Derivatives of erythromycin pharmaceutical composition based on them, the way they are received and intermediate compounds

 

(57) Abstract:

Derivatives of erythromycin General formula I, in which R is a group (CH2)nAr1where n is an integer from 0 to 6, AG1- carbocyclic C1-18-aryl group, possibly substituted by a carboxyl group in free form, in the form of a salt, complex, ester or amide, halogen atoms, a group of NO2WITH1-12-alkyl, O-(C1-12-alkyl); 5-6-membered heterocyclic aryl group containing one or two heteroatoms in the ring selected from nitrogen atoms, and sulfur; or R is a group hag2where X - C1-6-alkyl, which is interrupted by a group-NHC(O)-, Ar2represents the above-mentioned aryl or heteroaryl group AG1Z is a hydrogen atom or the residue of carbocyclic acids containing up to 18 carbon atoms, or their pharmaceutically acceptable salts of addition of the acid. Connection I have a very high antimicrobial activity against gram-positive bacteria, such as staphylococci, pneumococci. 5 C. and 16 h.p. f-crystals, 1 PL.

The present invention relates to new derivatives of erythromycin, method of production thereof, to pharmaceutical compositions based on them and to temporarily products of formula (I):

(I)

where:

or R represents a radical (CH2)nAr1n is an integer value from 1 to 6, and Ar1is:

or carbocyclic aryl radical with up to 18 carbon atoms, substituted by one or more radicals selected from the group consisting of carboxyl radicals, free, converted into a salt, ester or aminirovaniya, hydroxyl radicals, halogen atoms, radicals of NO2CN, radicals such as alkyl, linear, branched or cyclic, alkanniny and alkyl, linear or branched O-alkyl, O-alkanniny and On-alkynylaryl, S-alkyl, S-alkanniny or S-alkynylaryl and N-alkyl, N - alkanniny and N-alkynylaryl comprising up to 12 carbon atoms, with the possibility of substitution by one or more halogen atoms, the radical in which R1and R2identical or different, represent a hydrogen atom or an alkyl radical comprising up to 12 carbon atoms, the radical in which R3represents an alkyl radical comprising up to 12 carbon atoms, or a carbocyclic or heterocyclic radical, with the possibility of substitution, aryl, O-aryl or S-Arilyn or more heteroatoms; it is also possible to replace one or more substitutes of the numbers listed above,

or heterocyclic aryl radical, containing one or more heteroatoms, with the ability to replace one or more substitutes of the numbers listed above,

or R represents a radical hag2in which X represents an alkyl radical comprising up to 6 carbon atoms and interrupted by an oxygen atom, a sulfur atom, a group SO, a group of SO2group C=O group and Ar2represents the above-mentioned aryl or heteroaryl radical, unsubstituted or substituted by one or more possible substitutes Ar1and Z represents a hydrogen atom or the residue of carbocyclic acids comprising up to 18 carbon atoms, as well as added salts with acids of compounds of formula (I).

As an example, add data salts derived from inorganic or organic acids can be called salts formed with acids such as acetic, propionic, triperoxonane, maleic, tartaric, hydrochloric, sulfuric, phosphoric, methansulfonate, benzosulfimide, p-toluensulfonate, methyl P> In the definition of substitutes:

carbocyclic aryl radical is, first and foremost, phenyl or nattily radical;

Under the heterocyclic aryl radical understand or monocyclic heteroaryl radical with 5 or 6 atoms, containing one or more heteroatoms, or a condensed polycyclic system, each cycle of which contains 5 or 6 atoms and possibly one or more heteroatoms.

heterocyclic aryl radical comprises one or more heteroatoms, selected primarily from oxygen, sulfur and nitrogen;

monocyclic heteroaryl radical with 5 atoms is, first and foremost, thienyl, purely, pyrrolidinyl, diazolidinyl, oxazolidinyl, imidazolidinyl, thiadiazolidine, personilnya or isoxazolyl radical;

monocyclic heteroaryl radical with 6 atoms is, first and foremost, peredelnyj, pyrimidinyl, pyridazinyl or personilnya radical;

condensed polycyclic heteroaryl radical may be, for example, indaily, benzofuranyl, benzothiazolyl or finalininkiu radical or residue purine bases such as adenine;

alkyl, who saw, ISO-propyl, n-boutigny, isobutylene, tert-boutigny, decile or dodecylphenyl, vanilla, allyl, etinilnoy, prominently, propargyl, cyclobutenyl, cyclopentenyl or tsiklogeksilnogo;

halogen is, first and foremost, fluorine, chlorine or bromine;

alkyl radical substituted by a halogen atom, is primarily so radical as CHCL2, CHBr2, CHF2, CCl3, CBr3, CF3CH2CF3CH2CH2CCl3CH2CH2CF3;

carbocyclic acid residue is in the first place, acetyl, propylaniline, batilly, isobutylene, p-valelly, isovaleryl, tert-weleily and picalilly.

