FR2691464A1 - New 1-oxa-6-aza-cyclopentadecane-13,15-di:one derivs. - useful as antibiotics for treating wide range of bacterial infections - Google Patents

Abstract

1-oxa-6-aza-cyclopentadecane-13,15-dione derivs. of formula (I) and their acid addn. salts are new. R1 and R2 are H or Me; Z is H or 1-18C acyl; R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl or 7-18C aralkyl. Also claimed are intermediates of formula (III)-(V) where M is a protecting gp. Specifically claimed (2R-(2R star,3S star,4R star,5R star,8R star,10R star,11R star,12S star,14R star)) -3,4-dihydroxy-2 -ethyl-3,5,6,8,12,14 -heptamehyl- 10-methoxy-11-(3,4,6- trideoxy- 3-dimethylamino -beta-D-xylohexopyranosyloxy) -1-oxa-6-aza- cyclopentadecane-13,15-dione (Ia). M is a protecting gp. In an example, treatment of (II; R = R1 = Me, R2 = H) with HCl gave the corresp. cpd. (III), which was reacted with Ac20 to give (IV; R = R1 = Me, R2 = H, M = Ac). The prod. (380mg) was suspended in 6ml CH2Cl2 together with 0.618 ml DMSO and 667 mg EDC. The mixt. was treated with 627mg pyridinium trifluoroacetate in 2ml CH2Cl, stirred for 30 mins. and worked up to give 200 mg (V; R = R1 = Me, R2 = H, M = Ac). This was stirred in 10 ml MeOH for 20 hr. to give 117 mg of prod. which was chromatographed to give (Ia).

Description

 The present invention relates to new derivatives of l-oxa 6-azacyclopentadecane 13,15-dione, their preparation process and their use as medicaments.

dans lesquels - R1 et R2 identiques ou différents représentent un atome d'hydrogène ou un radical méthyle, - Z représente un atome d'hydrogène ou le reste d'un acide carboxylique renfermant jusqu'à 18 atomes de carbone, - R représente un radical alkyle, alkényle ou alkynyle linéaire, ramifié ou cyclique, ou un radical aralkyle renfermant jusqu'à 18 atomes de carbone, ainsi que les sels d'addition avec les acides des composés de formule (I).The subject of the invention is the compounds of formula (I)

in which - R1 and R2, which are identical or different, represent a hydrogen atom or a methyl radical, - Z represents a hydrogen atom or the remainder of a carboxylic acid containing up to 18 carbon atoms, - R represents a radical linear, branched or cyclic alkyl, alkenyl or alkynyl, or an aralkyl radical containing up to 18 carbon atoms, as well as the addition salts with acids of the compounds of formula (I).

 As examples of addition salts of the present derivatives with mineral or organic acids, mention may be made of the salts formed with acetic, propionic, trifluoroacetic, maleic, tartaric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, hydrochloric, hydrobromic, hydroiodic acids, sulfuric, phosphoric and especially stearic, ethylsuccinic or laurylsulfuric acids.

 In the definition of the substituents - the alkyl, alkenyl or alkynyl radical is preferably a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, terbutyl, decyl or dodecyl, vinyl, allyl, ethynyl, propynyl, cyclobutyl, cyclopentyl radical or cyclohexyl, - the aralkyl radical is preferably a (C6H5) - (CH2) a radical, a being an integer between 1 and 6, for example the number 1, 2, 3 or 4 or a naphthyl radical.

- The remainder of a carboxylic acid is preferably an acetyl, propionyl, butyryl, isobutyryl, n-valeryl, isovaleryl, tert-valeryl or pivalyl radical.

 Among the preferred compounds of the invention, mention may be made of the compounds of formula (I) in which R1 represents a methyl radical, those in which R2 represents a hydrogen atom as well as those in which R represents an alkyl radical containing up to with 4 carbon atoms, for example those in which R represents a methyl radical, as well as the compounds in which Z represents a hydrogen atom.

 As preferred compound of the invention, mention may be made of the compound of Example 1.

 The products of general formula (I) have antibiotic activity on gram bacteria - and gram bacteria such as staphylococci, streptococci, pneumococci and hemophiliacs.

