Semi-hydrochloride of 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid
The present invention relates to a semi-hydrochloride of 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid, to processes for its preparation and to antibacterial compositions comprising it. The semihydrochloride of 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid can be described by the following formula:
1. Semi-hydrochloride of 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
2. Semi-hydrochloride of 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (CCDC semihydrochloride), having an X-ray powder diffractogram with the following reflection signals (2 theta) of high and medium intensity
+74 +0 (2 Theta)
5.86
6.90
7.26
8.98
9.35
10.13
10.68
10.97
12.41
13.67
14.57
14.89
15.73
16.07
16.47
16.87
17.78
18.91
19.81
20.04
20.62
20.75
20.93
21.46
21.74
22.92
25.36
25.71
26.98
27.58
28.24
30.61
3. Semi-hydrochloride of 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]nonan-8-yl)-6-fluoro-1-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (CCDC semihydrochloride), having X-ray powder diffractogram with the following reflection signals (2 theta) of high and medium intensity
2 +74 +0 (2 Theta)
5.86
6.90
7.26
8.98
9.35
10.13
10.68
10.97
12.41
13.67
14.57
14.89
15.73
16.07
16.47
16.87
17.78
18.91
19.81
20.04
20.62
20.75
20.93
21.46
21.74
22.92
25.36
25.71
26.98
27.58
28.24
30.61
and a melting point, determined by differential thermoanalysis (DTA), of from 278° C. to 280° C.
4. A process for preparing CCDC semihydrochloride according to claim 1 , comprising reacting 7-halogeno-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of the formula (II)
in which
Hal represents chlorine
and (1S,6S)-2,8-diazabicyclo[4.3.0]nonane of the formula (III)
in the presence of a base in one of the following diluents or diluent mixtures:
a) aliphatic alcohols selected from the group consisting of butanol, isobutanol, 2-butanol, tert-butanol, and 1-pentanol,
b) mixture of aliphatic alcohols selected from the group consisting of propanol, isopropanol, butanol, isobutanol, 2-butanol, tert-butanol, and 1-pentanol_with N-methylpyrrolidone,
c) mixture of propanol and N,N-dimethylformamide,
or
d) mixture of ethanol with N-methyl-pyrrolidone with added tripropylamine, tributyl, N-ethylmorpholine, N-propylmorpholine and/or N-butylmorpholine base.
5. A process for preparing CCDC semihydrochloride according to claim 4 , wherein the diluent used is an aliphatic alcohol selected from the group consisting of butanol, isobutanol, 2-butanol, tert-butanol, and 1-pentanol or that an aliphatic alcohol selected from the group consisting of propanol, isopropanol, butanol, isobutanol, 2-butanol, tert-butanol, and 1-pentanol is used as component of a diluent mixture.
6. A process for preparing CCDC semihydrochloride according to claim 4 , wherein if an aliphatic alcohol selected from the group consisting of propanol, isopropanol, butanol, isobutanol, 2-butanol, tert-butanol, and 1-pentanol_is used as component of a diluent mixture, N-methyl-pyrrolidone is simultaneously employed as a further diluent in a ratio of from 1:1 to 3:1.
7. Process for preparing CCDC semihydrochloride according to claim 5 , wherein if propanol is used as component of a diluent mixture, N,N-dimethylformamide is simultaneously employed as further diluent in a ratio of from 1:1 to 3:1.
8. A pharmaceutical composition comprising, in addition to pharmaceutically acceptable auxilaries and excipients, CCDC semihydrochloride according to claim 1 .
9. A method of preparing a pharmaceutical composition comprising combining a CCDC semihydrochloride according to claim 1 with one or more pharmaceutically acceptable auxiliaries and excipients.
10. A process for treating bacteria comprising applying to a human or animal an antibacterial composition containing CCDC semihydrochloride as defined in claim 1 .
11. CCDC semihydrochloride according to claim 2 , obtainable by reacting 7-halogeno-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid of the formula (II)
in which
Hal represents chlorine,
and (1S,6S)-2,8-diazabicyclo[4.3.0]nonane of the formula (III)
optionally in the presence of a base, in one of the following diluents or diluent mixtures:
a) aliphatic alcohols having at least four carbons,
b) mixture of aliphatic alcohols having at least three carbon atoms with N-methylpyrrolidone,
c) mixture of propanol and N,N-dimethylformamide,
or
d) mixture of ethanol with N-methyl-pyrrolidone with added tripropylamine, tributylamine, N-ethylmorpholine, N-propylmorphine and/or N-butylmorphine base.
12. A process for preparing a CCDC semihydrochloride as defined in claim 2 , wherein 7-halogeno-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of the formula (II)
in which
Hal represents chlorine
and (1S,6S)-2,8-diazabicyclo[4.3.0]nonane of the formula (III)
are reacted in the presence of a base in one of the following diluents or diluent mixtures:
a) aliphatic alcohols having at least four carbon atoms,
b) mixture of aliphatic alcohols having at least three carbon atoms with N-methylpyrrolidone,
c) mixture of propanol and N,N-dimethylformamide,
or
d) mixture of ethanol with N-methyl-pyrrolidone with added tripropylamine, tributylamine, N-ethylmorpholine, N-propylmorpholine and/or N-butylmorpholine base.
13. A process for preparing a CCDC semihydrochloride as defined in claim 3 , wherein 7-halogeno-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of the formula (II)
in which
Hal represents chlorine
and (1S,6S)-2,8-diazabicyclo[4.3.0]nonane of the formula (III)
are reacted in the presence of a base in one of the following diluents or diluent mixtures:
a) aliphatic alcohols having at least four carbon atoms,
b) mixture of aliphatic alcohols having at least three carbon atoms with N-methylpyrrolidone,
c) mixture of propanol and N,N-dimethylformamide,
or
d) mixture of ethanol with N-methyl-pyrrolidone with added tripropylamine, tributylamine, N-ethylmorpholine, N-propylmorpholine and/or N-butylmorpholine base.
14. A pharmaceutical composition comprising, in addition to pharmaceutically acceptable auxiliaries and excipients, CCDC semihydrochloride according to claim 2 .
15. A pharmaceutical composition comprising, in addition to pharmaceutically acceptable auxiliaries and excipients, CCDC semihydrochloride according to claim 3 .
16. A method of preparing a pharmaceutical composition comprising combining a CCDC semihydrochloride as defined in claim 2 with one or more pharmaceutically acceptable auxiliaries and excipients.
17. A method of preparing a pharmaceutical composition comprising combining a CCDC semihydrochloride as defined in claim 3 with one or more pharmaceutically acceptable auxiliaries and excipients.
18. A process for treating bacteria comprising applying to a human or animal an antibacterial composition containing CCDC semihydrochloride as defined in claim 2 .
19. A process for treating bacteria comprising applying to a human or animal an antibacterial composition containing CCDC semihydrochloride as defined in claim 3 .