FR2732684A1 - Novel amine(s) are used to make new antibiotic erythromycin derivs. - Google Patents

Abstract

Erythromycin derivs. of formula (I) and their acid addn. salts are new. Z = H or an acid residue; R = -(CH2)nAr or a gp. of formula (i); n = 3-5; Ar = heterocyclic radical (opt. with one or more substits.) chosen e.g. from gps. (a)-(c) or (e); and W, X, Y = CH or N. Also claimed are amines of formula RNH2 (III).

Description

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

dans laquelle R représente un radical -(CH2)nAr, dans lequel n représente le nombre 3, 4 ou 5 et Ar représente un radical hétérocyclique, portant éventuellement un ou plusieurs substituants, choisi dans le groupe des radicaux

The subject of the invention is the compounds of formula (I)

in which R represents a radical - (CH2) nAr, in which n represents the number 3, 4 or 5 and Ar represents a heterocyclic radical, optionally bearing one or more substituents, chosen from the group of radicals

ou R représente un radical

et Z représente un atome d'hydrogène ou le reste d'un acide, ainsi que leurs sels d'addition avec les acides.

where R represents a radical

and Z represents a hydrogen atom or the remainder of an acid, as well as their addition salts with acids.

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

The heterocyclic radical may be substituted with one or more radicals chosen from the group consisting of free, salified, esterified and amidated carboxyl radicals, the hydroxyl radical, the halogen atoms, the NO2, CN radicals and the linear alkyl radicals. branched or cyclic alkenyl and alkynyl, linear or branched, O-alkyl, O-alkenyl and O-alkynyl, S-alkyl, S-alkenyl or S-alkynyl and Nalkyl, N-alkenyl and N-alkynyl, containing up to 12 carbon atoms optionally substituted by one or more halogen atoms, the radical

R1 and R2 identical or different, representing a hydrogen atom or an alkyl radical containing up to 12 carbon atoms, aryl, 0-aryl or S-aryl carbocyclic aryl or aryl, 0-aryl or S-aryl heterocyclic including one or more heteroatoms, optionally substituted with one or more of the substituents mentioned above and the radical

R3 representing an alkyl radical containing up to 12 carbon atoms, or an optionally substituted carbocyclic or heterocyclic aryl radical.

 When the heterocyclic radical comprises several (interconnected or condensed) rings, the substituent (s) may be on one and / or the other of the heterocyclic or carbocyclic rings; for example, if a heterocyclic ring is attached to or fused to an aryl radical, both the heterocyclic ring and the aryl ring may carry one or more substituents.

The aryl radical is preferably a phenyl or naphthyl radical, the alkyl, alkenyl or alkynyl radical is preferably a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, terbutyl, decyl or dodecyl, vinyl, allyl or ethyl radical. propyl, propynyl, propargyl, cyclobutyl, cyclopentyl or cyclohexyl, the halogen is preferably fluorine, chlorine or bromine, the alkyl radical substituted by a halogen atom is preferably a CHC12, CHBr2, CHF2 radical, CC13, CBr3, CF3,
CH2CF3, CH2CH2CC13, CH2CH2CF3, the carboxylic acid residue is preferably acetyl, propionyl, butyryl, isobutyryl, n-valeryl, isovaleryl, tert-valeryl and pivalyl.

 The invention more particularly relates to the compounds of formula (I), in which Z represents a hydrogen atom and the compounds of formula (I) in which n represents the number 4.

éventuellement substitué, ainsi que les composés de formule (I) dans lesquels R représente le radical

éventuellement substitué, ainsi que les composés de formule (I) dans lesquels Ar représente un radical

éventuellement substitué et tout particulièrement les composés de formule (I) dans lesquels Ar représente un radical

éventuellement substitué.The subject of the invention is especially those compounds of formula (I) in which Ar represents a radical

optionally substituted, as well as the compounds of formula (I) in which R represents the radical

optionally substituted, as well as the compounds of formula (I) in which Ar represents a radical

optionally substituted and most particularly the compounds of formula (I) in which Ar represents a radical

optionally substituted.

 The invention more particularly relates to the compounds of formula (I), the preparation of which is given below in the experimental part. Among the preferred compounds of the invention, mention may be made of the following compounds - 11,12-dideoxy-3 - ((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo-12,11- (oxycarbonyl) - ((4- (4-phenyl-1H-imidazol-1-yl) butyl) imino)) erythromycin, - 11,12-dideoxy 3-de (( 2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo-12,11- (oxy-carbonyl) (4- (3H-imidazo) 4,5-b) pyridin-3-yl) butyl) imino)) erythromycin, 11,12-dideoxy 3-de (2,6-dideoxy-3-C-methyl-3-O-methyl alpha-L) -ribohexopyranosyl) oxy) 6-O-methyl-3-oxo-12,11- (oxycarbonyl- (4- (1H-imidazo (4,5-b) pyridin-1-yl) butyl) imino)) erythromycin, -11, 12-dideoxy-3 - ((2,6-dideoxy-3-C-methyl-3-O-methylalpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo-12,11- (oxycarbonyl ( 4- (4- (4-Chlorophenyl) -1H-imidazol-1-yl) butyl) imino)) erythromycin, 11,12-dideoxy 3-de (2,6-dideoxy-3-C-methyl-3- O-methylalpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo-12,11- ( oxycarbonyl ((4- (4- (2-methoxyphenyl) -1H-imidazol-1-yl) butyl) imino)) erythromycin, 11,12-dideoxy 3-de (2,6-dideoxy-3-C) 3-methyl-3-O-methylalpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo-12,11-oxycarbonyl ((4- (4- (4-fluorophenyl) -1H-imidazol-1-yl) ) butyl) imino)) erythromycin, 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3 12,11- (oxycarbonyl) - ((4- (7-methoxy-4-quinolinyl) butyl) imino)) erythromycin, 11,12-dideoxy-3-de (2,6-dideoxy-3-C-) methyl-3-O-methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo-12,11- (oxycarbonyl) - ((4- (2- (2-pyridinyl) -4-thiazolyl) butyl) imino Erythromycin, 11,12-dideoxy-3 - ((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo-12, 11- (oxycarbonyl ((4- (3- (3-pyridinyl) -1H-1,2,4-triazol-1-yl) butyl) imino)) erythromycin, and most preferably 11,12-dideoxy 3 of (2,6-dideoxy-3-C-methyl-3-O-methyl alpha-L-ribo hexopyranosyl) oxy) 6-O-methyl-3-oxo-12,11- (oxycarbonyl) - ((4- (4- (3-pyridinyl) -1H-imidazol-1-yl) butyl) imino)) erythromycin.

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

 The compounds of the invention can therefore be used as medicaments in the treatment of infections with sensitive germs, and in particular in the case of staphylococci, such as staphylococcal septicemia, staphylococcal malignancies of the face or cutaneous, pyoderma, septic or festering wounds, boils, anthrax, phlegmons, erysipelas and acne, staphylococcal diseases such as acute or post-influenza acute tonsillitis, bronchopneumonia, pulmonary suppuration, streptococcal diseases such as acute tonsillitis, ear infections, sinusitis, scarlet fever, pneumococcal diseases such as pneumonia , bronchitis; brucellosis, diphtheria, gonorrhea.

The products of the present invention are also active against infections due to germs such as
Haemophilus influenzae, Rickettsiae, Mycoplasma pneumoniae,
Chlamydia, Legionella, Ureaplasma, Toxoplasma or germs of the genus Mycobacterium, Listeria, Meningococci and
Campylobacter.

 The subject of the present invention is therefore 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 inorganic or organic acids.

 The subject of the invention is more particularly, as medicaments and, in particular, antibiotic medicaments, the preferred products of formula (I) defined above, namely the products of Examples 1, 2, 3 and 29 to 35, as well as their salts. pharmaceutically acceptable.

 The invention also relates to pharmaceutical compositions containing as active ingredient at least one of the drugs defined above.

 These compositions can be administered orally, rectally, parenterally or locally by topical application to the skin and mucous membranes, but the preferred route of administration is the oral route.

 They can be solid or liquid and be in the pharmaceutical forms commonly used in human medicine, for example, tablets, single or coated tablets, capsules, granules, suppositories, injectables, ointments, creams, gels; they are prepared according to the usual methods. The active ingredient (s) can be incorporated into 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, parafferic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

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

 The dose administered varies according to the condition being treated, the subject, the route of administration and the product under consideration. It may be, for example, between 50 mg and 300 mg per day orally, in adults for the product of Example 1 or Example 2.

dans laquelle Z' représente le reste d'un acide, à l'action d'un composé de formule (III)
RNH2 (III) dans laquelle R est défini comme précédemment, pour obtenir le composé de formule

dans lesquels R et Z' conservent leur signification précédente, puis soumet le cas échéant, le composé de formule (IA) à l'action d'un agent de libération de la fonction hydroxyle en 2' et/ou le cas échéant, à l'action d'un acide pour en former le sel, - la réaction du composé de formule (II) avec le composé de formule (III) a lieu au sein d'un solvant tel que par exemple l'acétonitrile, le diméthylformamide ou encore le tétrahydrofuranne, le diméthoxy éthane ou le diméthylsulfoxyde, - l'hydrolyse de la fonction ester en 2' est réalisée à l'aide du méthanol ou de l'acide chlorhydrique aqueux, - la salification est réalisée au moyen d'acides selon les procédés classiques.The subject of the invention is also a process for the preparation of the compounds of formula (I), characterized in that a compound of formula (II) is subjected

in which Z 'represents the residue of an acid, to the action of a compound of formula (III)
RNH2 (III) in which R is defined as above, to obtain the compound of formula

in which R and Z 'retain their previous meaning, then subject, where appropriate, the compound of formula (IA) to the action of a hydroxyl-functional release agent at 2' and / or, where appropriate, at least action of an acid to form the salt, - the reaction of the compound of formula (II) with the compound of formula (III) takes place in a solvent such as for example acetonitrile, dimethylformamide or tetrahydrofuran, dimethoxyethane or dimethylsulfoxide, the hydrolysis of the ester function at 2 'is carried out using methanol or aqueous hydrochloric acid, the salification is carried out using acids according to the methods classics.

