WO1996034007A1

WO1996034007A1 - Quinolonylcarboxyerythromycin derivatives and pharmaceutical compositions containing them

Info

Publication number: WO1996034007A1
Application number: PCT/MX1995/000006
Authority: WO
Inventors: Miguel Angel Corpi Constantino
Original assignee: Laboratorios Aranda, S.A. De C.V.
Priority date: 1995-04-27
Filing date: 1995-10-04
Publication date: 1996-10-31
Also published as: AU3710695A

Abstract

The present invention relates to 2'-quinolonylcarboxyerythromycin derivatives and to pharmaceutical compositions containing them and which have an antimicrobial activity. It also relates to derivatives of 2'-quinolonylcarboxylate of erythromycin wherein the quinolonylcarboxylic nucleus is bound to the erythromycin forming an ester with oxydril in the position 2' of the aminosaccharide nucleus (desosamine) of the erythromycin. Derivatives of quinolonylcarboxylate of erythromycin wherin the quinolonylcarboxylic nucleus is bound to the erythromycin to form a salt with the tertiary amino group of the aminosaccharide (desosamine) nucleus of the erythromycin. These compounds will take henceforth the generic name of 'Derivatives of Quinolonylcarboxylate of Erythromycin'.

Description

TITLE OF THE INVENTION:

"DERIVATIVES OF CHINOLONYL CARBOXIERITROMYCIN AND COMPOSITIONS

PHARMACEUTICS THAT CONTAIN THEM "

Background of the Invention:

The present invention relates to the 2'-Quinolonylcarboxytrichthrin derivatives and their pharmaceutical compositions containing them and having an antimicrobial activity.

Erythromycin 2'-Quinolonylcarboxylate derivatives in which the quinolonylcarboxylic nucleus is attached to erythromycin forming an ester with the 2'-position oxyhydrile of the aminosaccharide nucleus (deosamine) of erythromycin.

Derivatives of the erythromycin quinolonylcarboxylate in which the quinolonylcarbυxycytic nucleus is bound to the erythromycin forming a sai with the tertiary amino group of the aminosaccharide nucleus (deosamine) of erythromycin.

These compounds are hereinafter generically referred to as "Erythromycin Quinolonylcarboxylate Derivatives."

A further object of this invention is related to the processes for the preparation of the same derivatives. The derivatives of the erythromycin quinolonylcarboxylate of the present invention have a marked activity against a wide range of GRAM (+) and Gram (-) microorganisms as well as an interesting action as promoters of hyprobiotic growth. Field of the invention:

The object of the present invention is related to the derivatives of "2'- Erythromycin Quinoionylcarboxylate" hereinafter referred to as "Erythromycin Quinolonylcarboxylate", to the process for its preparation and to pharmaceutical compositions containing these compounds that have an antimicrobial, promoting action of growth and probiotic action.

Erythromycin quinolonylcarboxylate derivatives, in which the quinolonylcarboxylic nucleus is linked to Erythromycin forming a salt with the amino group of the aminosaccharide nucleus (deosamine) of the Erythromycin to the process for its preparation and to pharmaceutical compositions containing these compounds an antimicrobial action, promoter of growth and probiotic action.

The Erythromycin quinolonylcarboxylate derivatives of this invention have a very high antimicrobial activity being effective against a wide range of Gram (+) and Gram (-) microorganisms and with a very interesting action as growth promoters and probiotics whose activities make these compounds useful in both veterinary and human use applications.

Especially the Quinolonic derivatives of this invention have the following structural formulas:

(IH)

Description of the preferred embodiments of the invention: OBTAINING DERIVATIVES OF 2'QUINOLONIL-ERYTHROMYCIN

2'-Quinolonyl Erythromycin derivatives

Esters in the 2 'position of the aminosaccharide nucleus (Desosamine) of Erythromycin

1-R ₁ -6-Fluor-7-R2-1, 4-dihydro-4-oxoquinolin-3-carboxylic acid

2 '- (6-fluorine quinolonyl carboxy) - Erythromycin

(IH)

In this: R ^ represents H, alkyl radical of 1 to 4 carbons (C) straight or branched chain, Cycloalkyl radical of 3 to 5 O

As radicals of 1 to 4 C, straight chain alkyl radicals, methyl, ethyl, propyl and butyl are considered, with ethyl being preferred.

