AU721732B2 - New derivatives of erythromycin, their preparation process and their use as medicaments - Google Patents

Description

New derivatives of erythromycin. their preparation process and their use as medicaments.

The present invention relates to new derivatives of erythromycin, their preparation process and their use as medicaments.

A subject of the invention is the compounds of formula ,,1I1 0-

N,

in which R represents: either a linear, branched or cyclic alkyl, alkenyl or alkynyl radical, containing up to 18 carbon atoms, optionally W substituted by one or more substituents chosen from halogen atoms, linear, branched or cyclic 0-alkenyl or O-alkynyl, Salkyl, S-alkenyl or S-alkynyl radicals, containing up to 12 carbon atoms, the NO 2 radicals, the C=N radicals, the following radicals: Ra

N

Rb in which Ra and Rb, identical or different, represent a hydrogen atom, a linear or branched alkyl radical containing up to 4 carbon atoms, the following radicals: Rc Si Rd Rf in which Rc, Rd and Rf, identical or different, represent a linear, branched or cyclic alkyl radical containing up to 4 carbon atoms, optionally substituted by one or more halogen atoms, Sor a (CH 2 )nAr radical in which n represents an integer ranging from 0 to 6 and Ar represents an aryl or heteroaryl radical, optionally substituted by one or more of the substituents indicated above, Z represents a hydrogen atom or the remainder of an acyl radical, containing up to 12 carbon atoms, as well as their addition salts with acids.

The aryl radical can be a phenyl or naphthyl radical.

The aryl radical can also be a heterocyclic radical substituted or not such as the thienyl, furyl, pyrolyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, pyrazolyl or isopyrazolyl radical, a pyridyl, pyrimidyl, pyridazinyl or pyrazinyl radical, or also an indolyl benzofuranyl, benzothiazyl or quinolinyl radical.

These aryl radicals can contain one or more groups chosen from the group constituted by hydroxyl radicals, halogen atoms, NO 2 radicals, C=N radicals, alkyl, alkenyl or alkynyl, 0-alkyl, 0-alkenyl or 0-alkynyl, S- alkyl, S-alkenyl or S-alkynyl and N-alkyl, N-alkenyl or N-alkynyl radicals, containing up to 12 carbon atoms optionally substituted by one or more halogen atoms, the Ra N radical, Ra and Rb identical or different Rb representing a hydrogen atom or an alkyl radical containing up to 12 carbon atoms, the 0

-C-R

3 radical, R 3 representing an alkyl radical containing up to 12 carbon atoms, or an optionally substituted aryl or heteroaryl radical, the carboxylic aryl, 0-aryl or S-aryl radicals, the heterocyclic aryl, 0-aryl or S-aryl radicals with 5 or 6 members containing one or more heteroatoms, optionally substituted by one or more of the substituents mentioned below.

As preferred heterocycle, the following can be mentioned amongst others:

N

Nk N.D4o

I

NQLN

I

ON

I

N

N

N

N

-N

(V N

N.,

N

N-

O N

,CN

S/

N

N-

N

N

N

(N

I

N

/I

zN 'No< C) N

N

N

N =S

N

a N N N

N

I

O

N N N N 0 H I

NCI

I

H3C H3C and the heterocyclic radicals envisaged in the European Patent Applications 487411, 596802, 676409 and 680987. These preferred heterocyclic radicals being able to be substituted by one or more functional groups.

Hal preferably represents a fluorine, chlorine or bromine atom.

Among the addition salts with acids, there can be mentioned the salts formed with the following acids: acetic, propionic, trifluoroacetic, malic, tartaric, methanesulphonic, benzenesulphonic, p-toluenesulphonic, and in particular stearic, ethylsuccinic or laurylsulphonic acids.

In particular a subject of the invention is the compounds of formula in which Z represents a hydrogen atom, the compounds of formula in which R represents a

(CH

2 )nAr radical in which n represents an integer ranging from 1 to 4 and Ar represents an optionally substituted aryl or heteroaryl radical, and in particular those in which Ar is an optionally substituted phenyl radical, as well as those in which R represents an optionally substituted radical: N aN I or A quite particular subject of the invention is the compounds the preparation of which is given hereafter in the experimental part and in particular the products of Examples 2 and 3.

The products of general formula have a very good antibiotic activity on gram bacteria such as staphylococci, streptococci, pneumococci.

