Derivatives of erythromycin, the method of production thereof, pharmaceutical compositions on their basis and intermediate compounds

 

(57) Abstract:

Describes new erythromycin derivatives of General formula (I), where R and Z are specified in paragraph (1 formulas, which Express the properties of antibiotics. The compounds can be used as medicaments in the treatment of infections sensitive germs, in particular staphylococcal infections, such as staphylococcal sepsis, etc. also Describes the method of production thereof, pharmaceutical compositions on their basis and intermediate compounds. 4 C. and 12 C.p. f-crystals, 1 PL.

The invention relates to new derivatives of erythromycin, method of production thereof, to pharmaceutical compositions based on them and to intermediate compounds.

The invention relates in particular to compounds

formula (I):

< / BR>
in which R represents the radical -(CH2)nAr in which n = 3, 4 or 5, and Ar represents a heterocyclic radical, bearing, if necessary, one or more deputies, chosen in the group of radicals:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
and Z represents a hydrogen atom or a residue of an acid, and their salts accession acids.

As PLI, formed with acids acetic, propionic, triperoxonane, maleic, tartaric, methansulfonate, benzosulfimide, paratoluenesulfonyl, hydrochloric, Hydrobromic, itestosterone, sulfuric, phosphoric and especially stearic acid, adelantarnos or euryceros.

Heterocyclic radical may be substituted by one or more radicals chosen from the group formed by C1-C6-alkyl, C1-C6-alkoxyl, triptoreline, halogen.

When the heterocyclic radical contains several cycles (linked or condensed), one or more of the substituents can be on the same and/or another of the cycles, heterocyclic or carbocyclic; for example, if the heterocyclic ring is connected or fused with an aryl radical, a heterocyclic ring and an aryl ring can both carry one or more substituents.

The alkyl radical is preferably the methyl radical, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl.

halogen is preferably fluorine, chlorine or bromine,

- the remainder of the carboxylic acid is preferably OST the Invention relates especially to compounds of the formula (I), in which Z represents a hydrogen atom, and compounds of formula (I) in which n is equal to the number 4.

More specifically the invention relates to compounds of formula (I) in which Ar represents the radical:

< / BR>
if necessary replaced, as well as compounds of formula (I) in which R represents the radical:

< / BR>
if necessary replaced, as well as compounds of formula (I) in which Ar represents the radical:

< / BR>
if necessary replaced, and especially compounds of the formula (I) in which Ar represents the radical:

< / BR>
if necessary replaced.

The invention relates especially to compounds of the formula (I), the receipt of which is described below in the experimental part. Among the compounds of the invention include the following compounds:

11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L - abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxy-carbonyl((4-(4 - phenyl-1H-imidazol-1-yl)butyl)imino)) - erythromycin;

11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L - abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(3H - imidazo(4,5-b)pyridine-3-yl)butyl)imino)) - erythromycin;

11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L - roboexotica the C-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L - abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(4-(4- chlorophenyl)1H-imidazol-1-yl)butyl)imino))erythromycin;

11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L - abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(4-(2- methoxyphenyl)1H-imidazol-1-yl)butyl)imino)) - erythromycin;

11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L - abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(4-(4- forfinal)1H-imidazol-1-yl)butyl)imino)) - erythromycin;

11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L - abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(7 - methoxy-4-chinoline)butyl)imino)) - erythromycin;

11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L - abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(2-(2- pyridinyl)4-thiazolyl)butyl)imino)) - erythromycin;

11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L - abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(3-(3- pyridinyl)1H-1,2,4-triazole-1-yl)butyl)imino)) - erythromycin;

and especially

11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L - abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(4-(3- pyridinyl)1H-imidazol-1-yl)butyl)(imino)) - erythromycin.

The products of General formula (I) have very high antibiotic activity against gram-positive bacteria such as staphylococci, streptococcaceae in the treatment of infections susceptible to drugs, in particular, staphyloccocal infections, such as staphylococcal sepsis, malignant Staphylococcus face or skin, pyodermia, septic or suppurative wounds, furuncles, carbuncles, cellulitis, erysipelas and acne, such staphylococcal diseases as acute or primary with molegrips angina, pneumonia, suppurative lung, and streptococcal infections, such as acute tonsillitis, otitis, sinusitis, scarlet fever, pneumococcal, such as pneumonia, bronchitis, brucellosis, diphtheria, and gonococcal infections.

Compounds of the present invention are also active against infections caused by microbes Haemophilus infuenzae, Rickettsies, Mycoplasma pneumoniae, Chlamydia, Legionella spp., Ureaplasma, Foxoplasma or microbes such as Mycobacterium, Listeria, Meningocoques and Campylobacter. The compounds of formula (I) and their salts attaching a pharmaceutically acceptable acids can be used as antibiotics.

As such antibiotics can be used, for example, to use the preferred compounds of formula (I) above, in particular, the compounds of examples 1, 2, 3, 29-35, as well as their pharmaceutically acceptable salts.

The invention also concerns pharmaceutical compositions containing as an active start, municipal, parenteral or applied locally on the skin and on the mucous membranes, but the preferred method of introduction is the oral route.

They can be solid or liquid and be the pharmaceutical forms commonly used in medicine, for example, simple tablets or coated tablets, gelatin capsules, granules, suppositories, injectable preparations, ointments, creams, gels; they are prepared by conventional methods. The active principle can be entered into the composition together with excipients which are usually used in these pharmaceutical compositions, such as talc, gum Arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or nonaqueous carriers, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting agents, dispersants or emulsifiers and preservatives.

These compositions can also be produced in powder form suitable for dilution as necessary in an appropriate solvent, for example, sterile pyrogen-free water.

Enter the dose varies depending on the type of illness, the patient, method of administration and from which connection to use. It may be, for example, from 50 mg to 300 mg per day for oral introduction to the I compounds of the formula (I), namely, the compound of formula (II):

< / BR>
in which Z' represents the residue of an acid, is subjected to the interaction with the compound of the formula (III):

RNH2,

in which R is defined above, to obtain compounds of formula (IA):

< / BR>
in which R and Z' have the above significance, then the resulting compound of formula (IA), if necessary, is subjected to the action agent release function of the hydroxyl in position 2' and/or, if necessary, the action of acid to salt;

and the reaction of the compound of formula (II) with the compound of the formula (III) is carried out in such a solvent, such as acetonitrile, dimethylformamide or tetrahydrofuran, dimethoxyethane or dimethylsulfoxide;

- hydrolysis function of ester at the 2' position carried out using methanol or aqueous hydrochloric acid;

and the salt formation is carried out using acids by classical methods.

