AP587A

AP587A - New erythromycin derivatives, their preparation process and their use as medicaments.

Info

Publication number: AP587A
Application number: APAP/P/1995/000743A
Authority: AP
Inventors: Constantin Agouridas; Yannick Benedetti; Jean-Francis Chantot (Deceased); Alexis Denis; Martret Odile Le
Original assignee: Aventis Pharma Sa
Priority date: 1994-04-08
Filing date: 1995-03-17
Publication date: 1997-04-29
Also published as: US5656607A; JO1850B1; PT676409E; FR2718450B1; NZ284498A; RO115634B1; CN1059445C; FI955913A; ATE234853T1; YU49221B; AU2310795A; JPH07278177A; RU2141965C1; CA2164638A1; JP3000023B2; YU21695A; LV11182A; ES2189820T3; FI111264B; SA97170757A

Abstract

A subject of the invention is the compounds of general formula

Description

New ervthromvcin derivatives, their preparation process and their use as medicaments.

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

A subject of the invention is the compounds of general formula (I) :

2 in which:

either R_x and R₂, identical or different, represent a hydrogen atom, or a hydrocarbon radical containing up to 24 carbon atoms, saturated or unsaturated, optionally interrupted by one or more heteroatoms and optionally . carrying one or more functional groups, or R_x and R₂ form with the nitrogen atom to which they are linked a heterocycle optionally containing one or more heteroatoms chosen from nitrogen, oxygen and sulphur, or R_x and R₂ together form a radical

\ in which and R'₂, identical or different, represent a hydrogen atom or a hydrocarbon radical containing up to 23 carbon atoms, saturated or unsaturated, optionally interrupted by one or more heteroatoms and optionally carrying one or more functional groups and 2 represents a hydrogen atom or the remainder of a carboxylic acid containing up to 18 carbon atoms, the wavy line in position 10 indicating that the methyl can be of R or S configuration or a mixture of R + S as well as the addition salts with acids of the compounds of formula (I) .

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

The hydrocarbon radical which can be represented by R^ or R₂ and R'^ or R'₂ can be interrupted by one or more heteroatoms chosen from nitrogen, oxygen and sulphur and can carry one or more groups chosen from the group constituted by hydroxyl radicals, halogen atoms, N0₂ radicals, C=N radicals, the following radicals: alkyl, alkenyl or alkynyl, 0-alkyl, O-alkenyl or O-alkynyl, S-alkyl, S-alkenyl or S-alkynyl and N-alkyl, N-alkenyl or N-alkynyl, containing up to 12 carbon atoms optionally substituted by one or more halogen atoms, the radical ^Ra , Ra and Rb, identical or different, representing Rb a hydrogen atom or an alkyl radical containing up to 12 carbon atoms, the radical 0

II

-C-R₃, R₃ representing an alkyl radical containing up to 12 carbon atoms, or an optionally substituted aryl or heteroaryl radical, carboxylic aryl, O-aryl or S-aryl radicals or heterocyclic aryl, O-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 above .

The hydrocarbon radical which can be represented by or R₂ and R^/1 or R^z2 can be an alkyl, alkenyl, alkynyl, aralkyl, aralkenyl or aralkvnyl radical. In the definition

AP . Ο Ο 5 8 7 of the substituents, the alkyl, alkenyl or alkynyl radical is preferably one of the following radicals: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, terbutyl, decyl or dodecyl, vinyl, allyl, ethynyl, propynyl, propargyl, cyclobutyl, cyclopentyl or cyclohexyl.

The aryl radical can be a phenyl or naphthyl radical.

The aryl radical can also be a substituted or nonsubstituted heterocyclic radical 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 of the above-mentioned groups.

When and R₂ form with the nitrogen atom to which they are linked a heterocyclic radical, it is preferably one of the following radicals: pyrrolyl, pyrrolidinyl, pyridyl, pyrazinyl, pyrimidyl, piperidinyl, piperazinyl, guinuclidinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, imidazolyl, benzimidazolyl, triazolyl, thiazolyl, azetidinyl, aziridinyl.

A more particular subject of the invention is the compounds of formula (I) in which Z represents a hydrogen c 25 atom, the compounds of formula (I) in which represents a hydrogen atom, the compounds of formula (I) in which R^ and R₂ each represents a hydrogen atom.

Among the preferred compounds of the invention, there can be mentioned the compounds of formula (I) in which

R'^ represents a hydrogen atom, there can be mentioned the compounds in which Rj^ and R₂ together form a radical:

=CH(CH₂)_nA_ri in which Ar_x represents an optionally substituted aryl or heteroaryl radical and n represents an integer which can vary from 0 to 8.

Ar^^ has as the preferred value, one or other of the preferred values indicated above for the aryl and heteroaryl radicals. The optional substituent or substituents of Ar·^ are those indicated above as functional groups.

Among the preferred compounds of the invention, there 5 can be mentioned the compounds of formula (I) in which Rj and

R₂ form together a radical:

A B

I I =CH(CH₂)p-C=C-(CH₂)qAr₂ in which p and q, identical or different, represent an integer varying from 0 to 6, A and B, identical or different, represent a hydrogen or halogen atom or an alkyl radical containing up to 8 carbon atoms, the geometry of the double bond being E or Z or an E + Z mixture, or A and B form a third bond with the carbon atoms to which they are linked and Ar₂ represents an optionally substituted mono- or polycyclic aryl or heteroaryl radical.

Among these compounds there can be mentioned quite particularly the compounds in which p and q represent the number 0, as veil as those in which A and B represent a hydrogen atom.

R₂ represents a radical:

e (CHjljAr, in which r represents an integer varying from 0 to 6 and Ar₃ represents an optionally substituted aryl or heterocyclic radical, and more particularly those in which Ar₃ represents a 4-quinolinyl radical optionally mono- or polysubstituted on one and/or the other of the 2 rings of the quinoline, for example those in which Ar₃ represents a non-substituted 435 quinolinyl radical, 4-quinoleinyi substituted by a methoxy radical or a thiazolyl radical substituted by a pyridyl radical.

A quite particular subject of the invention is the

AP. Ο Ο 5 8 7 compounds of formula (I) in which r represents an integer varying from 1 to 4.

Among the preferred compounds of the invention, there can be mentioned the compounds whose preparation is given hereafter in the experimental part and more particularly the compounds, the names of which follows:

- 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O-methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,ll-(oxycarbonyl (2-(3-(4-cpinoleinyl) propyl) hydrazono)) erythromy cine,

- 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O-methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,ll-(oxycarbonyl (2-(3-(7-methoxy-4-quinoleinyl) propyl) hydrazono)) erythromycine,

- 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O-methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,ll-(oxycarbonyl (2-(3-(2-(3-pyridinyl-4-thiazolyl) propyl) hydrazono)) erythromycine.

The products of general formula (I) possess 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 sensitive germs and notably, in that of staphylococcia, such

C 25 as staphylococcal septicemias, malignant staphylococcia of φ the face or skin, pyodermatitis, septic or suppurating sores, boils, anthrax, phlegmons, erysipelas and acne, staphylococcia such as primary or post-influenzal acute anginas, bronchopneumonia, pulmonary suppuration, streptococcal infection such as acute anginas, otitis, sinusitis, scarlet fever, pneumococcal infection 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, Rickettsia, Mycoplasma pneumoniae, Chlamydia,

Legionella, Ureaplasma, Toxoplasma, or by germs of

Mycobacterium type.

Therefore a subject of the present invention is also, as medicaments and in particular antibiotic medicaments, the products of formula (I) 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 5 or 11, 12 and 1 and their pharmaceutically acceptable salts.

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

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.

They can be solid or liquid and be presented in the pharmaceutical forms commonly 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 vith 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 vetting, dispersing or emulsifying agents, preservatives.

These compositions can also be presented in the form of a povder intended to be dissolved extemporaneously in an appropriate vehicle, for example apyrogenic sterile vater.

The dose administered 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 zZ mg and 303 mg per day by oral route, for an adult, for the product of Example 5.