 The compounds of formula (II) used as starting materials are described and claimed in European Patent Application 0 596 802.

 The compounds of formula RANI '2 are generally known products, however the precise compounds used for the preparation of the products of the examples are new and are in themselves an object of the invention, their preparation is given here. -after.

The compounds of formula (III)
RNH2 (III) can for example be prepared according to the methods described in J. Med. Chem (1982) vol. 25 p. 947 and following,
Tetrahedron Letters vol. 32, No. 14, p. 1699-1702, (1991); J.

Org. Chem. 54 (18) 4298, 301 (1989); J. Org. Chem. 28 (101) 2589 91 (1963) or German Patent 3,406,416; J. Org.

Chem. 6-895-901 (1941) or Synth. Common 17 (14) 1741-8 (1987).

 The invention particularly relates to the amines of formula (III) as defined above, the preparation of which is detailed below.

 The subject of the invention is particularly 4-phenyl-1H-imidazole-1-butanamine, 3H-imidazo (4,5-b) -pyridine-3-butanamine, 1H-imidazo (4,5-b). ) -pyridine 3-butanamine, 2-phenyl-4-quinolinebutanamine, 1H-benzotriazole 1-butanamine, 2H-benzotriazole 2-butanamine, 1-methyl-1H-imidazo (4,5-c) pyridine 2-butanamine, 3-methyl-3H-imidazo (4,5-c) -pyridine-2-butanamine, 5-chloro-1H-benzimidazole 1-butanamine, 7-methoxy-4-quinolenebutanamine, 1H-imidazo (4,5-c) pyridine 1-butanamine, 9H-purine 9-butanamine, 1-methyl-1H-indole 4-butanamine, 3-phenyl-1H-1,2,4-triazole 1-butanamine (hydrochloride), 5-phenyl 1H-tetrazole 1-butanamine (hydrochloride), 2-benzothiazolebutanamine, 4- (thieno (2,3-b) pyridine 4-yl butanamine, , 6-dimethyl-1H-benzimidazole 1-butanamine, 3-quinoline butanamine, 2-quinoline butanamine, 5H-imidazo [4,5-c] pyridine 5-butanamine, 1-methyl-1H-benzimidazole 2-goal anamine, 6-chloro-1H-benzimidazol 2-butanamine, 2-methyl-1H-benzimidazol 2-butanamine, 4- (4-chlorophenyl) -1H-imidazol-1-butanamine, 2- (3-pyridinyl) thiazol 5-butanamine, 7-methoxyquinoline 4-butanamine, 4- (4-fluorophenyl) -1H-imidazol 1-butanamine, 4- (2-methoxyphenyl) 1H-imidazol 1-butanamine, - 3 - (3-pyridinyl) 1H-1,2,4-triazol-1-butanamine, 4- (3-pyridinyl) -1H-imidazol-1-butanamine, 2- (2-pyridinyl) thiazol-4-butanamine, - 2-phenylthiazole 4-butanamine, 4- (4-methoxyphenyl) -1H-imidazol 1-butanamine, isoquinoline 4-butanamine, quinazoline 4-butanamine, 4,5-diphenyl-1H-imidazole butanamine, 4- (3-methoxyphenyl) 1H-imidazol-1-butanamine, 4- (4- (trifluoromethoxy) phenyl) -1H-imidazol-1-butanamine, 1,2,3,6-tetrahydro-1, 3-dimethyl 2,6-dioxo 7H-purine 7butanamine, 2- (4-pyridinyl) thiazol 4-butanamine, 1H-indol-1-butanamine, 2- (3-pyridinyl) thiazol 4-butanamine and that their addition of acids.

 The following examples illustrate the invention.

EXAMPLE 1: 12-Dideoxy-3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12.11 - (oxycarbonyl ((4- (4-phenyl-1H-imidazol-1-yl) butyl) imino)) erythromycin
A mixture of 0.705 g of the product of 2'-deoxy-10,11-didehydro-3-de (2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl acetate is heated to 6 ° C. oxy) 12-O - ((1H-imidazol-1-yl) carbonyl) 6-O-methyl-3-oxo-erythromycin prepared as indicated in Example 1C of European Patent Application EP. 0 596 802 in 3 ml of 10% water acetonitrile, and 1.08 g of 4- (4-phenyl-1H-imidazol-1-yl) butanamine. The reaction mixture is maintained at this temperature for 5 hours. Allowed to warm to room temperature, poured the reaction mixture over a solution of sodium hydrogen phosphate, extracted with ethyl acetate. The organic phases are washed with water, dried, filtered and concentrated.

1.5 g of a product are obtained, to which 210 ml of methanol are added. The mixture is stirred for 16 hours under a nitrogen atmosphere at room temperature. Concentrate and obtain 1.4 g of product which is purified by silica chromatography eluting CH2Cl2 - MeOH - NH4OH (93-7-0.4).

0.305 g of the crude desired product is concentrated and is recrystallized from isopropyl ether, washed and dried at 50 ° C. under reduced pressure to give 0.267 g of the desired product melting at 22 ° C.-23 ° C.

NMR CDCl3 ppm aD = +180 (c = 0.9 cHCl3) 0.84 (t): CH3-CH2; 1.01 (d) -1.17 (d) -1.24 (d): CH3-CH; 1.30 (d) -1.38 (d), 1.34 to 1.47: 6 and 12-Me; 2.27 (s)
N (Me) 2; 2.45 (-): H, 3; 2.61 (m): H8; 2.63 (s): 6-OMe 3.04 (-): H4; 3.13 (q): H10; 3.18 (dd): H'2; 3.53 (-)
H'5; 3.56 (s): H11; 3.67 (-), 3.75 (-): -C-NCH 2; O, 3.87 (q): H2; 3.99 (t): cH2Nc; 4.23 (d): H5; 4.27 (d)
H'1; 4.94 (dd): H13; 7.26 (s): H -5; 7.5 (s): H₂: 2.20: H, para; 7.35: H in meta; 7.76: H in ortho.

PREPARATION 1: 4- (4-phenyl-1H-imidazol-1-yl) butanamine
Step A: 2- (4- (4-phenyl-1H-imidazol-1-yl) butyl-1H-isoindole-1,3 (2H) -dione
A solution containing 5.05 g of 4-phenyl-1H-imidazole in 25 cm 3 of dimethylformamide in a mixture of 7 cm 3 of dimethylformamide and 2.02 g of sodium hydride is introduced dropwise over a period of 1 h 30 min. 10.86 g of N-4-bromobutylphthalimide in solution in 25 cm3 of dimethylformamide are then introduced. The solution obtained is brought to 700C for approximately 1 h 30. Allowed to warm to room temperature, concentrate the resulting solution, taken up in water, extracted with ethyl acetate. The organic phases are washed with water, dried, filtered and concentrated. 15 g of product are obtained which is recrystallized from ethyl acetate.

The product obtained is filtered off with suction, washed with ethyl acetate and dried under reduced pressure at 50 ° C. 5.5 g of desired product is obtained, melting at 130 ° to 1320 ° C.

NMR CDCl3 ppm 1.75 (m) (2H) -1.86 (m) (2H): central CH2; 3.74 (t): 2H 4.03: 2H; 7.22 (t): 2H H4; 7.26 (m): 1H H, 3; 7.36 (t) 2H H3 and H5; 7.56 (d): H, 5; 7.73 (m): 4H; - 7.86 (m)
H2 and H6.

Stage B: 4- (4-phenyl-1H-imidazol-1-yl) butanamine
A mixture of 3.45 g of the product obtained in Stage A, 100 ml of ethanol and 0.97 ml of hydrazine hydrate is refluxed for 8 hours. The reaction mixture is concentrated, approximately 50 ml of 2N sodium hydroxide are added and the mixture is extracted with ethyl acetate. The organic phases are washed with 2N sodium hydroxide and then with sodium chloride. Dry, filter and concentrate. 2.21 g of desired product are obtained.

