Derivatives of erythromycin, their preparation process and...

Details Derivatives of erythromycin, their preparation process and... Derivatives of erythromycin, their preparation process and...

2000-02-03

2001-11-06

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007400

Reexamination Certificate

active

06313101

ABSTRACT:

The present invention relates to novel derivatives of erythromycin, their preparation process and their use as medicaments.
A subject of the invention is the compounds of formula
in which X represents a CH
2
or NH radical, n represents an integer comprised between 1 and 8, Y represents a hydrogen or halogen atom, R represents a
radical, W and W′ representing a hydrogen atom, a halogen atom, an alkyl radical containing up to 8 carbon atoms optionally substituted by one or more halogen atoms and Z represents a hydrogen atom or the remainder of an acid as well as their addition salts with acids.
Among the addition salts with acids, there can be mentioned the salts formed with the following acids: acetic, propionic, trifluoroacetic, maleic, tartaric, methanesulphonic, benzenesulphonic, p-toluenesulphonic and especially stearic, ethylsuccinic or laurylsulphonic acids. When Y represents a halogen atom, it is for example, a fluorine, chlorine or bromine atom.
A more particular subject of the invention is the compounds of formula (I) in which X represents a CH
2
radical, those in which Y represents a hydrogen atom, those in which Y represents a fluorine atom, those in which n represents the number 4.
A more particular subject of the invention is the compounds the preparation of which is given hereafter in the experimental part, and quite particularly the products of Examples 1, 3 and 5.
The products of general formula (I) have a very good antibiotic activity on gram ⊕ bacteria such as staphylococci, streptococci, pneumococci.
The compounds of the invention can therefore be used as medicaments in the treatment of germ-sensitive infections and in particular, in that of malignant staphylococcia of the face or skin, pyodermitis, septic or suppurating wounds, boils, anthrax, phlegmons, erysipelas and acne, staphylococcia such as primitive or post-influenzal acute angina, bronchopneumonia, pulmonary suppuration, streptococcia such as acute angina, otitis, sinusitis, scarlatina, pneumococcia such as pneumonia, bronchitis, brucellosis, diphtheria, gonococcal infection.
The products of the present invention are also active against infections caused by germs such as Haemophilus influenzae, Rickettsia, Mycoplasma pneumoniae, Chlamydia, Legionella, Ureaplasma, Toxoplasma, or germs of the Mycobacterium genus.
Therefore, a subject of the present invention is also the products of formula (I) as defined above, as well as their addition salts with pharmaceutically acceptable mineral or organic acids, as medicaments and, in particular antibiotic medicaments.
A more particular subject of the invention is the products of Examples 1, 3 and 5 and their pharmaceutically acceptable salts, as medicaments and, in particular antibiotic medicaments.
A subject of the invention is also the pharmaceutical compositions containing at least one of the medicaments defined above, as active ingredient.
These compositions can be administered by buccal, rectal, parenteral route, or by local route as a topical application on the skin and mucous membranes, but the preferred administration route is the buccal route.
They can be solids or liquids and be presented in the pharmaceutical forms commonly used in human medicine, such as for example, plain or sugar-coated tablets, gelatin capsules, granules, suppositories, injectable preparations, ointments, creams, gels; they are prepared according to the usual methods. The active ingredient or ingredients can be incorporated with the excipients usually used in these pharmaceutical compositions such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives.
These compositions can also be presented in the form of a powder intended to be dissolved extemporaneously in an appropriate vehicle, for example, apyrogenic sterile water.
The dose administered is variable according to the affection treated, the patient in question, the administration route and the product considered. It can be, for example, comprised between 50 mg and 300 mg per day by oral route for an adult for the product of Example 1.
A subject of the invention is also a preparation process characterized in that a compound of formula (II):
in which Y retains its previous meaning,
M represents the remainder of an acid is subjected to the action of a compound of formula (III):
R(CH
2
)nXNH
2
  (III)
in which R, n and X retain the same meaning as in claim
1
in order to obtain the corresponding compound of formula (I), in which Z represents the remainder of an acid then optionally subjected to the action of an agent which releases the hydroxyl function in position 2′ in order to obtain the compound of formula (I) in which Z represents a hydrogen atom and/or subjected to the action of an acid in order to form the salt.
The compounds of formula (II) in which Y represents a hydrogen atom, used as starting products are described and claimed in the European Patent EP 0596802. The products of formula (II) in which Y is a halogen are described and claimed in the European Patent Application 0949268. A detailed example of the preparation of compounds of formula (I) in which Hal represents a fluorine atom is described hereafter. This process can be schematized as follows: compound A,
in which OZ represents a free or protected OH radical, is subjected to the action of a fluorination agent in order to obtain the corresponding compound of formula (B):
which is subjected to the action of carbonyldiimidazole, in order to obtain the corresponding compound of formula (II), in which Hal represents a fluorine atom.
The compounds of formula (III) used as starting products are novel and are in themselves a subject of the present invention. Their preparation is given hereafter in the experimental part.
A subject of the invention is also the compounds of formula (III) as defined above, as novel chemical products and especially the compounds of formula (III) in which n represents the number 3 and X represents a CH
2
radical.
The following examples illustrate the invention.


REFERENCES:
patent: 5747467 (1998-05-01), Agouridas et al.
patent: 0676409 (1995-10-01), None
patent: 0680967 (1995-11-01), None
patent: 0799833 (1997-10-01), None
patent: 2732023 (1996-09-01), None
patent: 2732684 (1996-10-01), None

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