New erythromycin derivatives, method for their production and use as medicaments

 

(57) Abstract:

The invention relates to a derivative of erythromycin formulas (I)

in which Y denotes a hydrogen atom or fluorine; n denotes an integer from 1 to 8; Z represents a hydrogen atom or a residue of carboxylic acid, and in which pyrazol cycle substituted heteroaryl radical, which contains one nitrogen atom; and their salt adducts with tilotama. The compounds of formula (I) possess antibiotic properties. The invention relates to a method for producing compounds of formula (I) containing their pharmaceutical compositions and intermediate compounds for their preparation. 4 N. and 8 C.p. f-crystals, 2 tab.

The present invention relates to new derivatives of erythromycin, method of their production and use as medicaments.

The object inventions are the compounds of formula (I):

where:

Y denotes a hydrogen atom or fluorine;

n denotes an integer from 1 to 8;

Z denotes a hydrogen atom or a residue of carboxylic acid, in which pyrazol cycle substituted by heteroaryl containing one nitrogen atom, as well as their salt adducts with acids.

As an example, salt adducts nastasi acids: acetic, propionic, triperoxonane, maleic, tartaric, methansulfonate, benzolsulfonat, p-toluensulfonate, hydrochloric, Hydrobromic, itestosterone, sulfuric, phosphoric and is particularly applicable stearic, atilanica or laurylsulphate.

More specifically, the present invention relates to compounds of formula 1 in which Z is a hydrogen atom, the compounds I, where n is equal to 4 and to compounds I in which the radical

substituted radical

More specifically, the present invention relates to compounds of the formula I in which Z is a hydrogen atom.

Of the preferred compounds it should be called a connection, which is shown below in the experimental part, and from the latter it is worth mentioning that compound obtained in example 1.

Compounds of General formula I have a very high antibiotic activity on gram-positive bacterial strains of staphylococci, streptococci and pneumococci.

Thus, the compounds of the present invention can be used as drugs in the treatment of infections, the media are susceptible to medicines, AOW infections of the face and skin, piodermitov, septic or suppurating wounds, boils, carbuncles, phlegmon, born and acne, such staphylococcal infections as primary or Poligraphia acute tonsillitis, pneumonia, pulmonary suppuration, such streptococcal infections such as acute tonsillitis, otitis, sinusitis, scarlet fever, pneumococcal infections such as pneumonia, bronchitis, and brucellosis, diphtheria and gonococcal infections.

Compounds of the present invention also have activity against infections caused by such bacteria like Haemophilus influenzae, Rickettsies, Mycoplasma pneumoniae, Chlamydia, Legionella spp., Ureaplasma, Toxoplasma or bacteria of the family of Mycobacterium.

The object of the invention is also the use as medicaments and, more specifically, as antibiotic medicines defined above of compounds of formula I and their pharmaceutically acceptable salt adducts with mineral and organic acids.

More specifically, the invention proposes to use as a medicinal product, namely antibiotic drug, the compound of example 1 and its pharmaceutically acceptable salts.

The invention relates also to pharmaceutical compositions, with the ti composition can be applied orally, rectally, parenterally or topically by application to the skin or mucosal tissue, however, the preferred method of administration is oral.

The above composition may be solid or liquid and is available in commonly used in medicine dosage forms, such as, for example, as prepared in the usual way simple or dragevent tablets, gelatin capsules, granules, suppositories, injectable preparations, ointments, creams, gels. The active principle or active principle may be incorporated in excipients commonly used in pharmaceutical compositions, such as talc, gum Arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous and non-aqueous solvents, animal and vegetable oils, paraffin derivatives, glycols, various moisturizing agents, dispersing agents or emulsifying agents, preservatives.

The composition can also be in the form of a powder intended for dilution at the time of application in a suitable diluent, such as sterile pyrogen-free water.

The dose administered depends on the nature of the disease, the patient, route of administration and drug used. This dose may, for example, be from 50 to 3000 mg per day for an adult at the PE the formula I, namely, the compound of formula II:

in which Y has the above value, and M denotes the remainder of the acid is treated with a compound of formula III:

in which the heterocyclic radical may be substituted as specified above, to obtain the compounds of formula 1 in which Z represents the balance of acid and then, if necessary, the connection 1 is subjected to the action agent release hydroxyl in position 2' agent in order to obtain the corresponding compounds of formula I in which Z is a hydrogen atom, followed, if desired, by adding acid to obtain the salt.

