Title of Invention

"NEW ERYTHROMYCIN COMPOUNDS, THEIR PREPARATION PROCESS AND THEIR USE AS MEDICAMENTS"

Abstract The erythromycin compounds of formula (I): in which R and Z are as described in the specification.
Full Text New erythromycin 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 formula (I):

(Figure Remove)
in which R represents a -(CH2)nAr radical, in which n represents the number 3, 4 or 5 and Ar represents a heterocyclic radical, optionally carrying one or more substituents, chosen from the following group of radicals:
and Z represents a hydrogen atom or an acid remainder, as well as their addition salts with acids.
As an example of addition salts of the present derivatives with mineral or organic acids, there can be mentioned the salts formed with the following acids: acetic, propionic, trifluoroacetic, maleic, tartaric, methane-sulphonic, benzenesulphonic, p-toluenesulphonic, hydrochloric, hydrobromic, hydroiodic, sulphuric, phosphoric and especially stearic, ethylsuccinic and laurylsulphuric acids.
The heterocyclic radical can be substituted by one or more radicals chosen from the group constituted by free, salified, esterified and amidified carboxyl radicals, hydroxyl radicals, halogen atoms, NO2 radicals, C=N radicals, linear, branched or cyclic alkyl radicals, linear or branched alkenyl or alkynyl radicals, the following radicals: O-alkyl, O-alkenyl and 0-alkynyl, S-alkyl, S-alkenyl or S-alkynyl and N-alkyl, N-alkenyl and N-alkynyl, containing up to 12 carbon atoms optionally substituted by one or more halogen atoms,
Rl the N radical, R1 and R2, identical or different,
R2
representing a hydrogen atom or an alkyl radical containing up to 12 carbon atoms, the O
II -C-R3 radical, R3 representing an alkyl radical containing
up to 12 carbon atoms, or an optionally substituted carbocyclic or heterocyclic aryl radical, carbocyclic aryl, 0-aryl or S-aryl radicals or heterocyclic aryl, O-aryl or S-aryl radicals containing one or more heteroatoms, optionally substituted by one or more of the substituents mentioned
above.
When the heterocyclic radical contains several rings (linked together, or condensed) the substituent or substituents can be found on one and/or the other of the heterocyclic or carbocyclic rings, it is thus for example that if a heterocyclic nucleus is linked to or condensed with an aryl radical, the heterocyclic nucleus and the aryl nucleus can both carry one or more substituents.
The aryl radical envisaged is preferably a phenyl or naphthyl radical,
- 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 halogen is preferably fluorine, chlorine or bromine,
- the alkyl radical substituted by a halogen atom is
preferably one of the following radicals: CHC12, CHBr2, CHF2,
CC12, CBr3, CF3, CH2CF3, CH2CH2CC13, CH2CH2CF3,
- the carboxylic acid remainder is preferably the acetyl,
propionyl, butyryl, isobutyryl, n-valeryl, isovaleryl, tert-
valeryl and pivalyl remainder.
A more particular subject of the invention is 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.
A quite particular subject of the invention is the compounds of formula (I) in which Ar represents a radical:

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

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



optionally substituted and non particularly the compounds of formula (I) in which Ar represents the radical:
(Figure Remove)
(Figure Remove)

aptionally substituted.
A more particular subject of the invention is the compounds of formula (I) whose preparation is given hereafter in the experimental part. Among the preferred compounds of bhe invention, there can be mentioned the compounds:
- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-
alpha-L-ribohexopyranosy1) oxy) 6-0-methyl 3-oxo 12,ll-(oxy-
zarbonyl ((4-(4-phenyl IH-imidazol-l-yl) butyl) imino))
srythromycin,
- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-
alpha-L-ribohexopyranosy1) oxy) 6-o-methyl 3-oxo 12,ll-(oxy-
zarbonyl ((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) 6-0-methyl 3-oxo 12,ll-(oxy-
carbonyl ((4-(lH-imidazo(4,5-b)pyridin-l-yl) butyl) imino))
erythromycin,
- 11,12-dideoxy 3-de((2,e-dideoxy-S-C-methyl-S-O-methyl-
alpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,ll-(oxy-
carbonyl ((4-(4-(4-chlorophenyl) IH-imidazol-l-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,ll-(oxy-
carbonyl ((4-(4-(2-methoxyphenyl) IH-imidazol-l-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,ll-(oxy-
carbonyl ((4-(4-(4-fluorophenyl) IH-imidazol-l-yl) butyl)
imino)) erythromyc in,
- 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-(oxy-
carbonyl ((4-(7-methoxy 4-quinoleinyl) butyl) imino))
erythromycin,
- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-
alpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,ll-(oxy-
carbonyl ((4-(2-(2-pyridinyl) 4-thiazolyl) butyl) imino))
ery thr omy c in,
- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-
alpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,ll-(oxy-
carbonyl ((4-(3-(3-pyridinyl) lH-l,2,4-triazol-l-yl) butyl)
imino)) erythromycin,
and more particularly the
- 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-(oxy-
carbonyl ((4-(4-(3-pyridinyl) IH-imidazol-l-yl) butyl)
imino)) erythromycin.
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 in particular in that of staphylococcia, such as staphylococcal speticemia, malignant staphylococcia of the face or skin, pyodermititis, septic or suppurating sores, boils, anthrax, phlegmons, erysipelas and acne, staphylococcia such as primary or post-influenzal acute anginas, bronchopneumonia, pulmonary suppurations, streptococcal infections such as acute anginas, otitis, sinusitis, scarlet fever, pneumococcal infections 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 the Mycobaterium, Listeria, Meningococci and Campylobacter 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 as antibiotic medicaments, the preferred products of formula (I) defined previously namely the products of Examples 1, 2, 3 and 29 to 35, as well as 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 or 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 can 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 with excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives.
These compositions can also be presented in the form of a powder intended to be dissolved extemporaneously in a suitable vehicle, for example apyrogenic sterile water.
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 50 mg and 300 mg per day by oral route, for an adult, for the product of Example 1 or Example 2.
Also a subject of the invention is a preparation process for the compounds of formula (I), characterized in that a compound of formula (II) :

(Figure Remove)
in which Z' represents an acid remainder, is subjected to the action of a compound of formula (III):in which R is defined as previously, in order to obtain the compound of formula (IA):