The compounds of the invention can therefore be used as medicaments in the treatment of infections caused by susceptible germs and in particular, in that of staphylococcia, such as staphylococcal septicemias, malignant staphylococcia of the face or skin, pyodermatitis, septic or suppurating wounds, boils, anthrax, phlegmons, erysipelas and acne, staphylococcia such as acute primary or post-influenzal angina, bronchopneumonia, pulmonary suppuration, streptococcia such as acute angina, otitis, sinusitis, scarlet fever, pneumococcia such as pneumonia, bronchitis; brucellosis, diphtheria, gonococcal infection.

The products of the present invention are also active against infections caused by germs such as Haemophilus influenzae, Rickettsies, Mycoplasma pneumoniae, Chlamydia, Legionella, Ureaplasma, Toxoplasma or by germs of the Mycobacterium genus.

Therefore a subject of the present invention is also, as medicaments and, in particular, antibiotic medicaments, the products of formula as defined above, as well as their addition salts with pharmaceutically acceptable mineral or organic acids.

A more particular subject of the invention is, as medicaments and, in particular antibiotic medicaments, the products of Examples 2 or 3 and their pharmaceutically acceptable salts.

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

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

These can be solid or liquid and be presented in the pharmaceutical forms currently used in human medicine, such as for example, plain or sugar-coated tablets, capsules, granules, suppositories, injectable preparations, ointments, creams, gels; they are prepared according to the usual methods. The active ingredient or ingredients can be incorporated with excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives.

These compositi6ns can also be presented in the form of a powder intended to be dissolved extemporaneously in an appropriate vehicle, for example, apyrogenic, sterile water.

The administered dose is variable according to the illness treated, the patient in question, the administration route and the product considered. It can be, for example, comprised between 50 mg and 300 mg per day by oral route, for an adult for the product of Example 2.

A subject of the invention is also a preparation process for the compounds of formula characterized in that a compound of formula (II): 0 ,Ill 0

NH

0 0 0 in which Z' represents the remainder of a carboxylic acid containing up to 12 carbon atoms, is subjected to the action of a blocking agent of the ketone function in position 3 in the form of an enol ether in order to obtain the compound of formula (III): 1111( 111111111110

(III)

0 in which Eth represents the remainder of an enol ether and Z' retains its previous meaning, is subjected to the action of a compound of formula (IV): Hal-CH 2 OR (IV) in which Hal represents a halogen atom, in order to obtain the corresponding compound of formula 0 ,0- 6111111111111111110 which is subjected, if desired, to the action of an agent which releases the ketone function in position 3 and/or to the action of an agent which releases the hydroxyl in position in order to obtain the corresponding compound of formula

OR

N

in which R retains its previous meaning.

The products of formula (II) used as starting products are known products, which can be prepared according to the process described in EP 487411 or in WO 9321199.

As a blocking agent of the ketone function in position 3, in the form of an enol ether, a halogenomethylether can be used and in particular a chloromethethylether, such as for example MEM chloride, or 2-methoxy ethoxy methyl chloride or also SEM chloride or 2-(trimethylsilyl) ethoxymethyl chloride, Hal preferably represents a chlorine atom, Z' preferably represents an acetyl radical, the agent for releasing the ketone function in position 3, the release of the hydroxyl in position 2' is carried out by methanolysis.

The compounds of formulae (III) and used during the preparation process are new and in themselves are a subject of the present invention.

The following examples illustrate the invention without however limiting it.

EXAMPLE 1: 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-Omethyl-alpha-L-ribo-hexopyranosyl) oxy]-6-0-methyl-3-oxo- 12,11-[oxycarbonyl [[(2-methoxyethoxy)methyl]imino]] erythromycin Stage A: 2,3-didehydro-11,12-dideoxy-3-0-de[(2,6-dideoxy-3-Cmethyl-3-O-methyl-alpha-L-ribo-hexopyranosyl)-6-0-methyl- 11,12-(iminocarbonyloxy)-3-O-[[(2-trimethylsilyl) ethoxy] methyl]-erythromycin 2'-acetate A solution containing 6 ml of DMF, 0.654 g of 11,12dideoxy-3-de[(2,6-dideoxy-3-C-methyl-alpha-L-ribohexopyranosyl) oxy]-6-O-methyl-3-oxo-11,12-(iminocarbonyloxy)-erythromycin 2'-acetate and 0.57 g of sodium hydride at 50% in oil is agitated for 10 minutes. The reaction mixture is heated to 40 0 C. After cooling down to -5 0 C, 0.177 pl of SEMCl is introduced dropwise. The reaction medium is diluted in 5 ml of DMF and adjusted to pH 7. 3 drops of water are added, the medium is brought to ambient temperature and the DMF is evaporated off, followed by taking up in 15 ml of ethyl acetate, washing with an aqueous solution of ammonium hydroxide, extracting with ethyl acetate, washing with water, drying, filtering and concentrating. 0.785 g of product is obtained which is dissolved in isopropyl ether.