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

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

the formation of salts is carried out using acids, using traditional methods.

The compounds of formula II in which Y is a hydrogen atom and which are used as starting compounds described and claimed in European patent is provided with means, below in the experimental part.

The invention relates to new chemical products. representing the compounds of formula III and, in particular, the compounds of formula III, which are given in the experimental part.

Example 1

11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-abovecaptionskip)oxy]-6-0-methyl-3-oxo-12,11-[oxycarbonyl[[4-[3-(3-pyridinyl)-1H-pyrazole-1-yl]butyl]imino]]-erythromycin.

A mixture of 26 cm3acetonitrile, 2.5 cm3water, 5,13 g obtained below (preparation 1) amine and 6.20 g of 2'-acetate and 12-(1H-imidazol-1-icarbonell)10,11-didehydro-11-deoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-abovecaptionskip)oxy]-6-0-methyl-3-oxo-erythromycin heated for 21 hours at 55C, pour the reaction mixture into water, extracted with ethyl acetate and dried. Get 8,02 g of product, which is injected in the 70 cm3of methanol. The reaction mixture is heated at boiling temperature under reflux for 1.5 hours resulting product chromatographic on silica gel, elwira a mixture of methylene chloride, methanol and ammonium hydroxide in the ratio 95:5:0.5. Get 3,59 g of the product with so pl. 143-S.

Results the cooking CLASS="ptx2">Stage A:

2-[4-[3-pyridinyl]-1H-pyrazole-1-yl]butyl]-1H-isoindole-1,3(2H)-dione.

15,45 g of 3-(1H-pyrazole-3-yl)pyridine obtained by the method described in SA R d (1968), added dropwise over 1 h to a mixture of 20 ml of dimethylformamide (DMF) and 6.13 g of sodium hydride, keeping the temperature below 30C or equal to 30C. Then add dropwise a solution of 29,90 g of 2-(4-bromobutyl)-1H-isoindole-1,3(2H)-dione and 110 ml of DMF, stirred for 30 min at room temperature, concentrated, poured into 300 ml) cooled to 10C water, extracted with ethyl acetate, washed with water, dried, filtered and concentrated. Absorb with methylene chloride, dried, filtered and concentrated. Get 35,87 g of the product, which crystallized from diethyl ether, drained, washed with water and dried, obtaining 22,93 g of the target product.

Stage:

3-(3-pyridinyl)-1H-pyrazole-1-butanamine

7 ml of hydrazine hydrate is added to the suspension containing 450 ml of ethanol and 22,33 g of the product of stage a and refluxed for 15 hours then evaporated ethanol, the reaction mixture is stirred with 200 ml of ethyl acetate, washed with salted water, dried, filtered and concentrated. Get 9.60 g of the target product.

Example 2

11,12-didel[[4-[3-(3-pyridinyl)-1H-pyrazole-1-yl]butyl]imino]]-erythromycin.

By repeating the above operations, but on the basis of the corresponding derivative of formula II containing fluorine in position 2, obtained as described below, obtain the target product with so pl. 117-S.

Obtaining the compounds of formula (II), which means a fluorine atom 2'-acetoxy-2-fluoro-12-oxycarbonate)-11-deoxy-10,11-didehydro-3-de[[2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-abovecaptionskip)oxy]-6-0-methyl-3-oxo-erythromycin.

Stage A:

11-deoxy-10,11-didehydro-3-de[(2,6-dideoxy-3-0-methyl-alpha-L-abovecaptionskip)oxy]-6-0-methyl-3-oxo-erythromycin

The mixture 8,722 g 2'-acetate 11-deoxy-10,11-didehydro-3-de[(2,6-dideoxy-3-0-methyl-alpha-L-abovecaptionskip)-oxy]-6-0-methyl-3-oxo-erythromycin and 350 ml of anhydrous methanol (EP 596802) is stirred for 44 h, receiving 8,794 g of the target product.

Stage:

2'-trimethylsilyloxy-11-deoxy-10,11-didehydro-3-de[(2,6-dideoxy-3-0-methyl-alpha-L-abovecaptionskip)-oxy]-6-0-methyl-3-oxo-erythromycin.

The mixture is 3.08 g of the product obtained in the previous phase, 340 mg of imidazole, 32 ml of anhydrous tetrahydrofuran (THF) and 1.06 ml hexamethyldisilazane stirred for 4 days at room temperature, evaporated to dryness and absorb a mixture of 60 ml of chloride METI irout with methylene chloride, dried and evaporated to dryness, obtaining 3,345 g of the target product.

