Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-11
2001-07-03
Powers, Fiona T. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S496000
Reexamination Certificate
active
06255335
ABSTRACT:
The invention relates to novel substituted N-[2-(indol-3-yl)-ethyl]-2-oxo-alkanamides, to processes for their preparation and to antibacterial compositions comprising them.
U.S. Pat. No. 5,569,668 discloses certain N-[2-(1H-indol-3-yl)-ethyl]-2-oxo-alkanamides and their antimycotic and antibacterial properties, in particular against staphylococci. A compound named nematophin, which is a natural compound formed by the bacterium
Xenorhabdus nematophilus,
is particularly emphasized. The action and properties of nematophin and certain derivatives have also been disclosed in Bioorganic & Medicinal Chemistry Letters, 7 (1997) 1349-1352.
The ever increasing number of multiresistant bacterial pathogens makes the search for novel antibacterially active substances an urgent task (Chemistry & Industry 1997, 131; Drug Discovery Today, 1997, 47). The antibacterial activity of nematophin and its known derivatives is not entirely satisfactory.
The present invention provides
1. Compounds of the general formula (I)
in which
R
1
represents optionally branched C
1
-C
8
-alkyl or C
4
-C
8
-cycloalkyl,
R
2
independently of R
3
represents hydrogen, C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy, C
1
-C
4
-thioalkyl, phenyl or halogen,
R
3
represents hydrogen, C
1
-C
4
-alkyl or halogen and
R
4
represents optionally branched C
1
-C
6
-alkyl, C
4
-C
6
-cycloalkyl, phenyl which is optionally mono- to trisubstituted by C
1
-C
3
-alkyl, C
1
-C
3
-alkoxy, C
1
-C
3
-thioalkyl, halogen, nitro or amino or benzyl which is optionally mono- to trisubstituted by C
1
-C
3
-alkyl, C
1
-C
3
-alkoxy, C
1
-C
3
-thioalkyl, halogen, nitro or amino.
The compounds of the general formula (I) can be present in the form of their racemates or as enantiomerically pure compounds and in the form of their pharmaceutically utilizable hydrates and acid addition salts.
2. Process for preparing compounds of the general formula (I)
in which
R
1
represents optionally branched C
1
-C
8
-alkyl or C
4
-C
8
-cycloalkyl,
R
2
independently of R
3
represents hydrogen, C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy, C
1
-C
4
-thioalkyl, phenyl or halogen,
R
3
represents hydrogen, C
1
-C
4
-alkyl or halogen and
R
4
represents optionally branched C
1
-C
6
-alkyl, C
4
-C
6
-cycloalkyl, phenyl which is optionally mono- to trisubstituted by C
1
-C
3
-alkyl, C
1
-C
3
-alkoxy, C
1
-C
3
-thioalkyl, halogen, nitro or amino or benzyl which is optionally mono- to trisubstituted by C
1
-C
3
-alkyl, C
1
-C
3
-alkoxy, C
1
-C
3
-thioalkyl, halogen, nitro or amino,
characterized in that substituted indoles of the formula (II)
in which
R
2
, R
3
, R
4
are as defined above
are reacted with &agr;-ketocarboxylic acid derivatives of the formula (III)
in which
Y represents OH or halogen and
R
1
is as defined above,
if appropriate in the presence of an acid binder and if appropriate in the presence of a diluent.
Compared to the known representatives of this structure type, the compounds of the general formula (I) according to the invention surprisingly have considerably higher antibacterial activity. They are therefore suitable for use as antibacterially active compounds for human and veterinary medicine.
Preference is given to compounds of the formula (I) in which
R
1
represents optionally branched C
1
-C
6
-alkyl or C
4
-C
6
-cycloalkyl,
R
2
independently of R
3
represents hydrogen, C
1
-C
2
-alkyl, C
1
-C
2
-alkoxy, C
1
-C
2
-thioalkyl, phenyl, fluorine, chlorine or bromine,
R
3
represents hydrogen, C
1
-C
2
-alkyl, fluorine or bromine and
R
4
represents optionally branched C
1
-C
4
-alkyl, C
4
-C
6
-cycloalkyl, phenyl which is optionally mono- to trisubstituted by C
1
-C
2
-alkyl, C
1
-C
2
-alkoxy, fluorine, chlorine, bromine, nitro or amino or benzyl which is optionally mono- to trisubstituted by C
1
-C
2
-alkyl, C
1
-C
2
-alkoxy, fluorine, chlorine, bromine, nitro or amino,
and their pharmaceutically utilizable hydrates and acid addition salts.