The compounds of formula (II) used as starting materials described and claimed in European patent application 0596802.

The compounds of formula RNH2are in General known products, however, the specific compounds used to get from the.

The compounds of formula (III);

RNH2< / BR>
can be obtained, for example, by methods described in J. Med.Chem. (1982), volume 25, page 947, and the following, Tetrahedron Letters, volume 32, No. 14, pp. 1699-1702, (1991); J. Org. Chem. 54 (18) 4298, 301 (1989); J. Orq.Chem. 28 (101) 2589 91 (1963) or patent Germany 3406416; J. Org.Chem. 6-895-901 (1941) or Synth. Commun. 17 (14) 1741-8 (1987).

More specifically the invention relates to amines of formula (III) defined above, the receipt of which is detailed below.

In particular, the invention relates to the following amines:

4-phenyl-1H-imidazol-1-butanamine,

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

1H-imidazo(4,5-b)-pyridine-1-butanamine,

2-phenyl-4-ginainstalled,

1H-benzotriazol-1 butanamine,

2H-benzotriazol-2-butanamine,

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

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

5-chloro-1H-benzimidazole-1-butanamine,

7-methoxy-4-ginainstalled,

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

9H-purine-9-butanamine,

1-methyl-1H-indol-4-butanamine,

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

5-phenyl-1H-tetrazol-1 butanamine (hydrochloride),

2-benzothiazolesulfenamide,

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

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

3-ginainstalled,

2-chinesemiracle-2-butanamine,

2-methyl-1H-benzimidazole-2-butanamine,

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

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

7-methoxyquinoline-4-butanamine,

4-(4-forfinal)-1H-imidazol-1 butanamine,

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

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

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

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

2-phenylthiazol-4-butanamine,

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

isoquinoline-4-butanamine,

hinzelin-4-butanamine,

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

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

4-(4-(triptoreline)phenyl)-1H-imidazol-1-butanamine,

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

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

1H-indole-1-butanamine,

2-(3-pyridinyl)thiazole-4-butanamine,

and also their salts joining with acids.

Example 1: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(4 - phenyl-1H-imidazol-1-yl)butyl)imino)) - erythromycin.

Heated to 63oC mixture 0,705 g of the product 2'-acetate-11-deoxy 10,11-didehydro-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L - abovecaptionskip))oxy)-12-O-((1H-imidazol) in 3 ml of acetonitrile, containing 10% of water, and 1.08 g of 4-(4-phenyl-1H-imidazol-1-yl)butanamine. Maintain the reaction mixture at this temperature for 5 hours. Leave to return to room temperature and pour the reaction mixture into a solution of acid phosphate, extracted with ethyl acetate. Washed the organic phase with water, dried, filtered and concentrated. Obtain 1.5 g of the product, to which is added 210 ml of methanol. Support with stirring for 16 hours in a nitrogen atmosphere at room temperature. Concentrate and obtain 1.4 g of product, which is purified by chromatography on silica, eluent CH2Cl2- MeOH - NH4OH 93-7-0,4). Concentrate and get 0,305 g of the desired crude product which is recrystallized from simple isopropyl ether, washed, dried at 50oC under reduced pressure. So get 0,267 g of the desired product with a melting point 222-231oC.

NMR CDCl3MRP.

D= +18o(c = 0,9 CHCl3).

0,84 (t): CH3-CH2; 1,01 (d)-1,17 (d)-1,24 (d): CH3-CH; 1,30 (d)-1,38 (d) of 1.34 to 1.47; 6 and 12 Me; 2,27 (s): N(Me)2; 2,45 (-): H'3; 2,61 (m): H8; 2,63 (s): 6-OMe; 3.04 from (-): H4; 3,13 (q): H10; 3,18 (dd): H'2; 3,53 (-): H'5; 3,56 (s): H11;

< / BR><> 7,20: H in the para-position; 7,35: H in the meta-position; 7,76: H in the ortho-position.

Preparation 1: 4-(4-phenyl-1H-imidazol-1-yl)butanamine.

Stage A: 2-(4-(4-phenyl-1H-imidazol-1-yl)butyl)-1H-isoindole-1,3(2H)dione.

Was added dropwise within 1 hour and 30 minutes a solution containing of 5.05 g of 4-phenyl-1H-imidazole in 25 cm3of dimethylformamide, the mixture of 7 cm3of dimethylformamide and 2.02 g of sodium hydride. Then enter 10,86 g of N-4-bromotryptamine dissolved in 25 cm3of dimethylformamide. Bring the resulting solution to 70oC for approximately 1 hour and 30 minutes. Leave to return to room temperature and concentrating the resulting solution, absorb water, extracted with ethyl acetate. Washed the organic phase with water, dried, filtered and concentrated. Get 15 grams of product which is recrystallized from ethyl acetate. Dry the resulting product is washed him with ethyl acetate and dried under reduced pressure at 50oC. Obtain 5.5 g of the desired product with a melting point of 130-132oC.

NMR CDCl3MRP.

1,75 (m) (2H)-1,86 (m) (2H): CH2Central; 3,74 (t): 2H; 4,03: 2H; 7,22 (t): 2H, H4; 7,26 (m): 1H H'3; of 7.36 (t): 2H, H3and H5; 7,56 (d): H'5; about 7,73 (m): 4H; about 7,86 (m): H2and H6 is a mixture of 3.45 g obtained at the stage of A product, 100 ml of ethanol and 0.97 ml of hydrazine hydrate is added. Concentrate the reaction mixture, add approximately 50 ml of 2 n sodium hydroxide, extracted with ethyl acetate. Washed the organic phase with 2 n sodium hydroxide and then sodium chloride. Dry, filter and concentrate. Gain of 2.21 g of the desired product.

NMR CDCl3MRP.

1,47 (m) - 1,87 (m): CH2Central; 2,73 (t), 3,97: -CH2-NH2; 7,20 (d): H'3; 7,50 (d): H'5; 7,37 (t Shir.) 2H: H3and H5; 7,24 (it) 1H: H4; to 7.77 (m) 2H: H2and H6.

Example 2: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(3H - imidazo(4,5-b)pyridine-3-yl)butyl)imino)) - erythromycin.