Crystallization is initiated, followed by separating, washing and drying at 70°C. The sought product is obtained melting at 100 0

C.

NMR CDC1 3 ppm Possible structure 0.07 Si(Me) 3 0.87 CH 3

-CH

2 -1 .03: CH 2 -Si; 1.10 1.12 (d)-1.14 (d)-1.24 CH 3 1.24 (s)-1.43 6 and 12

CH

3 1.95 2-Me; 2.08 OAc; 2.27 N(Me)2; 2.47 Ha; 2.68 H'3; 2.82 6-OMe; 3.04 3.31

H

4 3.48 H's; 3.73 J H 5 3.80-3.92: OCH2; 3.89 Hi; 4.69 4.78 H 2 4.99 5.04 OCH0O; 5.29 H, 3 Stage B: 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-Omethyl-alpha-L-ribo-hexopyranosyl) oxy]-6-O-methyl-3-oxo- 12,11-(oxycarbonyl[[(methoxymethyl)]imino]erythromycin 0.150 g of a mixture containing 0.150 g of the product of Stage A is dissolved in 1.5 ml of DMF.

The reaction mixture is cooled down to +10 0 C and 14 mg of sodium hydride at 50% in oil is added. The reaction mixture is cooled down to 0 C and 26 pl of MEM chloride in solution in 0.5 ml of DMF is introduced. Agitation is carried out for 25 minutes at 0 C, followed by pouring the mixture onto ice, concentrating, taking up in ethyl acetate, washing with water, extracting with ethyl acetate, drying, filtering and concentrating. A product is obtained which is diluted in 4 ml of methanol. The solution is taken to reflux for 2 hours, then returned to ambient temperature. 1 ml of a M solution of hydrochloric acid in methanol is added.

The methanol is evaporated off, followed by taking up in ethyl acetate, washing with ammonium hydroxide, diluting, extracting with ethyl acetate, drying, filtering and concentrating. 0.11 g of product is obtained which crystallizes. After purification, the crude sought product is obtained. M.p. 238-240 0

C.

NMR CDC1 3 ppm 0.88 CH 3

-CH

2 1.03 10-Me; 1.16 8Me; 1.25 5'Me; 1.32 4Me; 1.38 2Me; 1.34 and 1.51: O and 12Me; -1.57 and 1.38 CH 2 in position 14; -1.60 and 1.84:

CH

2 in position 7; -1.67 and 1.25: CH 2 in position 2.27 N(Me) 2 2.44 H' 3 2.62 H 8 2.67 6-OMe; 3.09 3.12 H 4 3.18 (dd) H'2; 3.36 OMe; -3.47: OH; 3.86 H 2 3.87 4.24 4.93 (d)-5.27 NCH20; 5.05 (dd) H, 3 EXAMPLE 2: 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-Omethyl-alpha-L-ribo-hexopyranosyl) oxy]-6-O-methyl-3-oxo- 12,11-[oxycarbonyl [[[2-[4-(3-pyridinyl)-1H-imidazol-1-yl] ethoxy] methyl] imino]]-erythromycin Stage A: 2,3-didehydro-11,12-dideoxy-3-O-de (2,6-dideoxy-3-Cmethyl-3-O-methyl-alpha-L-ribo-hexopyranosyl)-6-0-methyl- 12,11-[oxycarbonyl [[(2-bromoethoxy) methyl] imino]]-3-O-[[2- (trimethylsilyl) ethoxy] methyl]-erythromycin 2'-acetate 0.278 g of sodium hydride at 50% in oil is agitated in 2 ml of THF. The mixture is cooled down to 0°C and 510 mg of Stage A of Example 1, in solution in 8 ml of THF is added.