Particular preference is given to compounds of the formula (I) in which
R
1
represents optionally branched C
1
-C
6
-alkyl or C
4
-C
6
-cycloalkyl,
R
2
independently of R
3
represents hydrogen, C
1
-C
2
-alkyl, C
1
-C
2
-alkoxy, fluorine or chlorine,
R
3
represents hydrogen, C
1
-C
2
-alkyl, fluorine or chlorine and
R
4
represents optionally branched C
1
-C
4
-alkyl, C
4
-C
6
-cycloalkyl, phenyl which is optionally mono- or disubstituted by C
1
-C
2
-alkyl, C
1
-C
2
-alkoxy, fluorine, chlorine, nitro or amino or benzyl which is optionally mono- or disubstituted by C
1
-C
2
-alkyl, C
1
-C
2
-alkoxy, fluorine, chlorine, nitro or amino,
and their pharmaceutically utilizable hydrates and acid addition salts.
Very particular preference is given to compounds of the formula (I) in which
R
1
represents branched alkyl having up to 4 C atoms,
R
2
and R
3
represent hydrogen,
R
4
represents C
1
-C
4
-alkyl, phenyl or benzyl.
The process according to the invention for preparing the compounds of the formula (I) by reacting the compounds of the formula (II) with &agr;-ketocarboxylic acid derivatives of the formula (III) where Y is chlorine can be represented by the following reaction scheme:
The compounds of the formula (II) are known (for example J. Med. Chem. 37 (1994) 4307-4316) or can be prepared by known methods. Examples of compounds (II) which may be mentioned are:
1-methyl-3-(2-aminoethyl)-indole,
1-ethyl-3-(2-aminoethyl)-indole,
1-propyl-3-(2-aminoethyl)-indole,
1-isopropyl-3-(2-aminoethyl)-indole,
1-cyclopentyl-3-(2-aminoethyl)-indole,
1-phenyl-3-(2-aminoethyl)-indole,
1-benzyl-3-(2-aminoethyl)-indole,
1-(4-chlorobenzyl)-3-(2-aminoethyl)-indole,
1-(2,6-dichlorobenzyl)-3-(2-aminoethyl)-indole.
The compounds of the formula (III) are likewise known, and some of them are commercially available. Compounds of the formula (III) where Y is halogen, such as, for example, chlorine, can be prepared from compounds of the formula (III) where Y is OH according to known methods by reaction with halogenating agents such as, for example, with thionyl chloride or oxalyl chloride. Examples of compounds (III) where Y is OH which may be mentioned are:
pyruvic acid,
2-oxo-butyric acid,
2-oxo-valeric acid,
2-oxo-4-methyl-valeric acid,
2-oxo-3-methyl-valeric acid,
cyclobutyl-glyoxylic acid,
cyclopentyl-glyoxylic acid,
cyclohexyl-glyoxylic acid.
If the starting materials used are compounds of the formula (III) where Y is chlorine, the preparation of the compounds of the formula (I) is carried out in an inert solvent in the presence of an acid scavenger. Suitable solvents are, for example, halogenated hydrocarbons, such as, for example, methylene chloride, chloroform, carbon tetra-chloride, aliphatic or aromatic hydrocarbons, such as, for example, toluene, polar inert solvents, such as, for example, dimethylformamide, N-methylpyrrolidone, dimethyl sulphoxide or su ipholane. It is also possible to use mixtures of these solvents.
Suitable acid scavengers are customary acid binders such as, for example, alkali metal or alkaline earth metal carbonates, trimethylamine, triethylamine, tributylamine, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or pyridine.
The acid scavengers used are generally employed in an amount of from 80 to 200 mol %, based on the molar amount of the compound (III) where Y is chlorine. Preference is given to using an amount of from 110 to 150 mol %.
It is also possible to carry out the reaction in a large excess of pyridine which then acts simultaneously as solvent and acid scavenger.
The compounds of the formula (II) and (III) are generally employed in approximately equimolar amounts.
In this procedure, the reaction temperatures can be varied between −20 and 80° C. Preference is given to working between −10° C. and 25° C.
The reaction can be carried out at atmospheric pressure, but also under elevated pressure. In general, the reaction is carried out at pressures between 1 bar and 100 bar, preferably between 1 and 10 bar.
If the starting materials used are compounds of the formula (III) where Y is OH, the reaction is carried out in an i
Himmler Thomas
Pirro Franz
Akorli Godfried R.
Bayer Aktiengesellschaft
Gil Joseph C.
Powers Fiona T.
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