AP558A

AP558A - New erythromycin derivatives, their preparation process and their use as medicaments.

Info

Publication number: AP558A
Application number: APAP/P/1995/000744A
Authority: AP
Inventors: Constantin Agouridas; Jean-Francis Chantot (Deceased); Alexis Denis; Solange Gouin D'ambrieres; Martret Odile Le
Original assignee: Aventis Pharma Sa
Priority date: 1994-05-03
Filing date: 1995-05-02
Publication date: 1996-11-07
Also published as: HUT75698A; JP2007269810A; DE10299001I1; DE69505296T2; FR2719587B1; ES2122472T3; JP2992540B2; GEP19991538B; IL113245A0; ZA953501B; HU9904687D0; YU27095A; DE69505296D1; TJ313B; HK1010732A1; JP3998828B2; CN1229082A; LV11739B; BG63087B1; CZ293455B6

Abstract

The subject of the

Description

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):

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:

Ου

Z

AP/P/ 9 5/007

/

AP.00556 or R represents the radical —_{{CH }}

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 5 derivatives with mineral or organic acids, there can be mentioned the salts formed with the following acids: acetic, propionic, trifluoroacetic, maleic, tartaric, methanesulphonic, 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 O-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, x^Ri the N radical,'R_x and R₂, identical or different, representing a hydrogen atom or an alkyl radical containing 25 up to 12 carbon atoms, the

-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, O-aryl or S-aryl radicals or heterocyclic aryl, O-aryl or Saryl 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 10 naphthyl radical,

- the alkyl, alkenyl or alkynyl radical is preferably one of the following radicals: methyl, ethyl, propyl, isopropyl, nbutyl, 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, cci₂, cBr₃, cf₃, ch₂cf₃, ch₂ch₂cci₃, ch₂ch₂cf₃,

- the carboxylic acid remainder is preferably the acetyl, propionyl, butyryl, isobutyryl, n-valeryl, isovaleryl, tertvaleryl 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:

Ϊ i L U u / s 6 /d/dV optionally substituted, as well as the compounds of formula (I) in which Ar represents the radical:

AP.00558

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:

optionally 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 the invention, there can be mentioned the compounds:

- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0-methylalpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl ((4-(4-phenyl IH-imidazol-l-yl) butyl) imino)) erythromycin,

- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0-methylalpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,ll-(oxycarbonyl ((4-(3H-imidazo(4,5-b)pyridin-3-yl) butyl) imino)) erythromycin,

- 11,12-dideoxy 3-de((2,6-dideoxy-3-c-methy1-3-o-methy1alpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,ll-(oxycarbonyl ((4-(lH-imidazo(4,5-b)pyridin-l-yl) butyl) imino)) erythromycin,

- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methy1-3-O-methy1alpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,ll-(oxycarbonyl ((4-(4-(4-chlorophenyl) lH-imidazol-l-yl) butyl) imino)) erythromycin,

- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0-methylalpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,ll-(oxycarbonyl ((4-(4-(2-methoxypheny1) ΙΗ-imidazol-l-yl) butyl) imino)) erythromycin, ( - 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0-methyl15 alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,ll-(oxycarbonyl ((4-(4-(4-fluorophenyl) ΙΗ-imidazol-l-yl) butyl) imino)) erythromycin,

- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0-methylalpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,ll-(oxy20 carbonyl ((4-(7-methoxy 4-quinoleinyl) butyl) imino)) erythromyc in,

- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methy1-3-O-methy1alpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,ll-(oxycarbonyl ((4-(2-(2-pyridinyl) 4-thiazolyl) butyl) imino)) erythromycin,

O - 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methy1-3-O-methy1alpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,ll-(oxycarbonyl ((4-(3-(3-pyridinyl) 1H-1,2,4-triazol-l-yl) butyl) imino)) erythromycin, and more particularly the

- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methy1-3-O-methy1alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,ll-(oxycarbonyl ((4-(4-(3-pyridinyl) ΙΗ-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

AP.00558 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 ^cmedicaments 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 ι 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):

o <_

(II) >>/00/56 /d/tfv in which Z' represents an acid remainder, is subjected to the action of a compound of formula (III):

RNH₂ (III) in which R is defined as previously, in order to obtain the compound of formula (I_A):

AP.00558

c>

c in which R and Z' keep their previous meaning, then if appropriate the compound of formula (I_A) 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 knovn 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)

AF/P/ 9 5/0(74

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 5 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,