Also a subject of the invention is a preparation process for compounds of formula (I), characterized in that a

AP. Ο Ο 5 8 7 compound of formula (II):

in which Z retains its previous meaning, is either to the action of hydrazine NH₂NH₂ in the compound of formula (I_A):

subjected order to obtain

which is subjected if desired to the action of an R'₂CHO or 30 0

II of a cetone R'j-C-R'₂ in which R'j and R'₂ retain the same meaning as previously aldehyde in order to obtain the corresponding compound of formula (I_B):

ί’

OH in which R'^ and R'₂ retain the same meaning as previously, which is subjected if desired to the action of a reducing agent in order to obtain the corresponding compound of formula (I_c):

in which R'i and R'₂ retains its previous meaning, that is a compound of formula (I) in which is a hydrogen and R₂represents a CHR^/1R*₂ radical, then if desired, the compound of formula (1^) is subjected to the action of an agent capabl 30 e of replacing the hydrogen atom of the NH group by an R^ group as defined previously with the exception of the which hydrogen value, then if desired, the compound obtained is subjected to the action of an acid in order to form the salt and/or to the action of an esterification agent of the OH group in position 2'.

The compounds of formula (II) used as starting products of the process of the invention are described and claimed in the European Patent Application EP 0596802.

AP. 0 0 5 8 7

The preparation of the compounds of formula (II) is mentioned hereafter in the experimental part.

In a preferred embodiment of the invention:

- the operation is carried out in the presence of an excess of hydrazine, at a temperature greater than ambient temperature for example a temperature comprised between 40 and 80*C, in a solvent such as acetonitrile, dioxane, dimethylformamide, tetrahydrofuran, dimethoxy ethane or dimethylsulphoxide, (in the presence or in the absence of a base),

- the reaction with the aldehyde or the cetone takes place under the same temperature and solvent conditions,

- the reducing agent is NaBH₃CN or hydrogen in the presence of a catalyst such as palladium, platinum and either in the presence or in the absence of an acid such as hydrochloric acid or acetic acid,

- esterification in position 2' is carried out according to standard processes,

- salification is carried out using acids according to standard processes.

Also a subject of the invention is a variant of th· preceding process, characterized in that the compound of formula (II):

(II) in which Z retains its previous meaning, is subjected to the action of a compound of formula i.’H₂NHR₂ in order to obtain the compound of formula (I'_A):

(Ι'α)

Η which is subjected if desired, to the action of an agent capable of replacing the hydrogen atom of the NH group by an R-^ radical as defined previously with the exception of the hydrogen value or in order to obtain the corresponding compound of formula (I'_B):

which is subjected if desired, to the action of an esterification agent of the OH group in position 2' or to the action of an acid in order to form the salt, the preferred temperature and pressure conditions are those described above.

The following examples illustrate the invention.

EXAMPLE 1: 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 (hydrozono) erythromycin isomer 10 (R) and corresponding isomer 10(S)

353 mg of 11-deoxy 10,ll-didehydro 3-de(2,6-dideoxy

AP.0 0 5 8 7

3-C-methyl 3-O-methyl alpha-L-ribohexopyranosyl) oxy) 12-0((lH-imidazol-l-yl) carbonyl) 6-0-methyl 3-oxo erythromycin 2'-acetate prepared as indicated in the European Patent Application EP 0596802 and 0.097 ml of hydrazine hydrate are suspended in 5ml of methyl cyanide and 0.5 ml of water. The reaction mixture is heated to 60*c for 3 hours. The reaction mixture is poured into water, extraction is carried out with ethyl acetate, the extracts are washed and dried. The reaction mixture is chromato-graphed on silica, eluting with an isopropyl ether, triethylamine, methanol mixture (90/10/10). 101 mg of desired product (product A),

Rf = 0.45, and 106 mg of corresponding product 10(S) (product B) are obtained.

Product A:

Analysis % calculated % found

			Pdt (A)	Pdt (B)
	C	59.31	59.3	59.3
	H	8.51	8.4	8.4
	N	6.69	6.7	6.8
Product A:	NMR CDC1₃	ppm Product B: NMR	CDC1₃ ppm
3.09	H₁₀ (»)	3.53	H₁₀ (»)
3.59	^H11 <^s>	3.46 (d,J=3Hz)	Η_Χ1 (s)
1.35	12 Me (s)	1.32	12 Me (s)
5.03	H₁₃ (dd)	4.95	H₁₃ (dd)	•
0.86	15 Me (t)	0.87	15 Me (t)
3.85	H₂ (q)	3.88	h₂ (q)
2.30	N-Me (s)	2.31	N-Me (s)
2.67-6	OMe (s)	2.83	6-OMe (s)
4.44	NH (s)	3.84	NH (s)
2.67	H₈ (m)	2.78	H₈ (m)

EXAMPLE 2i 11,12-dideoxy 3-de(2,6-dideoxy 3-C-methyl 3-0methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11 (oxycarbonyl (2-(3-phenylpropylidene) hydrazono)) erythromycin

285 mg of product A obtained in Example 1 and 156 mg of 3-phenylpropionaldehyde are put in solution in 2 ml of THF with a molecular sieve (4A°). 100 m of a molecular sieve f

(4A°) is added and the whole is heated at 60°C for 24 hours. Filtration is carried out, followed by concentration and purification by chromatography on silica, eluting with an ethyl acetate, triethylamine mixture (96-4). The fractions of Rf = 0.41 are collected and 330 mg of desired product is obtained, Rf ” 0.3.

Analysis % calculated 1 found

64.58 64.3

8.26 8.3

5.65 5.5

NMR CDC1₃

3.04

4.46

5.05

3.85 2.38 2.79 7.96

2.86 ppm h₁₀ (q)

H_X1 (d, j = 3 HZ) H₁₃ (dd) h₂

NMe (s)

OMe (s)

N»CH (t)

CH₂-*

H aromatics

2.61 NH«CH-CH₂ (b).

gXAMPLg 3¾ 11,12-dideoxy 3-d·((2,«-dideoxy 3-C-eethyl 3-0m«thyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11 (oxyearbonyl (2-(3-phenylpropyl) hydrazono)) erythroaycin mg of sodium cyanoborohydride (NaBH₃CN) is added to a solution containing 1.5 ml of methanol, 88 mg of the product of Example 2 and 50 ul of acetic acid. After concentration, and taking up in ethyl acetate, water is added and the pH is adjusted to 8 using a solution of 2N soda. Decanting is carried out, followed by washing with a saturated solution of sodium chloride and drying. The product obtained is chromatographed on silica, eluting with an isopopyl ether - methanol - triethylamine mixture (90-10-10). The fractions of R_f = 0.33 are collected. The mixture obtained is taken up in an ether-per.tar.e mixture and filtered. After evaporation, 70 mg of the expected product is obtained.

Analysis % calculated % found

ΑΡ . 0 0 5 8 7

64.4 64.2

8.51 8.3

5.63 5.6

C

Η

Ν

NMR CDCl-j ppm
3.74	H₁₀ (s)
5.03	H₁₃ (dd)
3.86	h₂ (q)
2.27	N(CH₃)₂ (s)
2.64	6 OMe (s)
2.72	CH₂-·
7.13-7.28	H aromatics
5.35	H Of NH (t)

EXAMPLE 4; 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-0methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11 (oxycarbonyl (2-(3-(4-quinolinyl) 2(E)-propenylidene) hydrazono)) erythromycin

125 mg of product A prepared in Example 1, 73 mg of

4-quinolinyl propenal whose preparation is given hereafter and 40 μΐ of acetic acid are agitated at ambient temperature for 5 hours. The methanol is eliminated under reduced pressure and the resultant product is taken up in a methylene chloride- water mixture. The pH is adjusted to 9 using a concentrated ammonium hydroxide solution. The reaction medium is decanted, dried over magnesium sulphate, filtered and evaporated to dryness. 0.211 g of a product is obtained vhich is chromatographed on silica, eluting vith a methylene chloride - methanol mixture (92-8). The product of Rf 0.4 is impasted in an ethyl acetate - pentane mixture (1-1).

After separating, and rinsing with the minimum amount of ethyl acetate - pentane mixture, the product obtained is oven-dried under reduced pressure. In this way 109 mg of the desired product is obtained.