Among the preferred compounds of the present invention include:

a) the compounds of formula (I) in which Z represents a hydrogen atom, b) the compounds of formula (I) in which R represents the radical (CH2)4Ar1in which Ar1consistent with the above, the compounds of formula (I) in which Ar1represents a phenyl radical substituted by one of the above radicals, such as radicals, in which Ar1represents phenyl PAA, first and foremost, the compounds of formula (I) in which Ar1is a 4-chloraniline radical, or those in which Ar1represents a phenyl radical substituted by one or more O-alkyl radical with up to 4 carbon atoms, in particular, those in which Ar1represents a phenyl radical substituted by one or more metaxylene radicals, and, primarily, the compounds of formula (I) in which Ar1is a 4-metoksifenilny radical, g) the compounds of formula (I) in which Ar1represents a heterocyclic aryl radical with 5 atoms, with the possibility of substitution, for example, thienyl radical, with the possibility of substitution, and, first of all, unsubstituted thienyl radical or imidazolidinyl radical, with the possibility of substitution, and, first of all, unsubstituted imidazolidine radical.

Among the preferred compounds of the present invention include compounds of formula (I) in which Ar1represents biphenylyl radical with the possibility of substitution. Under biphenylyl understand radical

< / BR>
The subject invention include the compounds of formula (I) in which Ar1before the plants can also be called the compounds of formula (I), in which R represents the radical X1Ar2in which X1is an alkyl radical comprising up to 6 carbon atoms and interrupted by radical and Ar2saves the above value.

Among these compounds include, in particular, compounds in which R represents the radical:

< / BR>
and the phenyl radical may be substituted by one or more of the above substitutes.

The object of the present invention, first and foremost, are the compounds of formula (I), the receipt of which is described below, and, primarily, the compounds of examples 1,2,3,4,11 and 15.

Among the most interesting compounds can also be called the product of example 28 or the products of examples 38 and 39.

The products of General formula (I) possess very high antibiotic activity against gram-positive bacteria, such as staphylococci, streptococci, pneumococci.

Therefore, compounds that are the subject of the present invention can be used as medicaments in the treatment of infections with sensitive germs, in particular in the treatment of staphylococcal infections, such as staphylococcal septicemia, the person who carbuncles, phlegmons, erysipelas and acne, such staphylococcal infection as primary or post-acute flu-like illness, pneumonia, pulmonary suppuration, such streptococcal infection, acute tonsillitis, otitis, sinusitis, scarlet fever, such pneumococcal infections, pneumonia, bronchitis, brucellosis, diphtheria, gonococcal disease.

The products that are the subject of the present invention also have activity against infections caused by these microbes, as Haemophilus Influenzae, Rickettsies, Mycoplasma pneumoniae, Chlamydia, Legionella, Ureaplasta, Toxoplasma, or microbes such as mycobacteria, Listeria, meningococci and Campylobacter.

Thus, the object of the present invention on the medical level, in particular as antibiotic funds, are also the products of formula (I) as described above, as well as their added salt are acceptable from a pharmaceutical point of view, inorganic or organic acids.

The object of the present invention on the medical level, in particular as antibiotic funds are also above the preferred products of example 1, namely the products of examples 1,2,3,4,11 and 15, as well as their salts that are acceptable from a pharmaceutical point of view.< their salts, acceptable from a pharmaceutical point of view.

The object of the present invention are also pharmaceutical compounds comprising, as an active start, at least one of the above medicines.

These compositions can be applied orally, by rectal, parenteral or local application to the skin or on the mucous membranes, but it is preferable to apply inside.

These compositions can be solid or liquid and can be any pharmaceutical form which is widely used in the treatment of the person, as, for example, simple or dragevent tablets, capsules, granules, suppositories, injectable preparations, ointments, creams, gels; they are produced by conventional methods. Active principle (active start) is inserted into the base, usually used in the manufacture of pharmaceutical compositions, such as talc, Arabic gum, lactose, amidon, magnesium stearate, cocoa butter, aqueous or anhydrous binder, fats of animal or vegetable origin, derived paraffin, glycols, various moisturizing, dispersion or emulsion agents, preservatives.

These compositions can also be in the form of powder, designed the ASS="ptx2">

Commonly used doses depend on the disease to be treated, the characteristics of the patient, method of application and the product. In the case of the product of example 2 or example 11 they can be, for example, from 50 to 300 mg per day for adults by ingestion.

The object of the present invention is also a method of obtaining compounds of formula (I), characterized in that the compound of formula (II):

(II)

in which Z' represents a residue of carboxylic acids comprising up to 18 carbon atoms, is exposed to agent that can selectively activate the hydroxyl in position 11 to obtain the compounds of formula (III):

(III)

in which R1represents the balance easily group, which is exposed to the base to obtain the compounds of formula (IV):

(IV)

after which the compound of formula (IV) is subjected to:

or the effects of the compounds of formula (V):

R-N=C=O (V)

in which R has the above significance, to obtain the compounds of formula (VI):

(VI)

which tsiklitiria either spontaneously by heating, or exposed to tsiklitiria means for obtaining compounds of formula (IA):<>/BR>or the impact of carbonyldiimidazole to obtain the compounds of formula (VII):

(VII)

and then the effects of the compounds of formula (VIII):

RNH2(VIII)

in which R has the above significance, to obtain the above compounds of formula (VI), which spontaneously tsiklitiria by heating, or exposed to tsiklitiria means to obtain the corresponding compound of formula (IAthen, if necessary, the said compound of formula (IA) is subjected to an allocator hydroxyl functional group in position 2' and/or, if necessary, the effects of acid to obtain the salt.