 The compounds of the invention can therefore be used as medicaments in the treatment of infections with sensitive germs and, in particular, in that of staphylQcoccies, such as septicemia with staphylococci, malignant staphylococcias of the face or skin, pyoderma, septic or suppurative wounds , boils, carbuncles, phlegmons, erysipelas and acne, staphylococcal diseases such as primary acute or post-influenza angina, bronchopneumonia, pulmonary suppuration, streptococcias such as acute angina, otitis, sinusitis, scarlet fever, pneumococci pneumonia, bronchitis; brucellosis, diphtheria, gonococcal disease, but also against infections caused by germs such as Haemophilus influenzae, Rickettsiae, Mycoplasma pneumoniae, Chlamydia, Legionella, Ureaplasma, Toxoplasma.

 The present invention therefore also has as an object, as medicaments and, in particular antibiotic medicaments, the products of formula (I) as defined above, as well as their addition salts with pharmaceutically acceptable inorganic or organic acids.

 A more particular subject of the invention is, as medicaments and, in particular antibiotic medicaments, the product of Example 1 as well as its pharmaceutically acceptable salts.

 A subject of the invention is also the pharmaceutical compositions containing as active principle at least one of the medicaments defined above.

 These compositions can be administered by the oral, rectal, parenteral route or by the local route as a topical application to the skin and the mucous membranes, but the preferred route of administration is the oral route.

 They can be solid or liquid and come in the pharmaceutical forms commonly used in human medicine, such as for example, tablets, simple or coated, capsules, granules, suppositories, injections, ointments, creams, gels they are prepared according to the usual methods. The active ingredient (s) can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not , fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

 These compositions can also be in the form of a powder intended to be dissolved extemporaneously in an appropriate vehicle, for example pyrogen-free sterile water.

 The dose administered is variable depending on the condition treated, the subject in question, the route of administration and the product considered. It can be, for example, between 50 mg and 300 mg per day orally, in humans, with the product described in Example 1.

dans laquelle R1, R2 et R conservent leur signification précédente à l'action d'un acide en milieu aqueux pour obtenir le composé de formule (III)

dans laquelle R, R1 et R2 conservent leur signification précédente, que l'on soumet à l'action d'un agent de blocage de la fonction hydroxyle en 2' pour obtenir un composé de formule (IV) ::

dans laquelle OM représente un groupement hydroxyle bloqué et les autres substituants conservent leur signification précédente, que l'on soumet à l'action d'un agent d'oxydation de la fonction hydroxyle en 13 pour obtenir le composé de formule (V)

que l'on soumet si désiré à l'action d'un agent de libération de la fonction hydroxyle en 2', et éventuellement à l'action d'un agent capable d'introduire le radical Z, si celui-ci ne représente pas un atome d'hydrogène, puis si désiré soumet les composés de formule (I) ainsi obtenu à l'action d'un acide pour en former le sel.The subject of the invention is also a process for preparing the compounds of formula (I), characterized in that a compound of formula (II) is subjected

in which R1, R2 and R retain their previous significance to the action of an acid in an aqueous medium to obtain the compound of formula (III)

in which R, R1 and R2 retain their previous meaning, which is subjected to the action of an agent for blocking the hydroxyl function at 2 'to obtain a compound of formula (IV):

in which OM represents a blocked hydroxyl group and the other substituents retain their previous meaning, which is subjected to the action of an oxidizing agent of the hydroxyl function at 13 to obtain the compound of formula (V)

which is subjected if desired to the action of an agent for releasing the hydroxyl function at 2 ', and optionally to the action of an agent capable of introducing the radical Z, if the latter does not represent a hydrogen atom, then if desired subjects the compounds of formula (I) thus obtained to the action of an acid to form the salt.

 In a preferred embodiment of the process of the invention - the hydrolysis of cladinose is carried out by means of aqueous hydrochloric acid or in methanol, - the blocking of the hydroxyl at 2 ′ is carried out using an acid or a functional acid derivative, for example an acid anhydride, an acid halide, or silicon derivatives, - oxidation of the hydroxyl at 13 is carried out using either diimides in the presence of dimethylsulfoxide (DMSO) , or chromic anhydride in sulfuric acid diluted according to the Jones oxidation reaction.

Depending on the blocking agent used, the products of formula (V) may or may not constitute products of formula (I).

- the liberation of the hydroxyl function in 2 ′ is carried out by methanolysis, - the esterification in 2 is carried out according to conventional methods, - salification is carried out by means of acids according to conventional methods.

 The compounds of formula (II) used as starting materials are products which can be prepared according to the process described in European patent application 0.467.331, filed on July 17, 1991.

 The compounds used during the process are new products and are themselves an object of the present invention. The subject of the invention is therefore, as new chemicals, the compounds of formulas (III), (IV) and (V).

 The following examples illustrate the invention without, however, limiting it.