PREPARATION OF EXAMPLE 4: 4-quinoline propenal

3.9 g of 4-quinoline carboxaldehyde is put in solution in S3 ni of methylene chloride. The mixture is cooled down to 10°C ± 5^eC and 8.3 g of 3-(triphenylphosphine) propenal (C_gH₅)₃P=C-CHO is added over one hour 30 minutes while maintaining the temperature at 10®C. The temperature is left to return to 20°C and agitation is continued for 24 hours.

The reaction medium is cooled down again to 1O°C and 0.4 g of (CgH₅)₃P=C-CHO is added. Agitation is continued for 3 hours at ambient temperature. The methylene chloride is evaporated off and a product is obtained which is chromatographed on silica eluting with an ethyl acetate - cyclohexane mixture (4-6). 2.12 g of desired product is isolated. M.p. « approx. 90°C.

(LB 5: 11,12-dideoxy 3-de((2,6-dideoxy 3-c-aethyl 3-010 methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11 (oxycarbonyl (2-(3-(4-quinolinyl) 2-propyl) hydrazono)) erythromycin

0.38 g of the product prepared in Example 4 and 38 mg of platinum oxide are put in solution in 10 ml of ethyl acetate. Hydrogenation is carried out under vigorous agitation for 24 hours. After filtration, rinsing with ethyl acetate and evaporating under reduced pressure, 0.375 g of product is obtained which is taken up in 5 ml of methanol,

175 μΐ of acetic acid and 90 mg of sodium borohydride.

Agitation is carried out for 3 hours at ambient temperature. The methanol is driven off and the residue is taken up in a methylene chloride - water mixture. The pH is adjusted to 89 with a 28% ammonium hydroxide solution. After decanting, washing with water, drying, filtering and evaporating to dryness, 0;37 g of product is obtained which is chromatographed on silica, eluting with an ethyl acetate triethylamine mixture 96-4. 127 mg of a product is obtained (Rj = 0.25) which is separated, washed and dried. 90 mg of the desired product is obtained M.p. = 189°C.

EXAMPLE 6: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-0methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12, ll-(oxycarbonyl (2-(3-(ΙΗ-benzimidazol-l-yl) propyl) hydrazono)) erythromycin

A solution of 0.3 g of the product obtained in

Example 1, 0.163 g cf 3-ir.idazolyl-propanal (whose preparation is given hereafter) and 90 ml of acetic acid in 9 ml of methanol is agitated for 18 hours at ambient temperature, after this time 40 mg of sodium cyanoborohydride

AP.0 0 5 8 7 is added, agitation is continued for 5 hours then 120 mg of sodium cyanoborohydride and 200 μΐ of acetic acid are added. Agitation is continued for 48 hours, a methylene chloride and water mixture is added, the pH is adjusted to 8-9 with 32% ammonium hydroxide, the organic phase is separated off, dried and evaporated to dryness. 0.6 g of residue is obtained which is chromato-graphed on silica (eluant: ethyl acetate methanol - TEA: 92-6-2) , the product obtained is impasted in an ether - pentane mixture 1-5. 0.143 g of the crude desired product is collected which is dissolved in 1 ml of ethyl acetate, followed by filtration and crystallization by the addition of 3 ml of pentane, and after drying, 0.085 g of desired product is obtained (M.p. = 197°C).

Analysis for ^C41^H63^N5°10 ⁷⁸⁵·⁹⁸

C

62.65

62.5

H

8.08

8.1

N

8.91

8.8 % calculated % found HUB CDC1₃ ppm

3.18: H₁₀; 3.69 (s): H_n; 0.84 (t): 15 CH₃; 3.86 (q): H₂; 2.45: N-(CH₃)₂; 2.60 (s): 6 0CH₃; 5.56 (t) : NH; 2.81: NH-CH₂”; 4-50: -CH₂ ^_N » ⁷·^{26 to} 8*02: SH benzimidazole.

2.65PREPARATION OF EXAMPLE ¢: 3-imidaxolyl propan*1

Stage A; 2-(2-(3-imidazolyl) ethyl) 1,3-dioxolane

0.49 g of sodium hydride dispersed in oil at 50% is added to a solution of 1.2 g of benzimidazole in 15 ml of dimethylformamide. The temperature rises to 35*C, ten minutes after the end of the gaseous release, 1.2 ml of 2-(2bromoethyl) 1,3-dioxolane is added while allowing the temperature to rise to 35^eC. Agitation is carried out for two hours, water saturated with sodium chloride is added, extraction is carried out with ether, the extracts are dried, filtered and evaporated under reduced pressure, 2 g of residue is obtained which is chromatographed on silica eluting with methylene chloride - methanol (55-5). In this way 1.6 g of desired product is collected.

NMR CDC1₃:

2.25 and 4.35: CH₂'s of the ethyl; 3.85 to 4.00: CH₂'s of the dioxolane; 4.87: CH dioxolane; 7.29-7.45-7.81: 4H benzimidazole; 7.92: H in position 2 of the imidazole.

STAGE B: 3-imidazoly1 propanal

A solution of 1.6 g of the product obtained in Stage A, 1.45 g of paratoluene sulphonic acid in 60 ml of methanol is agitated for 5 hours under reflux. The pH is adjusted to 8 with potassium carbonate, the methanol is eliminated under reduced pressure, extraction is carried out with methylene chloride, followed by washing with water, drying and evaporating to dryness under reduced pressure, 1.45 g of intermediate dimethoxy cetal is obtained which is agitated at 40“C for 18 hours, in the presence of 70 ml of acetone and 34 ml of 2N hydrochloric acid, the acetone is evaporated off under reduced pressure and the pH is adjusted to 8-9 by the addition of 32% ammonium hydroxide, extraction is carried out with methylene chloride, the extracts are washed with water, dried and evaporated to dryness under reduced pressure, 1.13 g of product is collected which is chromatographed on silica, eluant: methylene chloride - methanol 95-5. 0.796 g of desired product is obtained.

NMR CDC1₃ 250 MHZ

3.07 (t)-4.52 (t): CH₂'s of the ethyl; 7.25 to 7.50:

thearomatics; 9.79 (s): CH of the aldehyde.

EXAMPLE 7: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-0methyl alpha-L-ribohaxopyranosyl) oxy) 6-O-methyl 3-oxo

12,11-(oxycarbonyl (2-(3-(2-phenyl 5-thiasolyl) propyl) hydrasono)) erythromycin mg of sodium cyanoborohydride are added to a mixture 200 mg of the product obtained in Example 1, 139 mg of 3-(2phenyl 5-thiazolyl) propanal (whose preparation is given hereafter), 180 ml of acetic acid and 7 ml of methanol are agitated for 4 hours at ambient temperature and their agitation takes place for 18 hours at ambiant temperature. Evaporation to dryness under reduced pressure is carried out, the residue is taker, up in a water - ethyl acetate mixture and the pH is adjusted to 9 with an aqueous ammonium hydroxide solution. Extraction is carried out with ethyl acetate, the extracts are washed with water, dried,

AP. Ο Ο 5 8 7 evaporated to dryness under reduced pressure. 354 mg of product is collected which is chromatographed on silica, eluant: ethyl acetate then ethyl acetate - triethylamine (96/4) . 170 mg of product is collected which is crystallized from an ethyl acetate - pentane mixture 1/5. In this way 80 mg of the desired product is obtained.

Analysis for C₄₃H₆₄N₄O₁₀S	829.07 N	S
c	H
% calculated 62.3	7.78	6.76	3.87
% found 62.0	7.8	6.8	4.0

NMR CDCl-j 300 MHz

3.17 (m): H₁₀; 1.07 (d) : 14 CH₃; 1.48: 15 CH₃; 3.87 (q): H₂; 2.26 (s) : N-(CH₃)₂; 3.53 (m) : 2ΌΗ; 2.67 (s) : 6-OCH₃; 5.43 (t) : NH; 2.86 (m)-1.95 (m)-3.03 (m): the propyl CH₂'s; 7.55 (s) : H of the thiazole; 7.39 (m) 3H and 7.89 (m) 2H:

aromatics; 1.19 (d): Hg.