As radicals 1 to 4 C of the straight chain, alkyl, methyl, ethyl, propyl and butyl radicals are considered, with ethyl being preferred.

As radical of 1 to 4 C with branched chain are considered: isopropyl, secondary butyl and tertiary butyl with isopropyl being preferred.

As cycloaiquil radical of 3 to 5 C, cyclopropyl, cyclobutyl and cidopentyl are considered cyclopropyl being preferred.

R2 represents a halogen atom or a heterocyclic nucleus selected from piperazin-1-yl, 4-methylpiperazin-1-yl, 4-ethylpiperaziπ-1-i¡.

As halogen atom (Hal) are considered: bromine, fluorine and chlorine, with chlorine being preferred.

Also included in the field of the present invention are salts formed with organic acids such as: ei stearate, ei aurii sulfate and ei ioctobionate, which can be obtained according to well known procedures. The compounds of this invention in which R2 represents a halogen atom are prepared by reacting the 1-R- _| -6-fluor-7-halogen-1, 4- dihydro-4-oxoquinolin-3-carboxylic. (II) in a properly activated form (IV) with erythromycin (I) and optionally when desired by introducing a substituent other than the halogen at position 7 of the quinolonylcarboxylic core (III). Particularly in the case represented with 1-R- chloride _| -6-fluor-7-halogen-1, 4-dihydro-4-oxoquine, n-3-carboxy, the piocess can be represented by the following route (A).

(IV)

In which the radical R- _j has the aforementioned meaning and Hal means a halogen atom. In the compounds of the formula (III) in which F? 2 represents a piperazin-1-yl radical or optionally 4-substituted with a methyl or ethyl radical, they are prepared by reacting the 7-derived halogen II IA with piperazine or optionally with 1-methyl piperazine or 1-ethyl piperazine according to the following reaction:

Where R- _j has the aforementioned meaning and R3 can be hydrogen, methyl or ethyl. These same compounds can be obtained by preparing the properly activated form of 1-Rι-6-fluor-7-R ₂ -1,4-dihydro-4-oxoquinolin-3-carboxylic acid. (IV) to make it react with erythromycin according to the following reaction:

Where R- _j has the aforementioned meaning and R2 can be a heterocyclic nucleus selected from piperazin-1-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl.

As an alternative route (B) instead of the aforementioned acid chloride (IV) a mixed anhydride with the appropriate acid can be used. These compounds can be obtained according to the procedure.

In particular, the compounds (IV) can be easily prepared by reacting the corresponding addendum (II) with the appropriate halogenated agent such as thionium chloride tri, or phosphorus pentadoride in a suitable solvent such as toluene, benzene, methiene chloride, acetone , dimethyl formamide or acetic acid.

The mixed anhydride of the compounds (II) with a suitable addendum can be reacted at a low temperature the corresponding compound (II) in its potassium salt form with the selected acid doride with trimethylacetyl chloride being preferred .

The required compounds (II) can be prepared from the compound (II) in which R- _j is H, with the corresponding alkyl halide R-Hal in a suitable solvent in the presence of a hydrazide (halogenhydric) acceptor as for example an alkali carbonate or an organic base preferably trialkiamine or pyridine. As a suitable solvent, one with a polar character and a boiling point of approximately 100 ° C can be selected.

The compounds (III) of the present invention possess a very high degree of antibacterial activity against a very wide range of Gram (+) and Gram (-) microorganisms, as well as a very interesting activity as growth and probiotic promoters. They can be suitably mixed with pharmaceutical excipients and formulated conveniently for oral, parenteral or topical administration.

Pharmaceutical compositions containing as an active ingredient an ephediva amount of one or more of the compounds of the formula (III) may presented in the form of tablets, dragees, capsules, granules, powders, emulsions, foams, creams or suppositories.