In preferred applications of the method which is the subject of the present invention:

a substance capable of selectively activate the hydroxyl in position 11 is sulfonovy anhydride, such as methanesulfonyl, paratoluenesulfonyl or triftormetilfullerenov anhydride,

the Foundation is able to create a double bond 10(11), is databaseconnection, for example DBU (or 1,8-diazabicyclo [5-4-0] undec-7-ene), Diisobutylene, 2,6-lutidine, 2,4,6-kallidin or tetramethylguanidine,

the reaction between the Tramin, morpholine, N-methylmorpholine, and cyclization of the compounds of formula (VI) occurs, either spontaneously or by heating at temperatures from +50oC to +100oC,

the reaction between the compound of formula (IV) and carbonyl diimidazol proceeds in the presence of a base such as sodium hydride, triethylamine, sodium carbonate, sodium bicarbonate or potassium, or in the absence of a base in a solvent such as methylene chloride, tetrahydrofuran or dimethylformamide,

the reaction between the compound of formula (VII) and compound RNH2flows in the environment of a solvent, such as acetonitrile, dimethylformamide or tetrahydrofuran, dimethoxyethane or dimethylsulfoxide, and the cyclization of the compounds of formula (VI) is, as a rule, during the reaction or due to the impact on the selected compound of formula (VI) such basis as tert-butyl potassium, in the environment of a solvent, such as tetrahydrofuran,

hydrolysis of the ester functional group in position 2' is carried out using methanol or aqueous hydrochloric acid,

the salt formation is carried out by conventional methods using acid.

Compounds of the formula (II) used as and the EC EEC 0.487.411.

Compounds of the formula RN=C=O and RNH2are also well-known products.

The compounds of formula RNH2can be obtained, for example by the method described in the journals of J. Med. Chem (1982), volume 25, page 947 and subsequent; Tetrahedron Letters, volume 32, No. 14, pages 1699-1702 (1991); J. Org. Chem. 54(18) 4298, 301 (1989); J. Org. Chem. 28 (101) 2589, 91 (1963) or in the German patent 3.406.416; J. Org. Chem. 6-895-901 (1941) or Synth. Commun 17 (14) 1741-8 (1987).

Some products of the formula (VIII) are new products and are themselves the subject of the present invention. Obtaining them is described below in the experimental part.

Thus, the following products are new products and are themselves the subject of the present invention:

4-(2-thienyl)butylamine,

4-(1,1 biphenyl)butylamine,

4-(4-were)butylamine,

4-(2,4-dimetilfenil)butylamine,

4-(2,4,6-trimetilfenil)butylamine,

4-(2-methoxyphenyl)butylamine.

The present invention naturally applies to products obtained by using the method of the present invention, namely, the products of formula (III), (IV), (VI) and (VII), in the first place, the connection of the formula (IV), the receipt of which is described below in the experimental part, and the corresponding connection 2i-3-de ((2,6-dideoxy-3-C-methyl-3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(4-chlorophenyl)butyl)imino)) - erythromycin

STEP A : 2'-acetate 3-de ((2,6-dideoxy-3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl-11-(methyl-sulfonyl)3-oxo erythromycin

In a nitrogen atmosphere with agitation add 17 g of 2'-acetate 3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl-3-oxo-eritromicina in 100 ml of pyridine. Then the mixture is cooled to +10oC and add 11,9 methanesulfonamido anhydride. Then the temperature is allowed to rise to the level of room and stand mixture, shaking, for 5 hours the precipitate is filtered. Then produce a concentrated, treated with water and extracted using ethyl acetate. The organic phase is washed with water, dried, filtered and concentrated. So get to 20.9 g of crude desired product, which was subjected to purification by salt formation using oxalic acid and allocation base with ammonia.

The result 15,16 g of the desired product (tPL210-212oC).

STAGE B : 2'-acetate 11-deoxy 10,11-didehydro 3-de (2,6-dideoxy-3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo erythromycin

When shaking injected compared to 8.26 g of the product obtained at Stage A, in 35 ml of acetone. Then on NUU mixture is treated with methylene chloride. The organic phase is washed with water, dried on sodium sulfate, filtered and concentrated. Thus obtain 10 g of the product, which is treated with ether. This is followed by centrifugation and washing with ethyl ether. The result 6,33 g of the desired product (tPL230-232oC).

STAGE: 2'-acetate 11-deoxy 10,11-didehydro 3-de (2,6-dideoxy-3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy)12-O-((1H-imidazol-1-yl)carbonyl) 6-O-methyl 3-oxo erythromycin

96 mg of a 50 percent solution of sodium hydride in oil is introduced into 15 ml of tetrahydrofuran. The resulting suspension is cooled to 0oC and one drop of injected solution 611 mg of the product obtained in the previous step, in 17 ml of tetrahydrofuran. Then at a temperature of 0oC enter a solution of 486 mg of carbonyldiimidazole in 15 ml of tetrahydrofuran. Stirring continued for 4 hours 30 minutes After the temperature of the reaction mixture is allowed to rise to the level of room and perform the filtering and concentrating. Then collect in ethyl acetate, washed with a solution of dihydrogenphosphate sodium, extracted using ethyl acetate, dried, filtered and concentrated. The result 852 mg of the desired product which is used without add the-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl ((4-(4-chlorophenyl)butyl)imino))erythromycin

In 852 mg of the product obtained in the previous step, add a solution comprising 1.1 g of 4-(4-chlorophenyl)butylamine (obtained as described in the journal J. Med.Chem. 1982, volume 25, No. 951), 3 ml of acetonitrile and 0.3 ml of demineralized water.