PREPARATION ΟΓ EXAMPLE 7: 2-phenyl 5-thiazole propan*1 Stage A: 2-phenyl 5-carbethoxy thiazole

A solution of ethyl formyl beta chloracetate in 240 ml of benzene is added to a suspension of 78 g of thiobenzamide in 200 ml of benzene. Heating under reflux is carried out for 3 hours 30 minutes while eliminating the water formed. The reaction medium is cooled down and 320 ml of a 20% solution of potassium carbonate and 220 cm³ of water are added slowly, extraction is carried out vith ether, followed by washing, drying and distillation under reduced pressure. 75.5 g of desired product is obtained.

Stage B: 2-phenyl 5-thiazole carboxylic acid

28.56 g of potash in pellets in solution in 410 ml of ethanol is added to a solution of 75.5 g of the product obtained in Stage A, in 130 ml of ethanol, the whole mixture is heated for 15 minutes under reflux, cooled down and the potassium salt is separated off, washed with ether and dried under reduced pressure. 53.5 g of intermediate potassium salt is obtained which is dissolved in 1.2 litres of water and acidified to pH 1 with a concentrated hydrochloric acid solution after filtration, 29 g of desired product is collected (M.p. = 192°C). 24.5 g of product is ΰ ,:

ml recrystallized from 750 ml of toluene, product is obtained. M.p. = 195°C. Analysis for C₁₀H₇N°₂S 205.2 g of desired % calculated % found

C

58.52

58.5

H

3.43

3.7

N

6.82

6.8

S

15.6

15.2

Stage C: methyl 2-phenyl 5-thiazole carboxylate

2.5 ml of acetyl chloride is added to a solution of 4.77 g of the acid obtained in Stage B in 160 ml of methanol, and the mixture is heated under reflux for 18 hours. After bringing to dryness under reduced pressure, taking up in ethyl acetate, filtration and concentration to a reduced volume, the crystals obtained are separated off. The mother liquors are washed with soda, extraction is carried out with ethyl acetate, followed by washing with water and evaporating to dryness, the 2 crystallized fractions are united to obtain 4.54 g of desired product (M.p. = 108°C).

Stage Di 2-phenyl 5-formyl thiazol Reduction:

A solution of 4.5 g of the product obtained in Stage

C in 35 ml of tetrahydrofuran is added over 20 minutes and while maintaining the temperature at 10°C to a suspension of 1.45 g of lithium-aluminium hydride in 65 ml of tetrahydrofuran cooled down to 10°C, the mixture is agitated for 45 minutes at 10’C, then for 2 hours at ambient temperature. 10 then 50% tetrahydrofuran in water is added while maintaining the temperature below 20°C, 15 ml of a solution of potassium and sodium tartrate is added, filtration is carried out followed by rinsing and bringing to dryness under reduced pressure; the residue obtained is impasted in hexane, separated and dried at 40°C, under reduced pressure, and 3.6 g of product is collected. M.p. = 82’C.

Oxidation:

3.57 g of the product obtained above is agitated for

5 2 hours 33 minutes at ambient temperature with 143 ml of toluene and 17.9 g of manganese dioxide. After filtration and bringing to dryness under reduced pressure, the residue is taken up in hexane, separated and dried at 40’C under

AP. 0 0 5 β 7 reduced pressure, and 3.09 g of desired product is collected.

M.p. - 94*C.

Stage E: 3-(2-phenyl 5-thiazolyl) propenal g of (formyImethylene) triphenylphosphorane is added over 10 minutes to a solution of 2.098 g of the product obtained in Stage D, and agitation is carried out for 27 hours at ambient temperature. After evaporating to dryness under reduced pressure, 6.60 g of product is collected which is chromatographed on silica eluting with ethyl acetate cyclohexane (2-8). 1.22 g of product is obtained which is impasted in pentane in order to obtain 1.047 g of the desired product (M.p. » 104°C).

NMR CDC1₃ (250 MHz)

8.04 (s): H triazole; 6.49 (ddJ = 7.5) and 7.69 (dJ « 15.5) the propene H's; 9.67 (J = 7.5) CHO; 7.50 (m) 3H and 7.97 (m) 2 H: the aromatics.

Stage F: 3-(2-phenyl 5-thiazolyl) propenol

900 mg of the aldehyde obtained in Stage B above is added in portions to a suspension of 475 mg of sodium borohydride in 50 ml of ethanol, then the mixture is agitated for 20 minutes at ambient temperature then the excess eodium borohydride is destroyed by adding acetone. Evaporation to dryness under reduced pressure is carried out followed by taking up in ethyl acetate, washing with salt water, drying and bringing to dryness under reduced pressure, and 960 mg of product ie obtained, used as it is for the following stage. Stage <5; 2-phenyl 5-thiazole propanol

Ά solution of 960 mg of the product obtained in Stage F in 10 ml of methanol is hydrogenated for 12 hours under 1 atmosphere then for 9 hours under 1.4 atmospheres in the presence of 150 mg of palladium on charcoal. After filtration, evaporation to dryness under reduced pressure is carried out and the residue is chromatographed on silica (eluant: ethyl acetate - cyclohexane (4-6)). 759 mg of desired product is collected.

NMR CDC1₃ 200 MHz

1.52 (m): OH; 3.74 (m) - 1.97 (m) - 2.92 (dt): the CHj's;

7.40 to 7.90 (m): 5H aromatics; 7.53 (t, J = 1): H thiazole.

t t..

Stage H: 2-phenyl 5-thiazole propanal

1.27 g of pyridinium sulphotrioxide complex is added to a solution cooled down to 10°C of 584 mg of the product obtained in the previous stage, 800 ul of dimethylsulphoxide, 1.15 ml of triethylamine and 8 ml of methylene chloride while maintaining the temperature at 10°C, the whole is agitated for one hour 15 minutes at l0^eC, then left to return to ambient temperature, extraction is carried out with methylene chloride, followed by washing with water, drying and evaporating to dryness under reduced pressure, 806 mg of product is collected which is chromatographed on silica (eluant: ethyl acetate - cyclohexane (3-7)) , and 450 mg of the desired product is obtained.

NMR CDC1₃ 200 MHz

2.88-3.20 (t): the propyl CH₂'s; 7.55 (s) : H thiazole; 7.40 (m): 3H and 7.87 (m) 2H: the aromatic H's; 9.85 (ws): CHO.

EXAMPLE 8: 11,12-dideoxy 3-d·((2,6-dideoxy 3-C-methyl 3-Omethyl alpha-L-ribohexopyrano«yl, oxy) 6-O-methyl 3-oxo

12,11-(oxycarbonyl (2-(3-(4-phenyl lH-imidasol 1-yl) propyl) hydrazono)) erythromycin

125 mg of the product obtained in Example 1, 80 mg of 3-(4-phenyl ΙΗ-imidazole 1-yl) propanal (whose preparation is given hereafter) and 2 ml of methanol are agitated for 20 hours. 54 mg of sodium cyanoborohydride is added.

Concentration under reduced pressure is carried out, the residue is taken up in 20 ml of ethyl acetate, washed with soda then with water saturated with sodium chloride, dried and evaporated to dryness under reduced pressure, and the residue is chromatographed on silica (eluant: chloroform methanol - ammonium hydroxide 95/5/0.5), the crude product is taken up in an ether - ethyl acetate mixture, filtered, evaporated to dryness and 85 mg of the desired product is collected. Analysis for % calculated % found ^C43^H65^N5°10 ⁸¹²·⁰²

c	H	i'1
63.6	8.07	8.62
63.4	8.2	8.3

NMR CDC1₃ 400 MHz

AP. 0 0 5 8 7

3.70 (s): H in position 11; 4.98 (dd): H₁₃; 3.86 (q): H in position 2; 2.26 (s): N-(CH₃)₂; 2.63: 6-OCH₃; 5.54 (t): NH;

4.27 and 1.97: the propyl CH₂'s; 7.3 (d) - 7.57 (d): 2H imidazole; 7.2 - 7.35 - 7.8: the aromatics.

PREPARATION 0Γ EXAMPLE 8: 3-(4-phenyl ΙΗ-imidazol 1-yl) propanal

Stage A : 3-(4-phenyl ΙΗ-imidazol 1-yl) ethyl 1,3-dioxolane

The operation is carried out as in Stage A of the preparation of Example 6, starting with 1.44 g of 4phenylimidazole and 1.17 ml of bromoethyldioxolane, and after chromatography on silica (eluant: ACOEt) 1.8 g of expected product is obtained.

