrin.

 Under the irritating effect of SO2, the bronchial epithelium reacts by a proliferation of cells, especially goblet cells. Hyperplasia is associated in many cases with bronchial hypertrophy. In some cases, there is an appearance in the peripheral bronchioles of cells secreting mucus.

3) Animals treated with RV 16 at a dose of
500 mg / kg orally
In animals that on macroscopic examination had an unobstructed free bronchial tree, histological examination revealed the presence of almost normal bronchi. Fithelial hyperplasia with numerous goblet cells and reduced intra-bronchial muco-purulent clusters was observed.

 The histological appearance of obstructed bronchial trees is quite similar to that of control animals.

4) Animals treated with RV 06 at a dose of
250 mg / kg intramuscularly
Histological examination of the macroscopically examined animals showed a bronchial tree free of obstructions and showed a practically normal appearance. In some animals, the presence of epithelial hyperplasia with goblet cells associated with intra-bronchial mucopurulent clusters was observed.

 Histological examination in animals with an obstructed bronchial tree showed an appearance similar to that of the control animals.

CONCLUSIONS
As a result of the toxicity tests, the erythromycin salts are toxic when administered orally. Injected, they can be slightly toxic and present in any case an LD50 quite comparable to that of erythromycin.

 In vitro antibacterial activities have shown that erythromycin salts are active in a proportion similar to erythromycin base.

 As a result of tests of in vivo antibacterial activity and pharmacodynamic tests, the RV 06 compounds are poorly absorbed orally and to the same extent as erythromycin base.

 Propionic derivatives (RV 16) are absorbed orally in a proportion substantially similar to erythromycin estolate. In contrast to erythromycin estolate, the drugs of the present invention have good mucolytic activity which is found in animals subjected to inhalation of SO.sub.2.

Claims (11)

 1. Thiol derivatives of erythromycin and propionic ester of erythromycin having the formula:  R - COO - X (I) where R represents a thenoyl-a-mercaptopropionylglycine radical

 and X represents the radical of erythromycin or propionyl ester of erythromycin, having the formula:

 where R1 is H, or CH3-CH2-CO  2. erythromycin salt with thenoyl-α-propionylglycine according to claim 1.  3. Erythromycin propionic ester salt with thenoyl-α-mercaptopropionylglycine according to claim 1.  4. Process for the preparation of the thiol derivatives of erythromycin and of the propionic ester of erythromycin in which the erythromycin base or its propionic ester reacts with the desired acid, characterized in that the reaction is carried out in an organic solvent , at a temperature between 20 and 400C and in the presence of water.  5. Preparation process according to claim 4, characterized in that the water present in the reaction solvent is not greater than 20% by volume of the reaction solvent.  6. Preparation process according to claim 5, characterized in that the volume of water is 4 to 5% of that of the reaction solvent.  7. Preparation process according to claim 4, characterized in that said organic solvent is acetone or methyl isobutyl ketone.  8. Pharmaceutical preparation, characterized in that it contains as active ingredient, a thiol derivative according to claim 1, as well as vehicles and supports of the usual type, and acceptable from a pharmaceutical point of view.  9. Pharmaceutical preparation with antibacterial and mucolytic activity, characterized in that it contains as active ingredient a derivative according to claim 1.  10. Pharmaceutical preparation according to one of claims 8 and 9, characterized in that it is in a form that allows it to be administered orally, particularly in the form of capsules and suspensions, and in that it contains as active ingredient a derivative of erythromycin according to claim 1, as well as excipients and usual vehicles.  11. Pharmaceutical preparation according to claims 8 and 9, characterized in that it is in a form that allows it to be administered parenterally and aerosolized and in that it contains as active ingredient, a derivative of the invention. propionic ester of erythromycin as well as the usual excipients and vehicles.