- ΙΗ-imidazo(4,5-b)-pyridine 3-butanamine,

- 2-phenyl-4-quinolinebutanamine,

- lH-benzotriazole 1-butanamine,

- 2H-benzotriazole 2-butanamine,

- 1-methyl ΙΗ-imidazo(4,5-c)-pyridine 2-butanamine,

- 3-m6thyl 3H-imidazo(4,5-c)-pyridine 2-butanamine,

- 5-chloro ΙΗ-benzimidazole 1-butanamine, • *

- 7-methoxy 4-quinolenebutanamine,

- lH-imidazo(4,5-c) pyridine 1-butanamine,

- 9H-purine 9-butanamine, ur,

- 1-methyl 1H-indole 4-butanamine,

- 3-phenyl lH-l,2,4-triazole 1-butanamine (hydrochloride),

- 5-phenyl ΙΗ-tetrazole 1-butanamine (hydrochloride),

- 2-benzothiazolebutanamine,

- 4-(thieno(2,3-b) pyridine 4-yl butanamine,

- 5,6-dimethyl ΙΗ-benzimidazole 1-butanamine,

- 3-quinoleine butanamine,

- 2-quinoleine butanamine,

- 5H-imidazo [4,5-c] pyridine 5-butanamine,

- 1-methyl ΙΗ-benzimidazol 2-butanamine,

- 6-chloro ΙΗ-benzimidazol 2-butanamine,

- 2-methyl ΙΗ-benzimidazol 2-butanamine,

- 4-(4-chlorophenyl) ΙΗ-imidazol 1-butanamine,

- 2-(3-pyridinyl) thiazol 5-butanamine,

- 7-methoxyquinoleine 4-butanamine,

- 4-(4-fluorophenyl) ΙΗ-imidazol 1-butanamine,

- 4-(2-methoxyphenyl) ΙΗ-imidazol 1-butanamine,

- 3-(3-pyridinyl) 1H 1,2,4-triazol 1-butanamine,

- 4-(3-pyridinyl) ΙΗ-imidazol l-butanamine,

AP.00558

- 2-(2-pyridinyl) thiazol 4-butanamine,

- 2-phenylthiazol 4-butanamine,

- 4-(4-methoxyphenyl) ΙΗ-imidazol 1-butanamine,

- isoquinoleine 4-butanamine,

- quinazoline 4-butanamine,

- 4,5-diphenyl ΙΗ-imidazol 1-butanamine,

- 4-(3-methoxyphenyl) ΙΗ-imidazol 1-butanamine,

- 4-(4-(trifluoromethoxy) phenyl) ΙΗ-imidazol 1-butanamine,

- 1,2,3,6-tetrahydro 1,3-dimethyl 2,6-dioxo 7H-purine 710 butanamine,

- 2-(4-pyridinyl) thiazol 4-butanamine,

- ΙΗ-indol 1-butanamine,

- 2-(3-pyridinyl) thiazol 4-butanamine, f as well as their addition salts with acids.

The following examples illustrate the invention.

EXAMPLE 1: 11,12-dideoxy 3-de((2,β-dideoxy-3-C-methy1-3-0ethyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

I2,ll-(oxycarbonyl ((4-(4-phenyl lH-imidazol-i-yl) butyl) imino)) erythromycin

A mixture of 0.705 g of 11-ddoxy 10,ll-did6hydro 3de(2,6-did6oxy 3-C-m6thyl 3-O-m6thyl alpha-L-ribohexopyranosyl) oxy) 12-0-((ΙΗ-imidazol-l-yl) carbonyl) 6-O-m6thyl 3-oxo drythromycine 2'-acdtate 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 1HC imidazol-l-yl) butanamine is taken to 63^eC. 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 - NH₄0H (93-7-0.4). After concentration 0.305 g of the crude desired product is obtained, which is

AP/P/ 9 5 / 0 0 7 4 4 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^eC-231°C.

NMR CD Cl-j ppm alpha_D =+18° (c = 0.9 CHC1₃)

0.84 (t) : CH₃-CH₂ ; 1.01 (d)-1.17 (d)-1.24 (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^z3 ; 2.61 (m) : Hg ;

2.63 (s) : 6-OMe ; 3.04 (-) : H₄ ; 3.13 (q) : H₁₀ ; 3.18 (dd): H'₂ ; 3.53 (-) : H'₅ ; 3.56 (s) : H_1X ; 3.67 (-)-3.75

I (-) : the -C-NCH₂'s ; : 3.87 (q) : H₂ ; 3.99 (t) : CH₂NC ;

4.23 (d) : H₅ ; 4.27 (d) : ; 4.94 (dd) : H₁₃ ; 7.26 (s) : -a

H”₅ ; 7.5 (s) : H₂ ; 7.20 : H in para position ; 7.35 : H ^r in meta position ; 7.76 : H in ortho position.