0 Z ' in which R and Z' keep their previous meaning, then if
appropriate the compound of formula (IA) is subjected to the action of an agent releasing the hydroxyl function in position 2' and/or if appropriate, to the action of an acid in order 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 also
tetrahydrofuran, dimethoxy ethane or dimethylsulphoxide,
- the hydrolysis of the ester function in position 2' is
carried out using methanol or aqueous hydrochloric acid,
- the salification is carried out using acids according to
standard processes.
The compounds of formula (II) used as starting products are described and claimed in the European Patent Application 0 596 802.
The compounds of formula RNH2 are generally known products, however the precise compounds used for the preparation of the products of the examples are new and are themselves a subject of the invention, their preparation is given below.
The compounds of formula RNH2 can be prepared for example according to the processes described by J. Med. Chem. (1982) vol. 25 p. 947 and subsequent, 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 the German Patent 3,406,416; J. Org. Chem. 6-895-901 (1941) or Synth. Commun 17 (14) 1741-8 (1987).
A quite particular subject of the invention is the amines III as defined above whose preparation is given in detail hereafter.
The invention has more particularly for subject:
- 4-phenyl-lH-imidazole 1-butanamine,
- 3H-imidazo(4,5-b)-pyridine 3-butanamine,
- IH-imidazo(4,5-b)-pyridine 3-butanamine,
- 2-phenyl-4-quinolinebutanamine,
- IH-benzotriazole 1-butanamine,
- 2H-benzotriazole 2-butanamine,
- 1-methyl IH-imidazo(4,5-c)-pyridine 2-butanamine,
- 3-methyl 3H-imidazo(4,5-c)-pyridine 2-butanamine,
- 5-chloro IH-benzimidazole 1-butanamine,
- 7-methoxy 4-quinolenebutanamine,
- IH-imidazo(4,5-c) pyridine 1-butanamine,
- 9H-purine 9-butanamine,
- 1-methyl IH-indole 4-butanamine,
- 3-phenyl lH-l,2,4-triazole 1-butanamine (hydrochloride),
- 5-phenyl IH-tetrazole 1-butanamine (hydrochloride),
- 2-benzothiazolebutanamine,
- 4-(thieno(2,3-b) pyridine 4-yl butanamine,
- 5,6-dimethyl IH-benzimidazole 1-butanamine,
- 3-quinoleine butanamine,
- 2-quinoleine butanamine,
- 5H-imidazo [4,5-c] pyridine 5-butanamine,
- 1-methyl IH-benzimidazol 2-butanamine,
- 6-chloro IH-benzimidazol 2-butanamine,
- 2-methyl IH-benzimidazol 2-butanamine,
- 4-(4-chlorophenyl) IH-imidazol 1-butanamine,
- 2-(3-pyridinyl) thiazol 5-butanamine,
- 7-methoxyquinoleine 4-butanamine,
- 4-(4-fluorophenyl) IH-imidazol 1-butanamine,
- 4-(2-methoxyphenyl) IH-imidazol 1-butanamine,
- 3-(3-pyridinyl) 1H 1,2,4-triazol 1-butanamine,
- 4-(3-pyridinyl) IH-imidazol 1-butanamine,
- 2-(2-pyridinyl) thiazol 4-butanamine,
- 2-phenylthiazol 4-butanamine,
- 4-(4-methoxyphenyl) IH-imidazol 1-butanamine,
- isoquinoleine 4-butanamine,
- guinazoline 4-butanamine,
- 4,5-diphenyl IH-imidazol 1-butanamine,
- 4-(3-methoxyphenyl) IH-imidazol 1-butanamine,
- 4-(4-(trifluoromethoxy) phenyl) IH-imidazol 1-butanamine,
- 1,2,3,6-tetrahydro 1,3-dimethyl 2,6-dioxo 7H-purine 7-
butanamine,
- 2-(4-pyridinyl) thiazol 4-butanamine,
- IH-indol 1-butanamine,
- 2-(3-pyridinyl) thiazol 4-butanamine,
as well as their addition salts with acids.
The following examples illustrate the invention. EXAMPLE 1; 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 ((4-(4-phenyl IH-imidazol-l-yl) butyl) imino)) erythromycin
A mixture of 0.705 g of 11-deoxy 10,11-didehydro 3-de(2,6-dideoxy 3-C-methyl 3-O-methyl alpha-L-ribohexopyra-nosyl) oxy) 12-O-((IH-imidazol-l-yl) carbonyl) 6-O-methyl 3-oxo erythromycine 2'-acetate obtained as indicated in example 1C of the European Patent application 0 596 802, 3 ml of acetonitrile with 10% water and 1.08 g of 4-(4-phenyl 1H-imidazol-1-yl) butanamine is taken to 63°C. The reaction mixture is maintained at this temperature for 5 hours. It is left to return to ambient temperature, the reaction mixture is poured into a solution of sodium acid phosphate, extraction is carried out with ethyl acetate. The organic phases are washed with water, dried, filtered and concentrated. 1.5 g of a product is obtained to which 210 ml of methanol is added. The whole is maintained under agitation for 16 hours, under a nitrogen atmosphere and at ambient temperature. After concentration, 1.4 g of product is obtained which is purified by chromatography on silica, eluant CH2C12 - MeOH - NH4OH (93-7-0.4). After concentration 0.305 g of the crude desired product is obtained, which is
recrystallized from isopropyl ether, followed by washing and
drying at 50°C under reduced pressure. In this way 0.267 g
of the desired product is obtained, melting at 222°C-231°C.
NMR CDC13 ppm
alphaD = +18° (c = 0.9 CHC13)
0.84 (t) : CH3-CH2 ; 1.01 (d)-l.iv (d)-l.24 (d) :
the CH3-CH's ; 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) : Hg ;
2.63 (s) : 6-OMe ; 3.04 (-) : H4 ; 3.13 (q) : HIQ ; 3.18
(dd) : H'2 ; 3.53 (-) : H'5 ; 3.56 (s) : HI:L ; 3.67 (-J-3.75
I (-) : the -C-NCH2's ; : 3.87 (q) : H2 ; 3.99 (t) : CH2NC ;
II O
4.23 (d) : H5 ; 4.27 (d) : H^ ; 4.94 (dd) : H13 ; 7.26 (s) : H"5 ; 7.5 (s) : H"2 ; 7.20 : H in para position ; 7.35 : H in meta position ; 7.76 : H in ortho position. PREPARATION 1; 4-(4-phenyl IH-imidazol 1-yl) butanamine Stage A; 2-(4-(4-phenyl IH-imidazol 1-yl) butyl IH-iso indole-l,3(2H)dione
A solution containing 5.05 g of 4-phenyl IH-imidazole in 25 cm of DMF is introduced dropwise over one hour 30 minutes into a mixture of 7 cm3 of DMF dried on siliporite and 2.02 g of sodium hydride. Then 10.86 g of 2-(4-bromobuty1) IH-iso-indole l,3(2H)dione N-4-bromobutyIphthalimide in solution in 25 cm3 of DMF is introduced. The solution obtained is taken to 70°C for about one hour 30 minutes. It is left to return to ambient temperature, the solution obtained is concentrated, taken up in water, extracted with ethyl acetate. The organic phases are washed with water, dried, filtered and concentrated. 15 g of product is obtained which is recrystallized from ethyl acetate. The product obtained is separated off, washed with ethyl acetate and dried under reduced pressure at 50°C. 5.5 g of desired product is obtained, melting at 130 - 132°C. NMR CDC13 ppm
1.75 (m) (2H)-1.86 (m) (2H) : central CH2's ; 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 ; approx. 7.73 (m) : 4H ;
approx. 7.86 (m) : H2 and Hg.
Stage B; 4-(4-phenyl IH-imidazol-l-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 maintained under reflux for 8 hours. The reaction mixture is concentrated, about 50 ml of 2N soda is added, extraction is carried out with ethyl acetate. The organic phases are washed with 2N soda, then with sodium chloride. After drying, filtering and concentrating, 2.21 g of desired product is obtained. NMR CDC13 ppm
1.47 (m)-1.87 (m) : central CH2's ; 2.73 (t)-3.97 : -CH2-NH2; 7.20 (d) : H'3 ; 7.50 (d) : H'5 ; 7.37 (wt) 2H : H3 H5 ; 7.24 (it) 1H : H4 ; 7.77 (m) 2H : H2 and H6.
EXAMPLE 2; 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 ((4-(3H-imidazo(4/5-b) pyridin-3-yl) butyl) imino)) erythromycin
708.2 mg of 11-deoxy 10,11-didehydro 3-de(2,6-dideoxy 3-C-methyl 3-O-methyl alpha-L-ribohexopyranosyl) oxy) 12-O-((IH-imidazol-l-yl) carbonyl) 6-O-methyl 3-oxo erythromycine 2'-acetate obtained as indicated in example 1C of the European Patent application 0 596 802, and 958 mg of (3H-
*>j
imidazo(4,5-b) pyridin-3-butanamine are dissolved in 2.82 cmj of acetonitrile and 0.28 cm3 of water. The reaction mixture is taken to 80°C. It is left to return to ambient temperature and poured into a solution of sodium acid phosphate. Extraction is carried out with methylene chloride followed by washing with water. The aqueous phases are collected and extraction is carried out again. After drying, filtering and rinsing, 826 mg of product is obtained. The