The amount of active prindpio that is administered directly may vary depending on the type of administration route selected, the age and condition of the patient.

The following examples are given to better illustrate the process of obtaining the invention without this being limiting. EXAMPLE 1

Preparation of erythromycin 1-ethyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-3-qunolnolyl carboxylate

13.5 (0.05 mol) of 1, ethyl-6-fluoro-7-doro-1, 4-dihydro-4-oxo-3-quinolonyl carboxylic acid are added at 55 ml. of glacial acetic acid and cooling the mixture to 15-20 ° C with agitadon dissolve the product. To this solderon, 30.3 grams of thionyl chloride are added slowly and with stirring allowing the temperature to rise to 25-30 ° C.

The mixture is stirred for 6 hours, cooled to 15 ° C and the crystallized product formed is filtered under vacuum by washing it with 150 ce of dry benzene, added to 150 ce of neutralized acetonitrile at pH 70 with triethylamine while stirring the mixture at 20 ° C.

29.4 g (0.04 mol) of base erythromycin are added to 150 ce of dimethylformamide by adding 3 ce of triethylamine while stirring to complete dissolution at 20 ° C. This soludon is added to the acid chloride suspension and is raised to the temperature with stirring at 60-65 ° C for 8 hours. After cooling to 20-25 ° C, it is filtered to remove the residual solid and the pH is adjusted to 9.5-10.0 with triethylamine, stirring for 30 minutes at the same temperature.

After cooling to 25 ° C with stirring for 30 minutes, it is filtered under vacuum by washing the solid with 100 ce of cold water, the filtered solder is adjusted to pH 9.5-10.0 with triethylamine, separating the organic and aqueous phase. The aqueous phase is concentrated by vacuum distillation and cooled to 25 ° C. The concentrated solution is filtered under vacuum and acetone is added in a proportion at this temperature overnight. The crystallized product is filtered under vacuum, washed with 150 ce of acetone and dried at 50 ° C. EXAMPLE 2

Preparation of 1-cyclopropyl-6-fluoro-7-chloro-1, 4-dihydro-4-oxo-3-quinolonyl carboxylate erythromycin 14.08 g (0.5 mol) of 1-ddopropyl-6-fluoro-7-chloro-1, 4-dihydro-4-oxo-3- quinolonyl carboxylic acid are dissolved in 55 ce of glacial acetic acid following the same procedure as in Example 1 to form the corresponding acid doruro which is subsequently reacdoned with 29.4 g (0.04 mol) of erythromidna following the procedure of example 1. The crystallized product obtained is dried under vacuum at a temperature of 40 ° C.

EXAMPLE 3

Preparation of 1-cyclopropyl-6-fluoro-7-chloro-1, 4-dihydro-4-oxo-3-quinolonyl carboxylate erythromycin

5.97 g (0.05 mol) of 1-ethyl-6-fluoro-7- (piperazin-1-yl) -1,4-dihydro-4-oxo-3- quinolonyl carboxylic acid dissolved in 70 ml. of acetone at 20 ° C and 6.4 ce of reactive grade hydrochloric acid (36.5% Hcl) are added slowly kept stirring for 2 hours at a temperature of 15 ° C the crystallized product is filtered under vacuum and washed with acetone (35 ml .) The product is dried under vacuum at 40-50 ° C and added to 55 ce of glacial acetic acid by slowly stirring 30 grams of thionyl chloride maintaining a temperature between 25-30 ° C for 4 hours, the product crystallized It is filtered under vacuum and washed with 150 ce of dry benzene. This acid chloride thus obtained is added to 150 ce of ethyl acetate by cooling to 10 ° C with stirring, neutralized to pH 7.0 with triethylamine. To this mixture is added with stirring a solder of 29.4 g (0.04 mol.) Of base erythromycin in 150 ce of άirπeíii formamide and 3 ce of triethylamine, stirring the mixture for 8 hours at 60-65 ° C cooled to 15 ° C and 200 ce of cold water are added stirring for 5 minutes. The pH is adjusted to 9.5-10.0 with triethylamine while stirring at 10-15 ° C, filtered under vacuum to remove the suspended solid that is washed with cold water and the organic and aqueous layers are separated by washing the organic and collecting the aqueous solution. The aqueous solution is cooled to

15 ° C and its pH is adjusted to 8.5 with dilute sulfuric acid added slowly. The solution is allowed to stand overnight at 5 ° C, the crystallized product is filtered under vacuum and washed with 100 ce of acetone water (1 to 1) and dried under vacuum at 40 ° C, melting point 200-208 ° C.