PREPARATION 1: 4-(4-phenyl lH-imidazol l-yl) butanamine

Stage A: 2-(4-(4-phenyl ΙΗ-imidazol l-yl) butyl ΙΗ-iso ιχ-, indole-1,3(2H)dione

A solution containing 5.05 g of 4-phenyl ΙΗ-imidazole in 25 cm³ 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-bromobutyl) lH-iso25 indole l,3(2H)dione N-4-bromobutylphthalimide 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 ^zs ; 3.74 (t) : 2H ;

4.03 : 2H ; 7.22 (t) : 2H H₄ ; 7.26 (m) : IH H'₃ ; 7.36 (t) :

AP. Ο Ο 5 5 8

2Η Η₃ and Hg ί 7.56 (d) : H'g ; approx. 7.73 (m) : 4H ; approx. 7.86 (m) : H₂ and H_g.

Stage B: 4-(4-phenyl ΙΗ-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'g ; 7.37 (wt) 2H : H₃ Hg ; 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-3-0methyl-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 ll-d6oxy 10,ll-did6hydro 3-de(2,6-diddoxy 3C-mdthyl 3-0-m6thyl alpha-L-ribohexopyranosyl) oxy) 12-0((lH-imidazol-l-yl) carbonyl) 6-0-mdthyl 3-oxo ferythromycine 2'-ac6tate obtained as indicated in example 1C of the European Patent application 0 596 802, and 958 mg of (3H25 imidazo(4,5-b) pyridin-3-butanamine are dissolved in 2.82 cm³of 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 cm³ 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

AP/P/ 95/0074 « obtained, melting at 200°C.

alpha_D = +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) : Ηθ ; 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_lx ; 3.6 to 3.8 : CH₂NC ;

|

O

3.85 (q) : H₂ ; 4.24 (d) : H₅ ; 4.29 (d) : H^/1 ; approx. 4.35 (m) : CH₂NC= ; 4.93 (dd) : H₁₃ ; 7.21 (dd) : H_g aromatic ;

( 8.04 (dd) : H₇ aromatic ; 8.11 (s) : H₂ aromatic ; 8.38 (dd):

H₅ aromatic.

EXAMPLE 3: 11,12-dideoxy 3-d·((2,6-dideoxy-3-C-methy1-3-0methyl-alpha-L-ribohexopyranoayl) oxy) 6-O-methyl 3-oxo

12,ll-(oxycarbonyl ((4-(lH-imidazo(4,5-b) pyridin-l-yl) butyl) imino)) erythromycin

708.3 mg of ll-d6oxy 10, ll-did6hydro 3-de(2,6-did6oxy 3C-mdthyl 3-O-m6thyl alpha-L-ribohexopyranosyl) oxy) 12-0((ΙΗ-imidazol-l-yl) carbonyl) 6-O-m6thyl 3-oxo 6rythromycine 2'-acdtate 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 3e 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

AP.00558 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.

alpha_D - 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 the chain ; 2.27 (s): N(CH₃)₂ ; 2.61 (s) : 6-OCH₃ ; 2.45 (m) : H'₃ ; approx. 2.60 (m in masked part) : Hg ; 3.07 (m) : H₄ ; approx. 3.15 (wq) :

H₁₀ ; 3.18 (dd) : H'₂ ; 3.56 (s) : Η_χι ; 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) : ; 4.91 (dd) :

H₁₃ ; 7.21 (dd, J = 5 and 8) : H_g ; 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-butenamine

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 bromobutylphthalimide 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^eC, and 3.9 g of product (B), M.p. = 172°C.

Stage BI: 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 O desired product is obtained.

C 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 ;

|

C

7.24 (dd, J = 8 and 5) : H_g ; 7.75 (dd, J = 8 and 1.5) : H_? ;

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-3-0methyl-alpha-L-ribohexoyranosyl) oxy) 6-O-methyl 3-oxo 12,11(oxycarbonyl) ((4-(thieno(2,3-b) pyridxn-4-yl) butyl) imino))

AP/P/ 95/00744

AP .0 0 5 5 8 erythromycin

178°C.

M.p. = alpha_D

176 - 178°C.