NMR CDCl3 ppm 1.47 (m) - 1.87 (m): central CH2; 2.73 (t), 3.97-CH 2 -NH 2; 7.20 (d): H, 3; 7.50 (d): H, 5; 7.37 (tl) 2H
H3 H5; 7.24 (it) 1H: H4; 7.77 (m) 2H: H2 and H6.

EXAMPLE 2: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12.11 - (oxycarbonyl ((4- (3H-imidazo (4,5-b) pyridin-3-yl) butyl) imino)) erythromycin
708.2 mg of 2'-acetate of 11-deoxy-10,11-dihydro-3-de (2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-oxohexopyranosyl) oxy) 12-O- (1H) was dissolved 1-imidazol-1-yl) carbonyl) 6-O-methyl-3-oxo-erythromycin prepared as indicated in Example 1C of European Patent Application EP 0 596 802 and 958 mg of (3H-imidazo) b) pyridin-3-butanamine in 2.82 cm3 of acetonitrile and 0.28 cm3 of water The reaction mixture is heated to 800 ° C. It is allowed to warm to room temperature and poured into a solution of sodium hydrogen phosphate. It is extracted with methylene chloride and washed with water.

The aqueous phases are collected and extracted again. Dry, filter, rinse and obtain 826 mg of product. The product obtained is dissolved in 16.5 cm 3 of methanol. The reaction solution is stirred at room temperature for 20 hours. 789 mg of crude desired product are obtained which is purified by chromatography, eluting with methylene chloride, methanol and ammonia.
(94-16-0,4). 327 mg of desired product melting at 2000C are obtained.

aD = +130 c = 1% CHCl3
NMR CDCl3 400 MHz ppm 0.85 (t): CH3-CH2; 1.01 (d) -1.16 (d) -1.25 (d): CH3-CH; 1.30 (d) -1.26 (d), 1.35 and 1.47: 6 and 12 Me; - 1.63 and - 1.98: the central CH2 of the chain; 2.27 (s): N (CH 3) 2 2.46 (m): H, 3; 2.59 (m): H8; 2.61 (s): 6-OMe; 3.07
(m): H4; 3.12 (ql): H10; 3.18 (dd): H'2; 3.54 (m)
H'5; 3.57 (s): H11; 3.6 to 3.8: CH 2 CN; 3.85 (q): H2; O 4.24 (d): H5; 4.29 (d): H'1; 4.35 (m): CH 2 CN; 4.93 (dd): H13; 7.21 (dd): H6; 8.04 (dd): aromatic H7; 8.11 (s): H2; 8.38 (dd): H5.

EXAMPLE 3: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-1-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12.11 - (oxycarbonyl ((4- (1H-imidazo (4,5-b) pyridin-1-yl) butyl) imino)) erythromycin
708 mg of 2'-acetate of 11-deoxy-10,11-dihydro-3-de (2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-oxohexopyranosyl) oxy) 12-O- (1H-imidazol) are added 1-yl) carbonyl) 6-O-methyl-3-oxo-erythromycin prepared as indicated in Example 1C of European Patent Application EP 0 596 802 in a solution containing 953 mg of (1H-imidazo (4,5 b) pyridine 3butanamine, 2.82 cm3 of acetonitrile and 0.28 cm3 of water .The reaction mixture is brought to 55 ° C. This temperature is maintained for 44 h and 0.5 cm3 of acetonitrile are added. The mixture is heated to 550 ° C. for 20 hours, allowed to warm to room temperature and poured into a saturated solution of sodium hydrogen phosphate, the aqueous phase is extracted with methylene chloride and the chloromethylenic phases are washed with water. sodium sulfate, filtered and evaporated to give 806 mg of product to which 16.1 cm3 of methanol are added, the reaction mixture is maintained at room temperature e for 24 hours and evaporate to dryness.

656 mg of a product is obtained which is chromatographed on silica eluting with CH2Cl2-MeOH-NH3 (94-6-0.4).

The crude desired product is obtained which is purified by chromatography on silica eluting with the mixture
CHCl3-MeOH-NH4OH (94-6-0.4). After dissolving the residue in a mixture of ethyl acetate-isopropyl ether, filtering and evaporation to dryness, the desired product is collected.

F = 2030C.

aD = 17.60 c = 1% of CHCl3.

0.81 (t): CH3-CH2; 1.00 (d) -1.17 (d) -1.25 (d) -1.31 (d) -1.38 (d): CH3-CH; 1.35 (s) -1.47 (s): 6 and 12-CH3; 1.68 (m) and 1.93 (m): central CH2 of the chain; 2.27 (s): N (CH3) 2; 2.61 (s): 6-OCH3; 2.45 (m): H, 3; -2.60 (m partly masked): H8; 3.07 (m): H4; 3.15 (ql): H10; 3.18 (dd):
H'2; 3.56 (s): H11; 3.53 (m): H, 5; 3.60 to 3.80 (m)
CO-N-CH2; 3.87 (q): H2; 4.25 (m): CH2-NC =; 4.24 (d)
H5; 4.28 (d): H'1; 4.91 (dd): H13; 7.21 (dd, J = 5 and 8): H6; 7.80 (dd, J = 8 and 1.5): aromatic H7; 8.56 (dd,
J = 5 and 1.5): H5; 8.15 (s): H2 + CH2Cl2.

PREPARATION 2: Preparation of Amines Used as Starting Products Examples 2 and 3 3-Imidazo (4ts-b) pyridine 3-butanamine and 1H-imidazo <4,5-b) pyridine 1-butanamine
Stadium a
To a solution of 5.95 g of 4-azabenzimidazole and 15.5 g of N-4 bromobutylphthalimide in 30 cm3 of dimethylformamide. 10.3 g of potassium carbonate are added. The mixture is stirred for 20 hours at room temperature. The insoluble material is filtered, rinsed with methylene chloride. The organic phase is washed with water, then dried over magnesium sulfate and evaporated; the oily residue obtained is washed with petroleum ether and then with isopropyl ether. 16.3 g of a crude product are thus obtained which is purified by chromatography on silica, eluting with methyleneacetone chloride to give 4.9 g of product (A), mp = 1430 ° C. and 3.9 g of product ( B), F = 1720C.

Step b1: 3H-imidazo (4,5-b) pyridine-3-butanamine (starting material of Example 2)
Refluxed for 19 hours, a mixture of 32.86 g of product (A) prepared as indicated in the preceding stage, 697 cm3 of ethanol and 20 cm3 of hydrazine. It is allowed to return to room temperature. It is filtered, rinsed and evaporated to dryness. It is taken up in methylene chloride, filtered, rinsed and evaporated to dryness. 18.87 g of desired product are obtained.

NMR CDCl3 - 250 MHz 1.52 (m) -2.00 (m): 2 central CH2; 1.63 (s wide): 2 mobile H; 2.76 (t): CH 2 -CH 2 -NH 2; 4.33 (t): = CN-CH2-CH2
C = O 7.24 (dd, J = 8 and 5): H6; 8.08 (dd, J = 8 and 1.5): H7; 8.40 (dd, J = 5 and 1.5): H5; 8.08 (s): H2.

Step b2: 1H-imidazo (4,5-b) pyridine 1-butanamine (starting material of Example 3)
Refluxed for 21 hours, a mixture of 32 g of product (B) of the preparation 3, 640 cm3 of ethanol and 24.8 cm3 of hydrazine. It is allowed to return to room temperature. It is filtered, rinsed with ethanol and evaporated under reduced pressure. It is taken up in methylene chloride, filtered, rinsed and evaporated to dryness. 19.5 g of desired product are obtained.

CDCl3 NMR 1.45 (m) -1.96 (m): 2 central CH2; 2.74 (t): CH 2 -NH 2; 1.45 (m): mobile; 4.23 (t): CN-CH2-CH2
C, 7.24 (dd, J = 8 and 5): H6; 7.75 (dd, J = 8 and 1.5): H7; 8.58 (dd, J = 5 and 1.5): H5; 8.13 (s): H2 + EtOH.

By operating as above, using the appropriate amines, the following products were prepared
EXAMPLE 4: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12.11 - (oxyearbonyl ((4- (thieno (2,3-b) pyridin-4-yl) butyl) imino)) erythromycin
Mp 176 ° -1780 ° C.

aD = +17 c = 0.9% in CHCl3
EXAMPLE 5: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-1H-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12 11- (oxycarbonyl) ((4- (3-phenyl-1H-1,2,4-triazol-1-yl) butyl) imino)) erythromycin
Mp = 208-210 C.

aD = +170 c = 1% in CHCl3
EXAMPLE 6: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexpyranosyl) oxy) 6-O-methyl-3-oxo 12,11- ( oxycarbonyl ((4- (1-methyl-1H-imidazo (4,5-c) pyridin-2-yl) butyl) imino)) erythromycin &alpha; D = + 190c = 1% CHCl3
EXAMPLE 7: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12.11 - (oxycarbonyl ((4- (3-methyl-3H-imidazo (4,5-c) pyridin-2-yl) butyl) imino)) erythromycin aD = + 160 CHCl3 = 1%
EXAMPLE 8: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-1H-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo, 11- (oxycarbonyl ((4- (7-methoxy-4-quinolinyl) butyl) imino)) erythromycin &alpha; D = + 15.80 c = 1% CHCl3
EXAMPLE 9: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12.11 - (oxycarbonyl ((4- (5-phenyl-1H-t-triazol-1-yl) butyl) imino)) erythromycin
M.p. 132 - 134C.

aD = +250 c = 1% CHCl3
EXAMPLE 10: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12,11- ( oxycarbonyl ((4- (2-benzothiazolyl) butyl) imino)) erythromycin
Mp 179-180 ° C.