Stage WITH:

2'-trimethylsilyloxy-2-fluoro-11-deoxy-10,11-didehydro-3-de[(2,6-dideoxy-3-0-methyl-alpha-L-abovecaptionskip)oxy]-6-0-methyl-3-oxo-erythromycin.

1,24 ml of 0.97 M solution of potassium tert-butylate in THF was added when the temperature is-12C in the atmosphere of argon to a solution of 668 mg of 2'-trimethylsilyloxy-de-11-deoxy-10,11-didehydro-3-de[(2,6-dideoxy-3-0-methyl-alpha-L-abovecaptionskip)-oxy]-6-0-methyl-3-oxo-erythromycin 6.7 ml of anhydrous THF. Stirred for 5 min and add 378 mg of N-fluoro-dibenzalacetone. Stirred for 10 min at-12C and within 1.5 h raise the temperature to room temperature. Then isolate and purify the desired product. Exit 695 mg

Stage D:

2-fluoro-11-deoxy-10,11-didehydro-3-de[(2,6-dideoxy-3-0-methyl-3-C-methyl-alpha-L-abovecaptionskip)oxy]-6-0-methyl-3-oxo-erythromycin.

The mixture 5,476 g of the product of example 2,50 ml THF and 11.2 ml of 1 M solution of tetrabutylammonium in THF is stirred for 3.5 h, the solvent is distilled off, add 37 ml of ethyl acetate, 37 ml of water and 7.5 ml of 20% ammonia solution, stirred for further 10 min, decanted and extracted with ethyl acetate. The extract solution is dried, filtered and evaporated to dryness. Poluotnosheniyam 99:1, then 98:2, 97:3, 96:4, 95:5. Get 2,452 g of the target product.

Stage E:

2'-acetoxy-2-fluoro-11-deoxy-10,11-didehydro-3-de[(2,6-dideoxy-3-0-methyl-alpha-L-abovecaptionskip)-oxy]-6-0-methyl-3-oxo-eritromicin.

of 1.02 g of the product of stage A, 10 ml of methylene chloride and 241 l acetic anhydride is maintained with stirring for 3 hours, evaporated and add 10 ml of water and 10 ml of ethyl acetate. After that, the temperature of the reaction mixture was raised to room for 1 hour with stirring, decanted, dried and evaporated. Obtain 1.01 g of the target product.

Stage F:

2'-acetoxy-2-fluoro-12-(oxycarbonate)-11-deoxy-10,11-didehydro-3-de[(2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-abovecaptionskip)oxy]-6-0-methyl-3-oxo-erythromycin.

0,388 g carbonyldiimidazole and 24 l 1,8-diazabicyclo[5.4.0]undec-7-ene added at 0C to a solution of 1.01 g of the product of the previous step in 10 ml of anhydrous THF, distilled THF and add 10 ml of water and 10 ml of ethyl acetate. The reaction mixture is then stirred for 10 min, extracted, dried and evaporated, getting 0,902 g of the crude desired product. Last chromatographic, elwira a mixture of ethyl acetate-triethylamine (96:4), receiving 0,573 the target product.

Example-3-de[(2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-abovecaptionskip)oxy]-6-0-methyl-3-oxo-12,11-[oxycarbonyl[[4-[4-(3-pyridinyl)-1H-pyrazole-1-yl]butyl]imino]]-erythromycin.

The mass spectrum of MN+=812+

An NMR spectrum (300 MHz, Dl3)

H2: 3,84 MD; H4: 3006 MD; H5: 4,22 MD; H7:1,58,1,83 MD; H8: 2,58 MD; N10: 3,12 MD; H11: 3,56 MD; H13: 4,92 MD; H14: 1,55,1,94 MD; n: 0,81 MD; me: 1,35 MD; me: 1,29 MD; me: 1,32 1,46 or MD; vial size: 8 IU: 1,16 MD; me: 1,01 MD; me: 1,32 or 1.46; me: 2,6 MD; 1': 4,27 MD; 2': 3,17 MD; 3': 2,44 MD; 4': 1,67 and 1,24 MD; 5': 3,55 MD; Nme2: of 2.26 MD; NCH3: 3,69 MD; CH2: 1,64,1,94 MD; CH2N: 4,19 MD; pyrazole: to 7.77 MD; pyridine: 8,76, 7,75, 7,27, 8,44 MD.