= +17°C c = 0.9% in CHC1

EXAMPLE 5: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-O5 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.

alpha_D - +17· c = 1% in CHC1₃

EXAMPLE 6: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methy1-3-0methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11-(oxycarbonyl ((4-(1-methyl-lH-imidazo(4,5-c)pyridin-2yl) butyl) imino)) erythromycinalpha_D = +19° C = 1% CHC1₃EXAMPLE 7: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-015 methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11-(oxycarbonyl ((4-(3-methyl-3H-imidazo(4,5-c)pyridin-2yl) butyl) imino)) erythromycin alpha_D = +16° CHC1₃ = 1%

EXAMPLE 8: 11,12-dideoxy 3-de( (2,6-dideoxy-3-c-methyl-3-o20 methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11-(oxycarbonyl ((4-(7-methoxy-4-guinolinyl) butyl) imino)) erythromycin alpha_D - +15.8· c = 1% CHC1₃

EXAMPLE 9: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-O25 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. alpha_D « +25· c = 1% CHC1₃

EXAMPLE 10: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-Omethyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11-(oxycarbonyl ((4-(2-benzothiazolyl) butyl) imino)) erythromycin

M.p. = 179 - 181^eC alpha_D = +18° c = 1% CHC1₃

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

12,11-(oxycarbonyl ((4-(2-(3-pyridinyl) 4-thiazolyl) butyl) imino)) erythromycin

M.p. = 150 - 152°C alpha_D = +17° c = 0.9% CHC1₃

EXAMPLE 12: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-aethyl-3-O5 methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11-(oxycarbonyl ((4-(2-(3-pyridinyl) 5-thiazolyl) butyl) imino)) erythromycin

M.p. = 155 - 159’C alpha_D = +12’ c = η CHC1₃

EXAMPLE 13ϊ 11,12-dideoxy 3-de((2,6-didaoxy-3-C-methyl-3-Omathyl-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-de((2,6-dideoxy-3-C-methyl-3-O15 methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12.11- (oxycarbonyl-((4-(ΙΗ-imidazo(4,5-c) pyridin-l-yl) butyl) imino)) erythromycin

R_f = 0.42 CHC1₃ + 8% of MeOH with 8% of NH^OH

EXAMPLE 15: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methy1-3-O20 methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12.11- (oxycarbonyl ((S-(lH-benzimidazol-l-yl) pentyl) imino)) arythromyc in

Prepared starting from 2-(4-bromophenyl) lH-iso-indole 1,3(2H)-dione.

EXAMPLE 16: 11,12-dideoxy 3-de((2,6-dideoxy-3-c-methyl-3-of' methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11-(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-Omethyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 12,11(oxycarbonyl ((4-(ΙΗ-indol-l-yl) butyl) imino)) erythromycin EXAMPLE 18: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 12,1135 (oxycarbonyl ((4-(l-methyl-lH-indol-4-yl) butyl) imino)) erythromycin alpha_D = 20%, c = 1% CHC1₃

EXAMPLE 19: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-019 methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12.11- (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-3-0methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12.11- (oxycarbonyl ((4-(ΙΗ-benzotriazol-i-yl) butyl) imino)) erythromycin

M.p. - 200-202’C.

EXAMPLE 21: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12.11- (oxycarbonyl ((4-(2H-benzotriazol-2-yl) butyl) imino)) erythromycin p M.p. - 164-166’C.

EXAMPLE 22: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,ll-(oxycarbonyl ((4-(5,6-dimethyl lH-benzimidazol-l-yl) butyl) imino)) erythromycin

M.p. - 174-176’C.

EXAMPLE 23: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,ll-(oxyearbonyl ((4-(3-quinolinyl) butyl) imino)) erythromyc in

M.p. = 195-197’C.

EXAMPLE 24: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0AP/P/ 9 5 / 0 0 7 A 4 methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11-(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-Omethyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11-(oxycarbonyl ((4-(2-methyl lH-benzimidazol-l-yl) butyl) imino)) erythromycin

M.p. = 128-132’C.

EXAMPLE 26: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11-(oxycarbonyl ((4-(6-chloro ΙΗ-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-Omethyl-alpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo

12,11-(oxycarbonyl ((4-(1-methyl lH-benzimidazol-2-yl) butyl) imino)) erythromycin

EXAMPLE 28: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11-(oxycarbonyl ((4-(SH-imidazo(4,5-c)pyridin-5-yl) imino)) erythromycin alphap = 12.2 c- 1% CHCl-j

EXAMPLE 29: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-Omethyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11-(oxycarbonyl ((4-(4-(4-chlorophenyl) lH-imidazol-l-yl) butyl) imino)) erythromycin

1 g of 11-deoxy 10,11-didehydro 3-de(2,6-dideoxy 3-Cmethyl 3-0-methyl alpha-L-ribohexopyranosyl) oxy) 12-0-((1Himidazol-l-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^eC in 4 cm³ of acetonitrile with 10% water with

1.4 g of 4-(4-(4-chlorophenyl) ΙΗ-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.