The reaction medium is returned to ambient temperature and 100 pl of ClCHOCH 2

CH

2 Br in solution in 4 ml of THF is introduced. The reaction medium is returned to 0°C, poured onto ice, extracted with ethyl acetate, washed with salt water, dried, filtered and concentrated. 0.709 g of sought product is obtained.

Stage B: 2,3-didehydro-11,12-dideoxy-3-O-de (2,6-dideoxy-3-Cmethyl-3-O-methyl-alpha-L-ribo-hexopyranosyl)-6-0-methyl- 12,11-[oxycarbony [[[2-[4-(3-pyridinyl)-1H-imidazol-1-yl] ethoxy] methyl] imino]]-3-0-[[2-(trimethylsilyl) ethoxy] methyl]-erythromycin 2'-acetate A solution of 3 ml of DMF and 0.377 g de 4-(3pyridinyl)-1H-imidazole are introduced into a solution containing 2 ml of DMF and 0.162 g of sodium hydride at in oil. Agitation is carried out for a quarter of an hour and 0.709 g of the product of Stage A of Example 2 in solution in 8 ml of DMF is introduced. Agitation is carried out for 3 hours at ambient temperature and for 15 minutes at 0 C. The reaction medium is poured onto ice, extracted with ethyl acetate, washed with salt water then with water, dried, filtered and concentrated. 0.644 g of product is obtained.

Stage C: 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribo-hexopyranosyl) oxy]-6-O-methyl-3-oxo- 12,11-[oxycarbonyl [[[2-[4-(3-pyridinyl)-1H-imidazol-1-yl] ethoxy] methyl] imino]]-erythromycin A solution containing 0.644 g of the product of Stage B and 8 ml of methanol is agitated for 48 hours at ambient temperature, then 0.565 g of the product obtained is diluted in 5 ml of ethyl acetate. The reaction medium is cooled down to 0°C and 2.5 ml of a 2.1N solution of hydrochloric acid in methanol is introduced and the whole is returned to ambient temperature. Agitation is maintained at ambient temperature for 1 hour. The solvents are evaporated off, followed by diluting with water, pouring into a saturated aqueous solution of sodium carbonate, filtering and concentrating.

0.508 g of an oil is obtained which is chromatographed on silica CH 2 Cl 2 /MeOH (93-7) then CH 2 Cl/MeOH/NH 4 OH (93-7-0.5).

The homogeneous fractions are concentrated by TLC, followed by taking up in ethyl acetate, washing with ammonium hydroxide, diluting, extracting with ethyl acetate, with water, drying, filtering and concentrating. 66 mg of sought product is obtained.

NMR CDC1 3 ppm 0.85 CH 3

-CH

2 1.00 1.15 1.25 1.31 1.40 CH 3 -CH; 1.34 and 1.51: 6 and 12 Me; 2.26 N(Me)2; 2.44 H' 4 2.60 H 8 2.68 6-OMe; 3.03

H

4 and H10; 3.18 H' 2 3.55 H'5; 3.76 3.92 -4.38 OCH 2

CH

2 N; 3.87 3.83 H 2 4.24

H

5 4.31 4.96 H 13 4.99 5.37 NCH 2 0.

7.36 7.54 H imidazole; 7.30 (ddd): H 5 8.08 (dt):

H

4 8.45 H 6 8.95 (ddd): pyridine.

EXAMPLE 3: 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribo-hexopyranosyl) oxy]-6-O-methyl-3-oxo- 12,11-[oxycarbonyl [[(2-phenylethoxy) methyl] imino]]erythromycin Stage A: 2,3-didehydro-11,12-dideoxy-3-O-de(2,6-dideoxy-3-Cmethyl-3-O-methyl-alpha-L-ribo-hexopyranosyl)-6-0-methyl- S 12,11-[oxycarbony [[(2-phenylethoxy) methyl] imino]]-3-O-[[2- (trimethylsilyl) ethoxy] methyl]-erythromycin 2'-acetate 18 mg of sodium hydride at 50% in oil is added at 10 0

C

to a solution containing 2 ml of DMF and 203 mg of the product obtained in Stage A of Example 1.

Agitation is carried out for 15 minutes, followed by cooling down to -5 0 C and 46 pl of chloromethylphenyl ether in solution in 0.5 ml of DMF is added.

The DMF is evaporated off, followed by taking up in ethyl acetate, washing with water, drying, filtering and concentrating. 0.277 g of sought product is obtained.