Dissolve 708,2 mg 2'-acetate-11-deoxy-10,11-didehydro-3-de((2,6 - dideoxy-3-C-methyl-3-O-methyl-alpha-L-abovecaptionskip)oxy)-12-O-((1H - imidazol-1-yl)carbonyl)6-O-methyl-3-oxo-erythromycin (obtained as described in example 1C European patent application EP 0596802) and 958 mg 3H-imidazo-(4,5-b)pyridine-3-butanamine in 2,82 cm3acetonitrile and 0.28 cm3water. Bring the reaction mixture to 80oC. Leave to return to room temperature and poured into a solution of acid phosphate. Extracted chloride thought 826 mg of product. Dissolve the resulting product 16.5 cm3of methanol. Support the reaction solution under stirring at room temperature for 20 hours. Receive 789 mg of the desired crude product which is purified by chromatography, eluant: a mixture of methylene chloride, methanol and ammonia solution (94-16-0,4). Obtain 327 mg of the desired product with a melting point of 200oC.

D= +13oc = 1% CHCl3.

NMR CDCl3400 MHz ppm.

0,85 (t): CH3-CH2; 1,01 (d)-1,16 (d)-1,25 (d): CH3-CH;1,30 (d) -1,26 (d) of 1.35 and 1.47: 6 and 12 Me; about 1,63 and approximately 1.98: Central CH2circuit; and 2.27 (s): N(CH3)2; 2,46 (m): H'3; about 2,59 (m): H82,61 (s) 6-OMe; 3,07 (m): H4; 3,12 (q width: H10; 3,18 (dd): H2; 3,54 (m): H'5; 3,57 (s): H11;

< / BR>
of 3.85 (q): H2; 4,24 (d): H5; 4,29 (d): H'1;

< / BR>
is 4.93 (dd): H13; 7,21 (dd): H6; 8,04 (dd): H7aromatic; 8,11 (s): H2; scored 8.38 (dd): H5.

Example 3: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L - abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(1H - imidazo(4,5-b)pyridine-1-yl)butyl)imino)) - erythromycin.

Add 708 mg of 2'-acetate-11-deoxy-10,11-didehydro-3-de((2,6 - dideoxy-3-C-methyl-3-O-methyl-alpha-L-abovecaptionskip)oxy)-12-O-((1H - emient EP 0596802) in the solution, contains 953 mg of 1H-imidazo(4,5-b)pyridine-1-butanamine, 2,82 cm3acetonitrile and 0.28 cm3water. Bring the reaction mixture to 55oC. Maintain at this temperature for 44 hours and add 0.5 cm3acetonitrile. Continue heating at 55oC for 20 hours. Leave to return to room temperature and poured into a saturated solution of acid phosphate. Extracted the aqueous phase with methylene chloride and washed with water chlormethiazole phase. Dried on sodium sulfate, filtered and evaporated. Get 806 mg of product, to which is added 16,1 cm3of methanol. Maintain the reaction mixture at room temperature for 24 hours and evaporated to dryness. Receive 656 mg of product, which chromatographic on silica; eluant: a mixture of CH2Cl2-MeOH-NH3(94-6-0,4).

Get a crude target product, which is purified by chromatography on silica gel, elwira a mixture of CHCl3-MeOH-NH4OH 94-6-0,4). After dissolving the residue in a mixture of ethyl acetate with simple isopropyl ether, filtration and evaporation to dryness obtain the target product.

So pl. = 203oC.

D= 17,6oc = 1% CHCl3.

0,81 (t): CH3-CH2; 1B>3)2; 2,61 (s): 6-OCH3; 2,45 (m): H'3; about 2,60 (m masked part): H8; 3,07 (m): H4; about 3.15 in (q, W): H10; 3,18 (dd): H'2; 3,56 (s): H11; 3,53 (m): H'5; 3,60-3,80 (m): CO-N-CH2; a 3.87 (q): H2; about 4,25 (m): CH2-N-C=; 4,24 (d): H5; 4,28 (d): H'1; 4,91 (dd): H13; 7,21 (dd, J = 5 and 8): H6; 7,80 (dd, J = 8 and 1.5): H7aromatic; 8,56 (dd, J = 5 and 1.5): H5; 8,15 (s): H2+ CH2Cl2.

Preparation 2: preparation of amines used as starting products in examples 2 and 3:

3H-imidazo(4,5-b)pyridine-3-butanamine and 1H-imidazo(4,5-b)pyridine-1 - butanamine.

Stage a:

In the solution 5,95 g of 4-azobenzenes and 15.5 g of N-4-bromotryptamine 30 cm3of dimethylformamide added 10.3 g of potassium carbonate. The mixture is stirred for 20 hours at room temperature. The undissolved product is filtered, rinse methylene chloride. The organic phase is washed with water, then dried on magnesium sulfate and evaporated; the resulting oily residue is washed with petroleum ether, then with isopropyl ether. Obtain 16.3 g of crude product which is purified by chromatography on silica, elwira a mixture of methylene chloride with acetone, and obtain 4.9 g of product (A), so pl. = 143oEsprimere 2).

Bring to the boiling temperature for 19 hours, the mixture 32,86 g of product (A) obtained above, 697 cm3ethanol and 20 cm3hydrazine. Leave to return to room temperature. Filter, rinse and evaporated to dryness. Absorb methylene chloride, filtered, rinse and evaporated to dryness. Get 18,87 g of the target product.

NMR CDCl3- 250 MHz.

of 1.52 (m) -2,00 (m): 2 CH2Central; 1,63 (s - W): mobile 2H; was 2.76 (t): CH2-CH2-NH2;

< / BR>
from 7.24 (dd, J = 8 and 5): H6; 8,08 (dd, J = 8 and 1.5): H7; to 8.40 (dd, J = 5 and 1.5): H5; 8,08 (s): H2.

Stage b2: 1H-imidazo(4,5-b)pyridine-1-butanamine (the original product in example 3).

Bring to the boiling temperature for 21 hours a mixture of 32 g of product (B) obtained above, 640 cm3ethanol and 24.8 cm3hydrazine. Leave to return to room temperature. Filter, rinse with ethanol and evaporated under reduced pressure. Absorb methylene chloride, filtered, rinse and evaporated to dryness. Obtain 19.5 g of the target product.

NMR CDCl3.

1,45 (m)-1,96 (m): 2 Central CH2; 2,74 (t): CH2-NH2; 1.45 (m): movable;

< / BR>
from 7.24 (dd, J = 8 and 5): H6; of 7.75 (dd, J = 8 relevant amines, receive the following products:

Example 4: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4- (thieno(2,3-b)pyridine-4-yl)butyl)imino)) - erythromycin.