EXAMPLE 1: (2R- (2R, 3S, 4R, 5R, 8R, 1OR, llR, 12S, 14R)) 3,4-dihydroxy 2-ethyl 3,5,6,8,10,12,14-heptamethyl 10 -methoxy 11 - ((3,4,6-trideoxy 3- (dimethylamino) beta-D-xylo hexopyranosyl) oxy) l-oxa 6-azacyclopentadecane 13,15-dione.

STAGE A: (2R- (2R *, 3S +, 4R *, 5R, 8R, 1OR, llR, 12S, 13S *, 14R *)) 2-ethyl 3,5,6,8,10,12,14-heptamethyl 10-methoxy 11 - ((3,4,6trideoxy 3- (dimethylamino) beta-D-xylo hexopyranosyl) oxy) 3,4,13-trihydroxy 1-oxa 6-azacyclopentadecan-15-one.

 One suspends in 15 cm3 of methanol 840 mg of (2R- (2R *, 3S *, 4R *, 5R *, 8R *, 10R *, llR *, 128 *, l3S *, 14R *)) 13- ( 2,6dideoxy 3-C-methyl 3-0-methyl alpha-L-ribo hexopyranosyl) oxy) 3,4-dihydroxy 2-ethyl 3,5,6,8,10,12,14-heptamethyl l0-methoxy 11- ((3,4,6-trideoxy 3- (dimethylamino) beta-D-xylo hexopyranosyl) oxy) 1-oxa 6-azacyclopentadecan-15-one. 0.3 cm3 of a 12N hydrochloric acid solution are added. The mixture obtained is stirred for 2 hours at room temperature. The pH is brought to basic by adding concentrated ammonia. The solution is concentrated under reduced pressure, taken up in methylene chloride, washed with water and then with a saturated solution of sodium chloride and dried. The solvent is evaporated off. The product obtained is chromatographed on silica, eluting with an ethyl acetate-triethylamine-methanol mixture (90-5-5). The product of Rf = 0.38 is collected. 530 mg of the sought product is thus obtained.

STAGE B: (2R- (2R, 3S *, 4R *, 5R *, 8R *, 10R *, llR, 12S *, 13S, 14R *)) 11 - ((2-O-acetyl 3,4,6- trideoxy-3- (dimethylamino) beta-D-xylohexopyranosyl) oxy) 2-ethyl 3,5,6,8,10,12, 14-heptamethyl 10methoxy 3,4,13-trihydroxy 1-oxa 6-azacyclopentadecan-15- one.

 530 mg of the product obtained in stage A is suspended in 7 cm 3 of acetone. 158 mg of potassium carbonate and 139 μl of acetic anhydride are then added at 0 ° C. The temperature of the reaction mixture is then left to return to room temperature, the reaction mixture is stirred for 48 hours, ice added and extracted with methylene chloride. The organic phase is washed with a saturated sodium chloride solution and dried. The crude product obtained is chromatographed, eluting with an ethyl acetate-methanol-triethylamine mixture (90-5-5). 380 mg of sought product is thus obtained.

NMR: CDC13 MHz.

STAGE C: (2R- (2R *, 3S *, 4R *, SR *, 8R *, 10R *, lîR *, 12S *, 14R *)) 11 - ((2-O-acetyl 3,4,6- trideoxy 3- (dimethylamino) beta-D-xylo hexopyranosyl) oxy) 3,4-dihydroxy 2-ethyl 3,5,6,8,10,12,14heptamethyl 10-methoxy 1-oxa 6-azacyclopentadecane 13,15dione.

 380 mg of the product prepared in Stage B, 0.618 cm3 of dimethyl sulfoxide and 667 mg of N, N-dimethyl aminopropyl-ethyl-carbodiimide hydrochloride are suspended in 6 cm 3 of methylene chloride. After dissolution, 672 mg of pyridinium trifluoroacetate in solution in 2 cm 3 of methylene chloride are added while maintaining the temperature at + 15 ° C. At the end of the addition, the temperature is allowed to return to ambient temperature and the mixture is stirred. 30 minutes, 5 cm 3 of methylene chloride, 5 cm 3 of a saturated solution of sodium chloride and added to basic pH with 2N sodium hydroxide are added, followed by extraction, washing with methylene chloride and drying.

The product obtained is chromatographed on silica, eluting with an ethyl acetate-triethylamine mixture (95-5). 200 mg of sought product is obtained Rf = 0.5.

NMR: CDCl3, 400 MHZ.

