Derivatives of erythromycin, the retrieval method, an intermediate product, pharmaceutical composition

 

(57) Abstract:

Describes new compounds of the formula

< / BR>
in which R and R1represent hydroxyl or O-aceally radical comprising from 2 to 10 carbon atoms, R2is a methyl radical, R3is either the radical -(CH2)mR4in which m=4, or a radical-N-(CH2)qR4in which q=3, a R4heterocyclic mono - or polycyclic radical, possibly substituted, such as imidazolyl, pyridinyl, thiazolyl, chinoline or 3H-imidazo [4,5-b] pyridinyl, and the Deputy is a phenyl group, and their acid additive salt. The compounds of formula I possess interesting antibiotic properties. The invention relates also to a method for producing compounds of formula 1 and to farmkompanijam based on them. 4 C. and 9 C.p. f-crystals, 1 table.

The present invention relates to new derivatives of erythromycin, to a method for their production and to their use in pharmaceutical compositions.

The object of the present invention are the compounds of formula (I)

< / BR>
in which R and R1represent hydroxyl or O-acyl radical comprising from 2 to 20 carbon atoms,
2)mR4in which m is an integer value from 1 to 6,

or a radical in which n and p are the same or different, are an integer value from 0 to 6,

and or a and b, identical or different, represent a hydrogen atom or halogen atom or an alkyl radical, containing up to 8 carbon atoms, and the geometry of the double bond is E or Z or a mixture of E + Z,

or a and b form together with the carbon atom to which they relate, triple bond,

or a radical-N-(CH2)qR4in which q is an integer value from 0 to 6, a R4heterocyclic mono - or polycyclic radical, with the possibility of substitution, as well as their acid additive salt.

As an example, the additive salts of these derivatives with mineral or organic acids can be called a salt obtained by using acetic, propionic, triperoxonane, maleic, tartaric, hydrochloric, sulfuric, phosphoric, methansulfonate, benzosulfimide, n - toluenesulfonic acid, hydrogen bromide, hydrogen iodide, and, first of all, stearic, acylethanolamines and laurylsulphate acid.

Acyl radical is, first of all, azet the left or phenylmethanesulfonyl radical.

Heterocyclic moiety includes one or more heteroatoms, selected primarily from oxygen, sulfur and nitrogen.

The heterocyclic radical may be a radical of 5 atoms, first of all, this radical, as thienyl, purely, pyrrolidinyl, diazolidinyl, oxazolidinyl, imidazolidinyl, thiadiazolidine, personilnya, isoxazolidine or diazolidinyl.

The heterocyclic radical may be radical, including 6 atoms in the first place, peredelnyj, pyrimidinyl, pyridazinyl or personilnya radical.

The heterocyclic radical can be condensed radical, such as, for example, benzimidazolinyl, indaily, benzofuranyl, benzothiazolyl or chinoline.

If we are talking about a substituted heterocyclic radical, it can be replaced, first, by one or more substituents selected among halogen atoms, hydroxyl, alkyl, alkylosing, aryl, Allexinno radicals comprising up to 18 carbon atoms.

The object of the present invention are, primarily, the compounds of formula (I) defined above, in which R and R1presents the texts in which R3represents the radical (CH2)mR4in which m and R4save the specified value, and, in particular, those in which m has a value of 4.

The object of the present invention, in particular, are the compounds of formula (I) in which R3represents a radical-N-(CH2)qR4in which q and R4retain the above value and, in particular, in which q has a value of 3.

The object of the present invention are, primarily, the compounds of formula (I), in which the heterocyclic radical R4includes at least one nitrogen atom, in particular, those in which the heterocyclic radical is such a radical, as imidazolidinyl, pyridinoline, diazolidinyl, chinoline or azobenzenecontaining, with the possibility of substitution, and, first of all, 4-phenyl-1H-imidazolidinyl or 4-chinoline radical.

The object of the present invention are, primarily, the compounds of formula (I), a description of which can be obtained are provided below in the experimental part. This concerns mainly the products of examples 1, 2, 3 and 4.

The object of the present invention is also a method of obtaining compounds of formula (I), Atena, Bn is benzyloxycarbonyl radical, and AC is the acyl radical, above, is exposed to the compounds of formula (III)

R3NH2< / BR>
in which R3retains its previous value, to obtain the compounds of formula (IV)

< / BR>
which is optionally exposed to agent cleavage of the ester functional group in position 2' to obtain the compounds of formula (I) in which R1is a radical, after which the thus obtained compound is subjected, if desired, the impact of reducing agent to break down benzyloxycarbonyloxy functional group in position 4" and obtain the product of formula (I) in which R represents a radical, after which the compound of formula (1) is subjected, if desired, acid to obtain the corresponding salt.

Compounds of the formula (II) used as starting products are widely known products described in the patent 0248279.

Amines of formula (III) are well known and can be obtained using methods described in the journal of Med. Chem. (1982), volume 25, page 947, and the following, as well as in the journal Tetrahedron L or aqueous hydrochloric acid.

Splitting benzyloxycarbonyloxy functional group in position 4"produced by the reduction, for example using hydrogen in the presence of a catalyst with palladium.

The salt formation is carried out using acid using conventional methods.

The compounds of formula (I) in which R3is a radical-N(CH2)qR4can be obtained by exposure hydrazinehydrate product of formula (II) for obtaining the compounds of formula (P), i.e. the product of formula (I) in which R3represents NH2that is exposed to aldehyde R4(CH2)q-1CHO to obtain the corresponding compound of formula (I). Compound of formula (P) is the product of the present invention as a new chemical product.

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

Thus, compounds which 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 stafilos the infection, pyoderma, septic or suppurative wounds, furuncles, carbuncles, cellulitis, 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 like 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, Moraxella catarrhalis, Rickettsies, Mycoplasma pneumoniae, Chlamydia, Legionella spp., Ureaplasma, Toxoplasma, or microbes such as Mycobacterium.