EXAMPLE 4

Using 1-ethyl-6-fluoro-7- (4-methyl-piperazin-1-yl) -1, 4-dihydro-4-oxo-3- quinolonylcarboxylic and erythromidna base gives 1-ethyl-6-fluoro- 7- (4-methyl-piperazin-

1-yl) -1, 4-dihydro-4-oxo-3-quinolonylcarboxylate erythromycin, in this case it is not it is necessary to prepare the hydrochloride as in example 3 and the acid doruro is directly prepared with the thionyl doruro. EXAMPLE 5

Using 1-ethyl-6-fluoro-7- (4-ethyl-piperazin-1-yl) -1, 4-dihydro-4-oxo-3- quinolonylcarboxylic and erythromidna base gives 1-ethyl-6-fluoro- 7- (4-methyl-pipe-razin-1-yl) -1, 4-dihydro-4-oxo-3-quinolonylcarboxylate erythromidna, in the same way as in the previous example it is not required to prepare the dorhydrate as in the Example 3 and the acid chloride is directly prepared with thionyl doride. EXAMPLE 6

Preparation of the salt of 1-Ethyl-6-fluoro-7- (piperazin-1-yl) -1,4-dihydro-4-oxo-3-quinolonylcarboxylate erythromycin.

14.7 g of base erythromycin (0.02 mol) are added to 200 ce of distilled water by adding dropwise with stirring at room temperature approximately 2.3 ce of reactive grade hydrochloric acid by adjusting the pH to 1.5 obtaining a complete solution. Separately, 6.4 g (0.02 mol) of 1-ethyl-6-fluoro-7- (piperazin-1-yl) -1,4-dihydro-4-oxo-3-quinolonylcarboxylic acid mixture is added with stirring to 150 ce of water distilled by dropping a 20% solution of sodium hydroxide (approx. 4.5 ce) to complete dissolution by adjusting the pH to 11.0, this solution after stirring at 20 ° C for 10 minutes is filtered under vacuum and slowly added with Stirring to the adducted solution of erythromidna, cooled to 10-15 ° C with stirring for one hour. The crystallized product is filtered under vacuum by washing it with 200 ce of cold water and 200 ce of acetone, drying under vacuum at 40 ° C.

Claims

Claims: 1. Quinolonylcarboxierithromycin derivatives and pharmaceutical compositions containing them, characterized by being derivatives of the 2 'Quinolonyl Carboxyte erythromycin, obtained as esters in the 2' position of the erythromycin nodule (deosamine) of the erythromycin attached to the quinolonylcarboxylic core.

Erythromidna (I)

1-R ₁ -6-Fluoro-7-Rr1, 4-dihydro-4-oxoquinolin-3-carboxylic acid, represented by the following structural formula:

(lll) 1) where R- _| , represents H, alkyl radical of 1 to 4 straight or branched chain carbons, cycloalkyl radical of 3 to 5 O

As radicals of 1 to 4 C, straight chain alkyl, methyl, ethyl, propyl and butyl radicals are considered ethyl being preferred. - As radical of 1 to 4 C with branched chain are considered: isopropyl, secondary butyl and tertiary butyl with isopropyl being preferred.

Cidoalkyl radicals from 3 to 5 C are considered cyclopropyl, cyclobutyl and dclopentyl, with cyclopropyl being preferred. R2 represents a halogen atom preferably Cl or a heterocyclic nucleus selected from piperazin-1-yl, 4-methyl piperazin-1-yl, 4-ethyl piperazin-1-yl.

