Aromatic derivatives substituted by a ribose, their method...

Details Aromatic derivatives substituted by a ribose, their method... Aromatic derivatives substituted by a ribose, their method...

1998-12-21

2002-02-26

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S028000, C536S004100, C536S016800

Reexamination Certificate

active

06350733

ABSTRACT:

The present invention relates to new aromatic derivatives, substituted by a ribose, their preparation process and their use as medicaments.
A subject of the invention is the compounds of formula (I):
in which:
R
1
represents a hydrogen atom, a hydroxyl radical, analkyl, alkenyl or alkynyl radical optionally interrupted by an oxygen, sulphur or nitrogen atom, containing up to 12 carbon atoms, linear, branched or cyclic, optionally substituted by one or more halogen atoms, one or more OH, C=N, NO
2
,
radicals, in which Ra and Rb, identical or different, represent a hydrogen atom, an alkyl radicalcontaining up to 8 carbon atoms, or Ra and Rb form with the nitrogen atom to which they are linked a heterocycle optionally containing another heteroatom chosen from nitrogen, sulphur or oxygen, or R
1
represents an alkoxy radical containing up to 8 carbon atoms, optionally substituted by one or more of the substituents indicated above, or R
1
represents an NRcRd radical in which Rc and Rd, identical or different, represent a hydrogen atom or an alkyl radical optionally interrupted by an oxygen, sulphur or nitrogen atom, containing up to 12 carbon atoms, optionally substituted by one or more of the substituents indicated above, or R
c
and R
d
form together with the nitrogen atom to which they are linked a heterocycle optionally containing another heteroatom chosen from nitrogen, sulphur or oxygen, X represents an oxygen atom, or an N-Nalk
1
or NOalk
2
radical in which alk
1
and alk
2
represent an alkyl radical containing up to 12 carbon atoms optionally substituted by one or more halogen atoms, by one or more
radicals in which Re and Rf, identical to or different from each other represent a hydrogen atom, an alkyl radical containing up to 8 carbon atoms, optionally substituted, or Re and Rf are able to form together with the nitrogen atom to which they are joined a heterocycle which in addition is able to contain an oxygen, sulphur atom and another nitrogen atom,
R
2
represents a hydrogen atom or a halogen atom,
R
3
represents a hydrogen atom, an alkyl radical containing up to 8 carbon atoms or a halogen atom,
R
4
represents an
radical in which Rg and Rh, identical to or different from each other, represent a hydrogen atom, a linear, branched, cyclic alkyl radical containing up to 8 carbon atoms, an optionally substituted aryl or heteroaryl radical, or Rg and Rh form together with the nitrogen atom to which they are linked a heterocycle which is able to contain in addition an oxygen atom, sulphur atom and another nitrogen atom, or R
4
represents an aryl or heteroaryl radical optionally substituted by one or more halogen atoms, one or more hydroxyl radicals, one or more alkyl or alkoxy radicals containing up to 8 carbon atoms,
R
5
represents a hydrogen atom, an O-alkyl radical containing up to 4 carbon atoms,
R
6
an alkyl or CH
2
—O-alkyl radical, in which alkyl represents an alkyl radical containing up to 8 carbon atoms,
R
7
represents a hydrogen atom or an alkyl radical containing up to 8 carbon atoms, as well as their salts.
As examples of salts there can be mentioned sodium, potassium, lithium, calcium or magnesium salts, the salts obtained with nitrogenous bases such as trimethylamine, triethylamine, methylamine, propylamine, N,N-dimethyl ethanolamine and tris (hydroxymethyl) methylamine.
As examples of salts there can also be mentioned the salts formed with the following acids: acetic, propionic, trifluoroacetic, maleic, tartaric, methanesulphonic, benzenesulphonic, p-toluenesulphonic, hydrochloric, hydrobromic, hydroiodic, sulphuric, phosphoric and especially stearic, ethylsuccinic or laurylsulphonic acids.
In the definition of the substituents:
the alkyl, alkenyl or alkynyl radical is preferably a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, terbutyl, decyl or dodecyl, vinyl, allyl, ethynyl, propynyl, cyclobutyl, cyclopentyl or cyclohexyl radical,