STAGE D: (2R- (2R *, 3S +, 4R *, 5R *, 8R *, 10R *, llR *, 12S *, 14R *)) 3, 4-dihydroxy 2-ethyl 3,5,6,8, 10,12,14-heptamethyl 10-methoxy 11- ((3,4,6-trideoxy 3- (dimethylamino) beta-D-xylo hexopyranosyl) oxy) 1-oxa 6-azacyclopentadecane 13,15-dione.

 200 mg of product prepared in the preceding stage are suspended in 10 cm 3 of methanol. The reaction mixture is kept under stirring at room temperature for 20 hours. It is concentrated under reduced pressure. The residue is chromatographed on silica (eluent methylene methanol-ammonia chloride (90-10-1)). 140 mg of product of Rf = 0.29 are collected and taken up with hot hexane and filtered. 117 mg of product are thus obtained which is chromatographed on silica eluting with a methylene chloride-methanol-ammonia mixture (90-10-1). The desired product is collected. Rf = 0.29.

NMR: CDCl3, 300 MHZ

EXAMPLES of pharmacological compositions
Compounds containing
Product of Example 1 ........................ 300 mg
Excipient qs .............................. 1 g
Details of the excipient: starch, talc, magnesium stearate.

PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION.

A) In vitro activity.

Liquid dilution method.

 A series of tubes is prepared in which the same quantity of sterile nutritive medium is distributed. Increasing quantities of the product to be studied are distributed in each tube, then each tube is seeded with a bacterial strain.

 After incubation for twenty-four hours in an oven at 37 ° C., the growth inhibition is assessed by transillumination, which makes it possible to determine the minimum inhibitory concentrations (C.M.I.) expressed in micrograms / cm3.

 The products of the invention exhibit activity on staphilococci, streptococci, pneumococci and hemophiliacs.

Claims (12)

1) The compounds of formula (I)

 in which - R1 and R2, which are identical or different, represent a hydrogen atom or a methyl radical, - Z represents a hydrogen atom or the remainder of a carboxylic acid containing up to 18 carbon atoms, - R represents a radical linear, branched or cyclic alkyl, alkenyl or alkynyl, or an aralkyl radical containing up to 18 carbon atoms, as well as the addition salts with acids of the compounds of formula (I). 2) The compounds of formula (I) as defined in claim 1, in which R1 represents a methyl radical. 3) The compounds of formula (I) as defined in claim 1 or 2, in which R2 represents a hydrogen atom. 4) The compounds of formula (I) as defined in any one of claims 1 to 3, in which R represents an alkyl radical containing up to 4 carbon atoms. 5) The compounds of formula (I) as defined in claim 4 in which R represents a methyl radical. 6) The compounds of formula (I) as defined in any one of claims 1 to 5, in which Z represents a hydrogen atom. 7) La (2R- (2R +, 3Sf, 4R *, 5R +, 8R *, 10R +, 11R +, 12S *, 14R *)) 3,4-dihydroxy 2-ethyl 3,5,6,8,10,12, 14-heptamethyl 10-methoxy 11- ((3,4, 6-trideoxy 3- (dimethylamino) beta-D-xylo hexopyranosyl) oxy) l-oxa 6-azacyclopentadecane 13,15-dione. 8) As medicaments the compounds of formula (I) as defined in any one of claims 1 to 6, as well as their addition salts with pharmaceutically acceptable acids. 9) As a medicament, the compound of formula (I) defined in claim 7, as well as its addition salts with pharmaceutically acceptable acids. 10) The pharmaceutical compositions containing as active principle at least one medicament defined in claim 8 or 9. 11) Process for preparing the compounds of formula (I) as defined in any one of claims 1 to 7, characterized in that a compound of formula (II) is subjected

 in which R1, R2 and R retain their previous significance to the action of an acid in an aqueous medium to obtain the compound of formula (III)

 in which R, R1 and R2 retain their previous meaning, which is subjected to the action of a blocking agent for the hydroxyl function at 2 'to obtain a compound of formula (IV)

 in which OM represents a blocked hydroxyl group and the other substituents retain their previous meaning, which is subjected to the action of an oxidizing agent of the hydroxyl function at 13 to obtain the compound of formula (V)

 which is subjected if desired to the action of an agent for releasing the hydroxyl function at 2 ', and optionally to the action of an agent capable of introducing the radical Z, if the latter does not represent not a hydrogen atom, then if desired subjects the compounds of formula (I) thus obtained to the action of an acid to form the salt. 12) As new industrial products, the compounds of formulas (III), (IV) and (V) as defined in claim 11.