Polyhydroxylated 8-cyan-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
The invention relates to crystalline polyhydroxylated 8-cyan-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 of formula (VI). Also described drug, possess antibacterial properties, on the basis of this connection. The technical result - the new form 8-cyan-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, which has a good solubility in water. 3 N. p. and 2 C.p. f-crystals, 6 ill., table 2.
The present invention relates to polyhydroxylated 8-cyan-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, its preparation and to its containing antibacterial agent. 8-Cyan-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 of the formula (I) will be denoted as CCDC.
CCDC is known from DE-A 19 633 805 or PCT application No. 97 903 260.4. It is obtained respectively by the reaction of 7-halo-8-cyan-1-cyclopropyl-6-the Hal - fluorine or preferably chlorine
with
(1S,6S)-2,8-diazabicyclo[4.3.0]nananom formula (III)
in the presence of an auxiliary base and a suitable solvent.
With CCDC formula (I) it is possible to achieve solubility in water of about 0.02% (weight/weight). This solubility is not sufficient for practical applications (solutions for injection or oral forms of application). For many other quinoline-carboxylic acids known that they are used in recipes in the form of certain salts. As salts are used at the same time, on the one hand, metal salts of quinoline-carboxylic acids (for example, alkali carboxylates), and acid adducts (protonation of the main center of balance amine substituted quinoline-carboxylic acid). As such acid adducts are often used, for example, mesylates, tozilaty and hydrochloride. Hydrochloride particularly simply manufactured, pharmaceutically acceptable and have clearly better solubility than the neutral connection.
CCDC-hydrochloride of the formula (IV)
known from WO 97/31001.
This connection can be characterized by its x-ray diffractor the gram powder represented as shown in Table 1 reflexes (2
(2 theta)) high and medium intensity ( >30% relative intensity).
X-ray diffractogram of the powder CCDC-hydrochloride of the formula (IV) is also shown in Fig.1.
Melting point CCDC-hydrochloride, was determined using DTA, is 305 - 307°C (decomposition). Differential-thermal chart shown in Fig.2.
The IR spectrum of the CCDC-hydrochloride of the formula (IV) shown in Fig.3.
CCDC-hydrochloride of the formula (IV) can be obtained in principle known methods. So, for example, possible solution CCDC formula (I) in water mixed with one mol equivalent of Hcl and the solution to evaporate to dryness. Another method is that the ethyl ester of 8-cyan-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 of formula (V)
its shades flooded with hydrochloric acid and precipitated CCDC-hydrochloride of the formula (IV) is allocated.
With CCDC-hydrochloride of the formula (IV) may be obtained solubility in water approximately equal to 2.8% (wt/wt). However, it is better soluble in water than CCDC formula (I), but not for all forms in the desired quantities.
According to this invention, it was found that the orim in the water. With CCDC-polyhydroxylated formula (VI) can be prepared 19% (wt/wt) solution in water.
The object of the invention is a crystalline CCDC-polyhydroxystearic formula (VI), which, among differs in that it has the x-ray powder diffraction pattern as shown in table 2 reflexes of high and medium intensity (>30% relative intensity)
X-ray diffractogram of the powder CCDC-polyhydroxylated formula (VI) shown in Fig.4.
CCDC-polyhydroxylated formula (VI) according to the invention, moreover, characterized in that the temperature of its melting point, determined by differential thermal analysis, is 278-280°C. the Corresponding differential-thermal chart shown in Fig.5.
CCDC-polyhydroxylated formula (VI) according to the invention, moreover, differs in that it has an infrared spectrum measured in CVG, shown in Fig.6.
CCDC-polyhydroxylated formula (VI) unknown crystalline forms can also in principle be manufactured in a known manner, for example, mixing an aqueous solution CCDC formula (I) with 0.5 mol equivalent of Hcl and evaporate the solution to dryness.
In exactly the same way in principle, it is possible to mix CCDC formula (I) and CCDC formula (IV) in the molar regarding the pairing dry.
In addition, according to this invention it has been found that unexpectedly can directly make CCDC-polyhydroxylated formula (VI), which is characterized through the above x-ray diffraction the diffraction pattern of the powder and the above differential-thermal chart.
The object of the present invention thus also is CCDC-polyhydroxylated formula (VI), which differs from that obtained by the reaction of 7-halo-8-cyan-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid of formula (II), in which the halogen is fluorine or preferably chlorine, with (1S,6S)-2,8-diazabicyclo[4.3.0]nananom formula (III), optionally, in the presence of a base in one of the following solvents or mixtures of solvents:
a) an aliphatic alcohol with at least four carbon atoms, such as butanol, Isobutanol, 2-butanol, tert-butanol, 1-pentanol.
b) a mixture of aliphatic alcohols with at least three carbon atoms, such as propanol, isopropanol, butanol, Isobutanol, 2-butanol, tert-butanol or 1-pentanol with the polar aprotic solvent is N-methyl-pyrrolidone.