The mixture is shaken for 4 hours at a temperature of +55oC. Then the reaction medium was poured into a solution of dihydrogenphosphate sodium is extracted using methylene chloride, washed with water, dried, filtered and concentrated. Thus obtain 1.4 g of a viscous liquid, which is subjected to chromatography on silica (eluant: methylene chloride/isopropanol (95: 5)). Homogeneous phase is collected in the SMS (SMS - thin layer chromatography) and concentrate. The result of 0.44 g of a viscous fluid, which is thickened simple isopropyl ether, centrifuged and dried at a temperature of +70oC. Thus receive 0,262 g of the desired product (tPL179-181oC).

STAGE D: 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl ((4-(4-harperbury)imino)) - erythromycin

A mixture comprising of 0.23 g of the product obtained in the previous step, and 6 ml of methanol, incubated with shaking for 15 h at Rennie (eluant: ethyl acetate/methanol/ammonia (9 : 1 : 0,01). Homogeneous phase is collected in the SMS (thin layer chromatography), filtered and concentrated. Thus obtained 0.14 g of product, which is thickened simple isopropyl ether, centrifuged and dried at a temperature of +80oC under reduced pressure. The result 0,094 g of the target product (tPL194-196oC).

D: + 23oC CHCl3(1%)

EXAMPLE 2: 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl ((4-(4-methoxyphenyl)butyl)imino)) - erythromycin

STEP A: 2'-acetate 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl ((4-(4-methoxyphenyl)butyl)imino))erythromycin

Treatment is carried out as in Stage G of example 1, on the basis of 0.8 g of 2'-acetate 11-deoxy 10,11-didehydro 3-de((-2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 12-O-((1H-imidazol-1-yl)carbonyl) 6-O-methyl 3-oxo erythromycin, 3 ml of acetonitrile and 1.0 g of 4-(4-methoxyphenyl)butylamine obtained in accordance with the method, described in the journal Tetrahedron Letters 32, 1699-1702, (1991). The result is 0.8 g of the desired product as a mixture of acetylated and deacetylating products in the 2' position. Chromatography is the Il 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((4-(4-methoxyphenyl)butyl)imino)erythromycin

Treatment is carried out as in Stage D of example 1, on the basis of 0.8 g of crude product obtained in the previous step. The result 0,237 g of the desired product (tPL193-195oC).

D: +22o3(C=1%CHCl3)

EXAMPLE 3: 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((4-(2-thienyl)butyl)imino))erothromycin

STEP A: 2'-acetate 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl ((4-(2-thienyl)butyl)imino))erythromycin

Treatment is carried out as in Stage G of example 1, on the basis of 0.85 g of 2'-acetate 11-deoxy 10,11-didehydro 3-de((-2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 12-O-((1H-imidazol-1-yl)carbonyl) 6-O-methyl 3-oxo erythromycin, 3 ml of acetonitrile and 0.3 ml of water and 0,822 g of 4-(2-thienyl)butylamine (the receipt of which is described below). The result 0,212 g of the desired product (tPL218-220oC).

STEP B: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((4-(2-thienyl)butyl)imino)erythromycin

Treatment is carried out as in Stage D of example 1, on the basis of 0.182 g of the product obtained in the previous step, and 6 ml of methane is3)

EXAMPLE 4: 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((4-(1,1'-biphenyl)4-yl)butyl)imino)) - erythromycin

STEP A: 2'-acetate 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl ((4-(1,1'-biphenyl)4-yl)butyl)imino))erythromycin

Within 5 h, heated at a temperature of +55oC mixture containing 3.5 ml of acetonitrile, 0.7 g 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-imidazol-1-yl)carbonyl) 6-O-methyl 3-oxo erythromycin, 0.3 ml of water, 1.1 g of biphenylamine (the receipt of which is described below).

Then the reaction medium was poured into a saturated aqueous solution of dihydrogenphosphate sodium, extracted using ethyl acetate and filtered. The aqueous phase allow to settle, and then extracted using ethyl acetate and washed with water, dried, filtered and concentrated. Thus obtained 1.1 g of the desired product.

STEP B: 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((4-(1,1' -biphenyl)4-yl)butyl)imino)) - erythromycin

1.1 g of product, parature. Then concentrate, diluted with 3 ml of methylene chloride, dried, filtered and concentrated. Thus receive the products, which are subjected to recrystallization in a mixture of simple isopropyl ether ethyl ether (9: 1). Then perform centrifugation, dried at a temperature of +80oC and get 0,148 g of the target product (tPL166~168oC).

Range of Yarm - CDCl3< / BR>
1,34 (s) and 1.47 (s) - 6 and 12CH3; 2.68 (m) - CH2-F; of 3.05 to 3.25 - H10H4and H'2; 3,60 (s) - H11; 3,67 (m) ~ 7,26-7,49 - internal phenyl, 7,31 H in the para-position, ~7,42 H in the meta-position, ~7,58 H in the ortho-position - external phenyl.