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): £H₃-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): H_g; 3.00 to 3.21: H₄, H₁₀ and H'₂; 3.55 (m) : H'₅; 3.56 (s) : H_1;L; 3.60 to 3.80 2H-3.99 (t) 2H: CH₂NC=; 3.87 (q): H₂; 4.23 (d): H₅; 4.28

AP/P/ 9 5/00

AP.00558 oo (d): H'p 4.93 (dd): H₁₃; 7.26 (d): Hg imidazole; 7.50 (d):

H₂ imidazole; 7.32-7.70: aromatics; 3.51: OH.

Preparation of 4-(4-chlorophenyl) lH-imidazole 1-butanamin· used at the start of Example 29.

Stage A: 4-(4-chlorophenyl) lH-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) lH-imidazol 1-yl) lH-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 20 obtained.

Stage C; 4-(4-chlorophenyl) ΙΗ-imidazol 1-butanamine.

The operation is carried out as in Stage B of the preparation of Example l 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-£H₂-N; 3.98 (m) : =C-N-CH₂-CH₂;

·>

*

-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-Omethyl-alpha-L-ribohexopyranosyl, oxy) 6-O-methyl 3-oxo

12,11-(oxycarbonyl ((4-(4-(2-methoxyphenyl) lH-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-(25 methoxyphenyl) lH-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 CDCl-j ppm

0.85 (t): £H₃-CH₂; 1.01 (d)-1.16 (d)-1.24 (d)-1.30 (d)-1.37 (d): the £H₃-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): Η_χχ; 3.66 (m)-3.74 (m): CH₂NC;

AP/P/ 95/00744

O

3.85 (q): H₂; 3.95 (s): f-OMe; 3.99 (wq): CH₂-N-C=; 4.24 (d): C H₅; 4.27 (d): Η'_χ; 4.93 (dd): Η_χ3; 6.97 (wd): H_g; 7.51 (s):

C the imidazole H's; 7.02: phenyl H_g; 7.19 (ddd) phenyl H₄ and

H₅; 8.19 (dd): H₂.

Preparation of 4-(2-methoxyphenyl) lH-imidazol-i-butanamine used at the start of Example 30.

Stage A: 4-(2-methoxyphenyl) lH-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:

AP. Ο Ο 5 5 8

CH₂Cl₂-MeOH-NH₄OH 95-5-0.4) and 6.15 g of expected product is obtained.

Stage B: 2-(4-(4-(2-methoxyphenyl) ΙΗ-imidazol 1-yl) butyl

ΙΗ-iso indol-1,3(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) ΙΗ-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 (CDCl-j) ppm

1.48 (m) 2H-1.87 (m) 2H: the central CH₂'s; 3.46: NH₂; 2.73 (t): CH₂N; 3.94 (s): Φ-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 O (dd): H₂.

C EXAMPLE 31: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo

I2,li-(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) ΙΗ-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,

AP/P/ 95/0074*

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 CDCl-j 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 H_lo;	3.56	(s) :	^Hll'	3.59 to	3.81:
10 CH₂-N-C; 3.98	(t): CH₂-N-C;

I I o

approx. 7.05 - approx. 7.73: fluorophenyl; 7.21 (d): H₅imidazole; 7.49 (d): imidazole H₂. <

Preparation of 4-(4-fluorophenyl) lH-imidazol-l-butanamine c used at the start of Example 31.

IT

Stage A: 4-(4-fluorophenyl) ΙΗ-imidazole.

10.85 g of 4-fluorophenacyl bromide in 60 ml of formamide is heated under reflux for 2 hours, the reaction 5C 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) ΙΗ-imidazol 1-yl) butyl ΙΗ-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-4bromobutyl phthalamide. 7.53 g of expected product is obtained. M.p. = 138-140’C.

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

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

AP. Ο Ο 5 5 8 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-CJJ₃; 3.98 (t): >N-Cfi₂-CH₂; 7.06 (t): >CH-F; 7.22 (m) : >CH-C-;

I

7.49 (s): imidazole H₂; 7.15 (s) : imidazole H₅.

EXAMPLE 32: 11,12-dideoxy

3-d·((2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl ((4-(7-methoxy (4-guinolinyl) butyl) imino)) erythromycin

706 mg of the starting compound of Example 29 (obtained f 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-guinolinyl) butanamine are heated at 50^eC 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 CDCI3 ppm

3.06 (m): -(CH₂)₂-CH<? 3.70 (m) : -N-CH₂-; 3.95 (s): -OCH₃;

7.12 (d)-7.19 (dd)-7.42 (d)-7.94 (d)-8.70 (d): pyridine. Preparation of 7-methoxy quinoline 4-butanamine used at the start of Example 32.