NMR CDC1₃

2.19 (d,t) and 4.13 (t): propyl CH₂; 3.8-4.05: the CH₂*s of dioxolane; 4.88 (t): H oxolane; 7.23 and 7.53: the imidazole CH's; 7.23 - 7.37 - 7.75: the aromatics.

Stage B: 3-(4-phenyl ΙΗ-imidazol 1-yl) propanal

1.77 g of the product obtained in Stage λ above, 35 ml of acetone and 30 ml of 2N hydrochloric acid are heated for 20 hours at 60*C. The acetone is then eliminated under reduced pressure and the solution is neutralized by adding sodium bicarbonate in sticks, then extraction is carried out with ethyl acetate, followed by drying and evaporating to dryness under reduced pressure. The residue is chromatographed-on silica (eluant: ethyl acetate - methanol (97-3)). 900 mg of desired product is collected.

HUB CDC1₃ 250 MHZ

9.81 (s): CHO; 7.10 to 7.76: the imidazole and aromatic H's; 3.01 (t) and 4.29 (t): the propyl H's.

EXAMPLE 9: 11,12-dideoxy 3-de( (2,6-dideoxy 3-C-methyl 3-0ethyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 12,11(oxycarbonyl (2-(3-(3-phenyl 1,2,4-oxodissol 5-yl) propyl) hydrazono) erythromycin

The operation is carried out as in Example 6 starting with 125 mg of the product obtained as in Example 1, using 40 mg of 3-(3-phenyl 1,2,4-oxadiazol 5-yl) propanal (whose preparation is described hereafter). After chromatography on silica, eluant: isopropyl ether 22 triethylamine - methanol (90-10-10) and crystallization from isopropyl ether - methanol, 107 mg of expected product is obtained.

Analysis for C₄₂H₆₃N₅O₁₁ 814.00

C Η N % calculated 61.97 7.8 8.6 % found 61.7 7.9 8.5

NMR CDC1₃ 300 MHz

3.74 (s): Η₁₃; 5.03 (dd): H₁₃; 3.87 (q): H₂; 2.27 (s) : 60CH₃; 2.27 (s): N-(CH₃)₂; 5.49 (t): NH; 3.17 (m) and 2.11 (m) : the propyl CH₂'s; 7.47 to 8.08: the aromatics. PREPARATION OF EXAMPLE 9: 3-(3-phenyl 1,2,4-oxadiazol 5-yl) propanal

Stage A: 3-(3-phenyl 1,2,4-oxadiazol 5-yl) propanol

A solution of 2.5 ml of borane-methyl sulphide complex, in 2M solution in tetrahydrofuran, 920 mg of 3-(3-phenyl

1,2,4-oxadiazol 5-yl) propanoic acid (prepared according to R.M. SRIRASTAVA et al. J. Heterocycl. Chem., 21, 1193 (1984) and 20 ml of tetrahydrofuran is agitated for one hour at ambient temperature. 10 ml of methanol is added over 5 minutes. Evaporation to dryness under reduced pressure is carried out and the residue is chromatographed on silica (eluant: ethyl acetate - hexane (6-4)). 485 mg of expected product is collected.

NMR CDC1₃ 250 MHZ

2.07 (vs): OH; 2.14 (a) - 3.10 (t) - 3.8 (t): the CH₂'s; 7.41 - 7.54 - 8.06: the aromatics.

Stage B: 3-(3-phenyl 1,2,4-oxadiazol 5-yl) propanal

1.07 g of pyridinium sulphotrioxide complex is added to a solution cooled down to 10°C of 460 mg of the product obtained in Stage A, 680 ul of dimethyl sulphoxide and 970 ul of triethylamine in 5 ml of methylene chloride while maintaining the temperature at 10°C, the reaction medium is left to return to ambient temperature, 15 ml of methylene chloride is added, followed by washing with water, drying, evaporating to dryness under reduced pressure and chromatographing on silica (eluant: ethyl acetate - hexane 4-6) and 365 mg of the desired product is obtained.

AP . Ο Ο 5 8 7

NMR CDC1₃

3.13 (m) - 3.26 (m) : the CH₂'s; 7.49 to 8.05: the aromatics. EXAMPLE 10: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-0methyl alpha-L-ribohexopyranosyl) oxy) 6-o-methyl 3-oxo

12,11—(oxycarbonyl (2-(3-(2-chlorophenyl) propyl) hydrasono) erythromycin

The operation is carried out as in Example 6 starting with 125 mg of the product obtained in Example 1, using 67 mg of 2-chlorophenyl propanal (whose preparation is given hereafter). After chromatography on silica (eluant: isopropyl ether -triethylamine - methanol (90-10-10)), 48 mg of desired product is collected.

Analysis for C₄₀H₆₂C1N₃0₁₀ 780.40

C Η N Cl % calculated 61.56 8.01 5.38 4.45 % found 61.4 8.0 5.4 4.5

NMR CDC1₃ 400 MHZ

3.73 (s): H in position 11; 5.13 (dd): H in position 13; 3.87 (q): H in position 2; 2.26 (s): N-(CH₃)₂; 2.64 (s): 6-OCH₃;

5.36 (t) : NH; 1.83 (m) - 2.70 (m) - 2.79 (a): the CH₂*s; 7.05 to 7.2: the aromatics.

PREPARATION OT EXAMPLE 10: 3-(2-chlorophenyl) propanal

Stage A: methyl 3-(2-chlorophenyl) propanoate

4.35 g of metachlorocinamic acid, 430 mg of palladium on activated charcoal and 70 ml of methanol are agitated for one hour under an inert atmosphere. Agitation im then carried out for 3 hours under a hydrogen atmosphere. The reaction medium is filtered and evaporated to dryness under reduced pressure and the residue is chromatographed on silica (eluant: ethyl acetate - hexane (2-8)), 3.1 g of desired product is obtained.

NMR CDC1₃ 250 MHz

2.6 (t) - 2.8 (t): the CH₂'s; 3.6 (s) : 0CH₃; 7.05 - 7.37: the aromatics.

Stage B: 3-(2-chlorophenyl) propanol ml of diisobutylaluminium hydride in a IM solution in tetrahydrofuran is added at 0^eC to a solution of 1.85 g of the product obtained in Stage A, in 20 ml of tetrahydrofuran.

4

C ²⁵ ©

The mixture is left to return to ambient temperature and agitated for 2 hours. A solution of mixed sodium-potassium tartrate is added, dilution is carried out with tetrahydrofuran, followed by filtration and evaporation to dryness under reduced pressure. The residue is chromatographed on silica (eluant: ethyl acetate - hexane (2-6)) and 1 g of desired product is obtained.

Stage C: 3-(2-chlorophenyl) propanal

The operation is carried out as in Stage B of

Preparation 9, starting with 1 g of the product obtained in Stage B above, using 2.5 ml of triethylamine, 1.75 ml of dimethyl sulphoxide and 2.8 g of pyridinium sulphotrioxide complex. After chromatography on silica, eluant: ethyl acetate - hexane (1-9), 425 mg (43%) of desired product is obtained.

NMR CDC1₃ 250 MHZ

2.79 (m) and 2.94 (m): the CH₂'s; 7.05 to 7.25: the aromatics; 9.82 (t): CHO.

BXAMPLB 11 : 11,12-dideoxy 3-de ((2,6-dideoxy 3-c-methyl 3-Omethyl alpha-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,11(oxycarbonyl (2-(3-(4-quinolinyl) 2-propyl) hydrasono)) erythromycin

Stage A: 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 (hydrazono) erythromycin isomer 10 (R) and corresponding isomer 10 (S).