C) a mixture of propanol and N,N-dimethylformamide or
g) a mixture of ethanol with N-methyl-pyrrolidone with Dobropolye and/or N-butylboron.
Preferred options with the solvent in the form of a mixture of b) or C) (mixed solvents) with ratio from 1:1 to 3:1 and particularly preferably with the option run from 1:1 to 2:1.
Suitable bases according to the production versions are solvents and mixed solvents from a) to b) in the form of tertiary amines, such as triethylamine, Tripropylamine, ethyldiethanolamine (strong base), tributylamine, N-ethylmorpholine, N-propylparaben, N-butylparaben.
When variants of manufacture from a) to d) a preferred form of execution at which it is applied, the excess of (1S,6S)-2,8-diazabicyclo [4.3.0]nonane of the formula (III).
When variants of manufacture from a) to d) is used per 1 mol of compound (II) predominantly from 1 to 2 mol of base, most preferably from 1.1 to 1.5 mol of the base.
The reaction for production versions from a) to g) occurs under normal or increased pressure between 1-100 bar, preferably between 1-20 bar.
The reaction for production versions from a) to g) occurs at a temperature of between 0 - 200°C, preferably between 20 and 150°C.
1 mol of compound (II) is preferably used 1-2 mol, most preferably about 1-1 .5 mole of compound (III).
CCDC-polyhedral who should be cleaned if necessary with water rinse with alcohol, used in the reaction.
The initial products of formulas (II) and (III) used for the manufacture of CCDC known (compare DE-A 19 633 805).
CCDC-polyhydroxylated formula (VI) has an effective activity against pathogenic bacteria in the field of medicine and veterinary medicine. Its wide use is based on the properties CCDC.
X-ray powder diffractogram for the crystalline characteristics of the modifications CCDC-hydrochloride and CCDC-polyhydroxylated was received on the transmission diffractometer STADI-P sensitive detector PSD2) company Stoe.
The melting temperature was obtained by means of DTA instrument DSC 820 company Mettler-Toledo. The heating of the samples was carried out in air in an aluminum crucible at a rate of 20 K/min
The infrared spectrum was obtained on the instrument FTS 60A company Biorad in CVG.
The following examples illustrate the invention without limiting its scope. Described solvents/system foundations the following examples are particularly preferred.
Comparative example
Getting D-hydrochloride of the formula (IV)
850 g of Ethyl ester of 8-cyan-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 is added in a mixture of 1600 ml of water and 800 ml of 10% hydrochloric acid. Heated the reaction mixture to agrevate for three hours at boiling. The mixture is then cooled to 50°C and add 1500 ml of ethanol. The reaction mixture was cooled to 0°C and stirred for 1 hour at this temperature. Filtered solid matter (sludge), washed it, and then 1000 ml of ethanol and dried at 60°C to constant weight. Get 845,5 g of substance beige color.
Elemental analysis (calculated formula for hydrochloride
C21H22ClFN4O3molecular weight 432,89);
Carbon: exp. 58,2% (calc. 58,27%)
Hydrogen: exp. 5,1% (calc. 5,12%)
Chlorine: exp. 8,1% (calc. 8,19%).
The product shows the x-ray powder diffraction pattern shown in Fig.1, diferencialna-thermal chart shown in Fig.2, and the infrared spectrum, shown in Fig.3.
Getting D-polyhydroxylated formula VI
Example 1
9.2 grams of 7-Chloro-8-cyan-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-hinolincarbonova acid is added in a mixture of 30 ml of butanol, 18 ml of N-methyl-pyrrolidone and 4,85 g strong bases. Heated to education back phlegmy and pin then to 4.17 g of (1S,6S)-2,8-diazabicyclo[4.3.0]nonane. After the addition is stirred for further 3 hours while flowing down the phlegm, then cooled to room temperature, filtered the solid, washed it in Ob g solid beige color which is shown in Fig.4 x-ray diffraction the powder diffraction pattern shown in Fig.5 chart DTA.
Elemental analysis (calculated formula for CCDC-polyhydroxylated C21H22,5Cl0,5FN4O3molecular weight 414,658):
Chlorine: exp. 4,2% (calc. 4,275%).
