Optionally substituted...

Details Optionally substituted... Optionally substituted...

2000-11-21

2001-08-21

Kifle, Bruck (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitriles

C558S416000

Reexamination Certificate

active

06278013

ABSTRACT:

The present invention relates to novel optionally substituted 8-cyano-1-cyclopropyl-7-(2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids and their derivatives, processes for their preparation and antibacterial compositions comprising them.
Quinolinecarboxylic acids and their antibacterial action have already been disclosed. Thus, ofloxacin, norfloxacin, enrofloxacin and danofloxacin are active compounds from this class of substance which are widely used in veterinary medicine. However, their use is not always satisfactory.
The present invention relates to optionally substituted 8-cyano-1-cyclopropyl-7-(2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids and their derivatives, of the general formula (I)
in which
R
1
represents hydrogen, C
1
-C
4
-alkyl which is optionally substituted by hydroxyl, methoxy, amino, methylamino or dimethylamino, or (5-methly-2-oxo-1,3-dioxol-4-yl)methyl,
R
2
represents hydrogen, benzyl, C
1
-C
3
-alkyl, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, radicals having the structures —CH═CH—COOR
3
, —CH
2
CH
2
COOR
3
, —CH
2
CH
2
CN, —CH
2
CH
2
COCH
3
or —CH
2
COCH
3
, in which R
3
represents methyl or ethyl, or a radical of the general structure R
4
—(NH—CHR
5
—CO)
n
—, in which R
4
represents hydrogen, C
1
-C
3
-alkyl or the radical —COO-tert-butyl, R
5
represents hydrogen, C
1
-C
4
-alkyl, hydroxyalkyl, aminoalkyl, thiloalkyl, carboxyalkyl or benzyl and n is 1 or 2, and
Y is oxygen or sulfur.
The compounds of the formula (I) can be present in the form of racemates or as enantiomerically pure compounds, and in the form of their pharmaceutically usable hydrates and acid addition salts, as well as in the form of their alkali metal, alkaline earth metal, silver and guanidinium salts.
The present invention relates to the process for the preparation of optionally substituted 8-cyano-1-cyclopropyl-7-(2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids, which is characterized in that compounds of the formula (II)
in which
R
1
and Y have the abovementioned meaning and
X represents halogen, in particular fluorine or chlorine,
are reacted with 2,8-diazabicyclo[4.3.0]nonanes of the formula (III)
in which
R
2
has the abovementioned meaning,
if appropriate in the presence of acid-binding agents. If appropriate, the carboxylic acid ester is then cleaved. If appropriate, compounds of the formula (I) in which R
2
represents hydrogen are then N-alkylated, N-alkenylated or N-acylated.
Compared with known representatives of this structural type, the compounds according to the invention have a more potent antibacterial action, in particular against
E. coli,
Staphylococci, Streptococci, Salmonellae and Mycoplasma. They are therefore suitable as active compounds for human and veterinary medicine. Their rapid degradation in the soil after excretion by the treated organism is advantageous.
Preferred compounds of the formula (I) are those in which
R
1
represents hydrogen, C
1
-C
4
-alkyl which is optionally substituted by hydroxyl, methoxy, amino, methylamino or dimethylamino, or (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl,
R
2
represents hydrogen, benzyl, C
1
-C
3
-alkyl, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, radicals of the structures —CH═CH—COOR
3
, —CH
2
CH
2
COOR
3
, —CH
2
CH
2
CN or —CH
2
COCH
3
, in which R
3
represents methyl or ethyl, or a radical of the general structure R
4
—(NH—CHR
5
—CO)
n
—, in which R
4
represents hydrogen, C
1
-C
3
-alkyl or the radical —COO-tert-butyl, R
5
represents hydrogen, C
1
-C
4
-alkyl, hydroxyalkyl, aminoalkyl, thioalkyl or benzyl and n is 1 or 2, and
Y represents oxygen,
and pharmaceutically usable hydrates and acid addition salts thereof, as well as the alkali metal, alkaline earth metal, silver and guanidinium salts of the carboxylic acids on which the compounds are based.