&alpha; D = +180 c = 1% CHCl3
EXAMPLE 11: 11,12-Dideoxy-3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12,11- (Oxycarbonyl ((4- (2- (3-pyridinyl) -4-thiazolyl) butyl) imino)) erythromycin
F = 150-1520C.

&alpha; D = +170 c = 0.9% CHCl3
EXAMPLE 12: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12.11 - (oxycarbonyl ((4- (2- (3-pyridinyl) 5-thiazolyl) butyl) imino)) erythromycin
F = 155-1590C.

&alpha; D = +120 c = 1% CHCl3
EXAMPLE 13: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12.11 - (oxycarbonyl ((4- (9H-purin-9-yl) butyl) imino)) erythromycin
EXAMPLE 14: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-1H-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12 11- (oxycarbonyl ((4- (1H-imidazo (4,5-c) pyridin-1-yl) butyl) imino)) erythromycin rf = 0.42 CHCl3 + 8% MeOH 8% NH40H
EXAMPLE 15: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) oO-methyl-3-oxo 12,11- ( oxycarbonyl ((5- (1H-benzimidazol-1-yl) pentyl) imino)) erythromycin
Prepared from 2- (4-bromopentyl) -1H-isoindole 1,3 (2H) dione.

EXAMPLE 16: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12.11 - (oxycarbonyl ((5-chloro-1H-benzimidazol-1-yl) butyl) imino)) erythromycin
F = 145-1480C.

EXAMPLE 17: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-12,11- (oxycarbonyl) (4- (1H-Indol-1-yl) butyl) imino)) erythromycin
EXAMPLE 18: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-riboxopyranosyl) oxy) 6-O-methyl-3-oxo-12,11 (oxycarbonyl) ((4- (1-methyl-1H-indol-4-yl) butyl) imino)) erythromycin &alpha; D = 20%, c = 1% CHCl3
EXAMPLE 19: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12.11 - (oxycarbonyl ((4- (2-phenyl-4-quinolinyl) butyl) imino)) erythromycin
Mp 195-1970 ° C.

EXAMPLE 20: 11,12-Dideoxy-3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo-12,11 (oxycarbonyl) ((4- (1H-benzotriazol-1-yl) butyl) imino)) erythromycin
F = 200-2020C.

EXAMPLE 21: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12,11- ( oxycarbonyl ((4- (2H-benzotriazol-2-yl) butyl) imino)) erythromycin
M.p. 164-166 ° C.

EXAMPLE 22: 11,12-Dideoxy 3 - ((2,6-didgoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12.11 - (oxycarbonyl ((4- (5,6-dimethyl-1H-benzimidazol-1-yl) butyl) imino)) erythromycin
Mp 174-1760 ° C.

EXAMPLE 23: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-1H-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12.11 - (oxycarbonyl ((4- (3-quinolinyl) butyl) imino)) erythromycin
Mp 195-197 C.

EXAMPLE 24: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-1H-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12 11- <oxycarbonyl ((4- (2-quinolinyl) butyl) imino)) erythromycin
Mp 179-18 ° C.

EXAMPLE 25: 11,12-Dideoxy 3 - ((2,6-didgoxy-3-C-methyl-3-O-methyl-1H-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12 11- (oxycarbonyl ((4- (2-methyl-1H-benzimidazol-1-yl) butyl) imino)) erythromycin
M.p. 128-1320 ° C.

EXAMPLE 26: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12,11- ( oxycarbonyl ((4- (6-chloro-1H-benzimidazol-1-yl) butyl) imino)) erythromycin
Mp 192-1940 ° C.

EXAMPLE 27: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12,11- ( oxycarbonyl ((4- (1-methyl-1H-benzimidazol-2-yl) butyl) imino)) erythromycin
EXAMPLE 28: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12,11- ( oxycarbonyl ((4- (SH-imidazo (4,5-c) pyridin-5-yl) imino)) erythromycin aD = 12.2 c = 1% CHCl3
EXAMPLE 29: 11,12-Dideoxy-3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12 11- (Oxycarbonyl ((4- (4- (4-chlorophenyl) -1H-imidazol-1-yl) butyl) imino)) erythromycin
7 hours at 750 ° C., 1 g of 2'-acetate of 11 deoxy-10,11-didehydro-3-de (2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy). -O - ((1H-imidazol-1-yl) carbonyl) 6-O-methyl-3-oxo-erythromycin prepared as indicated in Example 1C of European Patent Application EP 0 596 802 in 4 cm3 of 10% acetonitrile; % water with 1.4 g of 4- (4 (4-chlorophenyl) 1H-imidazol) butanamine.The mixture is allowed to come to room temperature, diluted with water, extracted with ethyl acetate, dried, evaporated the solvent and obtains 2.3 g of acetylated product in 2 '. 60 ml of methanol are added and the mixture is stirred for 16 hours, the solvent is evaporated off, the residue is chromatographed on silica (eluent: CH2Cl2-MeOH-NH4OH 955-0.4), the mixture is concentrated and the residue is crystallized from ether. The crystallized product is dried under reduced pressure at 800 ° C. and 381 mg of expected product is recovered. Mp 192-1940 ° C.

NMR CDCl3 ppm 0.83 (t): CH3-CH2; 1.00 (d) -1.16 (d) -1.24 (d) -1.30 (d) -1.38 (d): CH3-CH; 1.33 (s) -1.47 (s): 6 and 12 Me; 2.26 (s):
N (Me) 2; 2.44 (m): H, 3; 2.61 (s): 6-OMe; 2.60 (m): H8 3.00 to 3.21: H4, H10 and H'2; 3.55 (m): H, 5; 3.56 (s)
H11; 3.60 to 3.80 2H-3.99 (t) 2H: CH 2 CN; 3.87 (q): H2; 4.23 (d): H5; 4.28 (d): H'1; 4.93 (dd): H13; 7.26 (d)
H5 imidazole; 7.50 (d): imidazole H2; 7,32-7,70 aromatics; 3.51: OH.

Preparation of 4- (4-chlorophenyl) -1H-imidazole-1-butanamine used starting from Example 29

Step A: 4- (4-chlorophenyl) 1H-imidazole.

23.34 g of o-bromo-4-chloroacetophenone are refluxed for 1 hour in 150 ml of formamide; it is allowed to cool, basified with sodium hydroxide solution, extracted with dichloromethane, washed with water, dried, the solvent is evaporated, the residue is chromatographed on silica (eluent: CH 2 Cl 2 -MeOH
NH40H 8-2-0.04) and 13.4 g of expected product are obtained.

Mp 146-1480 ° C.

Step B: 2- (4- (4- (4-Chlorophenyl) -1H-imidazol-1-yl) 1H-isoindol-1,3 (2H) -dione.

 The procedure is as in Step A of the preparation of Example 1 using 12.2 g of the product obtained in Step A, 4.96 g of sodium hydride and 23.83 g of N-4-bromobutyl phthalimide.

9.7 g of expected product are obtained.

Stage C: 4- (4-chlorophenyl) 1H-imidazol-1-butanamine.

 The procedure is as in Step B of the preparation of Example 1, using 14.2 g of the product obtained as in Step B above and 3.6 ml of hydrazine hydrate in 200 ml of ethanol.

12 g of crude product is obtained which is chromatographed on silica (eluent: CH 2 Cl 2 -MeOH-NH 4 OH 8-2-0.04) and gives the product used as such for the synthesis.

7,19 (d, J=1,5)-7,50 (d, J=1,5) : H2 et H5 ; 7,33 et 7,70 aromatiques.NMR (CDCl3) ppm 1.22 (sl): mobile 2H; 1.47 (m) -1.88 (m): 2 central CH2; 2.74 (m): CH2-CH2-N

7.19 (d, J = 1.5) -7.50 (d, J = 1.5): H 2 and H 5; 7,33 and 7,70 aromatics.

EXAMPLE 30: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12.11 - (oxycarbonyl ((4- (4- (2-methoxyphenyl) -1H-imidazol-1-yl) butyl) imino)) erythromycin
706 mg of the starting compound of Example 29 (obtained as indicated in Example 1C of European patent application EP 0 596 802) are heated at 800 ° C. for 8 hours in 3 ml of acetonitrile and 908 mg of 4- (4- (2-methoxyphenyl) -1H-imidazol-1-yl) butanamine. Allowed to warm to room temperature, poured over a solution of sodium hydrogen phosphate (0.5M), extracted with ethyl acetate, washed with water, dried, the solvent evaporated, obtained 1.6 g of product Acetylated in 2 '. 50 ml of methanol are added, the mixture is stirred for 16 hours, the solvent is evaporated, the residue is chromatographed on silica (eluent: AcOEt-TEA at 4%) and crystallized in ether.