So pl. = 176 - 178oC.

D= +17oc = 0.9% in CHCl3.

Example 5: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(3 - phenyl-1H-1,2,4-triazole-1-yl)butyl)imino)) - erythromycin.

So pl. = 208 - 210oC.

D= +17oc = 1% in CHCI3.

Example 6: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(1 - methyl-1H-imidazo(4,5-c)pyridine-2-yl)butyl)imino)) - erythromycin.

D= +19oc = 1% CHCl3.

Example 7: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(3 - methyl-3H-imidazo(4,5-c)pyridine-2-yl)butyl)imino)) - erythromycin.

D= + 16oCHCl3= 1%

Example 8: 11,12-ldeaxi-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(7 - methoxy-4-chinoline)butyl)imino)) - erythromycin.

So pl. = 132 - 134oC.

D= +25oC C = 1% CHCl3.

Example 10: 11,12-dideoxy-3-((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(2 - benzothiazolyl)butyl)imino)) - erythromycin.

So pl. = 179-181oC.

D= +18oc = 1% CHCl3.

Example 11: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4- (2-(3-pyridinyl)-4-thiazolyl)butyl)imino)) - erythromycin.

So pl. = 150 - 152oC.

D= +17oc = 0,9% CHCl3.

Example 12: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4- (2-(3-pyridinyl)-5-thiazolyl)butyl)imino)) - erythromycin.

So pl. = 155 - 159oC.

D= 12oc = 1% CHCl3.

Example 13: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(9H - purine-9-yl)butyl)imino)) - erythromycin.

Example 14: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(1H - imidazo(4,5-c)pyridine-1-yl)butyl)imino)) - erythromycin.

Obtained from 2-(4-bromopentyl)-1H-ISO-indole-1,3-(2H)-dione.

Example 16: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((5 - chloro-1H-benzimidazole-1-yl)butyl)imino)erythromycin.

So pl. = 145 - 148oC.

Example 17: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-12,11-(oxycarbonyl((4-(1H - indol-1-yl)butyl)imino)) - erythromycin.

Example 18: 11,12-dideoxy-3-de(2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(1 - methyl-1H-indol-4-yl)butyl)imino)) - erythromycin.

D= 20%, c = 1% CHCl3.

Example 19: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(2 - phenyl-4-chinoline)butyl)imino)) - erythromycin.

So pl. = 195 - 197oC.

Example 20: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(1H - benzotriazol-1-yl)butyl)imino)) - erythromycin.

So pl. = 200 - 202oC.

Example 21: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(2H-the-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-methyl-3-oxo-12,11-(oxycarbonyl((4-(5,6 - dimethyl-1H-benzimidazole-1-yl)butyl)imino)) - erythromycin.

So pl. = 174 - 176oC.

Example 23: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(3 - chinoline)butyl)imino)) - erythromycin.

So pl. = 195-197oC.

Example 24: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(2 - chinoline)butyl)imino)) - erythromycin.

So pl. = 179 - 181oC.

Example 25: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(2 - methyl-1H-benzimidazole-1-yl)butyl)imino)) - erythromycin.

So pl. = 128 - 132oC.

Example 26: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(6 - chloro-1H-benzimidazole-1-yl)butyl)imino)) - erythromycin.

So pl. = 192 - 194oC.

Example 27: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(1 - methyl-1H-benzimidazole-2-yl)butyl)imino)) - erythromycin.

Example 28: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(5H - imidazo)-4,5-c)pyrid the 6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4- (4-(4-chlorophenyl)-1H-imidazol-1-yl)butyl)imino)) - erythromycin.

Heated 7 hours to 75oC 1 g 2'-acetate-11-deoxy-10,11-didehydro - 3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)-12-O-((1H-imidazol-1-yl)carbonyl)6-O - methyl-3-oxo-erythromycin (obtained as described in example 1C European patent application EP 0596802) 4 cm3acetonitrile containing 10% water with 1.4 g of 4-(4-chlorophenyl)-1H-imidazol-1-butanamine. Leave to return to room temperature, diluted with water, extracted with ethyl acetate, dried, the solvent is evaporated and obtain 2.3 g of the product, acetylated in position 2'. Add 60 ml of methanol and support 16 hours under stirring, the solvent is evaporated, chromatografic the residue on silica (eluent: CH2Cl2-MeOH-NH4OH 95-5-0,4), concentrated and the residue is crystallized from a simple ether. Dried crystallized product under reduced pressure at 80oC and receive 381 mg of the target product. So pl. 192 - 194oC.

NMR CDCl3MRP.

0,83 (t): 1.00 and (d) of 1.16 (d)-1,24 (d)-1,30 (d) 1,38 (d): 1,33 (s) to 1.47 (s): 6 and 12 Me; and 2.26 (s): N(Me)2; 2,44 (m): H'3; 2,61 (s): 6-OMe; 2,60 (m): H8; 3,00 - 3,21: H4H10and H'2; 3,55 (m): H'5; 3,56 (s): H11;

< / BR>
a 3.87 (q): H2; to 4.23 (d): H5; 4,28 (d): H'1; is 4.93 (dd) H13; 7,26 (d): H

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

Bring to the boiling point for 1 hour 23,34 g-bromo-4-chloroacetophenone in 150 ml of formamide; leave to cool, alkalinized with sodium hydroxide solution, extracted with dichloromethane, washed with water, dried, the solvent is evaporated, chromatografic the residue on silica (eluent: CH2Cl2-MeOH-NH4OH 8-2-0,04) and get to 13.4 g of the target product.

So pl. 146 - 148oC.

Stage B: 2-(4-(4-(4-chlorophenyl)-1H-imidazol-1-yl)butyl)-1H-ISO-indole - 1,3-(2H)-dione.

Work both on stage A of preparation 1 of example 1, using 12.2 g of the product obtained in the previous phase, 4,96 g of sodium hydride and 23,83 g of N-4-bromotryptamine.

Obtain 9.7 g of the target product.

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

Work as in stage B of preparation 1 of example 1, but using 14.2 g of the product obtained at stage B, and 3.6 ml of hydrazine hydrate is added 200 ml of ethanol.

Get 12 g crude product, which chromatographic on silica (eluent: CH2Cl2-MeOH-NH4OH 8-2-0,04) and get a product used as such for the synthesis.

2and H5; 7,33 and 7,70: aromatic.

Example 30: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4- (4-(2-methoxyphenyl)-1H-imidazol-1-yl)butyl)imino)) - erythromycin.