Microanalysis:

Calculated, %: 68.75 kilopascals; H 8,35; N 3,41;

Found, %: From 68.6; H 8,5; N 3,3.

The operation was carried out as described above on the basis of the 2'-acetate 11-deoxy 10,11-didehydro 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 12-O-((1H-imidazol-1-yl)carbonyl)6-O-methyl 3-oxo erythromycin and related amines. This has resulted in the following products:

EXAMPLE 5: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((4-(2-methoxyphenyl)butyl)imino)erythromycin

tPL190~192oC

alphaDXI) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((2-(feniletilic)ethyl)imino))eritromicin

tPL190~192oC

D: -11,5o(C = 1% CHCl3)

EXAMPLE 7: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((4-(4-nitrophenyl)butyl)imino)) - erythromycin

tPL200~202oC

D+15,5o(C = 1% CHCl3)

EXAMPLE 8: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((4-(2,4-dimetilfenil)butyl)imino)) - erythromycin

tPL183~185oC

D:: +21o(C = 1% CHCl3)

EXAMPLE 9: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((4-(4-were)butyl)imino)erythromycin

tPL200~202oC

D: +23o(C = 1% CHCl3)

EXAMPLE 10: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((4-(2,4,6-trimetilfenil)butyl)imino)) - erythromycin

tPL188~190oC

D: +24o(C = 1% CHCl3)

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

tPL212~214oC

D: +26,2-O-methyl 3-oxo 12,11-(oxycarbonyl((4-(3-methoxyphenyl)butyl)imino)) - erythromycin

tPL196~198oC

D: +18,8o(C = 1% CHCl3)

EXAMPLE 13: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((4-(phenylamino)4-oxobutyl)imino)) - erythromycin

tPL190~192oC

D: +8o(C = 1% CHCl3)

EXAMPLE 14: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((3-(phenylthio)propyl)imino)) - erythromycin

tPL204~206oC

D: +19o(C = 0.9% of CHCl3)

EXAMPLE 15: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((2-((phenylcarbamoyl)amino)ethyl)imino)) - erythromycin

tPL240oC

D: -2o(C = 1% CHCl3)

EXAMPLE 16: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((3-phenoxypropan)imino)) - erythromycin

tPL222~225oC

D: +20o(C = 0.9% of CHCl3)

EXAMPLE 17: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-((2-(phenylmethoxy)ethyl)imino)) - erythromycin

tPL207oC

EXAMPLE 18: 11,12-dideoxy 3-de((2,6-dideoxyinosine

tPL218~220oC

D: +15,5o(C = 1% CHCl3)

EXAMPLE 19: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((4-(1H-indol-yl)butyl)imino)) - erythromycin

tPL208~212oC

D: +22o(C = 1% CHCl3)

EXAMPLE 20: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((4-(3-AMINOPHENYL)butyl)imino)) - erythromycin

tPL200~202oC and 210oC

D: +23o(C = 1% CHCl3)

EXAMPLE 21: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((4-(2-chlorophenyl)butyl)imino)) - erythromycin

tPL193~195oC

D: +23o(C = 1% CHCl3)

EXAMPLE 22: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((4-(3-chlorophenyl)butyl)imino)) - erythromycin

tPL191~193oC

D: +22o(C = 1% CHCl3)

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

tPL220~222oC

EXAMPLE 24: 11,12-di is util)phenyl)butyl)imino)) - erythromycin

tPL134~136oC

EXAMPLE 25: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((4(4-(1-oxoethyl)phenyl)butyl)imino)) - erythromycin

tPL170~172oC

EXAMPLE 26: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((3-(phenylsulfonyl propyl)imino)) - erythromycin

tPL202~204oC

D: +21o(C = 1% CHCl3)

EXAMPLE 27: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((4-(4-butylphenyl)butyl)imino)) - erythromycin

tPL134~135oC

D: +19,5o(C = 1% CHCl3)

EXAMPLE 28: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((4-(4-chinoline)butyl)imino)erythromycin

tPL170~172oC

EXAMPLE 29: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((4-((2,2'-Bethoven)5-yl)butyl)imino)) - erythromycin

tPL147~149oC

EXAMPLE 30: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((3-oxo 3-((2-thiazol nanosil)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((4-(4-ethylphenyl)butyl)imino)) - erythromycin

tPL191~193oC

D: +20o(C = 1% CHCl3)

EXAMPLE 32: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl((4-(4-(4-chlorbenzoyl)3-were)butyl)imino)) - erythromycin

tPL143~145oC

D: +8o(C = 1% CHCl3)

EXAMPLE 33: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl(4-(N-fluoren-2-yl)butyl)imino)) - erythromycin

tPL215~217oC

D: +20o(C = 1% CHCl3)

EXAMPLE 34: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl(4-(6-amino-N-purine-9-yl)butyl)imino)) - erythromycin

D: +13o(C = 1% CHCl3)

EXAMPLE 35: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl(4-(4-phenoxyphenyl)butyl)imino)) - erythromycin

tPL154~156oC

D: +16o(C = 1% CHCl3)