194 mg of expected product is obtained. Mp 143-1450 ° C.

3,85 (q) : H2 ; 3,95 (s) : 4-OMe ; 3,99 (ql) : CH2-N-C= ; 4,24 (d) : H5 ; 4,27 (d) : H'1 ; 4,93 (dd) : H13 ; 6,97 (dl) : H6 ; 7,51 (s) : les H imidazole ; 7,02 : H6 phényl ; 7,19 (ddd) H4 et H5 phényl ; 8,19 (dd) : H2.NMR CDCl3 ppm 0.85 (t): CH3-CH2; 1.01 (d) -1.16 (d) -1.24 (d) -1.30 (d) -1.37 (d): CH3-CH; 1.34 (s) -1.47 (s): 6 and 12 Me; 2.26 (s):
N (Me) 2; 2.44 (m): H, 3; 2.60 (m): H8; 2.64 (s): 6-OMe 3.08 (m): H4; 3.12 (ql): H10; 3.17 (dd): H'2; 3.54 (m)
H'5; 3.57 (s): H11

3.85 (q): H2; 3.95 (s): 4-OMe; 3.99 (ql): CH2-NC =; 4.24 (d): H5; 4.27 (d): H'1; 4.93 (dd): H13; 6.97 (dl): H6; 7.51 (s): Imidazole H; 7.02: H6 phenyl; 7.19 (ddd) H4 and H5 phenyl; 8.19 (dd): H2.

Preparation of 4- (2-methoxyphenyl) -1H-imidazol-1-butanamine used starting from Example 30

Step A: 4- (2-methoxyphenyl) 1H-imidazole.

9.36 g of 2-bromo-2'-methoxyacetophenone are refluxed in 50 ml of formamide, allowed to come to room temperature, washed with 2N hydrochloric acid solution, filtered, basified to pH 8-9. 2N sodium hydroxide solution, extracted with dichloromethane, washed with water, dried, the solvent evaporated, the residue chromatographed on silica (eluent
95.5-0.4 CH2Cl2-MeOH-NH4OH) and gives 6.15 g of the expected product.

Step B: 2- (4- (4- (2-methoxyphenyl) -1H-imidazol-1-yl) butyl 1H-isoindol-1,3 (2H-dione.

 The procedure is as in Stage A of the preparation of Example 1 using 6 g of the product obtained in Stage A, 1.99 g of sodium hydride and 9.93 g of N-4-bromobutyl phthalimide.

6.15 g of expected product is obtained.

Stage C: 4- (2-methoxyphenyl) -1H-imidazol-1-butanamine (fumarate).

 The procedure is as in Stage B of the preparation of Example 1 using 5.65 g of the product obtained as in Step B above and 1.45 ml of hydrazine hydrate in 75 ml of ethanol.

3.8 g of crude product are obtained, which is dissolved in 4 ml of tetrahydrofuran and then 1.87 g of fumaric acid in solution in 20 ml of methanol are added. 10 ml of ether are added, the crystals formed are filtered off, dried at 800 ° C. under reduced pressure and 3.77 g of fumarate of the expected product are recovered.

F = 160-1620C.

NMR (CDCl3) ppm 1.48 (m) 2H-1.87 (m) 2H: central CH2; 3.46: NH 2; 2.73 (t): CH 2 N; 3.94 (s): # -OMe; 3.97 (t): CH2N-C; 6.94 (dd): H6; 7.04 (dt) -7.21 (ddd): H5 and H4; 7.51: H'2 and H'5; 8.19 (dd): H2.

EXAMPLE 31: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12.11 - (oxycarbonyl ((4- (4- (4-fluorophenyl) -1H-imidazol-1-yl) butyl) imino)) erythromycin
2.11 g of the starting compound of Example 29 (obtained as indicated in Example 1C of the European patent application EP 0 596 802) in 9 ml of acetonitrile and 2 ml of acetonitrile are heated at 600 ° C. for 4½ hours. 8 g of 4- (4- (4-fluorophenyl) -1H-imidazol-1-yl) butanamine. Allowed to warm to room temperature, poured into water, extracted with ethyl acetate, washed with water, dried, the solvent evaporated, 5.2 g of acetylated product obtained in 2 '. ml of methanol, stirred for 3.5 hours, the solvent evaporated, the residue chromatographed on silica (eluent: CH2Cl2-MeOH-NH4OH 95-50.3) and crystallized in ether. 1.34 g of expected product are obtained. F = 190-1920C.

- 7,05 - -7,73 : fluorophényl ; 7,21 (d) : H5 imidazole ; 7,49 (d) : H2 imidazole. NMR CDCl3 ppm 1.33 (s) -1.47 (s): 6 and 12 Me; 2.27 (s): N (Me) 2; 2.61 (s): 6-OMe; 3.0 to 3.18: H4 and H10; 3.56 (s): H11; 3.59 to

- 7.05 - -7.73: fluorophenyl; 7.21 (d): Imidazole H5; 7.49 (d): Imidazole H2.

Preparation of 4- (4-fluorophenyl) -1H-imidazol-1-butansmine used starting from Example 31.

Step A: 4- (4-fluorophenyl) 1H-imidazole.

10.85 g of 4-fluorophenacyl bromide are heated for 2 hours in 60 ml of formamide, allowed to come to room temperature, acidified to pH 2 with N hydrochloric acid, filtered, neutralized by the addition of aqueous ammonia. , extracted with dichloromethane, washed with water, dried, the solvent evaporated, the residue chromatographed on silica (eluent
CH2Cl2-MeOH-NH4OH 95-5-0.4) and obtains 5.8 g of the expected product. F = 130-1320C.

Step B: 2- (4- (4- (4-fluorophenyl) -1H-imidazol-1-yl) butyl-1H-isoindol-1,3 (2H-dione.

 The procedure is as in Step A of the preparation of Example 1 using 10 g of the product obtained in Step A, 1.95 g of sodium hydride and 11.80 g of N-4-bromobutyl phthalamide.

7.53 g of expected product are obtained. Mp 138-1400 ° C.

Stage C: 4- (4-fluorophenyl) 1H-imidazol-1-butanamine.

 The procedure is as in Stage B of the preparation of Example 1, using 3.64 g of the product obtained as in Step B above and 1 ml of hydrazine hydrate in 80 ml of ethanol. 2.4 g of crude product are obtained, which is chromatographed on sicil (eluent: CH 2 Cl 2 -MeOH-NH 4 OH 8-2-0.03) and the product used is obtained as such for the synthesis.

NMR (CDCl3) ppm 1.48 (m) -1.81 (m): central CH2; 2.74 (t): N-CH3; 3.98 (t):> N-CH 2 -CH 2; 7.06 (t):> CH-F; 7.22 (m): CH-C-; 7.49 (s): imidazole H2; 7.15 (s): Imidazole H5.

EXAMPLE 32: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12,11- (oxycarbonyl) 4- (4- (7-methoxy (4-quinolinyl) butyl) imino)) erythromycin
706 mg of the starting compound of Example 29 (obtained as indicated in Example 1C of the European patent application EP 0 596 802) are heated at 500 ° C. for 53 hours in 4 ml of acetonitrile and 1.43 g of 4- (4-7-methoxy-4-quinolinyl) butanamine. Allowed to warm to room temperature, poured over sodium hydrogenphosphate solution (0.5M), extracted with dichloromethane, washed with water, dried, evaporated the solvent, obtained 1.09 g of acetylated product in 2 '. 10 ml of methanol are added, the mixture is stirred for 16 hours, the solvent is evaporated and the residue is chromatographed on silica (eluent: CH2Cl2
MeOH 95-5) and crystallizes in ether. 295 mg of expected product is obtained. F = 110 OC.

NMR CDCl3 ppm 3.06 (m): - (CH2) 2-CH1; 3.70 (m): -N-CH 2 -; 3.95 (s) -OcH3; 7.12 (d) -7.19 (dd) -7.42 (d) -7.94 (d) -8.70 (d) pyridine.

Preparation of 7-methoxyquinoline 4-butanamine used starting from Example 32

Step A: Triphenyl phosphonium salt of N- (3-bromopropyl) phthalimide.

 13.4 g of N-bromopropylphthalimide and 13.15 g of triphenylphosphine are suspended under reflux for 44 hours in suspension in 75 ml of xylene. Allowed to warm to room temperature, the precipitate is filtered off, washed with ethyl ether and dried under reduced pressure at 600C. 24.88 g of expected product is recovered. Mp 220-22 ° C.

Step B: Z- (2- (4- (7-methoxyquinolinyl) -3-butenyl-1H-iso-indol-1,3 (2H) -dione.

 4 g of 7-methoxy-4-quinolinylcarboxaldehyde are added to a suspension of 12.47 g of triphenylphosphonium salt of 3-bromopropyl phthalimide in 200 ml of tetrahydrofuran.

Cooled to -500C, add 2.72 g of potassium tertbutylate, slowly raise the temperature to -60C, filter, concentrate the filtrate, take up the residue in ethyl acetate, wash with water, dry, evaporates the solvent and recovers 9.26 g of crude product which is chromatographed on silica (eluent: CHCl 3 -AcOEt 80-20 then 70-30). 3.575 g of expected product is recovered.

