Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-04-10
2004-03-16
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S007200, C536S007400
Reexamination Certificate
active
06706692
ABSTRACT:
The present invention relates to new derivatives of 6-deoxy erythromycin, their preparation process and their use as medicaments.
10-methyl 6-methoxy 3-oxo derivatives of erythromycin are known (cf. WO 98/03530. 6-demethoxy 10-demethyl erythromycin derivatives are also known (cf. FR A-2692579). erythromycin 3,11,12-trihydroxy derivatives which are used as intermediates in the synthesis of antibiotic products are also known (cf. WO 97/42205).
A subject of the invention is the compounds of formula (I)
in which
X represents an (NH)a, CH
2
or SO
2
radical or an oxygen atom, a represents the number 0 or 1,
Y represents a (CH
2
)m-(CH═CH)n-(CH
2
)o radical with m+n+o≦8, n=0 or 1,
Ar represents an aryl or heteroaryl radical, optionally substituted
W represents a hydrogen atom or a halogen atom
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.
The aryl radical is preferably a phenyl or naphthyl radical. methanesulphonic, benzenesulphonic, p-toluenesulphonic and especially stearic, ethylsuccinic, or laurylsulphonic acids.
The aryl radical is preferably a phenyl or naphthyl radical.
The heteroaryl can be thienyl, furyl, pyrolyl, thiazolyl, oxazolyl, imidazolyl radical, for example the 4-(3-pyridinyl) 1H-imidazolyl, thiadiazolyl, pyrazolyl or isopyrazolyl radical, a pyridyl, pyrimidyl, pyridazinyl or pyrazinyl radical, or also an indolyl, benzofurannyl, benzothiazyl or quinolinyl radical.
These aryl radicals can be substituted by one or more groups chosen from the group constituted by the hydroxyl, the halogen atoms, the NO
2
radicals, the C≡N, the alkyl, alkenyl or alkynyl, O-alkyl, O-alkenyl or O-alkynyl, S-alkyl, S-alkenyl or S-alkynyl and N-alkyl, N-alkenyl or N-alkynyl radicals, containing up to 12 carbon atoms optionally substituted by one or more halogen atoms, the
radical
R
a
and R
b
identical or different representing a hydrogen atom or an alkyl radical containing up to 12 carbon atoms, the
R
3
representing an alkyl radical containing up to 12 carbon atoms, aryl or heteroaryl with 5 or 6 mng members and comprising one or more heteroatoms, optionally substituted by one or more of the substituents mentioned above.
As preferred heterocycle, there can be mentioned amongst others
and the heterocyclic radicals envisaged in the European Patent Applications 487411, 596802, 676409 and 680967. These preferred heterocyclic radicals can be substituted by one or more functional groups.
Hal preferably represents a fluorine, chlorine or bromine atom.
Among the preferred compounds of the invention, there can be mentioned those in which Z represents a hydrogen atom, those in which W represents a hydrogen atom, those in which X represents a CH
2
radical, those in which Y represents a (CH
2
)
3
or (CH
2
)
4
radical, and in particular those in which Ar represents the
radical.
A quite particular subject of the invention is the product of Example 1.
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 staphylococcia such as staphylococcal septicaemias, malignant staphylococcia of the face or skin, pyodermitis, septic or suppurating wounds, boils, 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 the pharmaceutically acceptable mineral or organic acids, as medicaments and, in particular antibiotic medicaments.
A more particular subject of the invention is the products of the examples 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),
is subjected to the action of a cladinose hydrolysis agent in aqueous medium in order to obtain the compound of formula (III),
which is subjected to the action of a blocking agent of the hydroxyl function in position 2′ in order to obtain a compound of formula (IV):
in which OM represents a blocked hydroxyl group which is subjected to the action of an oxidizing agent of the hydroxyl group in position 3 in order to obtain the compound of formula (V):
then if desired, the hydroxyl in position 2′ is released in order to obtain the compound of formula (VI):
then if desired any one of products (V) or (VI) is subjected to the action of an agent capable of creating a double bond in position 11, 12 in order to obtain the compound of formula (VII)
in which OM′ represents a free or blocked hydroxyl radical which is subjected to the action of carbonyldiimidazole in order to obtain the compound of formula (VIII):
which is subjected to the action of a compound of formula ArYXNH
2
in which Y, X and Ar have the meaning indicated previously in order to obtain the corresponding compound of formula (IA)
in which W represents a hydrogen atom which is subjected if desired to the action of a halogenation agent in order to obtain the compound of formula (IB) in which W represents a halogen atom,
then if desired the hydroxyl in position 2′ is released and/or if appropriate subjected to the action of an acid in order to form the salt.
The compounds of formula (II) used as starting products of the process of the invention are known products described for example in EP 0216169, EP 41355 and EP 0180415.
Hydrolysis of cladinose is carried out using aqueous hydrochloric acid or in methanol.
Blocking of the hydrolysis in position 2′ is carried out by using an acid or a functional derivative of an acid for example an acid anhydride,
Auger Catherine Laurence
Auger Jean-Michel
Auger Pierre Michel
DeJean Nicole Noelle
Denis Alexis
Auger Catherine Laurence
Auger Pierre Michel
Aventis Pharma S.A.
DeJean Nicole Noelle
Muserlian Lucas and Mercanti
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