product obtained is dissolved in 16.5 cm of methanol. The reaction solution is maintained under agitation at ambient temperature for 20 hours. 789 g of crude desired product is obtained which is purified by chromatography, eluting with a mixture of methylene chloride, methanol and ammonium hydroxide (94-16-0.4). 327 mg of desired product is
obtained, melting at 200°C. alphaD = +13° c - 1% CHC13 NMR CDC13 400 MHz ppm
0.85 (t) : CH3-CH2 ; 1.01 (d)-1.16 (d)-1.25 (d)-1.30 (d)-1.26 (d) : the CH3-CH/s ; 1.35 and 1.47 : 6 and 12 Me ; approx. 1.63 and approx. 1.98 : the central CH2's of the chain ; 2.27 (s) : N(CH3)2 ; 2.46 (m) : H'3 ; approx. 2.59 (m) : H8 ; 2.61 (s) : 6-OMe ; 3.07 (m) : H4 ; 3.12 (wq) : H10 ; 3.18 (dd) : H'2 ; 3.54 (m) : H'5 ; 3.57 (s) : H±1 ; 3.6 to 3.8 : CH2NC ;
II
O
3.85 (q) : H2 ; 4.24 (d) : H5 ; 4.29 (d) : H^ ; approx. 4.35 (m) : CH2NC= ; 4.93 (dd) : H13 ; 7.21 (dd) : H6 aromatic ; 8.04 (dd) : H7 aromatic ; 8.11 (s) : H2 aromatic ; 8.38 (dd): H5 aromatic.
EXAMPLE 3; 11,12-dideoxy 3-de( 708.3 mg of 11-deoxy 10,11-didehydro 3-de(2,6-dideoxy 3-C-methyl 3-O-methyl alpha-L-ribohexopyranosyl) oxy) 12-O-((IH-imidazol-l-yl) carbonyl) 6-O-methyl 3-oxo erythromycine 2'-acetate obtained as indicated in example 1C of the European Patent application 0 596 802, is added to a solution containing 953 mg of (lH-imidazo(4,5-b) pyridine 3-butanamine, 2.82 cm3 of acetonitrile and 0.28 cm3 of water. The reaction mixture is taken to 55°C, maintained at this temperature for 44 hours and 0.5 cm3 of acetonitrile is added. The mixture is maintained at 55°C for a further 20 hours. It is allowed to return to ambient temperature and poured into a saturated solution of sodium acid phosphate. The aqueous phase is extracted with methylene chloride and the chloromethylene phases are washed with water. Drying over sodium sulphate is carried out, followed by filtration and evaporation. 806 mg of product is obtained to which 16.1 cm3 of methanol is added. The reaction mixture is maintained at ambient temperature for 24 hours and evaporated to dryness. 656 mg of a product is obtained which is
chromatographed on silica, eluting with a CH2Cl2-MeOH-NH3 mixture (94-6-0.4).
The crude desired product is obtained which is purified by chromatography on silica, eluting with a CHCl3-MeOH-NH4OH mixture (94-6-0.4). The residue is dissolved in an ethyl acetate - isoproyl ether mixture, followed by filtration and evaporation to dryness. In this way the desired product is collected. M.p. = 203°C. alphaD = 17.6° c = 1% CHC13.
0.81 (t) : CH3-CH2 ; 1.00 (d)-1.17 (d)-1.25 (d)-1.31 (d)-1.38 (d) : the CH3-CH's ; 1.35 (s)-1.47 (s) : 6 and 12-CH3 ; 1.68 (m) and 1.93 (m) : the central CH2's of tne chain ; 2.27 (s): N(CH3)2 ; 2.61 (s) : 6-OCH3 ; 2.45 (m) : H'3 ; approx. 2.60 (m in masked part) : H8 ; 3.07 (m) : H4 ; approx. 3.15 (wq) : H1Q ; 3.18 (dd) : H'2 ; 3.56 (s) : HI± ; 3.53 (m) : H'5 ; 3.60 to 3.80 (m) : CO-N-CH2 ; 3.87 (q) : H2 ; approx. 4.25 (m) : CH2-N-C= ; 4.24 (d) : H5 ; 4.28 (d) : H^ ; 4.91 (dd) : H13 ; 7.21 (dd, J = 5 and 8) : H6 ; 7.80 (dd, J = 8 and 1.5): aromatic H7's ; 8.56 (dd, J = 5 and 1.5) : H5 ; 8.15 (s) : H2 + CH2C12.
PREPARATION 2; Preparation of the amines used as starting products of Examples 2 and 3:
3H-imidazo(4,5-b)pyridine 3-butanamine and lH-imidazo(4,5-b) pyridine 1-butanamine Stage A;
10.3 g of potassium carbonate is added to a solution of 5.95 g of 4-azabenzimidazole and 15.5 g of N-4 bromobutyl-phthalimide in 30 cm3 of dimethylformamide. The mixture is agitated for 20 hours at ambient temperature. The insoluble part is filtered off, rinsed with methylene chloride. The organic phase is washed with water, then dried with magnesium sulphate and evaporated, the oily residue obtained is washed with petroleum ether then with isopropyl ether. In this way 16.3 g of a yellow solid is obtained which is purified by chromatography on silica, eluting with a methylene chloride -acetone mixture to give 4.9 g of product (A), M.p. = 143°C, and 3.9 g of product (B), M.p. = 172°C. Stage Bl; 3H-imidazo(4,5-b) pyridine-3-butanamine (starting
product of Example 2)
A mixture of 32.86 g of product (A) prepared in the previous stage, 697 cm3 of ethanol and 20 cm3 of hydrazine is taken to reflux for 19 hours. The mixture is allowed to return to ambient temperature, filtered, rinsed and evaporated to dryness. The residue is taken up in methylene chloride, filtered, rinsed and evaporated to dryness. 18.87 g of desired product is obtained. NMR CDC13 - 250 MHz
1.52 (m)-2.00 (m) : 2 central CH2's ; 1.63 (wide s) : 2 mobile H's ; 2.76 (t) : CH2-CH2-NH2 ; 4.33 (t) : =C-N-CH2-CH2; 7.24 (dd, J = 8 and 5) : H6 ;
I c=o
8.08 (dd, J = 8 and 1.5) : H7 ; 8.40 (dd, J = 5 and 1.5) : H5 ; 8.08 (s) : H2.
Stage B2; lH-imidazo(4,5-b) pyridine 1-butanamine (starting product of Example 3)
A mixture of 32 g of product (B) of Preparation 3, 640 cm3 of ethanol and 24.8 cm3 of hydrazine is taken to reflux for 21 hours. The mixture is allowed to return to ambient temperature. Filtration is carried out, followed by rinsing with ethanol and evaporating under reduced pressure. The residue is taken up in methylene chloride, followed by filtration, rinsing and evaporating to dryness. 19.5 g of desired product is obtained. NMR CDC13
1.45 (m)-1.96 (m) : 2 central CH2's ; 2.74 (t) : CH2-NH2 ; approx. 1.45 (m) : mobile ; 4.23 (t) : C-N-CH2-CH2 ;
I 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.
Operating as previously, the following products were obtained:
EXAMPLE 4: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexoyranosyl) oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl) ((4-(thieno(2,3-b) pyridin-4-yl) butyl) imino))
erythromycin
M.p. = 176 - 178°C.
alphaD = +17°C c = 0.9% in CHC13
EXAMPLE 5; 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-(3-phenyl lH-l,2,4-triazol-l-yl)
butyl) imino)) erythromycin
M.p. = 208 - 210°C.
alphaD = +17° c = 1% in CHC13
EXAMPLE 6; 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-(1-methyl-lH-imidazo(4/S-c)pyridin-2-
yl) butyl) imino)) erythromycinalphaD - +19° C = 1% CHC13
EXAMPLE 7! 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-(3-methyl-3H-imidazo(4,5-c)pyridin-2-
yl) butyl) imino)) erythromycin
alphaD = +16° CHC13 = 1%
EXAMPLE 8; 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-(7-methoxy-4-quinolinyl) butyl)
imino)) erythromycin
alphaD = +15.8° c = 1% CHC13
EXAMPLE 9; 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-(5-phenyl-lH-tetrazol-l-yl) butyl)
imino)) erythromycin
M.p. - 132 - 134°C.
alphaD - +25° C = 1% CHC13
EXAMPLE 10; 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-benzothiazolyl) butyl) imino))
erythromycin
M.p. = 179 - 181°C
alphaD = +18° c = 1% CHC13
EXAMPLE 11; 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-(3-pyridinyl) 4-thiazolyl) butyl)
imino)) erythromycin
M.p. = 150 - 152°C
alphaD = +17° C = 0.9% CHC13
EXAMPLE 12! 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 ((4-(2-(3-pyridinyl) 5-thiazolyl) butyl)
imino)) erythromycin
M.p. = 155 - 159°C
alphaD = +12° C - 1% CHC13
EXAMPLE 13; 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 ((4-(9H-purin-9-yl) butyl) imino))
erythromycin
EXAMPLE 14t 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 ((4-(lH-imidazo(4/5-c) pyridin-1-yl)
butyl) imino)) erythromycin
Rf = 0.42 CHC13 + 8% of MeOH with 8% of NH4OH
EXAMPLE 15; 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 ((S-(lH-benzimidazol-l-yl) pentyl) imino))
erythromycin
Prepared starting from 2-(4-bromophenyl) IH-iso-indole
l,3(2H)-dione.
EXAMPLE 16! 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 ((5-chloro-lH-benzimidazol-l-yl) butyl)
imino)) erythromycin
M.p. = 145-148°C.
EXAMPLE 17! 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0-
methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 12,11-
(oxycarbonyl ((4-(lH-indol-l-yl) butyl) imino)) erythromycin
EXAMPLE 18! 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0-
methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 12,11-
(oxycarbonyl ((4-(l-methyl-lH-indol-4-yl) butyl) imino))
erythromyc in
alphaD =20%, c = 1% CHC13
EXAMPLE 19! 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 ((4-(2-phenyl-4-quinolinyl) butyl) imino))
erythromycin
M.p. = 195-197°C.
EXAMPLE 20; 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 ((4-(lH-benzotriazol-l-yl) butyl) imino))
erythromycin
M.p. = 200-202°C.
EXAMPLE 21; 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0-
methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12fll-(oxycarbonyl ((4-(2H-benzotriazol-2-yl) butyl) imino))
erythromycin
M.p. = 164-166°C.
EXAMPLE 22; 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 ((4-(5,6-dimethyl IH-benzimidazol-l-yl)
butyl) imino)) erythromycin
M.p. = 174-176°C.
EXAMPLE 23; 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 ((4-(3-quinolinyl) butyl) imino))
erythromycin
M.p. = 195-197°C.
EXAMPLE 24; 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 ((4-(2-quinolinyl) butyl) imino))
erythromycin
M.p. = 179-181°C.
EXAMPLE 25; 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 ((4-(2-methyl IH-benzimidazol-l-yl) butyl)
imino)) erythromycin
M.p. = 128-132°C.
EXAMPLE 26; 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 ((4-(6-chloro IH-benzimidazol-l-yl) butyl)
imino)) erythromycin