Stage B: 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-Omethyl-alpha-L-ribo-hexopyranosyl) oxy]-6-O-methyl-3-oxo- 12,11-[oxycarbonyl [[(2-phenylethoxy) methyl] imino]]erythromycin 0.227 g of the product obtained in Stage A is introduced in one go into 0.33 ml of a 0.19N solution of hydrochloric acid in ethyl acetate cooled down to +5 0 C. The reaction medium is returned to ambient temperature and agitation is carried out for 2 hours. After cooling down to 0°C, water is added, the pH is adjusted to 9-10 with a concentrated solution of ammonium hydroxide, followed by extracting with ethyl acetate, washing with water, drying, filtering and S concentrating. 0.201 g of product is obtained which is diluted in 2.5 ml of methanol. The whole is taken to reflux for 2 hours 30 minutes. The methanol is evaporated off and 0.188 mg of product is obtained which is chromatographed on silica eluting with a methylene chloride-isopropanol-ammonium hydroxide mixture After concentration, the residue is taken up in methylene chloride, a drop of concentrated ammonium hydroxide is added, followed by agitation, drying, filtering and concentrating. 55 mg of product is obtained which is separated and dried at 80 0 C. 36 mg of product is obtained. M.p. 210 212 0

C.

NMR CDC13 ppm 0.88 CH 3

-CH

2 1.02 1.15 1.25 1.31 1.39 CH 3 -CH; 1.33-1.51: 6 and 12 Me; 2.27 N(Me) 2 2.45 H' 3 2.62 Hs; 2.70 6-OMe; 2.91 CH 2 0; 3.08 (ql) Ho 0 -3.15 H 4 3.18 (dd) H'2; -3.58 H's; -3.58 and 3.77: OCH 2 3.87 3.91 4.25 Hs; 4.32 H' 1 5.00 5.33 NCH20; 5.05 H 13 7.13 to 7.30: phenyl, ether mole).

By operating as indicated above, the following product was prepared: EXAMPLE 4: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribohexopyranosyl) oxy) 6-0-methyl-3-oxo- 12,11-(oxycarbonyl (((2-(trimethylsilyl) ethoxy) methyl) imino)) erythromycin.

M.p. 141-143 0 C; Rf 0.38 (AcOEt-TEA 95-5).

EXAMPLE OF PHARMACEUTICAL COMPOSITION Compounds were prepared containing: Product of Example 2. 150 mg Excipient s.q.f. 1 g Detail of excipient: starch, talc, magnesium stearate PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION Method of dilutions in liquid medium A series of tubes are prepared in which the same quantity of sterile nutritive medium is distributed.

Increasing quantities of the product to be studied are distributed into each tube, then each tube is sown with a bacterial strain. After incubation for twenty-four hours in a heating chamber at 37 0 C, the growth inhibition is evaluated by transillumination, which allows the minimal inhibitory concentrations to be determined, expressed in micrograms/cm 3 The following results were obtained: GRAM+ bacterial strains Products Ex. 2 Ex.3 Staphylococcus aureus 011UC4 Staphylococcus aureus 011G025I Staphylococcus epidermidis 012GO11I Streptococcus pyogenes group A 02A1UC1 Streptococcus agalactiae group B 02B1HT1 Streptococcus faecalis group D 02D2UC1 Streptococcus faecium group D 02D3HT1 Streptococcus sp group G 02GOGR5 Streptococcus mitis 02mitCB1 Streptococcus mitis 02mitGR16I Streptococcus agalactiae group B 02B1SJ1 Streptococcus pneumoniae 032UC1 0.08 0.08 0.08 0.04 0.15 0.08 0.02 5 0.02 0.02 0.02 0.02 5 0.02 0.02 0.08 0.02 0.02 0.02 0.04 0.02 0.02 0.02 0.02 .04 q.

S..

a a q.

a a.

0.02 In addition, the product of Example 1 has shown a useful activity on the following gram- bacterial strains: Haemophilus Influenzae 351HT3, 351CB12, 351CA1 and 351GR6.

Where the terms "comprise", "comprises", "comprised" or "comprising" are used in this specification, they are to be interpreted as specifying the presence of the stated features, integers, steps or components referred to, but not to preclude the presence or addition of one or more other feature, integer, step, component or group thereof.