Heated to 80oC within 8 hours of 706 mg of starting compound of example 29 in 3 ml of acetonitrile and 908 mg of 4-(2-methoxyphenyl)-1H-imidazol-1-butanamine. Cooled to room temperature, poured into a solution of sodium hydrogen phosphate (0.5 M), extracted with ethyl acetate, washed with water, dried, the solvent evaporated, to obtain 1.6 g of product, acetylated in position 2'. Add 50 ml of methanol, stirred for 16 hours, the solvent is evaporated, chromatografic the residue on silica (eluant AcOEt-TEA with 4%) and crystallized from simple ether. Obtain 194 mg of the target product. So pl. = 143 - 145oC.

NMR CDCl3MRP.

0,85 (t): 1,01 (d)-1,16 (d)-1,24 (d)-1,30 (d)-1,37 (d): 1,34 (s)-1,47 (s): 6 and 12 Me; and 2.26 (s) N(Me)2; 2,44 (m): H'3; 2,60 (m): H8; 2,64 (s): 6-OMe; is 3.08 (m): H4; 3,12 (q W): H10; 3,17 (dd): H'2; 3.54 (m): H'5; 3,57 (s): H11;

< / BR>
of 3.85 (q): H2; 3,95 (s): f-OMe; 3,99 (q width: CH2-N-C=; 4,24 (d): H5; 4,27 (d): H'1; is 4.93 (dd): H13; 6,97 (d Shir.: H6; Enie 4-(2-methoxyphenyl)-1H-imidazol-1-butanamine, used as the source in example 30.

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

Heated to the boiling point 9,36 g of 2-bromo-2'-methoxy-acetophenone in 50 ml of formamide, leave to return to room temperature, washed 2 N. hydrochloric acid, filtered, alkalinized to pH 8 to 9 with 2 n sodium hydroxide, extracted with dichloromethane, washed with water, dried, the solvent is evaporated, chromatografic the residue on silica (eluant: CH2Cl2-MeOH-NH4OH 95-5-0,4) and get x 6.15 g of the target product.

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

Work both on stage A of preparation 1 of example 1, but using 6 g of the product obtained at stage A, 1,99 g of sodium hydride and to 9.93 g of N-4-bromotryptamine. Get 6,15 g of the target product.

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

Work as in stage B of preparation 1 of example 1, but using the 5.65 g of the product obtained at stage B, and a 1.45 ml of hydrazine hydrate is added 75 ml of ethanol. Obtain 3.8 g of crude product which is dissolved in 4 ml of tetrahydrofuran, then added to 1.87 g of fumaric acid, dissolved in 20 ml of methanol. Priba superiror of 3.77 g fumarata the target product.

So pl. = 160 - 162oC.

NMR (CDCl3) ppm.

1,48 (m) 2H-1,87 (m) 2H: Central CH2; OF 3.46: NH2; 2,73 (t): CH3N; 3,94 (s): f-OMe;

< / BR>
6,94 (dd): H6;? 7.04 baby mortality (dt)-7,21 (ddd): H5and H4; 7,51: H'2and H'5; 8,19 (dd): H2.

Example 31: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4- (4-(4-forfinal)-1H-imidazol-1-yl)butyl)imino)) - erythromycin.

Heated to 60oC for 4 hours and 30 minutes 2,11 g of starting compound of example 29 in 9 ml of acetonitrile and 2.8 g of 4-(4-forfinal)-1H-imidazol-1-butanamine. Cooled to room temperature, poured into water, extracted with ethyl acetate, washed with water, dried, the solvent is evaporated, the gain of 5.2 g of the product, acetylated in position 2'. Add 20 ml of methanol, stirred for 3 hours 30 minutes, the solvent is evaporated, chromatografic the residue on silica (eluant: CH2Cl2-MeOH-NH4OH 95-5-0,3) and crystallized from simple ether. Gain of 1.34 g of the target product. So pl. = 190 - 192oC.

NMR CDCl3MRP.

1,33 (s)-1,47 (s): 6 and 12 Me; 2,27 (s): N(Me)2; 2,61 (s): 6-OMe; 3,0 - 3,18: H4and H10; 3,56 (s): H11;

< / BR>
about 7,05 about 7,73: CFT is-1 butanamine, used as the source in example 31.

Stage A: 4-(4-forfinal)-1H-imidazole.

Heated 2 hours at the reflux 10,85 g of methyl 4-florfenicol in 60 ml of formamide, leave to return to room temperature, acidified to pH 2 with 1 N. hydrochloric acid, filtered, neutralized by adding ammonia solution, extracted with dichloromethane, washed with water, dried, the solvent is evaporated, chromatografic the residue on silica (eluant: CH2Cl2-MeOH-NH4OH 95-5-0,4) and obtain 5.8 g of the target product. So pl. = 130 - 132oC.

Stage B: 2-(4-(4-(4-forfinal)-1H-imidazol-1-yl)butyl)-1H - isoindole-1,3(2H)-dione.

Work both on stage A of preparation 1 of example 1, but using 10 g of the product obtained at stage A, of 1.95 g of sodium hydride and 11,80 g of N-4-bromotryptamine. Get 7,53 g of the target product. So pl. = 138 - 140oC.

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

Work as in stage B of preparation 1 of example 1, but use of 3.64 g of the product obtained above in stage B, and 1 ml of hydrazine hydrate is added in 80 ml of ethanol. Obtain 2.4 g of the crude product, which chromatographic on silica (eluent: CH2Cl2-MeOH-NH4OH 8-2-0,03) received trannie CH2; 2,74 (t): 3,98 (t): >N- -CH2; 7,06 (t): >CH-F;

7,49 (s): H2imidazole; 7,15 (s): H5imidazole.

Example 32: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(7 - methoxy-4-chinoline)-butyl)imino)) - erythromycin.

Heated to 50oC for 53 hours 706 mg of starting compound of example 29 in 4 ml of acetonitrile and 1.43 g of 7-methoxyquinoline-4-butanamine. Leave to return to room temperature, poured into a solution of sodium hydrogen phosphate (0.5 M), extracted with dichloromethane, washed with water, dried, the solvent is evaporated, get 1,09 g of the product, acetylated in position 2'. Add 10 ml of methanol, stirred for 16 hours, the solvent is evaporated, chromatografic the residue on silica (eluant: CH2Cl2-MeOH 95-5) and crystallized from simple ether. Obtain 295 mg of the expected product. So pl. 110oC.