M.p. = 192-194°C.
EXAMPLE 27; 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 ((4-(l-methyl lH-benzimidazol-2-yl) butyl)
imino)) erythromycin
EXAMPLE 28i 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 ((4-(5H-imidazo(4/5-c)pyridin-5-yl)
imino)) erythromycin
alphaD = 12.2 c= 1% CHC13
EXAMPLE 29; 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 ((4-(4-(4-chlorophenyl) lH-imidazol-l-yl)
butyl) imino)) erythromycin
1 g of ll-deoxy 10,11-didehydro 3-de(2,6-dideoxy 3-C-methyl 3-0-methyl alpha-L-ribohexopyranosyl) oxy) 12-0-((1H-imidazol-1-yl) carbonyl) 6-O-methyl 3-oxo erythromycin 2'-acetate prepared as indicated in Example 1C of the European Patent Application EP 0,596,802 is heated for 7 hours at 75°C in 4 cm3 of acetonitrile with 10% water with 1.4 g of 4-(4-(4-chlorophenyl) IH-imidazol) butanamine. The reaction medium is left to return to ambient temperature, diluted with water, extraction is carried out with ethyl acetate, followed by drying, the solvent is evaporated off and 2.3 g of product acetylated in position 2' is obtained. 60 ml of methanol is added and the mixture is maintained under agitation for 16 hours, the solvent is evaporated off, the residue is chromatographed on silica (eluant: CH2Cl2-MeOH-NH4OH 95-5-0.4), followed by concentration and the residue is crystallized from ether. The crystallized product is dried under reduced pressure at 80°C and 381 mg of expected product is recovered. M.p. = 192-194°C. NMR CDC13 ppm
0.83 (t): CH3-CH2; 1.00 (d)-1.16 (d)-1.24 (d)-1.30 (d)-1.38 (d): the CH3-CH's; 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): Hg; 3.00 to 3.21: H4, H10 and H'2; 3.55 (m) : H'5; 3.56 (s) : H1;L; 3.60 to 3.80 2H-3.99 (t) 2H: CH2NC=; 3.87 (q): H2; 4.23 (d): H5; 4.28
(d) : H'!/ 4.93 (dd) : H13; 7.26 (d) : H5 imidazole; 7.50 (d) :
H2 imidazole; 7.32-7.70: aromatics; 3.51: OH.
Preparation of 4-(4-chlorophenyl) IH-imidazole l-butanamine
used at the start of Example 29.
Stage A; 4-(4-chlorophenyl) IH-imidazole.
23.34 g of -bromo 4-chloro acetophenone in 150 ml of formamide is taken to reflux for one hour; the reaction medium is left to cool down, alkalinized with a soda solution, extraction is carried out with dichloromethane, the extracts are washed with water, dried, the solvent is evaporated off, the residue is chromatographed on silica (eluant: CH2Cl2-MeOH-NH4OH 8-2-0.04) and 13.4 g of expected product is obtained. M.p. = 146-148°C.
Stage B; 2-(4-(4-(4-chlorophenyl) IH-imidazol 1-yl) IH-iso indol-1,3(2H)-dione.
The operation is carried out as in Stage A of the preparation of Example 1 using 12.2 g of the product obtained in Stage A, 4.96 g of sodium hydride and 23.83 g of N-4-bromobutyl phthalamide. 9.7 g of expected product is obtained. Stage C; 4-(4-chlorophenyl) IH-imidazol l-butanamine.
The operation is carried out as in Stage B of the preparation of Example 1 using 14.2 g of product obtained as in Stage 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 (eluant: CH2Cl2-MeOH-NH4OH 8-2-0.04) and the product is obtained, which is used as it is for the synthesis. NMR (CDC13) ppm
1.22 (ws): mobile 2H's; 1.47 (m)-1.88 (m): 2 central CH2's; 2.74 (m): CH2-CH2-N; 3.98 (m): =C-N-CH2-CH2;
I I -C=
7.19 (d, J=1.5)-7.50 (d, J=1.5): H2 and H5; 7.33 and 7.70: aromatics.
EXAMPLE 30; 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,ll-(oxycarbonyl ((4-(4-(2-methoxyphenyl) IH-imidazol-l-yl)
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) in 3 ml of acetonitrile and 908 mg of 4-(4-(2-methoxyphenyl) IH-imidazol-l-yl) butanamine are heated at 80°C for 8 hours. The reaction medium is left to return to ambient temperature, poured into a solution of sodium hydrogen phosphate (0.5M), extraction is carried out with ethyl acetate, the extracts are washed with water, dried, the solvent is evaporated off, 1.6 g of product acetylated in position 2' is obtained. 50 ml of methanol is added, agitation is carried out for 16 hours, the solvent is evaporated off, the residue is chromatographed on silica (eluant: AcOEt-TEA at 4%) and crystallization from ether is carried out. 194 mg of expected product is obtained. M.p. = 143-145°C. NMR CDC13 ppm
0.85 (t): £H3-CH2; 1.01 (d)-1.16 (d)-1.24 (d)-1.30 (d)-1.37 (d): the CH3-CH's; 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 (wq): H10; 3.17 (dd): H'2; 3.54 (m): H'5; 3.57 (s): H1X; 3.66 (m)-3.74 (m): CH2NC;
II O
3.85 (q): H2; 3.95 (s): *-OMe; 3.99 (wq): CH2-N-C=; 4.24 (d):
H5; 4.27 (d) : H^; 4.93 (dd) : H13; 6.97 (wd) : H6; 7.51 (s) :
the imidazole H's; 7.02: phenyl H6; 7.19 (ddd) phenyl H4 and
H5; 8.19 (dd): H2.
Preparation of 4-(2-methoxyphenyl) IH-imidazol-l-butanamine
used at the start of Example 30.
Stage A: 4-(2-methoxyphenyl) IH-imidazole.
9.36 g of 2-bromo 2'-methoxyacetophenone in 50 ml of formamide is heated under reflux, the reaction medium is left to return to ambient temperature, washed with a 2N hydrochloric acid solution, followed by filtration, alkalinizing to pH 8-9 using 2N soda, extraction with dichloromethane, washing with water, drying, evaporating the solvent and chromatographing the residue on silica (eluant:
CH2Cl2-MeOH-NH4OH 95-5-0.4) and 6.15 g of expected product is
obtained.
Stage B; 2-(4-(4-(2-methoxyphenyl) IH-imidazol 1-yl) butyl
IH-iso indol-l,3(2H)-dione.
The operation is carried out 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) IH-imidazol 1-butanamine (fumarate).
The operation is carried out as in Stage B of the preparation of Example 1 using 5.65 g of the product obtained as in Stage B above and 1.45 ml of hydrazine hydrate in 75 ml of ethanol. 3.8 g of crude product is obtained which is dissolved in 4 ml of tetrahydrofuran then 1.87 g of fumaric acid in solution in 20 ml of methanol is added. 10 ml of ether is added, the crystals formed are separated off, dried at 80°C under reduced pressure and 3.77 g of the fumarate of the expected product is recovered. M.p. = 160-162°C. NMR (CDC13) ppm
1.48 (m) 2H-1.87 (m) 2H: the central CH2's; 3.46: NH2; 2.73 (t): CH2N; 3.94 (s): *-OMe; 3.97 (t): CH2N-C; 6.94 (dd): H6;