Example 2
A mixture of 9.2 grams of 7-chloro-8-cyan-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-hinolincarbonova acid, 60 ml of butanol and 4,85 g of a strong base, heated to education back phlegmy. Pin of 4.17 g of (1S,6S)-2,8-diazabicyclo[4.3.0]nonane and then stirred for 3 hours while flowing down the phlegm. The solid is filtered off at room temperature, washed with a total of 20 ml of butanol and dried to constant weight. Obtain 10.6 g of a solid substance beige, differential-thermal chart which corresponds CCDC-polyhydroxylated formula (VI).
Elemental analysis (calculated formula for CCDC-polyhydroxylated C21H22,5Cl0,5FN4O3molecular weight 414,658):
Carbon: exp. 60,55% (calc. 60,83%
Hydrogen: exp. 5,3% (calc. 5,23%)
Chlorine: exp. 4,2% (calc. 4,275%).
Nitrogen: exp. 13,5% (calc. 13,51%)
Oxygen: exp. 11,7% (calc. 11,58%).
Example 3
A mixture of 4.6 g of 7-chloro-8-cyan-1-cyclopropyl-6-FPO is I heated before the formation of the reverse phlegmy. Pin of 2.08 g of (1S,6S)-2,8-diazabicyclo [4.3.0]nonane and then stirred for 3 hours while flowing down the phlegm. Solid otfiltrovat at room temperature, washed with a total of 10 ml of propanol and dried to constant weight. Obtain 4.6 g of a solid substance beige, differential-thermal chart which corresponds CCDC - polyhydroxyamide.
Elemental analysis (calculated formula for CCDC-polyhydroxylated C21H22,5Cl0,5FN4O3molecular weight 414,658):
Chlorine: exp. 4,3% (calc. 4,275%).
Example 4
A mixture of 4.6 g of 7-chloro-8-cyan-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-hinolincarbonova acid, 15 ml of isopropanol, 9 ml of N-methyl-pyrrolidone and 2,42 g of a strong base, heated to education back phlegmy. Pin of 2.08 g of (1S,6S)-2,8-diazabicyclo[4.3.0] nonane and then stirred for 3 hours while flowing down the phlegm. The solid is filtered off at room temperature, washed with a total of 10 ml of isopropanol and dried to constant weight. Get 5.3g solid beige color.
Elemental analysis (calculated formula for CCDC-polyhydroxylated21H22,5CL0,5FN4O3molecular weight 414,658):
Chlorine: exp.4,2% (vicinity, 15 ml of 2-butanol, 9 ml of N-methyl-pyrrolidone and 2,42 g of a strong base, heated to education back phlegmy. Was added dropwise of 2.08 g of (1S,6S)-2,8-diazabicyclo [4.3.0]nonane and then stirred for 3 hours while flowing down the phlegm. The solid is filtered off at room temperature, washed with a total of 10 ml of 2-butanol and dried to constant weight. Obtain 4.6 g of a solid substance beige, differential-thermal chart which corresponds CCDC-polyhydroxylated formula (VI).
Elemental analysis (calculated formula for CCDC-polyhydroxylated C21H22,5Cl0,5FN4O3molecular weight 414,658):
Chlorine: exp.4,2% (calc. 4,275%).
Example 6
A mixture of 4.6 g of 7-chloro-8-cyan-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-hinolincarbonova acid, 15 ml of Isobutanol, 9 ml of N-methyl-pyrrolidone and 2,42 g of a strong base, heated to education back phlegmy. Pin of 2.08 g (18,68)-2,8-diazabicyclo[4.3.0] nonane and then stirred for 3 hours while flowing down the phlegm. The solid is filtered off at room temperature, washed with a total of 10 ml of Isobutanol and dried to constant weight. Get 4,99 g solids beige, differential-thermal chart which sooda C21H22,5Cl0,5FN4O3molecular weight 414,658):
Chlorine: exp. 4,2% (calc. 4,275%).
Example 7
A mixture of 4.6 g of 7-chloro-8-cyan-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-hinolincarbonova acid, 15 ml of tert-butanol, 9 ml of N-methyl-pyrrolidone and 2,42 g of a strong base, heated to education back phlegmy. Was added dropwise of 2.08 g of (1S,6S)-2,8-diazabicyclo[4.3.0] nonane and then stirred for 3 hours while flowing down the phlegm. The solid is filtered off at room temperature, washed with a total of 10 ml of warmed tert-butanol and dried to constant weight. Get 5,38 g solids beige, differential-thermal chart which corresponds CCDC-polyhydroxylated formula (VI).