Stage C: 2- (4- (7-methoxy-4-quinolinyl) butyl) -1H-isoindol-1,3 (2H) -dione.

 3.50 g of the product obtained in Stage B are dissolved in 50 ml of methanol, 0.36 g of palladium on activated carbon and hydrogen are added for 3 hours under 600 mbar. Filtered, the solvent evaporated and collected 3.48 g of expected product.

Stage D: 7-methoxy quinolin-4-butanamine.

 3.46 g of the product obtained in Stage C are dissolved in hot water in 70 ml of ethanol, 1.86 ml of hydrazine hydrate are added, the mixture is refluxed for 17 hours, the precipitate is filtered off, the solvent is evaporated off, the residue is taken up in 70 ml of dichloromethane, filtered, the solvent is evaporated off and 2.19 g of expected product are recovered.

NMR (CDCl3) ppm 1.6 (m) -1.79 (m): central CH2; 2.75 (t):> -CH 2 - (CH 2) 3; 3.05 (t): CH 2 -NH 2; 3.95 (s): O-CH3; 7.10 (d, J = 4.5) -7.21 (dd) -7.92 (d) -8.71 (d, J = 4.5): quinoline.

EXAMPLE 33: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12.11 - (oxycarbonyl ((4- (2- (2-pyridinyl) -4-thiazolyl) butyl) imino)) erythromycin
705 mg of the starting compound of Example 29 (obtained as indicated in Example 1C of the European patent application EP 0 596 802) are heated at 600 ° C. for 5 hours for 5 hours in 3 ml of acetonitrile and 0.705 g of 4- (2- (2-pyridinyl 4-thiazolyl) butanamine, allowed to warm to room temperature, poured into water, extracted with ethyl acetate, washed with water, dried, the solvent evaporated, obtained 1, 8 g of acetylated product at 2 'are added 15 ml of methanol, heated under reflux for 2 hours, the solvent is evaporated, the residue is chromatographed on silica (eluent: CH2Cl2-MeOH-NH4OH 95-5-0.3 then
AcOEt-TEA 9-1) and crystallizes in ether. 194 mg of expected product is obtained. Mp 157-1590 ° C.

7,03 (s) : H5 thiazole ; 7,27 (ddd) : H5 pyridyne ; 7,77 (dt): H4 pyridyne ; 8,18 (dd) H3 pyridyne ; 8,53 (ddd) : H6 pyridyne.NMR (CDCl3) ppm 1.33 and 1.47: 6 and 12 Me; 2.26 (s): N (CH3) 2; 2.86 (t)

7.03 (s): H5 thiazole; 7.27 (ddd): H5 pyridyne; 7.77 (dt): H4 pyridyne; 8.18 (dd) H3 pyridyne; 8.53 (ddd): H6 pyridyne.

Preparation of 2- (2-pyridinyl) thiazol 4-butanamine used starting from Example 33.

Stage A: 2-aminocarbonyl pyridine.

 50 ml of a diazomethane solution (0.4 M / l) in a solution comprising 2 g of picolinic acid, 20 ml of dichloromethane and 5 ml of methanol are added dropwise.

After stirring for 30 minutes at room temperature, the solvent is evaporated off under reduced pressure, the residue is chromatographed on silica (petroleum ether (60-80) -AcOEt 5-5) and 1.48 g of methyl ester are recovered. 1.42 g of ester are heated at 500 ° C. for 4 hours in 5 ml of aqueous ammonia, the mixture is allowed to return to ambient temperature, the mixture is extracted with ether, washed with water, dried, the solvent is evaporated and 1.05 g recovered. expected product. F = 1050C.

Stage B: 2-pyridine carbothioamide.

 43 g of phosphorus pentasulfide are slowly added to 46.8 g of the amide obtained in stage A in 700 ml of tetrahydrofuran. It is stirred for 4 hours at room temperature, poured into water, extracted with ether, dried and the solvent evaporated under reduced pressure. After chromatography on silica (eluent: CH 2 Cl 2 -AcOEt 8-2), 10 g of expected product are collected. F = 1370C.

Stage C: Ethyl 2- (2-pyridinyl) 4-thiazole carboxylate.

 16.3 ml of ethyl bromopyruvate are added dropwise to 15.9 g of the product prepared as in Stage B in 250 ml of ethanol and are heated for 5 hours under reflux. The solvent is evaporated off under reduced pressure, the residue is chromatographed on silica (eluent: hexane-AcOEt 1-1) and 10.2 g of expected product are obtained. Mp 69.10 ° C.

Stage D: 2- (2-pyridyl) -4-thiazole methanol.

 40 ml of methanol are slowly added to a mixture comprising 9.3 g of the ester prepared in Stage C and 4.1 g of sodium borohydride in 100 ml of tetrahydrofuran and heated for 2 hours under reflux. Allowed to warm to room temperature, poured into water, neutralized with N hydrochloric acid, extracted with dichloromethane, the organic phase dried and the solvent evaporated under reduced pressure, chromatography residue on silica (eluent: AcOEt- CH2C121-1) and obtains 5.8 g of the expected product. F = 1000C.

Stage E: 2- (2-pyridyl) -4-thiazole carboxaldehyde.

 5.8 g of the product obtained in Stage D in 60 ml of toluene are heated under reflux for 2 hours in the presence of 13 g of manganese oxide, filtered and the solvent is evaporated off under reduced pressure. 5 g of expected product are obtained. F = 1310C.

Stage F: (Z) 2- (4- (2- (2-Pyridinyl) -4-thiazolyl) -3-butenyl) -1H-isoindole 1,3 (2H) -dione.

 The process is carried out as in Stage A of Preparation 32 using 5.70 g of the aldehyde prepared as in Stage E above and 15.9 g of triphenylphosphonium salt of 3-bromopropyl phosphonium and 3.70 g of toluene tert-butylate. potassium. 8.73 g of expected product are obtained. Mp 139-1410 ° C.

Stage G: (2- (4- (2- (2-pyridinyl) -4-thiazolyl) butyl) -1Hisoindol 1,3 (2H) -dione.

 The procedure is as in Stage B of Preparation 32 using 7.22 g of the product of Step F above, and 1.5 g of active palladium on charcoal, hydrogenating for 2 hours at 1800 mbar. 6.33 g of expected product is obtained. Mp 119-12 ° C.

Stage H: 2- (2-pyridinyl) thiazol-4-butanamine.

 The procedure is as in Stage C of Preparation 32 using 5.45 g of the product obtained in Stage G above and 1.6 ml of hydrazine hydrate and heating for 6 hours under reflux. The solvent is evaporated, the residue is taken up in ethyl acetate, washed with water, dried, the solvent is evaporated off, the residue is chromatographed on silica (eluent: CH 2 Cl 2 -MeOH-NH 4 OH 9-1-0.03) and 1.65 g of expected product.

NMR (CDCl3) ppm 1.50 (m) -1.82 (m): central CH2; 2.76 (t) -2.85 (t)
CH2-C = and CH2-NH2; 7.85 (s): H5 thiazole; 7.31 (m): H, 5; 7.78 (dt): H, 4; 8.18 (dt): H, 3; 8.61 (ddd): H, 6; 1.40 (s): NH2.

EXAMPLE 34: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-1H-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12.11 - (oxycarbonyl ((4- (4- (3-pyridinyl) -1H-imidazol-1-yl) butyl) imino)) erythromycin
1 g of the starting compound of Example 29 (obtained as indicated in Example 1C of the European patent application EP 0 596 802) is heated at 700 ° C. for 20 hours in 4 ml of acetonitrile and 936 mg of 4- (4- (3-pyridinyl-1H-imidazol-1-yl) butanamine, allowed to warm to room temperature, poured into water, extracted with ethyl acetate, washed with water, dried, the solvent evaporated 1.34 g of acetylated product is obtained in 2 '. 40 ml of methanol are added thereto, the mixture is stirred for 2 hours, the solvent is evaporated off and the residue is chromatographed on silica (eluent: CH2Cl2-MeOH-NH4OH 95-5-0.4 ) and crystallized from ether to give 310 mg of expected product, mp 187-1880 ° C.

NMR (CDCl3) ppm 0.83 (t): CH3-CH2; 1.01 (d) -1.17 (d) -1.25 (d) -1.31 (d) -1.38 (d): CH3-CH; 1.34 (s) -1.47 (s): 6 and 12 Me; 2.27 (s):
N (Me) 2; 2.45 (m): H, 3; 2.62 (s): 6-OMe; 2.60 (m): H8 2.85-3.25: H4 and H10, H'2; 3.52 (m): H, 5; 3.56 (s)
H11; 3.60 to 3.85 (m): CH 2 CN; 4.23 (d): H5; 4.27 (d): H'1; 4.93 (dd): H13; 7.29 (ddd): H5 pyridine; 8.08 (dt): H4 pyridinye; 8.45 (dd): H6 pyridine; 8.97 (dd): H2 pyridine; 7.35 (d) and 7.53 (d): H2 and H5 imidazole.