II 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-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,ll-(oxycarbonyl ((4-(4-(4-fluorophenyl) lH-imidazol-l-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 2.8 g of 4-(4-(4-fluorophenyl) IH-imidazol-l-yl) butanamine are heated at 60°C for 4 hours 30 minutes. The reaction medium is left to return to ambient temperature, poured into water, extraction is carried out with ethyl acetate, the extracts are washed with water, dried, the solvent is evaporated off,
5.2 g of product acetylated in position 2' is obtained. 20 ml of methanol is added to it, agitation is carried out for 3 hours 30 minutes, the solvent is evaporated off, the residue is chromatographed on silica (eluant: CH2Cl2-MeOH-NH4OH 95-5-0.3) and crystallization from ether is carried out. 1.34 g of expected product is obtained. M.p. = 190-192°C. NMR CDC13 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 3.81: CH2-N-C; 3.98 (t): CH2-N-C;
approx. 7.05 - approx. 7.73: fluorophenyl; 7.21 (d): H5
imidazole; 7.49 (d): imidazole H2.
Preparation of 4-(4-fluorophenyl) IH-imidazol-l-butanamine
used at the start of Example 31.
Stage A; 4-(4-fluorophenyl) IH-imidazole.
10.85 g of 4-fluorophenacyl bromide in 60 ml of formamide is heated under reflux for 2 hours, the reaction medium is left to return to ambient temperature, acidified to pH 2 using N hydrochloric acid, followed by filtration, neutralizing by the addition of ammonium hydroxide, extraction with dichloromethane, washing with water, drying, evaporating the solvent, chromatographing the residue on silica (eluant: CH2Cl2-MeOH-NH4OH 95-5-0.4) and 5.8 g of expected product is obtained. M.p. = 130-132°C. Stage B; 2-(4-(4-(4-fluorophenyl) IH-imidazol 1-yl) butyl IH-iso indol-1,3(2H)-dione.
The operation is carried out as in Stage A of the preparation of Example 1 using 10 g of the product obtained in Stage A, 1.95 g of sodium hydride and 11.80 g of N-4-bromobutyl phthalamide. 7.53 g of expected product is obtained. M.p. = 138-140°C. Stage C; 4-(4-fluorophenyl) IH-imidazol 1-butanaraine.
The operation is carried out as in Stage B of the preparation of Example 1 using 3.64 g of product obtained as in Stage B above and 1 ml of hydrazine hydrate in 80 ml of ethanol. 2.4 g of crude product is obtained which is
chromatographed on silica (eluant: CH2Cl2-MeOH-NH4OH 8-2-0.03) and the product is obtained which is used as it is for the synthesis. NMR (CDC13) ppm
1.48 (m)-1.81 (m) : the central CH2's; 2.74 (t): N-CH3; 3.98
(t): >N-CH2-CH2; 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-de((2,6-dideoxy-3-c-methyl-3-o-aethyl-alpha-L-ribohexopyra-nosyl) oxy) 6-o-methyl 3-oxo 12,11-(oxycarbonyl ((4-(7-me-thoxy (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) in 4 ml of acetonitrile and 1.43 g of 4-(4-7-methoxy 4-quinolinyl) butanamine are heated at 50°C for 53 hours. The reaction medium is left to return to ambient temperature, poured into a solution of sodium hydrogen phosphate (0.5M), extraction is carried out with dichloromethane, the extracts are washed with water, dried, the solvent is evaporated off, 1.09 g of product acetylated in position 2' is obtained. 10 ml of methanol is added to it, agitation is carried out for 16 hours, the solvent is evaporated off, the residue is chromatographed on silica (eluant: CH2Cl2-MeOH 95-5) and crystallization from ether is carried out. 295 mg of expected product is obtained. M.p. - approx. 110°C. NMR CDC13 ppm
3.06 (m): -(CH2)2-CH Stage A; triphenyl phosphonium salt of N-(3-bromopropyl) phthalimide.
13.4 g of N-bromopropylphthalimide and 13.15 g of triphenylphosphine in suspension in 75 ml of xylene are heated under reflux for 44 hours. The reaction medium is left to return to ambient temperature, the precipitate is
separated off, washed with ethyl ether and dried under reduced pressure at 60°C. 24.88 g of expected product is recovered. M.p. = 220-222°C.
Stage B; Z-(2-(4-(7-methoxyquinolinyl) 3-butenyl IH-iso-indol-1,3(2H)-dione.
4 g of 7-methoxy 4-quinolinylcarboxaldehyde is added to a suspension of 12.47 g of the triphenylphosphonium salt of 3-bromopropyl phthalimide in 200 ml of tetrahydrofuran. The reaction medium is cooled down to -50°C, 2.72 g of potassium terbutylate is added, the temperature is allowed to rise slowly to -6°C, followed by filtration, the filtrate is concentrated, the residue is taken up in ethyl acetate, washed with water, dried, the solvent is evaporated off and 9.26 g of crude product is recovered which is chromatographed on silica (eluant: CHCl3-AcOEt 80-20 then 70-30). 3.575 g of expected product is recovered.
Stage C; 2-(4-(7-methoxy 4-quinolinyl) butyl) IH-isoindol l,3(2H)-dione.
3.50 g of the product obtained in Stage B is dissolved in 50 ml of methanol, 0.36 g of palladium on activated charcoal is added and the mixture is hydrogenated for 3 hours under 600 mbars. Filtration is carried out, the solvent is evaporated off and 3.48 g of expected product is collected. Stage D; 7-methoxy quinolin-4-butanamine.
3.46 g of the product obtained in Stage C is dissolved hot in 70 ml of ethanol, 1.86 ml of hydrazine hydrate is added, the reaction medium is taken to reflux for 17 hours, the precipitate is eliminated by filtration, the solvent is evaporated off, the residue is taken up in 70 ml of dichloromethane, filtration is carried out, the solvent is evaporated off and 2.19 g of expected product is collected. NMR (CDC13) ppm
1.6 (m)-1.79 (m): central CH2's; 2.75 (t): >-CH2-(CH2)3; 3.05 (t): CH2-NH2; 3.95 (s) : 0-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-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-0-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) in 3 ml of acetonitrile and 0.705 g of 4-(2-(2-pyridinyl 4-thiazolyl) butanamine are heated at 60°C for 5 hours. The reaction medium is left to return to ambient temperature, poured into water, extraction is carried out with ethyl acetate, the extracts are washed with water, dried, the solvent is evaporated off, 1.8 g of product acetylated in position 2' is obtained. 15 ml of methanol is added to it, the resultant medium is heated under reflux for 2 hours, the solvent is evaporated off, the residue is chromatographed on silica (eluant: CH2Cl2-MeOH-NH4OH 95-5-0.3 then AcOEt-TEA 9-1) and crystallization from ether is carried out. 194 mg of expected product is obtained. M.p. = 157-159°C. NMR (CDC13) ppm