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 co 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 Β: Z-(2-(4-(7-methoxyquinolinyl) 3-butenyl lH-iso5 indol-1,3(2H)-dione.

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^eC, 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) lH-isoindol 1,3(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): 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-de((2,6-dideoxy-3-C-methyl-3-0methyl-alptaa-L-ribohexopyranosyl) oxy) 6-o-methyl 3-oxo

AP/P/ 95/00;

AP. Ο Ο 5 5 8

12,11-(oxycarbonyl ((4-(2-(2-pyridinyl) 4-thiazolyl) butyl) latino)) 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^ec 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

T 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) : H_lo; 3.60 (s) : H_llz· 3.66 (m): CH₂-N-C;

S

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 H₆.

Preparation of 2-(2-pyridinyl) thiazol 4-butanamine used at \ the start of Example 33.

t Stage A: 2-aminocarbonyl pyridine.

ml of a diazomethane solution (0.4 M/l) is added dropwise to a solution containing 2 g of picolinic acid, 20 ml of dichloromethane and 5 ml of methanol. After agitation for 30 minutes at ambient 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 is recovered. 1.42 g of the ester is heated at 5O°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.

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. ir

Stage D: 2-(2-pyridinyl) 4-thiazole methanol. ° 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-CH₂Cl₂1-1) 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) ΙΗ-isoindole 1,3(2H)-dione.

The operation is carried out as in Stage A of

ΑΡ . 0 0 5 5 8

Iv Ο Ο

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 phosphonium 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) lH-isoindol 1,3(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): 25 H'₄; 8.18 (dt): H'₃; 8.61 (ddd): H'₆; 1.40 (s): NH₂·

EXAMPLE 34: 11,12-dideoxy 3-da((2,6-dideoxy-3-C-methyl-3-0~ methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,ll-(oxycarbonyl ((4-(4-(3-pyridinyl) lH-imidazol-l-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 lH-imidazol-1- 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 5 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 CH₃-CH^zs; 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) : H^; 3.60 to 3.85 (m): CH₂NC; 4.23 (d): H₅;

I

C' 4.27 (d): H'jj 4.93 (dd): H₁₃; 7.29 (ddd): pyridine H₅; 8.08 ( (dt): pyridine H₄; 8.45 (dd): pyridine H_g; 8.97 (dd):

pyridine H₂; 7.35 (d) and 7.53 (d): imidazole H₂ and H₅.

Preparation of 4-(3-pyridinyl) lH-iaidazol-l-butanamine used at the start of Example 34.

Stage A: 2-(4-(3-pyridinyl) ΙΗ-imidazol l-yl) butyl lH-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 ΙΗ-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.

o Stage B: 4-(3-pyridinyl) ΙΗ-imidazol 1-butanamine.

O 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;

I =c7.29 (d, J=l)-7.55 (d, J=l): H₂ and H₅; 7.30 (partly masked):

AP/P/ 95/00744

AP.00558

H'₅; 8.09 (dt, J—8 and 2): H'₄; 8.47 (dd, J=5 and 2): H'_g;

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-omethyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11-(oxycarbonyl ((4-(3-(3-pyridinyl) 1H-1,2,4-triazol-iyl) butyl) imino)} erythromycin 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 ^r 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): £H₃-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): Ηθ; 2.61 (s): 6-OMe; 3.06 C? (m): H₄; 3.12 (q) : H₁₀; 3.17 (dd): H'₂; 3.52 (m): H'₅; 3.56 o (s): H_u; 3.64 to 3.75 (-): CH₂NC;

«

3.85 (q): H₂; approx. 4.25: H'_v Hg 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 H_g; 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) 1H-1,2,4-triazol-l-yl) butyl ΙΗ-isoindol-l,3(2H)-dione.

f ri 0 0 / bi /4/e(V nn

The operation is carried out as in Stage A of the preparation of Example 1 using 2.1 g of 3-pyridinyl 1H-1,2,4-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^eC.

Stage B: 3-(3-pyridinyl) lH-l,2,4-triazol-l-butanamine (fumarate).

The operation is carried out as in Stage B of the 10 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-£H₂-;

4.24: =N-N-£H₂; 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-methy1-3-0methyl-alpha-L-ribohexopyranosyl) oxy, 6-0-methyl 3-oxo

12,ll-(oxycarbonyl ((4-(3-guinolinyl) butyl) imino)) £ erythromycin -* r

M.p. = 190-192°C.