EXAMPLE 36: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl(4-(2-phenyl-1H-imidazol-1-yl)butyl)imino)) - erythromycin

tPL132-134oC

D: +13o(C = 1% Snxo 12,11-(oxycarbonyl(4-(4-forfinal)butyl)imino)) - erythromycin

tPL180oC

EXAMPLE 38: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl(4((1H-benzimidazole-1-yl)butyl)imino)) - erythromycin

tPL194-196oC

Rf = 0,43 (CHCl2+ MeOH + NH4OH(95 : 5 : 0,2))

EXAMPLE 39: 11,12-dideoxy 3-de((2,6-dideoxy 3-C-methyl 3-O-methyl-L-abovecaptionskip)oxy) 6-O-methyl 3-oxo 12,11-(oxycarbonyl(4-(2-phenyl-5-thiazolyl)butyl)imino)) - erythromycin

tPL118-120oC

Rf = 0,24 (AcOEt c 4% TEA)

Acting in the aforementioned manner, there were obtained the following compounds of formula (I) (see end of text).

PREPARATION 1 : 4-(2-thienyl)butylamine

STAGE A: 4-(2-thienyl)butylamide

For 3 hours at a temperature of +60oC shake the mixture consisting of 40 ml of dichloroethane, 5,1 ml 4-(2-thienyl) butane acid and 10.2 ml of chloride tiomila. Then the dichloromethane is evaporated, the resulting product is poured into concentrated ammonia, cooled to a temperature of 0oC. the resulting product is centrifuged and dried. So get the 4.29 g of the product, which is subjected to chromatography on silica (eluant: methylene chloride/methanol (92: 8)). Homogeneous phase is collected in the SMS, concentrated and filtered. The floor is g of the desired product (tPL84-86oC).

STAGE B: 4-(2-thienyl)butylamine

At a temperature of 0oC drop impose 1.1 g of 4-(2-thienyl)butylamide in a mixture comprising 30 ml of tetrahydrofuran and 1.06 g of hydride layalina. Then the temperature is allowed to rise to the level of room, shaken at room temperature for 4 h 30 min and then for 1 h at a temperature of +30oC and for 16 h at room temperature. Then cooled to 0oC, add 3 ml of a mixture of water and tetrahydrofuran (2:1), and then 8 ml of water and 6 ml of a saturated solution of double potassium-sodium tartrate salt. After that, filter and concentrate. The resulting product absorb ethyl ether, washed with sodium carbonate and then with water, and extracted the aqueous phase using ethyl ether. The organic phases are collected, dried on sodium sulfate, filtered and canceryou. So get of 0.91 g of product which was dissolved in 12 ml of a mixture of ethyl acetate and ethanol (95: 5). Then cooled to a temperature of 0oC and add the soda solution of hydrochloric acid in ethyl acetate. The hydrochloride of the desired product precipitates. After that, perform centrifugation, dried and receive 0,675 g of the target product in video, extraction with use of ethyl acetate, drying on sodium sulfate, filtration and concentration.

PREPARATION 2: 4-[(1,1'-biphenyl)-4-yl] 3-butylamine

STEP A: N-[(1,1'-biphenyl)-4-yl] 3-butenyl]phthalimide

The suspension, containing 150 ml of tetrahydrofuran, 5,46 g of 4-phenylbenzene and 15.9 g of bromide triphenylphosphine N-(3-bromopropyl) phthalimide, cooled to a temperature of -40oC. Then injected 3,37 g of potassium tert-butylate. The temperature is allowed to rise to -15oC and incubated, shaking at -15oC for 1 h

After that, the mixture was poured on ice, extracted using ethyl acetate, washed with water, dried the organic phase in Na2SO4filter and concentrate. Thus obtain 19 g of the product, which is dissolved in methylene chloride and subjected to chromatography on silica (eluant: ethyl acetate/hexane (3:7)). Then execute the concentration, and thicken with hexane, centrifuged, and dried under reduced pressure and release 8.5 g of the desired product (tPL112~114oC).

Microanalysis:

Calculated, %: C 81,56; H 5,42; N 3,96;

Found, %: From 81.4; H 5,3; N 3,8.

STAGE B: 4-[(1,1'-biphenyl)4-yl]3-butenylamine

The boiling point is brought secure allowed to sink to the level bedroom, the precipitate is filtered and washed with ethanol. Then concentrated, poured into 2 n hydrochloric acid and extracted using ethyl acetate. Then the organic phase is washed with water, dried, filtered and concentrated under reduced pressure. The result 2,89 g of the desired product (tPL188~ 194oC).

STAGE B: 4-[(1,1'-biphenyl)4-yl]3-butylamine

In hydrogenation installation placed 17 ml of methanol, 1,74 g of the product obtained at Stage B, and 0.17 g of catalyst Pd 10% on coal. The hydrogenation is performed in throughout the night. Then filtered, washed and concentrated. The resulting product is condensed with ethyl acetate, frozen, centrifuged and dried under reduced pressure at a temperature of +80oC. the result of 1.55 g of the target product (tPL260oC).