1.33 and 1.47: 6 and 12 Me; 2.26 (s): N(CH3)2; 2.86 (t): CH2-C; 3.12 (wq) : HIO; 3.60 (s) : H1;L; 3.66 (m) : CH2-N-C;
II O
7.03 (s): thiazole H5; 7.27 (ddd): pyridine H5; 7.77 (dt): pyridine H4; 8.18 (dd) pyridine H3; 8.53 (ddd): pyridine Hg. Preparation of 2-(2-pyridinyl) thiazol 4-butanamine used at the start of Example 33. Stage A; 2-aminocarbonyl pyridine.
50 ml of a diazomethane solution (0.4 M/l) is added iropwise to a solution containing 2 g of picolinic acid, 20 ml of dichloromethane and 5 ml of methanol. After agitation Cor 30 minutes at ambient temperature, the solvent is svaporated off under reduced pressure, the residue is shromatographed on silica (petroleum ether (60-80)-AcOEt 5-5) and 1.48 g of methyl ester is recovered. 1.42 g of the ester is heated at 50°C for 4 hours in 5 ml of ammonium hydroxide, the reaction medium is left to return to ambient temperature, extraction is carried out with ether, the extracts are washed with water, dried, the solvent is evaporated off and 1.05 g
of expected product is recovered. M.p. = 105°C. Stage B; 2-pyridine carbothioamide.
43 g of phosphorus pentasulphide is added slowly to 46.8 g of the amide obtained in Stage A in 700 ml of tetrahydrofuran. Agitation is carried out for 4 hours at ambient temperature, the reaction medium is poured into water, extracted with ether, the extracts are dried and the solvent is evaporated off under reduced pressure. After chromatography on silica (eluant: CH2Cl2-AcOEt 8-2), 10 g of expected product is collected. M.p. = 137°C. Stage C; ethyl 2-(2-pyridinyl) 4-thiazole carboxylate.
16.3 ml of ethyl bromopyruvate is added dropwise to 15.9 g of the product prepared as in Stage B in 250 ml of ethanol and the whole is heated under reflux for 5 hours. The solvent is evaporated off under reduced pressure, the residue is chromatographed on silica (eluant: hexane-AcOEt 1-1) and 10.2 g of expected product is obtained. M.p. = 69.1°C. Stage D; 2-(2-pyridinyl) 4-thiazole methanol.
40 ml of methanol is added slowly to a mixture containing 9.3 g of the ester prepared in Stage C and 4.1 g of sodium borohydride in 100 ml of tetrahydrofuran and the whole is heated under reflux for 2 hours. The reaction medium is left to return to ambient temperature, poured into water, neutralized using N hydrochloric acid, extraction is carried out with dichloromethane, the organic phase is dried and the solvent is evaporated off under reduced pressure, the residue is chromatographed on silica (eluant: AcOEt-CH2Cl2 1-1) and 5.8 g of expected product is obtained. M.p. = 100°C. Stage E; 2-(2-pyridinyl) 4-thiazole carboxaldehyde.
5.8 g of the product obtained in Stage D in 60 ml of toluene is heated under reflux for 2 hours in the presence of 13 g of manganese oxide, filtration is carried out and the solvent is evaporated off under reduced pressure. 5 g of expected product is obtained. M.p. = 131°C. Stage F; (Z) 2-(4-(2-(2-pyridinyl) 4-thiazolyl) 3-butenyl) IH-isoindole 1,3(2H)-dione.
The operation 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 the triphenylphosphonium salt of
3-bromopropyl phosphoniura and 3.70 g of potassium
terbutylate. 8.73 g of expected product is obtained.
M.p. = 139-141°C.
Stage G; (2-(4-(2-(2-pyridinyl) 4-thiazolyl) butyl) IH-iso-
indol l,3(2H)-dione.
The operation is carried out as in Stage B of Preparation 32 starting with 7.22 g of the product prepared in Stage F above, and 1.5 g of palladium on activated charcoal, hydrogenating for 2 hours under 1800 mbars. 6.33 g of expected product is obtained. M.p. = 119-121°C. Stage H; 2-(2-pyridinyl) thiazol-4-butanamine.
The operation is carried out 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 under reflux for 6 hours. The solvent is evaporated off, the residue is taken up in ethyl acetate, washed with water, dried, the solvent is evaporated off, the residue is chromatographed on silica (eluant: CH2Cl2-MeOH-NH4OH 9-1-0.03) and 1.65 g of expected product is obtained. NMR (CDC13) ppm
1.50 (m)-1.82 (m): central CH2's; 2.76 (t)-2.85 (t): CH2-C= and CH2-NH2; 7.85 (s): thiazole H5; 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-de((2,6-dideoxy-3-C-methyl-3-O— methyl-alpha-L-ribohexopyranosyl) oxy) 6-o-methyl 3-oxo 12/ll-(oxycarbonyl ((4-(4-(3-pyridinyl) lH-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) in 4 ml of acetonitrile and 936 mg of 4-(4-(3-pyridinyl IH-imidazol-l- yl) butanamine are heated at 70°C for 20 hours. The reaction medium is left to return to ambient temperature, poured into water, extraction is carried out with ethyl acetate, the extracts are washed with water, dried, the solvent is evaporated off, 1.34 g of product acetylated in position 2' is obtained. 40 ml of methanol is
added to it, agitation is carried out for 2 hours, the solvent is evaporated off, the residue is chromatographed on silica (eluant: CH2Cl2-MeOH-NH4OH 95-5-0.4) and crystallization from ether is carried out. 310 mg of expected product is obtained. M.p. = 187-188°C. NMR (CDC13) ppm
0.83 (t): CH3-CH2; 1.01 (d)-1.17 (d)-1.25 (d)-1.31 (d)-1.38 (d): the £H3-CH's; 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 to 3.25: H4 and H10, H'2; 3.52 (m) : H'5; 3.56 (s) : H1;L; 3.60 to 3.85 (m): CH2NC; 4.23 (d): H5;
I
4.27 (d) : H'^j 4.93 (dd) : H13; 7.29 (ddd) : pyridine H5; 8.08 (dt): pyridine H4; 8.45 (dd): pyridine H6; 8.97 (dd): pyridine H2; 7.35 (d) and 7.53 (d): imidazole H2 and H5. Preparation of 4-(3-pyridinyl) IH-imidazol-l-butanamine used at the start of Example 34.
Stage A; 2-(4-(3-pyridinyl) IH-imidazol 1-yl) butyl IH-iso indol-1,3(2H)-dione.