Particularly preferred compounds of the formula (I) are those in which
R
1
represents hydrogen, C
1
-C
4
-alkyl or (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl,
R
2
represents hydrogen, methyl, (5-methyl-2oxo-1,3-dioxol-4-yl)methyl, radicals of the structures —CH═CH—COOR
3
, —CH
2
CH
2
COOR
3
, —CH
2
CH
2
CN or —CH
2
COCH
3
, in which R
3
represents methyl or ethyl, or a radical of the general structure R
4
—(NH—CHR
5
—CO)
n
—, in which R
4
represents hydrogen, C
1
-C
3
-alkyl or the radical —COO-tert-butyl, R
5
represents hydrogen, C
1
-C
4
-alkyl, hydroxyalkyl, aminoalkyl, thioalkyl or benzyl and n is 1 and 2, and
Y represents oxygen,
and pharmaceutically usable hydrates and acid addition salts thereof, as well as the alkali metal, alkaline earth metal, silver and guanidinium salts of the carboxylic acids on which the components are based.
If, for example, 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 2,8-diazabicyclo[4.3.0.]nonane are used for the preparation of compounds of the formula (I), the course of the reaction can be represented by the following equation:
Compounds of the formula (I) can also be obtained be a procedure in which, after the reaction of a compound of the formula (II) with 2,8-diazabicyclo[4.3.0]nonane, a further reaction of the resulting product is carried out. Thus, compounds of the formula (I) where R
2
is a radical —CH═CH═COOEt, for example, can be obtained is accordance with the following equation:
Compounds of the formula (I) in which R
1
represents hydrogen can be N-alkylated, N-alkenylated or N-acylated in a manner known per se.
For the N-alkylation, the alkyl halides or hydroxides corresponding to the radical R
2
or the alkenyls corresponding to the radical R
2
are used.
For the N-alkenylation, the alkinyls corresponding to the radical R
2
are used.
For the N-acylation, the acyl halides, in particular chlorides, or anhydrides corresponding to the radical R
2
are used.
Alkyl halides which may be mentioned are: benzyl chloride, C
1-3
-alkyl iodides, bromides or chlorides, methyl or ethyl chloroethanecarboxylate and chiloroacetone;
alkenyls or alkinyls which may be mentioned are: methyl or ethyl propinylcarboxylate, ethyl acrylate and acrylonitrile; and
acyl halides or anhydrides which may be mentioned are: acetyl chloride, pivaloyl chloride and N-tert-butyloxycarbonyl-L-alanine N-carboxyanhydride.
The N-alkylation with alkyl halides is preferably carried out in a diluent, such as, for example, dimethyl sulfoxide, N,N-dimethlylformamide, sulfolane or acetonitrile.
Acid-binding agents which can be used are the customary inorganic and organic acid-binding agents, such as, for example, alkali metal hydroxides, alkali metal carbonates or organic amines.
The reaction temperatures can be varied within a substantial range here. The reaction is in general carried out between 20 and 200° C., preferably between 50 and 150° C.
The N-alkylation with alkenyls corresponding to the radical R
2
and the N-alkenylation with alkinyls corresponding to the radical R
2
are preferably carried out in a diluent, such as, for example, dimethyl sulfoxide, N,N-dimethylformamide, N-methyl-pyrrolidone, glycol, methylglycol or diethylene glycol.
The reaction temperatures can be varied here in a substantial range. In general, the reaction is carried out between 20 and 200° C., preferably between 50 and 180° C.
The N-acylation with acylhalides or anhydrides corresponding to the radical R
2
is preferably carried out in a diluent, such as, for example, dimethyl sulfoxide, N,N-dimethylformamide, sulfolane or N-methylpyrrolidone.
The reaction can be carried out without an acid-binding agent or also in the presence of such an agent.
Acid-binding agents which can be employed are the customary inorganic and organic acid-binding agents, such as, for example, triethylamine, 1,4-diaxabicyclo[2.2.2]octane and diazabicyclo[5.4.0]undec-7-ene.
The reaction temperatures can be varied within a substantial range here. In general, the reaction is carried out between −10° C. and 200° C., preferably

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