Mass spectrum

812+:MH+

850+:MK+

The starting amine was obtained in accordance with Preparation 1 based on the product obtained according to the following scheme:

Example 4

11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-abovecaptionskip)oxy]-2-fluoro-6-0-methyl-3-oxo-12,11-[oxycarbonyl[[4-[4-(3-pyridinyl)-1H-pyrazole-1-yl]butyl]imino]]-erythromycin

An NMR spectrum (300 MHz, Dl3)

H4: 3,53 MD; H5: 4,05 MD; H7: 1,51,1,88 MD; H8: 2,61 MD; N10: 3,10 MD; H11: 3,42 MD; H13: 4,86 MD; H14: 1,63,1,95 MD; n: 0,85 MD; me: 1,75 MD; me: 1,29 MD; me: 1,31 1,49 or MD; vial size: 8 IU: 1,17 MD; me: 1,00 MD; me: 1,31 1,49 or; me: of 2.51 MD; 1': 4,30 MD; 2': 3,19 MD; 3': 2,48 MD; 4': 1,68 and 1.26 MD; 5': 3,53 MD; me: 1,24; Nme2:2,28 MD; NCH2:from 3,55 to 3,80 MD; CH2:1,61,1,93 MD; CH2N: 4,19 MD; pyrazole: 7,75, 7,78 MD; pyridine: 8,77, to 7.77, 7,27, 8,44 MD.

+H

The example of the pharmaceutical composition

The prepared tablets containing:

the product of example 1, 150 mg

excipient in sufficient quantity to 1 g

Part of the filler: starch, talc, magnesium stearate

Pharmacological study of the products of the invention

And Method the dilution liquid medium

Prepare a series of tubes, in which are placed the same amount of sterile nutrient medium. Then in tubes placed increasing number of investigational product, after which each tube is impregnated bacterial strain. After incubation for 24 hours in a thermostat at S assess the inhibition of growth by x-ray that allows you to set the minimum concentration of inhibition expressed in g/cm3. For the product of example 1 the following results are obtained (after soaking for 24 hours.

Used bacterial strains were gram-positive. The results of their use are shown in table 2.

Along with this, the product of example 1 has, in particular, significant activity against gram-negative bacterial strains of Haemophilus Influenzae 351 npov, V, SA and 351G;

n denotes an integer from 1 to 8;

Z denotes a hydrogen atom or a residue of carboxylic acid,

and in which pyrazol cycle substituted heteroaryl radical, which contains one nitrogen atom,

as well as their salt adducts with acids.

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

3. Derivatives of erythromycin formula (I) under item 1 or 2, in which n is the number 4.

4. Derivatives of erythromycin on PP.1, 2 or 3, in which the radical

substituted radical

5. Derivatives of erythromycin formula (I) under item 1, in which Y denotes a hydrogen atom.

6. A derivative of erythromycin 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-[3-(3-pyridinyl)-1H-pyrazole-1-yl]butyl]-imino]]-erythromycin.

7. Derivatives of erythromycin formula (I) according to any one of paragraphs.1-5, as well as their salt adducts with acids as antibiotic medicines.

8. A derivative of erythromycin formula (I) under item 6, as well as its salt adducts with acids as antibiotic medicines.

9. Pharmaceutical is whether 8, has antibiotic activity.

10. The method of obtaining erythromycin derivatives of the formula (I) described in any of paragraphs.1-6, characterized in that the compound of formula (II)

in which Y is specified in paragraph 1 value;

M stands for the remainder of the acid, is treated with a compound of the formula (III)

in which pyrazol cycle is substituted as specified in paragraph 1, to obtain the compounds of formula (I) in which Z represents the residue of an acid, and then, if desired, the resulting compound of formula (I) is subjected to the action agent release hydroxyl in position 2’ to obtain the corresponding compound of formula (I) in which Z is a hydrogen atom, followed, if desired, by adding acid to obtain the salt.

11. The compounds of formula (III)

in which n denotes an integer from 1 to 8, and pyrazol cycle substituted heteroaryl radical, which contains one nitrogen atom.

12. The compounds of formula (III) under item 11, which represents a 3-(3-pyridinyl)-1H-pyrazole-1-butanamine and 4-(3-pyridinyl)-1H-pyrazole-1-butanamine.

 

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< / BR>
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< / BR>
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