The operation is carried out as in Stage A of the preparation of Example 1 using 290 mg of 3-pyridinyl IH-imidazole prepared as indicated in J. Chem. Soc. 753-5 (1938), 115 mg of sodium hydride and 633 mg of N-bromobutyl phthalimide. 277 mg of expected product is obtained. M.p. = 150-152°C. Stage B; 4-(3-pyridinyl) IH-imidazol 1-butanamine.
The operation is carried out as in Stage B of the preparation of Example 1 using 1.66 g of the product obtained as in Stage A above and 0.46 ml of hydrazine hydrate in 30 ml of ethanol. 936 mg of product is obtained, which is used as it is for the synthesis. NMR (CDC13) ppm 1.49 (m)-1.89 (m): the central CH2's; 2.75 (t): CH2-CH2-N;
I 4.01 (t): =C-N-CH2-CH2;
7.29 (d, J=l)-7.55 (d, J=l): H2 and H5; 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 (ws): approx. mobile 2H's. EXAMPLE 35; 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-O-metbyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,ll-(oxycarbonyl {(4- 1 g of the starting compound of Example 29 (obtained as indicated in Example 1C of the European Patent Application EP 0,596,802) in 4 ml of acetonitrile and 1.21 g of 4-(3-(3-pyridinyl lH-l,2,4-triazol-l-yl) butanamine are heated at 75°C for 8 hours. The reaction medium is left to return to ambient temperature, poured into water, extraction is carried out with ethyl acetate, the extracts are washed with water, dried, the solvent is evaporated off, 2 g of product acetylated in position 2' is obtained. 40 ml of methanol is added to it, agitation is carried out for 16 hours, the solvent is evaporated off, the residue is chromatographed on silica (eluant: CH2Cl2-MeOH-NH4OH 90-10-0.04) and crystallization from ether is carried out. 292 mg of expected product is obtained. M.p. = 190-192°C. NMR (CDC13) 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): the central CH2's; 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; 3.52 (m): H'5; 3.56 (s) : H1:L; 3.64 to 3.75 (-) : CH2NC;
II O
3.85 (q) : H2; approx. 4.25: H'^ H5 and CH2NC;
II 4.91 (dd): H13; 8.15 (s): triazole H; 7.35 (dd): pyridine H5;
8.34 (dt): pyridine H4; 8.62 (dd): pyridine H6; 9.31 (wd):
pyridine H2.
Preparation of 3-(3-pyridinyl) 1H-1,2/4-triazol-l-butanamine
used at the start of Example 35.
Stage A; 2-(4-(3-(3-pyridinyl) lH-l,2,4-triazol-l-yl) butyl
IH-isoindol-l,3(2H)-dione.
The operation is carried out as in Stage A of the preparation of Example 1 using 2.1 g of 3-pyridinyl lH-l,2,4-triazole prepared as indicated in J. Org. Chem. (44) No. 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 is obtained. M.p. = 150-152°C.
Stage B; 3-(3-pyridinyl) lH-l,2,4-triazol-l-butanamine (fumarate).
The operation is carried out as in Stage B of the preparation of Example 1 using 3.46 g of the product obtained as in Stage 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 the fumarate as indicated in Preparation 30 and 1.13 g of the fumarate of the expected product is obtained. M.p. = approx. 190-192°C. NMR (CDC13) ppm
1.50 (m)-2.01 (m) : the central CH2's; 2.76 (t) : NH2-CH2-; 4.24: =N-N-CH2; 7.37 (ddd): H5; 8.35 (dt): H4; 8.63 (dd): H6; 9.32 (dd): H2; 8.12 (s): triazole =CH.
Operating as previously using the appropriate amines, the following products were prepared:
EXAMPLE 36; 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 ((4-(3-quinolinyl) butyl) imino)) erythromycin M.p. = 190-192°C.
EXAMPLE 37: 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 ((4-(4-(4-methoxyphenyl) IH-imidazol-l-yl) butyl) imino)) erythromycin M.p. = 152-154°C.
EXAMPLE 38; 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 ((4-(2-phenyl 4-thiazolyl) butyl) imino)) erythromycin M.p. = 141-143°C.
EXAMPLE 39; 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 ((4-(4-(3-methoxyphenyl) lH-imidazol-1-yl)
butyl) imino)) erythromycin
M.p. = 144-146°C.
EXAMPLE 40! ii,12-dideoxy 3-de((2,6-dideoxy-3-c-methyl-3-0-
methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
12,ll-(oxycarbonyl ((4-(4,5-diphenyl) IH-imidazol-l-yl)
butyl) imino)) erythromycin
M.p. = 180-182°C.
EXAMPLE 41i 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-O-
methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo
I2,ll-(oxycarbonyl ((4-(4-quinazolinyl) butyl) imino))
erythromycin
M.p. - 212-214°C.
EXAMPLE 42; 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 ((4-(2-(4-pyridinyl) 4-thiazolyl) butyl)
imino)) erythromycin
M.p. = 192-194°C.
EXAMPLE 43! 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-(1,2,3,6-tetrahydro-l,3-dimethyl
2,6-dioxo 7H-purin-7-yl) butyl) imino)) erythromycin
M.p. = 251-253°C.
EXAMPLE 44! 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-(4-(4-trifluoromethoxy) phenyl) lH-imidazol-4-yl) butyl) imino)) erythromycin M.p. = 168-170°C.
The amines used as starting products are prepared according to the following methods: A - When the chain is attached to a carbon for example
(Figure Remove)
one can start with 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 in the following way:
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 - Certain amines are prepared in a particular way: the heterocycle is constructed and the chain is introduced at the same time (Example 6, 7, 10 and 27). EXAMPLES OF PHARMACEUTICAL COMPOSITIONS
Compounds were prepared containing:
Product of Example 1 150 mg
Excipient s.g.f 1 g
Detail of the excipient: starch, talc, magnesium stearate
Product of Example 2 150 mg
Excipient q.s.f 1 g
Detail of the excipient: starch, talc, magnesium stearate
Product of Example 3 150 mg
Excipient s.g.f 1 g
Detail of the excipient: starch, talc, magnesium stearate PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION Method of dilutions in liquid medium
A series of tubes is prepared into which an equal quantity of sterile nutritive medium is divided. Increasing quantities of the product to be 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 trans-illumination which permits the minimal inhibiting concentrations (M.I.C.) to be determined expressed in micrograms/cm3.
The following results were obtained:
GRAM"1" 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
012GO11I
Streptococcus 0,04 pyogenes
group A 02A1UC1
Streptococcus agalactiae
group B 02B1HT1
Streptococcus 0,04 faecalis
group D 02D2UC1