17.65 g of 11-deoxy 10,11-didehydro 3-de(2,6-dideoxy 3C-methyl 3-0-methyl alpha-L-ribohexopyranosyl) oxy) 12-0((ΙΗ-imidazol-l-yl) carbonyl) 6-0-methyl 3-oxo erythromycin 2'-acetate is put in solution in 176 ml of methyl cyanide. 4.07 g of caesium carbonate and 25.5 ml of hydrazine hydrate are added. After heating for 10 minutes at 85°C, the solvent is driven off under reduced pressure at 40°C, extraction is carried out with methylene chloride, followed by washing with water and drying, the solvent is evaporated off, the residue is taken up in methanol, the precipitate is separated out, dried at 50“C under reduced pressure and 6.04 g of product is collected. The mother liquors are concentrated to dryness,

AP . Ο Ο 5 8 7 the residue is chromatographed on silica (eluant: isopropyl ether - methanol - triethylamine 80-10-10) and 0.83 g of isomer A (R_f = 0.4) and 2.65 g of isomer B (R_f · 0.2) are collected.

Stage B: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-Omethyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11(oxycarbonyl (2-(3-(4-quinolinyl, 2-propyl) hydrazono)) erythromycin.

g of the product obtained as in Stage A and 4.66 g of 10 4-quinoline propanal prepared as indicated below are suspended in 130 ml of methanol. 4.8 ml of acetic acid is added and agitation is carried out for 20 hours at ambient temperature. Next 5.3 g of sodium cyanoborohydride is added then agitation is continued for 4 hours. The methanol is eliminated under reduced pressure, extraction is carried out with ethyl acetate, followed by washing vith an aqueous solution of N soda then vith vater; the solvent is evaporated from the organic phase, the residue is chromatographed on silica (eluant: ethyl acetate - triethylamine 97-3) and 12.7 g of product is obtained, R_f * 0.15. After another chromatography on silica (eluant: methylene chloride methanol 95-5 then 85-15) and crystallization from isopropyl ether, the pure product is obtained, M.p. = 183°C, the analyses of vhich are identical to those of Example 5.

Q 25 PBEPARATIWOfEXAMPLE XI» 4-guinoliae propanal.

θ Stage A: 2-(4-quinolinyl ethenyl) 1,3-dioxolane.

3.15 g of 4-quinoline carboxaldehyde and 8.6 g of (1,3(dioxalan-2-yl) methyl] triphenylphosphonium bromide are suspended in 40 ml of tetrahydrofuran, the suspension is cooled down to -30°c then 2.5 g of potassium terbutylate is added and agitation is carried out for one hour. The reaction medium is allowed to return to ambient temperature, agitated for 3 hours, poured into a water/ice mixture, extraction is carried out with methylene chloride, followed by washing with water and drying, the solvent is evaporated off under reduced pressure, the residue is taken up in an ethyl ether - pentane mixture 3-7, agitation is carried out for 2 hours, followed by filtration, and the solvent is evaporated from the filtrate and 3.99 g of expected product is obtained.

Stage B: 2-[2-(4-quinolinyl) ethyl] 1,3-dioxolane.

4.3 g of the product obtained in Stage A is dissolved in 40 ml of methanol, 0.215 g of activated charcoal with 10% palladium is added and hydrogenation is carried out for 2 hours under a pressure of 1500 mbars. After filtration, rinsing with methanol, the solvent is evaporated off and 4.2 g of expected product is collected which is used as it is for the following stage.

Stage C: 4-quinoline propanal.

4.2 g of the product obtained in Stage B is dissolved in 70 ml of acetone and 70ml of 2N hydrochloric acid is added. Heating is carried out for 6 hours at 40®C, the acetone is eliminated under reduced pressure, extraction is carried out with ethyl acetate, followed by washing with water, the aqueous phase is adjusted to pH - 9 with an aqueous solution of ammonium hydroxide. Extraction is carried out with ethyl acetate, the organic phases are united, dried and the solvent is evaporated off. After chromatography on silica (eluant: ethyl acetate - cyclohexane 6-4) 1.36 g of expected product is obtained.

EXAMPLE 12: 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~(3-(7-methoxy-4-quinolinyl) propyl) hydrasono)) erythromycin.

299 mg of 7-methoxy 4-quinoline propanal prepared as indicated below and 313.9 mq of product A prepared in Example 1 and 120 μΐ of acetic acid are dissolved in 2 ml of methanol. Agitation is carried out for 2 hours 15 minutes at ambient temperature then 62.84 g of sodium cyanoborohydride is added. Agitation is continued for 20 hours at ambient temperature. The reaction medium is poured into 50 ml of ethyl acetate, washed with 15 ml of N soda then with water, dried, the solvent is evaporated off under reduced pressure and 549 mg of product is collected which is purified by chromatography on silica (eluant: isopropyl ether-methanoltriethylamine 80-10-10) then (chloroform-methanol-ammonium

AP. Ο Ο 5 8 7 hydroxide 96-4-0,4). collected, Rf = 0.2. Analysis

C % calculated 63.84 % found 63.8

37.2 mg of expected product is

Η N

8.04 6.77

8.1 6.6

NMR CDC1₃ 300 MHz

3.74 (s): H_X1; 3.17 (m): NH-£H₂; 3.95 (s): OCH₃ of the quinoline; 7.16-7.41 (d)-8.00 (d)-8.70 (d): H quinoline; 3.87 (q); H₂; 2.65 <s): 6-OCH₃; 2.65 (a): H₈; 0.82 (t): £H₃-CH₂. PREPARATION Of EXAMPLE 12: 7-methoxy 4-quinoline propanal. Stage A: 2-((7-methoxy 4-quinolinyl) ethenyl] 1,3-dioxolane.

The operation is carried out as in the preparation of Example 11, Stage A starting with 787 mg of 7-methoxy 415 quinoline carboxaldehyde. 2.61 g of product is obtained which is chromatographed on silica (eluant: chloroform ethyl acetate 7-3). 931 mg of expected product is obtained.

Stage B: 2-(2-(7-methoxy 4-quinoline) ethyl] 1,3-dioxolane.

The operation is carried out as in the preparation of

Example 11 Stage B using 931 mg of the product prepared in Stage A and 869 mg of expected product is obtained.

Stage C: 2-(7-methoxy 4-quinoline) propanal.

The operation is carried out as in the preparation of Example 11 Stage C using 845 mg of the product obtained in

Stage B. 310 mg of expected product is obtained, Rf « 0.15. mxaitet.· m 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 1-0° ethyl alpha-l-ribohexopyranosyl)oxy, 6-O-methyl 3-oxo 12,11(oxycarbonyl 2-(3-(2-{3-pyridinyl-4-thiazolyl) propyl) hydrazono)) erythromycin.

The operation is carried out as in Example 12, starting with 158 mg of 2-(3-pyridinyl) 4-thiazole propanal, 370 mg of product A prepared in Example 1 and 70 μΐ of acetic acid in

3.7 ml of methanol then after agitation for 4 hours at ambient temperature, 75 mg of sodium cyanoborohydride is added. After agitation for 16 hours at ambient temperature, another 16 mg of aldehyde and 20 mg of reducing agent are added and agitation is continued for 3 hours. Hater and ethyl acetate are added, followed by alkalinizing to pH - 9 using ammonium hydroxide, the organic phase is washed with water, dried and the solvent is evaporated off under reduced pressure. After chromatography on silica (eluant: isopropyl ether - methanol - triethylamine 80-10-10) , 203 mg of expected product is obtained.

3.18 (m): H₁₀; 3.74 (s): Η_χ1; 7.05 (s): H₅ thiazole; 7.37 (dd)-8.24 (ddd)-8.62 (dd)-9.13 (dd): pyridine; 3.86 (q): H₂; 2.65 (s): 6-OCH₃; 2.66 (m) ; Hg; 0.85 (t) : CH₃-CH₂.

PREPARATION OF EXAMPLE 13s 2-(3-pyridinyl) 4-thiasole propanal.

Stage A: [[2-(3-pyridinyl) 4-thiazolyl] ethenyl) 1,3dioxolane.

The operation is carried out as in the preparation of Example 11 Stage A starting with 2.6 g of 2-(3-pyridinyl) 4thiazolyl carboxaldehyde. After chromatography on silica (eluant: ethyl acetate - hexane 2-1) 4.8 g of expected product is obtained (Rf = 0.35 used as it is for the following stage.

Stage B: 2-(2-((3-pyridinyl) 4-thiazolyl) ethyl] 1,3dioxolane.