the halogen is preferably fluorine or chlorine, or bromine,
the aryl radical is preferably the phenyl radical,
the heterocyclic radical is preferably the pyrrolyl, pyrrolidinyl, pyridyl, pyrazinyl, pyrimidyl, piperidinyl, piperazinyl, quinuclidinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, imidazolyl, benzimidazolyl, triazolyl, thiazolyl, azetidinyl, aziridinyl radical.
Among the preferred compounds of the invention, there can be mentioned the compounds in which R
2
represents a hydrogen atom, those in which R
3
represents a methyl radical, those in which R
6
represents a methyl radical, those in which R
7
represents a hydrogen atom or a methyl radical and those in which R
5
represents an OCH
3
radical.
Quite especially a subject of the invention is the compounds of formula (I), in which R
4
represents a
radical, or also those in which R
4
represents an NH-cyclopropyl radical.
Among the compounds of the invention, there can be quite particularly mentioned the compounds of formula (I) in which X represents an oxygen atom, those in which X represents an NOR radical, R representing an alkyl radical, optionally substituted by one or more halogen atoms and optionally interrupted by an oxygen, nitrogen, sulphur atom and optionally carrying an optionally substituted heterocyclic radical, for example those in which X represents an NOCH
3
radical, there can also be mentioned as preferred compounds, the compounds of formula (I) in which R
1
represents an alkyl radical optionally interrupted by an oxygen or sulphur atom, an O-alkyl radical, optionally interrupted by an oxygen or sulphur atom, an NH
2
radical, for example the compounds in which R
1
is a CH
3
,
the compounds of formula (I) in which R
1
represents a methyl or O-ethyl radical.
Among the preferred compounds of the invention, there can be quite especially mentioned the compounds whose preparation is given hereafter in the experimental part and in particular the following compounds:
5-methyl-1H-pyrrole-2-carboxylic acid 3′-ester of 3-acetyl-7-((6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexop yranosyl)oxy)-4-hydroxy-8-methyl-2H-1-benzopyran-2-one,
5-methyl-1H-pyrrole-2-carboxylic acid 3′-ester of ethyl 7((6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranosyl)oxy)-4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-carboxylate,
5-methyl-1H-pyrrole-2-carboxylic acid 3′-ester of 7-((6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranosyl)oxy)-4-hydroxy-3-(1-(methoxyimino)-ethyl)-8-methyl-2H-1-benzopyran-2-one,
5-methyl-1H-pyrrole-2-carboxylic acid 3′-ester of 7-((6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranosyl)oxy)-3-(ethoxyacetyl)-4-hydroxy-8-methyl-2H-1-benzopyran-2-one,
5-methyl-1H-pyrrole-2-carboxylic acid 3′-ester of 3-(cyclopropylcarbonyl)-7-((6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranosyl)-oxy)-4-hydroxy-8-methyl-2H-1-benzopyran-2-one,
5-methyl-1H-pyrrole-2-carboxylic acid 3′-ester of 7-((6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranosyl)oxy)-4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-carboxamide,
The products of general formula (I) have a very good antibiotic activity on gram
+
bacteria such as staphylococci, streptococci, pneumococci, enterococci, listeria, anaerobes.
The compounds of the invention can therefore be used as medicaments in the treatment of infections caused by susceptible germs and in particular, in that of staphylococcia, such as staphylococcal septicemias, malignant staphylococcia of the face or skin, pyodermatitis, septic or suppurating wounds, boils, anthrax, phlegmons, erysipelas and acne, staphylococcia such as acute primary or post-influenzal angina, bronchopneumonia, pulmonary suppuration, streptococcia such as acute anginas, otitis, sinusitis, scarlet fever, pneumococcia such as pneumonia, bronchitis and diphteria. The products of the present invention are also active against infections caused by germs such as Haemophilus influenzae.
Therefore a subject of the invention is the compounds of formula (I) as medicaments.
A more particular subject of the invention is, as medicaments, the compounds indicated above as preferred compounds.
A subject o

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