NMR CDCl3MRP.

3,06 (m): -(CH2)2; 3,70 (m): 3,95 (s): -OCH3; 7,12 (d)-7,19 (dd)-7,42 (d)-7,94 (d)-8,70 (d): pyridine.

Preparation of 7-methoxyquinoline-4-butanamine used as the source in example 32.

Stage A: salt triphenylphosphine N-(3-bromopropyl)phthalimide.

oC. Recuperat are 24.88 g of the target product; So pl. = 220 - 222oC.

Stage B: (Z)-2-(4-(7-methoxy-4-chinoline)-3-butenyl)-1H-ISO-indole - 1,3(2H)-dione.

Add 4 g of 7-methoxy-4-chinainternational in suspension 12,47 g of salt triphenylphosphine 3-bromopropylamine in 200 ml of tetrahydrofuran. Cooled to -50oC add of 2.72 g of potassium tert-butylate, leave to slowly raise the temperature to -6oC, filter, concentrate the filtrate, absorb the residue in ethyl acetate, washed with water, dried, the solvent is evaporated and Recuperat 9,26 g crude product, which chromatographic on silica (eluant: CHCl3-AcOEt 80-20, then 70-30). Recuperat 3,575 g of the target product.

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

Dissolve 3.50 g of the product obtained at stage B, 50 ml of methanol, added 0.36 g of palladium on charcoal and hydronaut 3 hours at 600 mbar. Filtered, the solvent evaporated and the gain of 3.48 g of the expected product.

Stage D: 7-methoxyquinoline-4-butanamine.

Reddering at reflux for 17 hours, remove the precipitate by filtration, the solvent is evaporated, absorb the balance in 70 ml of dichloromethane. Filtered, the solvent is evaporated and taken 2,19 g of the target product.

NMR (CDCl3) ppm.

1,6 (m)-1,79 (m): the Central CH2; 2,75 (t): >-CH2-(CH2)3; 3,05 (t): 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-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4- (2-(2-pyridinyl)-4-thiazolyl)butyl)imino)) - erythromycin.

Heated to 60oC for 5 hours 705 mg of starting compound of example 29 (obtained as described in example 1C European patent application EP 0596802) in 3 ml of acetonitrile and 0,705 g 2-(2-pyridinyl)-thiazole)-4-butanamine. Leave to return to room temperature, poured into water, extracted with ethyl acetate, washed with water, dried, the solvent evaporated, to obtain 1.8 g of product, acetylated in position 2'. Add 15 ml of methanol, heated to boiling point for 2 hours, the solvent is evaporated, chromatografic the residue on silica (eluent: CH2Cl2-MeOH-NH4OH 95-5-0,3, then AcOEt-TEA 9-1) and crystallized from simple ether. Obtain 194 mg CE is>2;

< / BR>
of 3.12 (q, W): H10; 3,60 (s): H11;

< / BR>
7,03 (s): H5thiazole; 7,27 (ddd): H5pyridine; to 7.77 (dt): H4pyridine; 8,18 (dd) H3pyridine; 8,53 (ddd): H6pyridine. Preparation of 2-(2-pyridinyl)-thiazole-4-butanamine used as the source in example 33.

Stage A: 2-aminocarbonylmethyl.

Was added dropwise 50 ml of a solution of diazomethane (0.4 M/l) in a solution containing 2 g pikolinos acid, 20 ml of dichloromethane and 5 ml methanol. After 30 minutes stirring at room temperature the solvent is evaporated under reduced pressure, chromatografic the residue on silica (petroleum ether (60-80)-AcOEt 5-5) and Recuperat 1.48 g of methyl ether. Heated to 50oC for 4 hours 1.42 g of ester in 5 ml of hydroxide ammonium leave to return to room temperature, extracted with simple ether, washed with water, dried, the solvent is evaporated and Recuperat of 1.05 g of the expected product. So pl. = 105oC.

Stage B: 2-pyridinecarboxamide.

Slowly add 43 g pentasulfide phosphorus to of 46.8 g of the amide obtained in stage A, in 700 ml of tetrahydrofuran. Stirred for 4 hours at room temperature, poured into water, extracted mne (eluent: CH2Cl2-AcOEt 8-2) extract 10 g of the expected product. So pl. = 137oC.

Stage C: 2-(2-pyridinyl)-4-thiazolecarboxamide.

Pin of 16.3 ml of ethyl-bromopyruvate to 15.9 g of the product obtained as in stage B in 250 ml of ethanol, and heated for 5 hours under reflux. The solvent is evaporated under reduced pressure, chromatografic the residue on silica (eluant: hexane-AcOEt 1-1) and obtain 10.2 g of the target product. So pl. = 69,1oC.

Stage D: 2-(2-pyridinyl)-4-thiazoleethanol.

Slowly add 40 ml of methanol in a mixture containing 9.3 g of ester obtained in stage C, and 4.1 g of sodium borohydride in 100 ml of tetrahydrofuran and heated for 2 hours under reflux. Leave to return to room temperature, poured into water, neutralized with 1 N. hydrochloric acid, extracted with dichloromethane, the organic phase is dried and the solvent is evaporated under reduced pressure, chromatografic the residue on silica 1 (eluant: AcOt-CH2Cl21-1) and teaches 5.8 g of the expected product. So pl. = 100oC.

Stage E: 2-(2-pyridinyl)-4-thiazolecarboxamide.

Support 2 hours at the reflux of 5.8 g of the product obtained in stage D, in 60 ml of toluene in the presence of the ukta. So pl. = 131oC.

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

Work as in stage B of preparation example 32, using 5,70 g of the aldehyde obtained in stage E, and 15.9 g of salt triphenylphosphine 3-bromopropylamine and 3.70 g of potassium tert-butylate. Get 8,73 g of the target product. So pl. = 139 - 141oC.

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

Work both on stage C of preparation of example 32, using as source 7,22 g of the product obtained in stage F, and 1.5 g of palladium on charcoal, hydrogenase 2 hours at 1800 mbar. Get 6,33 g of the target product. So pl. = 119 - 121oC.

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

Work both on stage D preparation of example 32, using the 5.45 g of the product obtained above in the previous phase, and 1.6 ml of hydrazine hydrate is added, and heated for 6 hours at phlegm. The solvent is evaporated, absorbed with ethyl acetate, washed with water, dried, the solvent is evaporated, chromatografic the residue on silica (eluant: CH2Cl2-MeOH-NH4OH 9-1-0,03) to obtain 1.65 g of the expected product.