The operation is carried out as in the preparation of Example 11 Stage B starting with 4.8 g of the product prepared in Stage A and after chromatographing the residue on silica (eluant: ethyl acetate - cyclohexane 2-1) 1.4 g of expected product is obtained.

Stage C: 2-(3-pyridinyl) 4-thiazolyl propanal.

The operation is carried out as in the preparation of Example 11 Stage C starting with 1.2 g of the product prepared in Stage B. After chromatography on silica (eluant: ethyl acetate - hexane 2-1) 468 mg of expected product is obtained.

By operating as in the previous examples starting with the compound of Example 1 and the appropriate aldehyde, the following products were prepared:

EXAMPLE 14: 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-0methyl alpha-L-ribohexopyranosyl) oxy) 6-o-methyl 3-oxo

12,11-(oxycarbonyl 2-(3-(lH-imidazol-l-yl) propyl) hydrazono)) erythromycin.

AP . Ο Ο 5 β 7

NMR (CDC1₃) 300 MHz:

0.83 (t): £H₃-CH₂; 1.08 (d)-1.17 (d)-1.25 (d)-1.3 (d)-1.35 (d): the £H₃-CH's; 1.3 (s)-1.47 (s): 6 and 12 Me; 2.12 (m) : CH₂-£H₂-CH₂; 2.27 (s): N(Me)₂; 2.45 (m) : H'₃; 2.59 (s): 65 OMe; 3.05 (m): H₄; 2.6 to 3.2: H'₂, H₁₀: H₈ and £H₂NH; 3.53 (Β): H'₅; 3.72 (β): Η_χχ; 3.85 (q): H₂; 4.27: Η*_χ and H_s; 4.63 (m): OI₂-N; 4.99 (dd): H₁₃; 5.46 (t): NH-CH₂; 7.10-7.64-7.667.97: aromatics.

EXAMPLE 15: 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-010 methyl alpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo

12,11-(oxycarbonyl 2-(3-(3H-imidazo (4,5-b)pyridin-3-yl) propyl) hydrazono)) erythromycin.

_f. NMR (CDC1₃) 300 MHz:

0.85 (t): £H₃-CH₂; 1.09-1.19 (d)-1.25 (d)-1.31 (d)-1.34 (d) : 15 the £H₃CH's; 1.33 and 1.48: 6 and 12 Me; 1.57 and 1.96: CH₂ in position 14;

1.66 and 1.87: CH₂ in position 7; 2.05 and 2.18: CH^-CH^-q^: 2.26 (s): N(£H₃)₂; 2.44 (m): H'₃; 2.6 (s): 6-OCH₃; 2.66 (m): H_g; 2.70 to 2.85: £H₂NH; 3.04 (m) : H₄; 3.18: H₂, H₁₀; 3.70 (s): Η_χχ; 3.85 (q): H₂; 4.27: H'_x and H₅; 4.42 to 4.70: £H₂N; 4.97 (dd): Η_χ3; 5.56 (t): NH; 8.22 (dd)-8.05 (d)-8.28 («)8.38 (d): aromatics.

EXAMPLE 16: 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-Oethyl alpha-L-ribohexopyranosyl) oxy 6-0-methyl 3-oxo 12,ΪΙC. 25 (oxycarbonyl 2-(3-(1,1'-biphenyl-4-yl) propyl) hydrazono)) θ erythromycin.

MMR (CDC1₃) 300 MHz:

0.87 (t): £H₃-CH₂; 1.08 (d)-1.18 (d)-1.23 (d)-1.32 (d)-1.38 (d): the CH₃-CH's: 1.34 (s) and 1.48 (s): 6 and 12 Me; 2.26 (s): N(CH₃)₂; 2.44 (m): H'₃; 2.65 (s): 6-OCH₃; 2.65 (m) H_g;

2.77 (m) CH₂-Ar; 2.85 (t): £H₂NH; 3.07 (m) : H₄; 3.18 (m):

H'₂, H_xo; 3.25 (m): H'₅; 3.76 (s): Η_χχ; 3.87 (q): H₂; 4.27:

Η'_χ and H_s; 5.04 (dd): Η_χ3; 5.37 (t): NH-CH₂; 7.25 to 7.6: aromatics.

EXAMPLE 17: ll,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-(3-(2-phenyl 4-thiazolyl) propyl) hydrazono)) erythromycin.

NMR (CDC1₃) 300 MHz:

0.86 (t) : £iJ₃-CH₂; 1.07 (d)-1.19 (d)-1.24 (d)-1.31 (d)-1.35 (d): the CH₃-CH; 1.32 (s)-1.48 (s): 6-CH₃ and 12-CH₃; 2.26 (s): N(CH₃)₂; 2.65 (s): 6-OCH₃: 2.45 (m) : H'₃; 2.65 (m): H₈;

2.8 to 3.25 (m) : H₄, H₁₀, H'₂, SH₂-Ar and SH₂ ^N; 3.53 (m) :

H'₅; 3.76 (m) : Η_χι; 3.86 (q): H₂; 4.27 (d) : Η'_χ and H₅; 5.04 (dd): H₁₃; 5.36 (t): EH; 6.96-7.40-7.93: aromatics.

EXAMPLE 18: 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-0methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,ll-(oxyearbonyl 2-(3-(5-phenyl l,2,4-thiadiazol-3-yl) propyl) hydrazono)) erythromycin.

NMR (CDC1₃) 300 MHz:

0.87 (t): £H₃~CH₂; 1.33 and 1.47: 6 and 12 Me; 2.17 (m) : CH₂CH₂-CH₂; 2.26 (s): N(CH₃)₂; 2.67 (s): 6-OCH₃; 2.67 (s) : H₈;

3.76 (s): Η_χ1; 3.85 (q) : H₂; 5.06 (dd): Η_χ3; 5.39 (t) : NH~ CH₂; 7.49-7.94: aromatics.

example 19: ll, 12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-0methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11-(oxyearbonyl 2-(3-(4-(4-ehlorophenyl-lH-imidasol-i-yl) propyl) hydrazono)) erythroaycin.

By operating as previously, the compounds of formula (I) were prepared in which the radical

represents the radical

EXAMPLE 20: ll, 12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-0methyl alpha-L-ribohexopyranosyl)oxy) 6-O-methyl 3-oxo 12,11(oxycarbonyl 2-(3-(6-methoxy-4-quinolinyl) propyl) hydrazono)) erythromycin.

The operation is carried out as in exemple 12 and the expected product is obtained.

NMR CDC1₃ 300 MHz

3,74 (s) : H_n ; 5,52 (tl) : NH-CH₂ ; 3,98 (s) : OCH-j de la quinoline ; 7,25-7,35 (d)-7,99 (d)-8,65 (d) : H quinoline ;

3,87 (q) : H₂ ; 2,64 (s) : 6-OCH₃ ; 2,64 (m) : H₈ ;

5,02 (dd) : H₁₃.

AP. Ο Ο 5 8 7

- ) 3

X = F , Sr

X = C 1 . F

X = H, Cl, F

EXMPLB 0, MMUttCtOTIOl· COMPO3ITIQH

Tablets vere prepared containing:

Product of Example 5 .......................... 150 mg Excipient s.q.f............................... lg

Detail of the excipient: starch, talc, magnesium stearate

PHARMACOLOGICAL STUDY OP THE PRODUCTS OF THE INVENTION Method of dilutions in liquid media

A series of tubes was prepared into which an equal quantity of sterile nutritive medium is distributed. Increasing quantities of the product being studied is distributed into each tube, then each tube is seeded with a bacterial strain.

After incubation for twenty-four hours in a heating chamber at 37’C, the growth inhibition is evaluated by trans32 concentrations (M.I.C.) to be determined, expressed in micrograms/cm³.