Thus, the object of the present invention are new compounds as the antibiotic of funds, in particular, the compounds of formula (I) above, as well as their additive salts with acceptable from a pharmaceutical point of view, inorganic or organic acids.

As antibiotic means, first and foremost, the preferred products of formula (I) defined above, namely the products of examples 1, 2, 3 and 4, and their salts that are acceptable from a pharmaceutical point of view.

The object of the present invention also avlsi connections.

These compositions can be applied orally, by rectal, parenteral or locally, drawing on the skin or on the mucous membranes, but it is preferable to ingest.

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 introduced (injected) into the framework commonly 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 a powder intended to be dissolved before taking in the appropriate binder, for example, sterile pyrogen-free water.

Commonly used doses depend on the disease to be treated, the characteristics of the patient, shall be, for example, from 50 to 300 mg per day for adults when administered. Compounds classified as slightly toxic.

The following examples illustrate the present invention, however, limiting it. Examples 1 to 8 are given in the end of the text.

Example 9: 6-O-methyl-12,11-(oxycarbonyl(2-(3-(3H-imidazo (4,5-B)-pyridine-3-yl)propyl)hydrazono))erythromycin

Rf= 0,2 (simple isopropyl ether-methanol - triethylamine(80:10:10)).

Example 10: 6-O-methyl-12,11-(oxycarbonyl(2-(3-(2-phenyl 4 - thiazolyl)propyl)hydrazono))erythromycin

Rf= 0,14 (simple isopropyl ether-methanol - triethylamine(80:10:10)).

Examples of pharmaceutical compositions

There were prepared compositions, including:

The product of example 1 ...150 mg

The basis for the finished tablet ... 1 g

Detailing the basics of: starch, talc, magnesium stearate

The product of example 2A...150 mg

The basis for the finished tablet...1 g

Detailing the basics of: starch, talc, magnesium stearate

The product of example 4...150 mg

The basis for the finished tablet...1 g

Detailing the basics of: starch, talc, magnesium stearate

Pharmacological study of the products of the invention

Method of cultivation in liquid medium

Podstaw each tube pour in increasing the number of the investigated product, then each tube is sown bacterial strain.

After incubation in an oven for 24 h at a temperature of +37oC the growth inhibition was evaluated by x-ray that gives the possibility to determine the minimum inhibitory concentration (M. I. K.), expressed in micrograms per cm3.

Thus were obtained the results presented in the table after the claims.

1. Derivatives of erythromycin a General formula I

< / BR>
in which R and R1represent a hydroxyl group or O-acyl having from 2 to 10 carbon atoms;

R2is a methyl radical;

R3is either the radical -(CH2)mR4in which m = 4, or a radical-N-(CH2)qR4in which q = 3, R4means heterocyclic mono - or polycyclic radical, possibly substituted, such as imidazolyl, pyridinyl, thiazolyl, chinoline or 3H-imidazo[4,5-b]pyridinyl, and the Deputy is a phenyl group, and their acid additive salt.

2. Derivatives of erythromycin formula I under item 1, in which R and R1represent hydroxyl radicals.

3. Derivatives of erythromycin formula I according to any one of paragraphs.1 - 3, in which R3is the radical -(CH2)mR4in which m and R4retain the value specified in paragraph 1.

5. Derivatives of erythromycin formula I according to any one of paragraphs.1 to 3, in which R3is a radical-N-(CH2)qR4in which q and R4retain the value specified in paragraph 1.

6. Derivatives of erythromycin formula I according to any one of paragraphs.1 to 5, in which the heterocyclic radical R4includes at least one nitrogen atom.

7. Derivatives of erythromycin formula I under item 1, in which R4means a radical 4-phenyl-1H-imidazolyl or 4-chinoline.

8. Derivatives of erythromycin formulas I through p. 1, representing the following connections: 11,12-dideoxy-6-O-methyl-12,11-(oxycarbonyl-((4-(4-phenyl-1H-imidazol-2-yl)butyl)imino)erythromycin, 11,12-dideoxy-6-O-methyl-12,11-(oxycarbonyl-((4-(4-chinoline)butyl)imino)) - erythromycin, 11,12-dideoxy-6-O-methyl-12,11-(oxycarbonyl-(4-(1,2,3,4-tetrahydro)4-chinoline)butyl)imino)) - erythromycin, 11,12-dideoxy-6-O-methyl-12,11-(oxycarbonyl-(2-(3-(4-chinoline)propyl)hydrazono)erythromycin.

9. The method of obtaining erythromycin derivatives of the formula I defined in one of the paragraphs. 1 - 8 claims, characterized in that the compound of formula AUX radical;

Ac is the acyl radical, as defined in paragraph 1,

expose the compounds of formula III

R3NH2< / BR>
in which R3matter specified in paragraph 1,

and get the connection formula IV

< / BR>
which, if desired, is subjected to the action of an agent splitting of the ester functional group in position 2', obtaining the compounds of formula I in which R1is a radical, after which the thus obtained compound is subjected, if desired, the impact of reducing agent for the removal of benzyloxycarbonyl functional group in position 4" and obtain the product of formula I in which R represents a radical, after which the compound of formula I is subjected, if desired, acid to obtain the corresponding salt.

10. 11,12-dideoxy-6-O-methyl-12,11-(oxycarbonyl-(2-hydrazono)erythromycin as a chemical intermediate.

11. Derivatives of erythromycin under item 1, has antibiotic properties.

12. Derivatives of erythromycin under item 8, has antibiotic properties.

13. Pharmaceutical composition having antibiotic activity containing the active nocalorie formula I in an effective amount.

 

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