Preparation of 4- (3-pyridinyl) -1-imidazol-1-butanamine used starting from Example 34

Step A: 2- (4- (3-pyridinyl) -1H-imidazol-1-yl) butyl-1H-isoindol-1,3 (2H) -dione.

 The procedure is as in Step A of the preparation of Example 1 using 290 mg of 3-pyridinyl 1H-imidazole prepared as indicated in J. Chem. Soc. 753-5 (1938), 115 mg of sodium hydride and 633 mg of N-4-bromobutyl phthalimide.

277 mg of expected product is obtained. F = 150-1520C.

Step B: 4- (3-pyridinyl) -1H-imidazol-1-butanamine.

 The procedure is as in Stage B of the preparation of Example 1 using 1.66 g of the product obtained as in Step A above and 0.46 ml of hydrazine hydrate in 30 ml of ethanol.

936 mg of product used as such for the synthesis are obtained.

7,29 (d, J=1)-7,55 (d, J=l) : H2 et H5 ; 7,30 (en partie masqué) : H'5 ; 8,09 (dt, J=8 et 2) : H'4 ; 8,47 (dd, J=5 et 2) : H'6 ; 8,96 (d, J=2) : H'2 ; 1,49 (sl) : z 2H mobiles.NMR (CDCl3) ppm 1.49 (m) -1.89 (m): central CH2; 2.75 (t): CH 2 -CH 2 -N;

7.29 (d, J = 1) -7.55 (d, J = 1): H 2 and H 5; 7.30 (partly masked): H'5; 8.09 (dt, J = 8 and 2): H'4; 8.47 (dd, J = 5 and 2): H'6; 8.96 (d, J = 2): H'2; 1.49 (sl): z 2H mobile.

EXAMPLE 35: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12.11 - (oxycarbonyl ((4- (3- (3-pyridinyl) -1H-1,2,4-triazol-1-yl) butyl) imino)) erythromycin
1 g of the starting compound of Example 29 (obtained as indicated in Example 1C of the European patent application EP 0 596 802) is heated at 750 ° C. for 8 hours in 4 ml of acetonitrile and 1.21 g of 4- (3- (3-pyridinyl-1H-1,2,4-triazol-1-yl) butanamine The mixture is allowed to warm to room temperature, poured into water, extracted with ethyl acetate, washed with water, dried, evaporated the solvent, 2 g of acetylated product in 2 ', 40 ml of methanol, stirred for 16 hours, evaporated the solvent, chromatography residue on silica (eluent: CH2Cl2-MeOH-NH4OH 90 -10-0.04) and crystallized from ether to give 292 mg of expected product, mp 190-1920 ° C.

3,85 (q) : H2 ; # 4,25 : H'1, H5 et CH2NC ; 4,91 (dd) : H13 ; 8,15 (s) : H triazole ; 7,35 (dd) : H5 pyridine ; 8,34 (dt) : H4 pyridine ; 8,62 (dd) : H6 pyridine; 9,31 (dl) : H2 pyridine.NMR (CDCl3) ppm 0.84 (t): CH3-CH2; 1.01 (d): OMe; 1.16 (d): 8Me; 1.25 (d): 5Me; 1.30 (d): 4Me; 1.34 (d): 2Me; 1.33 (s) and 1.47 (s): 6 and 12 Me; 1.67 (m) -1, 99 (m): central CH2; 2.26 (s): N (Me) 2; 2.44 (m): H, 3; 2.58 (m): H8; 2.61 (s): 6-OMe; 3.06 (m): H4; 3.12 (q): H10; 3.17 (dd): H'2.2 3.52 (m): H'5; 3.56 (s): H11

3.85 (q): H2; # 4.25: H'1, H5 and CH2NC; 4.91 (dd): H13; 8.15 (s): H triazole; 7.35 (dd): H5 pyridine; 8.34 (dt): H4 pyridine; 8.62 (dd): H6 pyridine; 9.31 (dl): H2 pyridine.

Preparation of 3- (3-pyridinyl) -1H-1,2,4-triazol-1-butanamine used starting from Example 35.

Step A: 2- (4- (3- (3-pyridinyl) -1H-1,2,4-triazol-1-yl) butyl-1H-isoindol-1,3 (2H) -dione.

 The procedure is as in Step A of the preparation of Example 1 using 2.1 g of 3-pyridinyl 1H-1,2,4-triazole prepared as described in J. Org. Chem. (44) 33, 4160-4164 (1979), 1.02 g of sodium hydride and 4.13 g of N-4-bromobutyl phthalimide. 2.4 g of expected product are obtained.

F = 150-1520C.

Step B: 3- (3-pyridinyl) -1H-1,2,4-triazol-1-butanamine (fumarate).

 The procedure is as in Stage B of the preparation of Example 1 using 3.46 g of the product obtained as in Step A above and 1 ml of hydrazine hydrate in 50 ml of ethanol. 2.1 g of crude product is obtained which is converted into fumarate as indicated in Preparation 30 and gives 1.13 g of fumarate of the expected product. F = 190-1920C.

NMR (CDCl3) ppm 1.50 (m) -2.01 (m): central CH2; 2.76 (t): NH 2 -CH 24.24: = N-N-CH 2; 7.37 (ddd): H5; 8.35 (dt): H4; 8.63 (dd): H6; 9.32 (dd): H2; 8.12 (s): = CH triazole.

By operating as before using the appropriate amines, the following products were prepared:
EXAMPLE 36: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12.11 - (oxycarbonyl ((4- (3-quinolinyl) butyl) imino)) erythromycin
F = 190-1920C.

EXAMPLE 37: 11,12-Dideoxy-3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12.11 - (oxycarbonyl ((4- (4- (4-methoxyphenyl) 1H-imidazol-1-yl) butyl) imino)) erythromycin
Mp 152-1540 ° C.

EXAMPLE 38: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12.11 - (oxycarbonyl ((4- (2-phenyl-4-thiazolyl) butyl) imino)) erythromycin
M.p. 141-1430C.

EXAMPLE 39: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12.11 4- (4- (4- (3-Methoxyphenyl) -1H-imidazol-1-yl) butyl) imino)) erythromycin oxycarbonyl
Mp 144-1460 ° C.

EXAMPLE 40: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12,11- ( oxycarbonyl ((4- (4,5-diphenyl) 1E-imidazol-1-yl) butyl) imino)) erythromycin
F = 180-1820C.

EXAMPLE 41: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12,11- ( oxycarbonyl ((4- (4-quinazolinyl) butyl) imino)) erythromycin
Mp 212-2140 ° C.

EXAMPLE 42: 11,12-Dideoxy-3 - ((2,6-Dideoxy-3-c-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12.11 - (oxyearbonyl ((4- (2- (4-pyridinyl) -4-thiazolyl) butyl) imino)) erythromycin
Mp 192-1940 ° C.

EXAMPLE 43: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12,11- ( oxycarbonyl ((4- (1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-purin-7-yl) butyl) imino)) erythromycin
Mp 251-25 ° C.

EXAMPLE 44: 11,12-Dideoxy 3 - ((2,6-Dideoxy-3-c-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo 12.11 - (oxycarbonyl) - ((4- (4- (4-trifluoromethoxy) phenyl) -1H-imidazol-4-yl) butyl) imino)) erythromycin
Mp 168-1700 ° C.

on peut partir des aldéhydes correspondants

The amines used as starting materials are prepared according to the following methods
A - When the chain is attached to a carbon for example

we can start from the corresponding aldehydes

 The amines used for the preparation of the products of Examples 4, 8, 11, 12, 18, 19, 23 and 24 were prepared in this way.

B - When the chain is attached to a nitrogen, the amines can be prepared as follows

 The amines used for the preparation of the products of Examples 1, 2, 3, 5, 9, 13, 14, 15, 16, 17, 20, 21, 22, 25, 26 and 28 were prepared in this way.

C - Some amines are prepared in a particular way the heterocycle is built and the channe is introduced at the same time (Examples 6, 7, 10 and 27).

EXAMPLES OF PHARMACEUTICAL COMPOSITIONS
Compounds containing
Product of ingredient 1 .................... 150 mg
Excipient qsp .......................... 1 g
Detail of the excipient: starch, talc, magnesium stearate
Product of Example 2 .................... 150 mg
Excipient qsp .......................... 1g
Detail of the excipient: starch, talc, magnesium stearate
Product of Example 3 .................... 150 mg
Excipient qsp .......................... 1 g
Detail of the excipient: starch, talc, magnesium stearate LTVDE PHARMACOLOGY OF THE PRODUCTS OF THE INVENTION
Method of dilutions in liquid medium
A series of tubes are prepared in which the same amount of sterile nutrient medium is distributed. Each tube is distributed with increasing amounts of the product to be studied, and then each tube is inoculated with a bacterial strain. After incubation for twenty-four hours in an oven at 370 ° C., inhibition of growth is assessed by transillumination, which makes it possible to determine the minimum inhibitory concentrations (MIC) expressed in micrograms / cm 3.