EXAMPLE 37: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribohexopyranosyl, oxy) 6-0-methyl 3-oxo

12,ll-(oxycarbonyl ((4-(4-(4-methoxyphenyl) lH-imidazol-l-yl) butyl) imino)) erythromycin M.p. = 152-154°C.

EXAMPLE 38: 11,12-dideoxy 3-de((2,6-dideoxy-3-c-methyl-3-0methyl-alpha-L-ribohexopyranosyl) oxy) 6-0-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-3-0Or methyl-alpha-L-ribohexopyranosyl, oxy) 6-0-methyl 3-oxo

AP.00558

12,11-(oxycarbonyl ((4-(4-(3-methoxyphenyl) lH-imidazol-l-yl) butyl) imino)) erythromycin M.p. = 144-146’C.

EXAMPLE 40: 11,12-dideoxy 3-de( (2,6-dideoxy-3-C-methyl-3-05 methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11-(oxycarbonyl ((4-(4,5-diphenyl) lH-imidazol-l-yl) butyl) imino)) erythromycin M.p. = 180-182’C.

EXAMPLE 41: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-O10 methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12.11- (oxycarbonyl ((4-(4-quinazolinyl) butyl) imino)) erythromycin

M.p. = 212-214’C.

EXAMPLE 42: il,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-O15 methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12.11- (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-aethyl-3-O20 aethyl-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. ί

EXAMPLE 44: 11,12-dideoxy 3-de((2,6-dideoxy-3-C-aethyl-3-O25 methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

M.p. - 168-170’C.

The amines used as starting products are prepared 30 according to the following methods:

A - When the chain is attached to a carbon for example one can start with the corresponding aldehydes:

N ϊ i t 11 9

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:

c

C 10 ^AP/P/ 9 5 / _{0 0 7 4 4}

AP.00558

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, and 28 vere 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 vere prepared containing:

Product of Example 1 ............................. 150 mg

Excipient s.q.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.q.f. ................................. 1 g

Detail of the excipient: starch, talc, magnesium stearate PHARMACOLOGICAL STUDY OP THE PRODPCTS 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 transillumination which permits the minimal inhibiting concentrations (M.I.C.) to be determined expressed in micrograms/cm³.

The following results were obtained:

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Claims

- 1,2,3,6-tetrahydro 1,3-dimethyl 2,6-dioxo 7H-purine 75 butanamine,

- 2-(4-pyridinyl) thiazol 4-butanamine,

- ΙΗ-indol l-butanamine,

- 1-methyl ΙΗ-benzimidazol 2-butanamine,

- 6-chloro ΙΗ-benzimidazol 2-butanamine,

- 2-methyl ΙΗ-benzimidazol 2-butanamine,

- 4-(4-chlorophenyl) ΙΗ-imidazol 1-butanamine,

- 2-(3-pyridinyl) thiazol 5-butanamine,

- 7-methoxyquinoleine 4-butanamine,

- 4-(4-fluorophenyl) ΙΗ-imidazol 1-butanamine,

- 4-(2-methoxyphenyl) ΙΗ-imidazol 1-butanamine,

- 3-(3-pyridinyl) 1H 1,2,4-triazol 1-butanamine,

- 4-(3-pyridinyl) ΙΗ-imidazol 1-butanamine,

- 2-(2-pyridinyl) thiazol 4-butanamine,

- 2-phenylthiazol 4-butanamine,

- 4-(4-methoxyphenyl) ΙΗ-imidazol 1-butanamine,

- isoquinoleine 4-butanamine,

- quinazoline 4-butanamine, ftp . Ο Ο 5 5 6

S'

- 4,5-diphenyl lH-imidazol l-butanamine,

- 4-(3-methoxyphenyl) lH-imidazol l-butanamine,

- 4-(4-(trifluoromethoxy) phenyl) lH-imidazol l-butanamine,

- 1-methyl ΙΗ-indole 4-butanamine,

- 3-phenyl lH-l,2,4-triazole 1-butanamine (hydrochloride),

- 5-phenyl ΙΗ-tetrazole 1-butanamine (hydrochloride),

- 2-benzothiazolebutanamine,

- 4-(thieno(2,3-b) pyridine 4-yl butanamine,

- 5,6-dimethyl ΙΗ-benzimidazole 1-butanamine,

- 3-quinoleine butanamine,

- 2-quinoleine butanamine,

- 5H-imidazo [4,5-c] pyridine 5-butanamine,

- 1-methyl lH-imidazo(4,5-c)-pyridine 2-butanamine,

- 3-methyl 3H-imidazo(4,5-c)-pyridine 2-butanamine,

- 5-chloro ΙΗ-benzimidazole 1-butanamine,

- 7-methoxy 4-quinolenebutanamine,

- lH-imidazo(4,5-c) pyridine 1-butanamine,

- 9H-purine 9-butanamine,

1) The compounds of formula (I):

in which R represents a -(CH₂)_nAr radical, in which n represents the number 3, 4 or 5 and Ar represents a