NMR (CDCl3) ppm.

1,50 (m)-1,82 (m): the Central CH2; 2> 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-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4- (4-(3-pyridinyl)-1H-imidazol-1-yl)butyl)imino)) - erythromycin.

Heated to 70oC for 20 hours, 1 g of starting compound of example 29 in 4 ml of acetonitrile and 936 mg of 4-(4-(3-pyridinyl)-1H-imidazol-1-yl)butanamine. Leave to return to room temperature, poured into water, extracted with ethyl acetate, washed with water, dried, the solvent is evaporated, the gain of 1.34 g of the product, acetylated in position 2'. Add 40 ml of methanol, stirred for 2 hours, the solvent is evaporated, chromatografic the residue on silica (eluant: CH2Cl2-MeOH-NH4OH 95-5-0,4) and crystallized from simple ether. Obtain 310 mg of the target product. So pl. 187 - 188oC.

NMR (CDCl3) ppm.

0,83 (t): 1,01 (d)-1,17 (d)-1,25 (d)-1,31 (d)-1,38 (d): 1,34 (s)-1,47 (s): 6 and 12 Me; 2,27 (s): N(Me)2; 2,45 (m): H'3; 2,62 (s): 6-OMe; 2,60 (m); H8; 2,85-3,25: H44and H10H'2; 3,52 (m): H'5; 3,56 (s): H11; 3,60-3,85 (m):

to 4.23 (d): H5; 4,27 (d): H'1; is 4.93 (dd): H13; 7,29 (ddd): H3pyridine; 8,08 (dt): H4pyridinyl; to 8.45 (dd): H6pyridine; 8,97 (dd): HIspolzuemogo as the source in example 34.

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

Working as A stage of preparation of example 1, using 290 mg 3-pyridinyl-1H-imidazole obtained as described in J. Chem. Soc. 753-5 (1938), 115 mg of sodium hydride and 633 mg of N-4-bromotryptamine. Obtain 277 mg of the expected product. So pl. = 150 - 152oC.

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

Work both on stage In the preparation of example 1, using 1.66 g of the product obtained at stage A, and 0.46 ml of hydrazine hydrate is added in 30 ml of ethanol. Receive 936 mg of the product used as such for the synthesis.

NMR (CDCl3) ppm.

1,49 (m)-1,89 (m): the Central CH2; 2,75 (t): CH2-CH2-N

< / BR>
7,29 (d, J = 1)one-7,55 (d, J = 1): H2and H5; 7,30 (masked): H'5; of 8.09 (dt, J = 8 and 2): H'4; of 8.47 (dd, J = 5 and 2): H'6; 8,96 (d, J = 2): H'2; 1,49 (s W): 2H moving.

Example 35: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4- (3-(3-pyridinyl)-1H-1,2,4-triazole-1-yl)butyl)imino)) - erythromycin.

Heated to 75oC within 8 hours 1 g of starting compound of example 29 in 4 ml of acetonitrile and to 1.21 g of 4-(3-(3-pyridinyl)-1H-1,2,4 - triazole-1-yl)mutant water, dried, the solvent is evaporated, receive 2 g of the product, acetylated in position 2'. Add 40 ml of methanol, stirred for 16 hours, the solvent is evaporated, chromatografic the residue on silica (eluant: CH2Cl2-MeOH-NH4OH 90-10-0,04) and crystallized from simple ether. Get 292 mg of the expected product. So pl. = 190 - 192oC.

NMR (CDCl3) ppm.

0,84 (t): 1,01 (d): OMe; to 1.16 (d): 8 Me; 1,25 (d): 5 Me; 1,30 (d): 4 Me; 1,34 (d): 2 Me; 1,33 (s) and 1.47 (s): 6 and 12 Me; 1,67 (m)-1,99 (m): the Central CH2; and 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): H11;

< / BR>
of 3.85 (q): H2; about 4,25: H'1H5and 4,91 (dd): H13; 8,15 (s): H of triazole: to 7.35 (dd): H5pyridine; a 8.34 (dt): H4pyridine; to 8.62 (dd): H6pyridine; 9,31 (d width): H2pyridine.

Preparation of 3-(3-pyridinyl)-1H-1,2,4-triazole-1-butanamine used as the source in example 35.

Stage A: 2-(4-(3-(3-pyridinyl)-1H-1,2,4-triazole-1-yl)butyl-1H - isoindole-1,3(2H)-dione.

Work both on stage A of preparation 1 of example 1, using 2.1 g of 3-pyridinyl-1H-1,2,4-triazole, obtained as described in J. Org. Chem. (44) N 33, 4160-4164 (1979), of 1.02 g of sodium hydride and 4.13 g of N-4-brombeer)-1H-1,2,4-triazole-1-butanamine (fumarate).

Work as in stage B of preparation 1 of example 1, using of 3.46 g of the product obtained at stage A, and 1 ml of hydrazine hydrate is added in 50 ml of ethanol. Obtain 2.1 g of crude product, which was converted into the fumarate, as described in preparation of example 30, and receive 1.13 g fumarata the expected product. So pl. 190 - 192oC.

NMR (CDCl3) ppm.

1,50 (m)-2,01 (m): the Central CH2; was 2.76 (t): 4,24: = 7,37 (ddd): H5; 8,35 (dt): H4; 8,63 (dd): H6; to 9.32 (dd): H2; 8,12 (s): =CH triazole.

Work as above but using the appropriate amines, receive the following products:

Example 36: 11,12-dideoxy-3-de(2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(3 - chinoline)butyl)imino)) - erythromycin.

So pl. = 190 - 192oC.

Example 37: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4- (4-(4-methoxyphenyl)-1H-imidazol-1-yl)butyl)imino)) - erythromycin.

F = 152-154oC.

Example 38: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(2 - phenyl-4-thiazolyl)butyl)imino)) - erythromycin.

F = 141 - 143oC.

F = 144 - 146oC.

Example 40: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4- (4,5-diphenyl)-1H-imidazol-1-yl)butyl)imino)) - erythromycin.

F = 180 - 182oC.

Example 41: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(4 - hintline)butyl)imino)) - erythromycin.

F = 212 - 214oC.

Example 42: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4- (2-(4-pyridinyl)-4-thiazolyl)butyl)imino)) - erythromycin.

F = 192 - 194oC.

Example 43: 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl - alpha-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4- (1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-purine-7-yl)butyl)imino)) - erythromycin.

F = 251 - 253oC.