PREPARATION of 3: 4-(2,4,6-trimetilfenil)butylamine

The operations are carried out as in preparation 2. The result is the target product in the form of hydrochloride.

tPL218~220oC

PREPARATION 4: 4-(4-were)butylamine

The operations are carried out as in preparation 2. The result is the target product.

tPL202~204oC

Prigot target product.

tPL126~128oC

PREPARATION 6: 4-(2-methoxyphenyl)butylamine

The operations are carried out as in preparation 2. The result is the target product.

tPL122~124oC

PREPARATION 7: 4-(4-phenoxyphenyl)butylamine

The operations are carried out as in preparation 2. The result is the target product in the form of hydrochloride (tPL172-174oC), which in turn amine by extraction using ethyl acetate in an ammonia environment.

Preparation 8: 4-(2-phenyl-1H-imidazol-1-yl)butylamine

STEP A: N-[4-(2-phenyl-1H-imidazol-1-yl)butyl]phthalimide

At room temperature for 1 h 15 min 1.73 g of sodium hydride in 5 cm3of dimethylformamide add 4,32 g of 2-phenylimidazole dissolved in 25 cm3of dimethylformamide. Then add 10,97 g of N-(4-bromobutyl)phthalimide 33 cm3of dimethylformamide and shaken for 48 h at room temperature. Then perform the extraction using ethyl acetate, dried, the solvent is evaporated, chromatografic the residue on silica (eluant: ethyl acetate/methylethylamine (95:5)), absorb residue with ether, frozen, centrifuged crystals, dried and gain of 1.11 g of the desired primerate add at 5.64 g of the product, the obtained Phase And dissolved in 175 cm3of ethanol. Then for 16 h, heated at the boiling point, remove the solvent, absorb the residue in 25 cm32 N. sodium hydroxide and 50 cm3water, extracted using ethyl acetate, dried, the solvent is evaporated, chromatografic the residue on silica (eluant: methylene chloride/methanol/ammonia (9:1:0,02) and gain of 1.95 g of the desired product. Rf = 0,12.

PREPARATION 9: 4-(6-amino-N-purine-9 yl)butylamine

STEP A: N-[4-(6-amino-N-purine-9-yl)-3-butenyl]phthalimide

3.4 g of sodium hydride is added to 9.6 g of adenine 270 cm3of dimethylformamide. Then shaken for 2 h 30 min, add 20 g of N-(4-bromobutyl)phthalimide, shaken at room temperature for 74 h, filtered, evaporated the solvent of the filtrate, washed the residue with ether, water, ethanol and again with ether, after which vyshivayut. The residue is dissolved in methanol at a temperature of +65oC, freeze and get 15,00 g of the desired product.

STAGE B: 4-(6-amino-N-purine-9-yl)butylamine

For 22 h heated at boiling temperature under reflux 14,01 g of the product obtained in the previous step, 728 cm3ethanol and 2.02 cm3izhitsa to the level of the room, filtered, evaporated ethanol, dried and receive a 10.5 g of crude product.

8,72 g crude product absorb 50 cm3of methylene chloride, add 9,42 cm3triperoxonane acid was incubated for 16 h at room temperature, treated residue in ether, filtered, dried and receive 10,24 g of the desired product in the form of triptoreline.

PREPARATION 10: 4-(1H-benzimidazole-1-yl) butylamine

Operations are performed as in preparation 8, using at the initial stage of 4.13 g of benzimidazole. There were thus obtained of 7.96 g of the intermediate phthalimide (tPL136-138oC), which enter into reaction with 2.5 cm3hydrazine hydrate is added. The result of 4.99 g of the target product with oxalic acid converted into the oxalate (tPL190-192oC).

PREPARATION 11: 2-phenyl-5-(4-aminobutyl)thiazole

Operations are performed as in preparation 9. The result is the target product (tPL62-64oC).

To illustrate the claimed pharmaceutical compositions described below are examples of possible pharmaceutical forms:

For tablets containing the active substance 150 mg, mg:

Active substance - 150,00

Monohydrate BR> Colloidal anhydrous silica - 9,00

Purified water, a Sufficient quantity of

For tablets weighing 300 mg

For gelatine capsules with a content of active substance 5 mg, mg:

Active substance - 5,00

Lactose - 276,50

Modified maize starch - 50,0

Talc - 25,00

Colloidal anhydrous silica - 0,50

Magnesium stearate - 1,00

For gelatine capsules 358 mg

For gelatine capsules with a content of active substance 100 mg, mg:

The active substance is 100.00

Lactose - 276,50

Modified maize starch - 50,00

Talc - 25,00

Colloidal anhydrous silica - 0,50

Magnesium stearate - 1,00

For gelatine capsules 453 mg

Pharmacological study of the products of the invention

Method of cultivation in liquid medium.

Prepare a series of tubes, which is allocated the same amount of sterile nutrient medium. Then in each tube pour in increasing the number of used product, after which each tube is sown bacterial strain.

After incubation in an oven for 24 h at a temperature of +37oC inhibition of growth is estimated by p is in micrograms per cm3.

Thus were obtained the following results (see table 1).

In addition, the products of examples 1,2,3,4,11 and 15 showed significant activity against gram-negative bacterial strains of Haemophilus Influenzae 351HT3, 351CB12, 351CA1 and 351GR6.