GRAM"1" bacterial strains (continued) Products Ex 1 Ex.2 Ex.3 Ex.29 Ex.31 Ex.32 Ex.34 Ex.35
Streptococcus faecium
group D 02D3HT1
Streptococcus sp 0,04 group G 02GOGR5
Streptococcus mitis 02mitCBl
Streptococcus 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 pneumoniae 030SJ5


We claim:
1) The erythromycin compounds of formula (I):

(Formula Removed)
in which R represents a - (CH2)nAr radical, in which n represents the number 3, 4 or 5 and Ar is an optionally substituted heterocyclic selected from the group consisting of:

(Formula Removed)
2] The compounds of formula (I) as claimed in claim 1, wherein R represents the radical
(Formula Removed)
and Z represents a hydrogen atom or an acid remainder, as well as their addition salts with acids.
3) The compounds of formula (I) as claimed in claim 1, in which Z represents a hydrogen atom.
4) The compounds of formula (I) as claimed in claims 1 to 3, in which n represents the number 4.
5) The compounds of formula (I) as claimed in claims 1 to 4, in which Ar represents a radical:

optionally substituted.
6) The compounds of formula (I) as claimed in claims 1 to 4, in which Ar represents the radical:
(Formula Removed)

optionally substituted.
7) The compounds of formula (I) as claimed in claims 1 to 4, in which Ar represents the radical :
(Formula Removed)
optionally substituted.
8) The compounds of formula (I) as claimed in claim 1 to 4, in which Ar represents the radical:
(Formula Removed)

optionally substituted.
9) The compounds of formula (I) as claimed in claim 1 selected from the group comprising:
- 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-(oxy- carbonyl ((4-(4-phenyl lH-imidazol-1-yl) butyl) imino)) erythromycin,
- 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-(oxy- carbonyl ((4-(3H-imidazo(4, 5-b)pyridine-3-yl) butyl) imino)) erythromycin,
- 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 ((4-(lH-

imidazo(4,5-b)pyridin-l-yl) butyl) imino)) erythromycin, -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-(oxy-carbonyl ((4-(4-(4-chlorophenyl) lH-imidazol-1-yl) butyl) imino)) erythromycin, -11, 12-dideoxy 3-de( (2, 6-dideoxy-3-C-methyl-3-0-rnethyl— alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11- (oxycarbonyl ((4-(4-(2-methoxyphenyl) 1 H-imidazol-1-yl) butyl) imino)) erythromycin, -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 ((4-(4-(4-fluorophenyl) lH-imidazol-1-yl) butyl) imino)) erythromycin, -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-(oxy- carbonyl ((4-(7-methoxy 4-quinoleinyl) butyl) imino)) erythromycin,
-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-(oxy- carbonyl ((4-(2-(2-pyridinyl) 4—thiazolyl) butyl) imino)) erythromycin, -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-(oxy- carbonyl ((4-(3-(3-pyridinyl) 1H—1, 2, 4-triazol-l-yl) butyl) imino)) erythromycin.
10) The compounds of formula (I) as claimed in claim 1 which is:
- 11, 12-dideoxy 3-de( (2, 6-dideoxy-3-C-methyl-3-0:methyl- alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12, 1 l-(oxy-carbonyl ((4-(4-(3-pyridinyl) lH-imidazol-1-yl) butyl) imino)) erythromycin.
11) The compounds of formula (I) as claimed in any one of claims 1 to 8, as well
as their addition salts with pharmaceutically acceptable acids for the
preparation of medicaments for the treatment of infection caused by sensitive
germs.

12) Process for the preparation of compounds of formula (I) as claimed in claim 1, wherein a compound of formula (II):


(Formula Removed)
in which Z' represents an acid remainder, is subjected to the action of a compound of formula (III):
(Formula Removed)
in which R is defined as in claim 1, in order to obtain the compound of formula (IA):
(Formula Removed)



in which R and Z' keep their previous meaning, then if appropriate the compound of formula (IA) is subjected to the action of an agent releasing the hydroxyl function in position 2' and/or if appropriate, to the action of an acid in order to form the salt, wherein the reaction of the compounds of formula (II) and (III) is effected in a solvent.
13) Process for the preparation of the compounds of formula I as claimed in claim 1 substantially as herein described with reference to the foregoing examples.



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abstract.jpg


Patent Number 222077
Indian Patent Application Number 1167/DEL/1995
PG Journal Number 35/2008
Publication Date 29-Aug-2008
Grant Date 17-Jul-2008
Date of Filing 23-Jun-1995
Name of Patentee AVENTIS PHARMA S.A.
Applicant Address 20 AVENUE RAYMOND-ARON, F-92160 ANTONY, FRANCE.
Inventors:
# Inventor's Name Inventor's Address
1 CONSTANTIN AGOURIDAS 107, BOULEVARD DE STRASBOURG, F-94130 NOGENT SUR MARNE, FRANCE
2 JEAN-FRANCOIS CHANTOT 7, 37 RUE PASTEUR, F-94130 NOGENT SUR MARNE, FRANCE
3 ALEXIS DENIS 37 RUE GODEFROY CAVAIGNAS, F-75011 PARIS, FRANCE
4 SOLANGE GOUDIN D'AMBRIERES 17 RUE LIS FRANC, F-75020 PARIS, FRANCE
5 ODILE LE MARTRET 42 AVENUE DE VERSAILLES, F-75016 PARIS, FRANCE
PCT International Classification Number C07H17/08
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 95 04089 1995-04-06 France