The following results were obtained GRAM + bacterial strains
Products Ex 1 Ex.2 Ex.3 Ex.29 Ex.31 Ex.32 Ex.34 EX.35
Staphylococcus 0.04 0.04 0.08 0.04 0.04 0.08 0.04 0.08 aureus 011UC4
Staphylococcus 0.08 0.15 0.15 0.15 0.08 0.15 0.08 0.6 aureus 011G025I
Staphylococcus 0.08 0.04 0.15 0.04 0.4 0.08 0.04 epidermidis 012G011I
Streptococcus 0.04 # 0.02 0.04 # 0.02 # 0.02 # 0.02 # 0.02 # 0.02 pyogenes group A 02A1UC1
Streptococcus # 0.02 # 0.02 # 0.02 # 0.02 # 0.02 # 0.02 # 0.02 # 0.02 agalactiae group B 02B1HT1
Streptococcus 0.04 # 0.02 0.04 # 0.02 # 0.02 # 0.02 # 0.02 # 0.02 faecalis group D 02D2UC1 GRAM + bacterial strains (continued)
Products Ex 1 Ex.2 Ex.3 Ex.29 Ex.31 Ex.32 Ex.34 Ex.35
Streptococcus # 0.02 # 0.02 0.04 # 0.02 # 0.02 # 0.02 0.3 # 0.02 faecium group D 02D3HT1
Streptococcus sp 0.04 # 0.02 0.04 # 0.02 # 0.02 # 0.02 # 0.02 # 0.02 group G 02G0GR5
Streptococcus # 0.02 # 0.02 # 0.02 # 0.02 # 0.02 # 0.02 # 0.02 # 0.02 mitis 02mitCB1
Streptococcus # 0.02 0.15 0.04 # 0.02 # 0.02 # 0.02 # 0.02 # 0.02 mitis 02mitGR16I
Streptococcus 0.08 0.08 0.04 - 0.08 0.04 0.04 0.08 agalactiae group B 02B1SJ1
Streptococcus 0.04 0.04 0.15 0.04 0.15 0.15 # 0.02 # 0.02 pneumoniae 030SJ5
In addition, the products of Examples 1, 2 and 3 showed an interesting activity on the following bacterial gram strains: Haemophilus Influenzae 351HT3, 351CB12, 351CA1 and 351GR6.

Claims (16)

1) The compounds of formula (I):

 in which R represents a radical - (CH2) nAr, in which n represents the number 3, 4 or 5 and Ar represents a heterocyclic radical, optionally bearing one or more substituents, chosen from the group of radicals  and Z represents a hydrogen atom or the remainder of an acid, as well as their addition salts with acids.

  where R represents a radical

 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, wherein n represents the number 4.  optionally substituted.

 The compounds of formula (I), as defined in claim 1, 2 or 3, in which Ar represents a radical 5) The compounds of formula (I), as defined in claim 1, 2 or 3 in which R represents a radical:

 optionally substituted. 6) The compounds of formula (I), as defined in claim 1, 2 or 3 in which Ar represents a radical

  optionally substituted.  optionally substituted.

 The compounds of formula (I) as defined in claim 1, 2 or 3 in which Ar represents a radical 8) As new chemical products the compounds of formula (I), as defined in claim 1, whose names follow - 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl) 3-O-methylalpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo-12,11- (oxycarbonyl) - ((4- (4-phenyl-1H-imidazol-1-yl) butyl) imino)) Erythromycin, 11,12-dideoxy-3 - ((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo-12,11- (oxycarbonyl ((4- (3H-imidazo (4,5-b) pyridin-3-yl) butyl) imino)) erythromycin, 11,12-dideoxy-3-ene ((2,6-dideoxy-3) -C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo-12,11- (oxycarbonyl) (4- (1H-imidazo) (4,5-b)) pyridin-1-yl) butyl) imino)) erythromycin, 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methylalpha-L-ribohexopyranosyl) oxy) 6- O-methyl-3-oxo-12,11- (oxycarbonyl ((4- (4- (4-chlorophenyl) -1H-imidazol-1-yl) butyl) imino)) erythromycin, - 11,12-dideoxy 3-de (( 2,6-dideoxy-3-C-methyl-3-O-méthylalpha-L-ri bohexopyranosyl) oxy) 6-O-methyl-3-oxo-12,11- (oxycarbonyl- (4- (4- (2-methoxyphenyl) -1H-imidazol-1-yl) butyl) imino)) erythromycin, - 11,12- dideoxy 3 - ((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo-12,11- (oxycarbonyl 4- (4-fluorophenyl) -1H-imidazol-1-yl) butyl) imino)) erythromycin, 11,12-dideoxy 3-de (2,6-dideoxy-3-C-methyl-3-O-methylalpha) L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo-12,11- (oxycarbonyl) - ((4- (7-methoxy-4-quinolinyl) butyl) imino)) erythromycin, - 11,12-dideoxy 3- ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo-12,11- (oxycarbonyl) (2-pyridinyl) 4-thiazolyl) butyl) imino)) erythromycin, 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methylalpha-L-ribohexopyranosyl) oxy 6-O-methyl-3-oxo-12,11- (oxycarbonyl) - ((4- (3- (3-pyridinyl) -1H-1,2,4-triazol-1-yl) butyl) imino)) erythromycin. 9) As a new chemical compound of formula (I), as defined in claim 1, whose name follows - 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl) 3-O-methylalpha-L-ribohexopyranosyl) oxy) 6-O-methyl-3-oxo-12,11- (oxycarbonyl) - ((4- (4- (3-pyridinyl) -1H-imidazol-1-yl) butyl ) imino)) erythromycin. 10) As medicaments the compounds of formula (I), as defined in any one of claims 1 to 7, and their addition salts with pharmaceutically acceptable acids. 11) As medicaments the compounds defined in claim 8, and their addition salts with pharmaceutically acceptable acids. 12) As medicaments the compound defined in claim 9, and its addition salts with pharmaceutically acceptable acids. 13) Pharmaceutical compositions containing as active ingredient at least one drug according to any one of claims 10 to 12. 14) Process for the preparation of the compounds of formula (I), as defined in claim 1, characterized in that a compound of formula (II) is subjected

 in which R and Z 'retain their previous meaning, then subject, where appropriate, the compound of formula (IA) to the action of a hydroxyl-functional release agent at 2' and / or, where appropriate, at least action of an acid to form the salt.

 RNH2 (III) wherein R is defined as in claim 1, to obtain the compound of formula (IA): Z 'represents the residue of an acid, with the action of a compound of formula (III)  (II) in which 15) The compounds of formula (III) as defined in claim 14. 16) The amines of formula (III) as defined in claim 15, whose names follow - 4-phenyl-1H-imidazole 1-butanamine, - 3H-imidazo (4,5-b) -pyridine 3- butanamine, 1H-imidazo (4,5-b) -pyridine 3-butanamine, 2-phenyl-4-quinolinebutanamine, 1H-benzotriazole 1-butanamine, 2H-benzotriazole 2-butanamine, 1-methyl-1H-imidazo (4,5-c) -pyridine-2-butanamine, 3-methyl-3H-imidazo (4,5-c) -pyridine 2-butanamine, 5-chloro-1H-benzimidazole butanamine, 7-methoxy-4-quinolenebutanamine, 1H-imidazo (4,5-c) pyridine 1-butanamine, 9H-purine 9-butanamine, 1-methyl-1H-indole 4-butanamine, 3-phenyl-1H-1,2,4-triazole 1-butanamine (hydrochloride), 5-phenyl-1H-tetrazole-1-butanamine (hydrochloride), 2-benzothiazolebutanamine, 4- (thieno (2, 3-b) pyridine 4-yl butanamine, 5,6-dimethyl-1H-benzimidazole 1-butanamine, 3-quinoline butanamine, 2-quinoline butanamine, 5H-imidazo [4,5-c] pyrid 5-butanamine, 1-methyl-1H-benzimidazol 2-butanamine, 6-chloro-1H-benzimidazol 2-butanamine, 2-methyl-1H-benzimidazol 2-butanamine, 4- (4-chlorophenyl) 1H-imidazol 1-butanamine, 2- (3-pyridinyl) thiazol-5-butanamine, 7-methoxyquinoline 4-butanamine, 4- (4-fluorophenyl) -1H-imidazol-1-butanamine, 4- (2-methoxyphenyl) -1H-imidazol-1-butanamine, 3- (3-pyridinyl) -1H-1,2,4-triazol-1-butanamine, 4- (3-pyridinyl) -1H-imidazol-1-butanamine, 2- (2-pyridinyl) thiazol 4-butanamine, 2-phenylthiazol-4-butanamine, 4- (4-methoxyphenyl) 1H-imidazol-1-butanamine, isoquinoline-4-butanamine, quinazoline 4 -butanamine, 4,5-diphenyl-1H-imidazol-1-butanamine, 4- (3-methoxyphenyl) -1H-imidazol-1-butanamine, 4- (4- (trifluoromethoxy) phenyl) -1H-imidazole; butanamine, 1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-purine-7-butanamine, 2- (4-pyridinyl) thiazol-4-butanamine, 1H-indol-1-butanamine , - l 2- (3-pyridinyl) thiazol-4-butanamine and their addition salts with acids.