The following results were obtained with the product of Example 5: (reading after 24 hours)

GRAM⁺ bacterial strains

Staphylococcus aureus 011UC4 0.02

Staphylococcus aureus 011G025I 0.08

Staphylococcus epidermidis 012GO11I 0.04

Streptococcus pyogenes £ 0.02 group A 02A1UC1

Streptococcus agalactiae < 0.02 group Β 02B1HT1

Streptococcus faecalis < 0.02 group D 02D2UC1

Streptococcus faecium < 0.02 group D 02D3HT1

Streptococcus sp £ 0.02 group G 02G0GR5

Streptococcus mitis S 0.02

02mitCBl

Streptococcus agalactiae < 0.02 group B 02B1SJ1

Streptococcus pneumoniae £ 0.02

032UC1

Streptococcus pneumoniae £ 0.02

030SJ5

Moreover, the product of Example 5 demonstrated a useful activity on the GRAM” bacterial strains Haemophilus Influenzae 351HT3, 351CB12, 351CA1 and 351GR6.

The compounds of examples 12 and 13 have equally demonstrated an excellent activity on the gram (-) and gram (+) bacterial strains.

In this way, operating as indicated previously, the following results were obtained with the compounds of examples 12 and 13 (reading after 24 hours).

AP. Ο Ο 5 8 7

	GRAM* bacterial strains		Ex. 12	Ex.13
	Staphylococcus aureus		0,08	0,04
	011UC4
5	Staphylococcus aureus		0,08	0,15
	011G025I
	Staphylococcus epidermidis		0,04	0,04
	012G011I
	Streptococcus pyogenes	£	0,02	£ 0,02
10	02A1UC1
	Streptococcus agalactiae	£	0,02	£ 0,02
	02B1HT1
	Streptococcus faecalis	£	0,02	£ 0,02
	02D2UC1
15	Streptococcus faecium	<	0,02	£ 0,02
	02D3HT1
	Streptococcus pneumoniae		0,04	£ 0,02
	O32UC1
	Streptococcus pneumoniae	£	0,02	£ 0,02
20	030SJ5I
	Streptococcus pneumoniae		0,6	0,6
	030CR18C
	Haemophilus inflienzae		1,2	0,6
	351HT3
25	Haemophilus inflienzae		1,2	1,2

3S1CB12

Claims

1/) The compounds of formula (I) as defined in any one of claims 10 to 14, in which r represents an integer varying from 1 to 4.

20 16) The compound of formula (I) the name of which follows:

1) The compounds of general formula (I):

in which:

either Rj and R₂, identical or different, represent a hydrogen atom, or a hydrocarbon radical containing up to 24 carbon atoms, saturated or unsaturated, optionally interrupted by one or more heteroatoms and optionally carrying one or more functional groups, or R_x and R₂ form with the nitrogen atom to which they are linked a heterocycle optionally containing one or more heteroatoms chosen from nitrogen, oxygen and sulphur, or R^ and R₂ together form a radical

R ·, in which R'^ and R'₂, identical or different, represent a hydrogen atom or a hydrocarbon radical containing up to 23 carbon atoms, saturated or unsaturated, optionally interrupted by one or more heteroatoms and optionally carrying one or more functional groups and Z represents a hydrogen atom or the remainder of a carboxylic acid containing up to 18 carbon atoms, the wavy line in position 10 indicating that the methyl can be of R or S configuration or a mixture of R + S, as well as the addition salts with

AP. Ο Ο 5 8 7 acids of the compounds of formula (I) .

2) The compounds of formula (I) as defined in claim 1 in which Z represents a hydrogen atom.

3) The compounds of formula (I) as defined in claim 1 or 2

4) The compounds of formula (I) as defined in claim 1 or 2 in which R_x and R₂ each represent a hydrogen atom.

5 ingredient at least one medicament defined in claim 17 or 18.

20) Preparation process for the compounds of formula (I) as defined in claim 1, characterized in that a compound of (ID

20 in vhich Z retains the meaning indicated in claim 1, is subjected either to the action of hydrazine NH₂NH₂ in order to obtain the compound of formula (I_A):

<*A>

I aldehyde or of a cetone R'j-C-R'j in which R'₃ and R'₂ retain the meaning indicated in claim 1 in order to obtain the corresponding compound of formula (I_B):

in which R'^ and R'₂ retain the same meaning as previously, which is subjected if desired to the action of a reducing agent in order to obtain the corresponding compound of

15 formula (I_c):

C 25 in which R*₃ and R'₂ retain the previous meaning, that is a compound of formula (I) in which R^ represents hydrogen atom and R₂ represents a CHR'jR'₂ radical, then if desired, the

30 compound of formula (1^) is subjected to the action of an agent capable of replacing the hydrogen atom of the NH group by an R_x group as defined in claim 1 vith the exception of the hydrogen value, then if desired, the compounds obtained are subjected to the action of an acid in order to form the

35 salt and/or to the action cf an esterification agent of the OH group in position 2'.

21) Process according to claim 20, characterized in that the compound of formula (II):

C 25 e

AP.0 0 5 8 7 (II) subjected to the action of a compound of formula NH₂NHR₂ in which R₂ retains the meaning indicated in claim 1 in order to obtain the compound of formula (I'_A):

which is subjected if desired, to the action of an agent capable of replacing the hydrogen atom of the NH group by an R_x radical as defined in claim 1 with the exception of the hydrogen value or in order to obtain the corresponding compound of formula (I'_B):

i λ* <I'b>

in which Rj and R₂ have the previous meaning, which is subjected if desired, to the action of an esterification agent of the OH group in position 2' or to the action of an

5 radical.

5) The compounds of formula (I) as defined in claim 1 or 2 in which R'^ represents a hydrogen atom.

10

5 in which R₁ represents a hydrogen atom.

6) The compounds of formula (I) as defined in claim 1, 2 or 5 in which R^ and R₂ together form a radical:

-CH(CH₂)_nAr₁

15 in which Arj represents an optionally substituted aryl or heteroaryl radical and n represents an integer which can vary from 0 to 8.

7) The compounds of formula (I) as defined in claim 1, 2 or 5 in vhich R_x and R₂ form together a radical:

λ B

I I

-CH (CH₂ ) p-OC- (CH₂) gAr ₂ <-· 25 in vhich p and q, identical or different, represent an e integer varying from 0 to 6, A and B, identical or different, represent a hydrogen or halogen atom or an alkyl radical containing up to 8 carbon atoms, the geometry of the double bond being E or Z or an E + Z mixture,

30 or A and B form a third bond vith the carbon atoms to which they are linked and Ar₂ represents an optionally substituted mono- or polycyclic aryl or heteroaryl radical.

8, in vhich A and B represent a hydrogen atom.

8) The compounds of formula (I) as defined in claim 1 or 2, in which p and q represent the number 0.

35

9) The compounds of formula (I) as defined in claim 7 or

10 which Ar₃ represents a non-substitut ed 4-quinolinyl radical.

10) The compounds of formula (I), as defined in claim 1, 2 or 3 in which R₂ represents a radical:

(CH₂)_rAr₃ in which r represents an integer varying from 0 to 6 and Ar₃represents an optionally substituted aryl or heteroaryl

- 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-0-methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,ll-(oxy35 carbonyl (2-(3-(2-(3-pyridinyl-4-thiazolyl) propyl) hydrazono)) erythromycine.

17) As medicaments, the compounds of formula (I) as defined in any one of claims 1 to 15 as well as their addition salts

AP.00587 with pharmaceutically acceptable acids.

18) As medicaments the compound defined in claim 16 as well as its addition salts vith pharmaceutically acceptable acids.

19) The pharmaceutical compositions containing as active

- 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-0-methyl

30 alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl (2-(3-(7-methoxy-4-guinoleinyl) propyl) hydrazono)) erythromycine,

- 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-0-methyl alpha L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11(oxycarbonyl (2-(3-(4-quinolinyl) 2-propyl) hydrazono)) erythromycin,

25 - 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-0-methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl (2-(3-(4-quinoleinyl) propyl) hydrazono)) erythromycine,

11 j The compounds of formula (I) as defined in claim 10, in which Ar₃ represents a 4-quinolinyl radical optionally mono- or polysubstituted on one and/or the other of the 2 rings of the quinoline.

12) The compounds of formula (I) as defined in claim 10, in

13) The compounds of formula (I) as defined in claim 10, in which Ar₃ represents a 4-quinolinyl radical substituted with a methoxy radical.

14) The compounds of formula (I) as defined in claim 10, in

15 which Ar₃ represents a thiazolyl radical, substituted by a pyridyl radical.

15 acid in order to form the salt.