2. Quinolonylcarboxieritromidna derivatives and pharmaceutical compositions containing them, in accordance with the claims in clause 1, which also include salts formed with organic acids such as stearate, lauryl sulfate and lactobionate.

3. Quinolonylcarboxiertromidine derivatives and pharmaceutical compositions containing them, in accordance with the claims in clause 1, where the 5 derivatives of the 2'Quinolonylcarboxieritromidna represent in Ri, a radical selected from cyclopropyl and ethyl.

4. Quinolonylcarboxieritromidna derivatives and pharmaceutical compositions containing them, in accordance with the claims in clause 1, wherein the 2'Quinolonylcarboxieritromidna derivatives represent in R2 a halogen atom or a heterocyclic nucleus selected from piperazin-1-l , 4-methylpiperazin-1- or il, 4-ethylpiperazin-1-yl.

5. Quinolonylcarboxieritromidna derivatives and pharmaceutical compositions containing them, in accordance with claim 1, characterized by containing 1-Ethyl-6-fluoro-7-Chloro-1, 4-dihydro-4-oxo-3-quinolonylcarboxylate of erythromycin.

6. Quinolonylcarboxierithromycin derivatives and pharmaceutical compositions containing them, in accordance with the claims in clause 1, characterized by containing 1-Ethyl-6-fiuoro-7- (piperazin-1-yl) -1, 4-dihydro- Erythromycin 4-oxo-3-quinolonylcarboxylate.

7. Quinolonylcarboxierithromycin derivatives and pharmaceutical compositions containing them, in accordance with claim 1, characterized for containing 1-Ethyl-6-fluoro-7- (4-methylpiperazin-1-yl) -1, 4-dihydro-4-oxo-3- quinolonylcarboxylate of erythromidna.

8. Quinolonylcarboxieritromidna derivatives and pharmaceutical compositions containing them, in accordance with claim 1, characterized by containing 1-Ethyl-6-fluoro-7- (4-ethyl piperazin-1-yl) -1, 4- Erythromidna dihydro-4-oxo-3- quinolonylcarboxylate.

9. Quinolonylcarboxierithromycin derivatives and pharmaceutical compositions containing them, as claimed in clause 1, characterized by containing 1-cyclopropyl-6-fluoro-7- (chlorine) -1, 4-dihydro-4-oxo-3 Erythromycin-quinolonylcarboxylate.

10. Quinolonylcarboxieritromidna derivatives and pharmaceutical compositions containing them, in accordance with claim 1, characterized by containing 1-cyclopropyl-6-fluoro-7- (piperazin-1-yl) -1, 4-dihydro-4 -oxo-3- erythromycin quinolonylcarboxylate.

11. Quinolonylcarboxierithromycin derivatives and pharmaceutical compositions containing them, in accordance with claim 1, characterized in that they contain 1-ddopropyl-6-fluoro-7- (4-methyl piperazin-1-yl) -1, 4- Erythromycin dihydro-4-oxo-3- quinolonyl carboxylate.

12. Quinolonylcarboxierithromycin derivatives and pharmaceutical compositions containing them, in accordance with claim 1, characterized by containing 1-cyclopropyl-6-fluoro-7- (4-ethyl piperazin-1-yl) -1, 4- Erythromycin dihydro-4-oxo-3-quinolonyl carboxylate.

13. Quinolonylcarboxieritromidna derivatives and pharmaceutical compositions containing them, in accordance with claim 1, characterized in that the derivatives of erythromycin Quinolonylcarboxylate in which the Quinoloncarboxylic nucleus is linked to erythromycin forming a salt with the amino group of the nucleus aminosaccharide (desosamine) of erythromycin. Represented by the following structural formula:

Where R- _j , represents H, alkyl radical of 1 to 4 straight or branched chain carbons, cidoalkyl radical of 3 to 5 O

As radical of 1 to 4 C straight chain alkyl considered, methyl, ethyl, propyl and butyl radicals _Q ethyl being preferred.