1. Derivatives of erythromycin a General formula I

< / BR>
in which R is a group (CH2)nAr1where n is an integer from 1 to 6; Ar1- carbocyclic aryl group containing up to 18 carbon atoms, substituted by one or more substituents selected from the group comprising a carboxyl group in free form, in the form of salts, esters or amides; halogen atoms; groups of NO2; linear or branched alkyl groups containing up to 12 carbon atoms, or linear or branched O-alkyl groups containing up to 12 carbon atoms; - 5 - 6-membered heterocyclic aryl group containing one or two heteroatoms in the ring selected from nitrogen atoms, and sulfur;

or R is a group XAr2where X is an alkyl group containing up to 6 carbon atoms and interrupted by a group Ar2- the above-mentioned aryl or heteroaryl group Ar1;

Z is a hydrogen atom or the residue of carbocyclic.

2. The compound of formula (I) under item 1, where Z represents a hydrogen atom.

3. The compound of formula (I) under item 1 or 2, where R is a group (CH2)4Ar1in which Ar1matter specified in paragraph 1.

4. The compound of formula (I) according to any one of paragraphs.1 to 3, where Ar1represents phenyl, substituted one of the radicals listed in paragraph 1.

5. The compounds of formula (I) under item 4, where Ar1represents phenyl substituted by one or more halogen atoms.

6. The compounds of formula (I) under item 5, where Ar1represents phenyl substituted by one or more chlorine atoms.

7. The compounds of formula (I) under item 6, where Ar1represents 4-chlorophenyl.

8. The compounds of formula (I) under item 4, where Ar1represents phenyl substituted by one or more O-alkyl groups containing up to 4 carbon atoms.

9. The compounds of formula (I) under item 8, where Ar1represents phenyl substituted by one or more metaxylene groups.

10. The compounds of formula (I) under item 9, where Ar1represents a 4-methoxyphenyl.

11. The compounds of formula (I) PP.1 to 3, where Ar1represents a 5-h is yet thienyl.

13. The compounds of formula (I) under item 11, where Ar1is imidazolyl.

14. The compounds of formula (I) according to any one of paragraphs.1 to 3, where R is a radical XAr2where X is an alkyl radical containing up to 6 carbon atoms and interrupted by a group where Ar2have the above values.

15. The compounds of formula (I) according to any one of paragraphs.1 to 3, where R represents a group

< / BR>
where phenyl is substituted by one or more substituents specified in paragraph 1 for the group Ar1.

16. The compounds of formula (I) under item 1, representing the following connections: 11, 12 dideoxy-3-de((2,6-dideoxy-3-C-methyl-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl ((4-(4-chlorophenyl)butyl)imino)) - erythromycin, 11, 12 dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-L-abovecaptionskip)oxy)6-O-methyl-3-oxo 12,11-(oxycarbonyl((4-(4-methoxyphenyl)butyl)imino)erythromycin, 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(2-thienyl)butyl)imino)erythromycin, - 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(1H)-imidazol-1-yl)butyl)imino)erythromycin, 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-is in.

17. The pharmaceutical composition of antibacterial action, containing the active beginning of the erythromycin derivative, characterized in that as a derivative of erythromycin, it contains an effective amount of at least one of the compounds described in paragraphs 1 - 16.

18. The method of obtaining compounds of formula (I) specified in paragraph 1, characterized in that the compound of formula II

< / BR>
where Z1represents the balance of carboxylic acids containing up to 18 carbon atoms,

subjected to the interaction of the agent is capable of selectively activate the hydroxyl in position 11, such as sulfonovy anhydride, for example, methanesulfonyl, paratoluenesulfonyl or triftormetilfullerenov anhydride, to obtain the compounds of formula III

< / BR>
where R1represents the balance lakodalmas group, which is subjected to interaction with the substrate and is capable of forming a double bond at position 10 or 11, for example, databaseconnection, diisobutylaluminum, 2,6-lutidine, 2,4,6-collidine or tetramethylguanidine, obtaining the compounds of formula IV

< / BR>
after which the compound of formula IV is subjected to or interaction with the compound of the formula V
arbitrarily cichlisuite when heated with obtaining the compounds of formula IAND< / BR>
< / BR>
corresponding to the compound of formula I, where Z is not a hydrogen atom, or interaction with carbonyl diimidazol with obtaining the compounds of formula VII

< / BR>
further interaction with the compound of the formula VIII

RNH2,

where R has the above significance,

with obtaining the above compounds of formula VI, which spontaneously cyclizes when heated to obtain the corresponding compounds of formula IANDafter which, if necessary, the specified connection formula IANDsubjected to interaction with gidrolizuut agent to obtain the hydroxyl group in position 2' and/or, if necessary, with an acid to obtain the salt.

19. Intermediate compounds on p. 18 of formulas III, IV, VI and VII.

20. The intermediate connection method according to p. 19, which represents a 2'-acetate-11-deoxy-10,11-didehydro-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-L-abovecaptionskip)oxy)6-O-methyl-3-oxo-erythromycin or the corresponding 2'-hydroxyl derivative.

21. Intermediate compounds of the method according to p. 19 formula VIII, a 4-(2-thienyl)butylamine, 4-(1,1-biphenyl)butylamine, 4-(4-were)butylamine, 4-(2,4-timetype is riznica:

02.07.93 corresponds to the last two compounds p. 16 claims;

05.11.92 - all other features of the invention in PP.1 - 12, 14 - 21.

 

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