Example 44: 11,12-dideoxy-3-de((2,6-3-C-methyl-3-O-methyl-alpha-L - removeserver)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(4-(4- triptoreline)phenyl)-1H-imidazol-4-yl)butyl)imino)) - erythromycin.

F = 168 - 170oC.

Amines used as starting materials, receive the following methods:

A - When the circuit is ispolzuemye to obtain products of examples 4, 8, 11, 12, 18, 19, 23 and 24, received in this way.

B - When the circuit is connected with nitrogen, it is possible to obtain the amides in the following way:

< / BR>
Amines used to obtain products of examples 1, 2, 3, 5, 9, 13 - 17, 20, 21, 22, 25, 26 and 28 received in this way.

C - Some amines receive a special way: form a heterocycle and at the same time introducing the chain (examples 6, 7, 10 and 27).

Examples of pharmaceutical compounds

Received compounds containing:

The product of example 1, 150 mg; excipient, in sufficient quantity - 1 year; part of excipients: starch, talc, magnesium stearate.

The product of example 2, 150 mg; excipient, in sufficient quantity - 1 year; part of excipients: starch, talc, magnesium stearate.

The product of example 3, 150 mg; excipient, in sufficient quantity - 1 year; part of excipients: starch, talc, magnesium stearate.

Pharmacological study of the products according to the invention

Method of dissolution in a liquid medium.

Prepare a series of tubes, in which are placed the same amount of sterile nutrient medium. Distribute to each tube of the increasing number of the investigated product, then each tube is seeded with a bacterial strain. After incubat is employed to determine the minimum concentration of inhibition (C. M. I.), expressed in micrograms/cm3.

The following results were obtained (see table).

In addition, the products of examples 1, 2 and 3 showed an interesting activity on bacterial sources regarding the following Gram: Haemophilus Influenzae 351HT3, 351CB12, 351CA1 and 351GR6.

1. Derivatives of erythromycin formulas (I)

< / BR>
in which R is -(CH2)nAr in which n = 3, 4 or 5, Ar is a heterocyclic radical, bearing, if necessary, one or more substituents, which represents a C1- C6-alkyl, C1- C6-alkoxy, triptoreline and halogen, and selected from the group of radicals

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
Z is a hydrogen atom or a residue of an acid,

and also their salts joining with acids.

2. The compounds of formula (I) under item 1, in which Z is a hydrogen atom.

3. The compounds of formula (I) PP.1 and 2 in which n = 4.

4. The compounds of formula (I) PP.1 to 3, in which the Ar radical

< / BR>
if necessary replaced.

5. The compounds of formula (I) PP.1 to 3, in which R is the radical

< / BR>
if necessary replaced.

6. Sedimentogenesis formula (I) PP.1 - 3, in which the Ar radical

< / BR>
if necessary replaced.

8. Compounds of General formula (I) under item 1, predstavlyayushie the following connections:

11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-abovecaptionskip)oxy) 6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(4-phenyl-1H-imidazol-1-yl)butyl)imino)) - erythromycin;

11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-abovecaptionskip)oxy) 6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(3H-imidazo(4,5-b)pyridine-3-yl)butyl)imino)) - erythromycin;

11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-abovecaptionskip)oxy) 6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(1H-imidazo(4,5-b)pyridine-1-yl)butyl)imino)) - erythromycin;

11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-abovecaptionskip)oxy) 6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(4-(4-chlorophenyl)1H-imidazol-1-yl)butyl)imino)) - erythromycin;

11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-abovecaptionskip)oxy) 6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(4-(2-methoxyphenyl)1H-imidazol-1-yl)butyl)imino)) - erythromycin;

11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-abovecaptionskip)oxy) 6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(4-(4-forfinal)1H-imidazol-1-yl)butyl)imino)) - erythromycin;

11,12-dideoxy-3-delaine)butyl)imino)) - erythromycin;

11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-abovecaptionskip)oxy) 6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(2-(2-pyridinyl)4-thiazolyl)butyl)imino)) - erythromycin;

11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-abovecaptionskip)oxy) 6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(3-(3-pyridinyl)1H-1,2,4-triazole-1-yl)butyl)imino)) - erythromycin.

9. The compound of General formula (I) under item 1, representing 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-abovecaptionskip)oxy) 6-O-methyl-3-oxo-12,11-(oxycarbonyl)((4-(4-(3-pyridinyl)1H-imidazol-1-yl)butynyl)imino)) - erythromycin.

10. Compounds of General formula (I) or their salts attaching a pharmaceutically acceptable acid according to any one of paragraphs.1 to 7, which have antibacterial activity.

11. Compounds of General formula (I) or their salts attaching a pharmaceutically acceptable acid on p. 8, which have antibacterial activity.

12. The compound of General formula (I) or its salt accession pharmaceutically acceptable acid on p. 9, which have antibacterial activity.

13. The pharmaceutical composition containing the active principle and a pharmaceutically acceptable excipient, characterized in that day shall (I) under item 1, characterized in that the compound of formula (II)

< / BR>
in which Z' is the residue of an acid,

subjected to interaction with the compound of the formula (III)

RNH2,

in which R is defined in paragraph 1,

obtaining the compounds of formula (IA)

< / BR>
in which R and Z' have the above values,

which, if necessary, expose the agent to release the function of the hydroxyl in position 2' and/or, if necessary, the action of acid to obtain the salt.

15. Amine of formula (III) under item 14 as intermediate compounds for the synthesis.

16. Amines of formula (III) under item 15, which are:

4-(4-phenyl-1H-imidazol-1-yl)butanamine,

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

1H-imidazo(4,5-b)-pyridine-1-butanamine,

4-(4-chlorophenyl)-1H-imidazol-1-butanamine, 4-(2-methoxyphenyl)-1H-imidazol-1-butanamine,

7-methoxyquinoline-4-butanamine,

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

4-(4-forfinal)-1H-imidazol-1-butanamine,

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

4-(3-pyridinyl)-1H-imidazol-1-butanamine, 3-(3-pyridinyl)-1H-1,2,4-triazole-1-butanamine.

 

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< / BR>
where R1is methyl,

R2- benzimidazole-2-yl, unsubstituted or substituted in position 1 by the stands, imidazol-4-yl substituted in position 1 by alkyl with 1 to 3 carbon atoms, substituted in position 2 by morpholinopropan, 5,6,7,8-tetrahydro-imidazo[1,2 - a]pyridine-2-yl or propanesultone-1-Il,

R3- nonbranched alkyl with 2 to 4 carbon atoms,

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