As the cycloalkyl radical of 3 to 5 C, cyclopropyl, cyclobutyl and dclopentyl are considered cyclopropyl being preferred. R2 represents a halogen atom preferably Cl or a heterocyclic core 5 selected from piperazin-1-yl, 4-methyl piperazin-1-yl, 4-eti ^' l piperazin-1-yl.

14. Quinolonylcarboxiertromidine derivatives and pharmaceutical compositions containing them, as claimed in clause 13, characterized in that the salts of erythromycin Quinolonylcarboxylate in R- _j represent a radical selected from clopropyl and ethyl.

15. Quinolonylcarboxierithromycin derivatives and pharmaceutical compositions containing 0, in accordance with claim 13, characterized in that the salts of erythromycin Quinolonylcarboxylate, in R2 represent a halogen atom or a heterocyclic nucleus selected from piperazin-1- il, 4-methyl piperazin-1-yl, 4-ethyl piperazin-1-yl.

16. Quinolonylcarboxieritromidna derivatives and pharmaceutical compositions containing them, in accordance with the claim in clause 13, characterized in that the salts of erythromidna quinolonylcarboxylate containing 1-Ethyl-6-fluoro-

Erythromycin 7-doro-1,4-dihydro-4-oxo-3-quinolonylcarboxylate.

17. Quinolonylcarboxierithromycin derivatives and pharmaceutical compositions containing them, as claimed in clause 13, characterized in than the salts of erythromycin quinolonylcarboxylate containing 1-Ethyl-6-fluoro-7- (piperazin-1-yl) -1, 4-dihydro-4-oxo-3-quinolonylcarboxylate erythromycin.

18. Quinolonylcarboxierithromycin derivatives and pharmaceutical compositions containing them, in accordance with claim 13, characterized in that the salts of erythromycin Quinolonylcarboxylate containing 1-Ethyl-6-fluoro-7- (4-methylpiperazin-1 -il) -1, 4-dihydro-4-oxo-3-quinolonylcarboxylate erythromycin.

19. Quinolonylcarboxierithromycin derivatives and pharmaceutical compositions containing them, in accordance with claim 13, characterized in that the salts of erythromycin quinolonylcarboxylate containing 1-Ethyl-6-fluoro-7- (4-ethyl piperazine- 1-yl) -1,4-dihydro-4-oxo-3-quinolonylcarboxylate erythromycin.

20. Quinolonylcarboxierithromycin derivatives and pharmaceutical compositions containing them, in accordance with claim 13, characterized in that the salts of erythromycin quinolonylcarboxylate containing 1-cyclopropyl-6- fluoro-7- (doro) -1, Erythromycin 4-dihydro-4-oxo-3-quinolonylcarboxylate.

21. Quinolonylcarboxieritromidna derivatives and pharmaceutical compositions containing them, in accordance with claim 13, characterized in that the salts of erythromycin quinolonylcarboxylate containing 1-cyclopropyl-6-fluoro-7- (piperazin-1-yl ) -1, 4-dihydro-4-oxo-3-quinolonylcarboxylate erythromycin.

22. Quinolonylcarboxierithromycin derivatives and pharmaceutical compositions containing them, in accordance with claim 13, characterized in that the salts of erythromycin quinolonylcarboxylate containing 1-cyclopropyl-6-fluoro-7- (4-methyl piperazine- 1-yl) -1,4-dihydro-4-oxo-3-quinolonylcarboxylate erythromycin.

23. Quinolonylcarboxierithromycin derivatives and pharmaceutical compositions containing them, in accordance with claim 13, characterized in that the salts of erythromycin quinolonylcarboxylate containing 1-cyclopropyl-6-fluoro-7- (4-ethyl-piperazin -1-yl) -1, 4-dihydro-4-oxo-3-quinolonylcarboxylate erythromycin.

24. Quinolonylcarboxieritromidna derivatives and pharmaceutical compositions containing them, as claimed in the preceding clauses, caraderized because they have a growth-promoting antimicrobial addivity that contains a therapeutically effective amount of one or more of the components in mixtures with pharmaceutically suitable diluents. and acceptable.