15 heterocyclic radical, optionally carrying one or more tsubstituents, chosen from the following group of radicals: ^c tr c

f·' *20

AP.00558 ζ

AD/D/ or R represents the radical and Z represents a hydrogen atom or an acid remainder, as well as their addition salts with acids.

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

3) The compounds of formula (I), as defined in claim 1 or 2, in which n represents the number 4.

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

I opt iona1ly substituted.

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

I optionally substituted.

6.- The compounds of formula (I), as defined in claims 1, 2 or 3, in which Ar represents the radical :

N or optionally substituted.

7.- The compounds of formula (I), as defined in claim 1, 2 or 3, in which Ar represents the radical :

ΑΡ . Ο Ο 5 5 8

Q nJ optionaly substituted.

8) The compounds of formula (I),

10 as defined in claim 1, the names of vhich follow:

- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0-methylalpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11-(oxy carbonyl ((4-(4-phenyl ΙΗ-imidazol-l-yl) butyl) imino)) erythromycin,

15 - 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0-methylalpha-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-methyl20 alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11-(oxy carbonyl ((4-(ΙΗ-imidazo(4,5-b)pyridin-l-yl) butyl) imino)) erythromycin,

- 11,12-dideoxy 3-de((2,6-dideoxy-3-c-methyl-3-0-methylalpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11-(oxy

25 carbonyl ((4-(4-(4-chlorophenyl) ΙΗ-imidazol-l-yl) butyl) imino)) erythromycin,

- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0-methylalpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl ((4-(4-(2-ιηάthoxyphenyl) ΙΗ-imidazol-l-yl) butyl)

30 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-fluorophenyl) ΙΗ-imidazol-l-yl) butyl) imino)) erythromycin,

35 - 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-O-methylalpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,ll-(oxycarbonyl ((4-(7-methoxy 4-quinoleinyl) butyl) imino)) ery thr omy c i n,

S'

- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0-methylalpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,11-(oxycarbonyl ((4-(2-(2-pyridinyl) 4-thiazolyl) butyl) imino)) erythromycin,

5 - 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0-methylalpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,11-(oxycarbonyl ((4-(3-(3-pyridinyl) 1H-1,2,4-triazol-l-yl) butyl) imino)) erythromyc in.

9. - The compound of formula (I), as

10 defined in claim, the name of whicn follows:

- 11,12-dideoxy 3-de((2,6-dideoxy-3-C-methyl-3-0-methylalpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,11-(oxycarbonyl ((4-(4-(3-pyridinyl) lH-imidazol-l-yl) butyl) imino)) erythromycin.

10. - As medicaments, the compounds of formula (I) as defined in any one of claims 1 to 7, as well as their addition salts with pharmaceutically acceptable acids.

11. - As medicaments, the compounds defined in claim 8, as

20 well as their addition salts with pharmaceutically acceptable acids.

12. - As medicaments, the compound defined in claim 9 as well as its pharmaceutically acceptable addition salts with acids.

13. - Pharmaceutical compositions containing as active

25 principle at least one medicament according to any one of claims 10 to 12.

14. - Preparation process for the compounds of formula (I), as defined in claim 1, characterized in that a compound of formula (II) :

(II)

AP. 0 0 5 5 8 in which Z' represents an acid action of a compound of formula remainder, (HI) :

is subjected to the rnh₂ (HI) in which R is defined as in claim 1, in order to obtain the compound of formula (I_A):

oo in which R and Z' keep their previous meaning, then if appropriate the compound of formula (I_A) is subjected to the

35 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.

15.- The compounds of formula (III) as defined in claim 14.

16.- The compounds of formula (III) as defined in claim 15, the names of which follow:

- 4-phenyl-lH-imidazole 1-butanamine,

- 3H-imidazo(4,5-b)-pyridine 3-butanamine,

- lH-imidazo(4,5-b)-pyridine 3-butanamine,

- 2-phenyl-4-quinolinebutanamine,

- ΙΗ-benzotriazole 1-butanamine,

- 2H-benzotriazole 2-butanamine,
- 2-(3-pyridinyl) thiazol 4-butanamine, as well as their addition salts with acids.