Elemental analysis (calculated formula for CCDC-polyhydroxylated C21H22,5Cl0,5FN4O3molecular weight 414,658):
Chlorine: exp. 4,2% (calc. 4,275%).
Example 8
A mixture of 4.6 g of 7-chloro-8-cyan-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-hinolincarbonova acid, 15 ml of 1-pentanol, 9 ml of N-methyl-pyrrolidone and 2,42 g of a strong base, heated to education back phlegmy. Was added dropwise of 2.08 g of (1S,6S)-2,8-diazabicyclo[4.3.0] nonane and then stirred for 3 hours while flowing down the phlegm. Solid watanoha weight. Obtain 3.0 g of a solid substance beige, differential-thermal chart which corresponds CCDC - polyhydroxylated formula (VI).
Elemental analysis (calculated formula for CCDC-polyhydroxylated21H22,5CL0,5FN4About3molecular weight 414,658):
Chlorine: exp. 4,3% (calc. 4,275%).
Example 9
A mixture of 4.6 g of 7-chloro-8-cyan-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-hinolincarbonova acid, 15 ml of ethanol, 9 ml of N-methyl-pyrrolidone and 3,47 g tributylamine heated to education back phlegmy. Was added dropwise of 2.08 g of (1S,6S)-2,8-diazabicyclo[4.3.0]nonane and then stirred for 3 hours while flowing down the phlegm. The solid is filtered off at room temperature, washed with a total of 10 ml of ethanol and dried to constant weight. Receive 5.0 g solid beige color, differential-thermal chart which corresponds CCDC-polyhydroxylated formula (VI).
Elemental analysis (calculated formula for CCDC-polyhydroxylated21H22,5CL0,5FN4O3molecular weight 414,658):
Chlorine: exp. 4,2% (calc. 4,275%).
Example 10
A mixture of 4.6 g of 7-chloro-8-cyan-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-hinolincarbonova acid, 15 ml of ethanol, 9 ml of N-methyl-PIO[4.3.0] nonane and then stirred for 3 hours while flowing down the phlegm. The solid is filtered off at room temperature, washed with a total of 10 ml of ethanol and dried to constant weight. Get 5,4 g solid beige color.
Elemental analysis (calculated formula for CCDC-polyhydroxylated C21H22,5Cl0,5FN4O3molecular weight 414,658):
Chlorine: exp. 4,3% (calc. 4,275%).
Example 11
A mixture of 4.6 g of 7-chloro-8-cyan-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-hinolincarbonova acid, 15 ml of propanol, 9 ml of N,N-dimethylformamide and 2,42 g of a strong base, heated to education back phlegmy. Was added dropwise of 2.08 g of (1S,6S)-2,8-diazabicyclo[4.3.0] nonane and then stirred for 3 hours while flowing down the phlegm. The solid is filtered off at room temperature, washed with a total of 10 ml of propanol and dried to constant weight. Get 4.4 g solid beige color.
Elemental analysis (calculated formula for CCDC-polyhydroxylated C21H22,5Cl0,5FN4O3molecular weight 414,658):
Chlorine: exp. 4,2% (calc. 4,275%).
Claims
1. Polyhydroxylated 8-cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-o-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid(CCDC-polyhydroxylated), with x-ray diffraction the diffraction pattern of the powder with the following reflexes (2 theta) of high and medium intensity:
2(2 theta)
5,86
6,90
7,26
8,98
9,35
10,13
for 10.68
10,97
12,41
13,67
of 14.57
14,89
15,73
16,07
16,47
16,87
17,78
18,91
19,81
20,04
vs. 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. Polyhydroxylated 8-cyan-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 (CCDC-polyhydroxylated) under item 1 or 2, having installed using a DTA melting temperature 278-280°C.
4. CCDC-polyhydroxylated under item 1 or 2, obtained by reacting 7-halo-8-cyan-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid of formula (II)
where Hal is fluorine or chlorine,
with (1S,6S)-2,8-diazabicyclo[4.3.0]nananom formula (III)
in the environment of one of the following solvents or mixtures of solvents:
a) an aliphatic alcohol with at least four carbon atoms.
b) a mixture of, for example, aliphatic alcohols with at least three carbon atoms with the solvent N-methyl-Pirro>the) mixture of ethanol with N-methyl-pyrrolidone with the addition of a base selected from the group of Tripropylamine, tributylamine, N-ethylmorpholine, N-propiolactone and/or N-butylnitrone.
5. Antibacterial drug,characterized in that, along with excipients and fillers contains CCDC-polyhydroxylated on one of the PP.1-4.
][1,3] benzimidazole of General formula
where 1 R=NO2, R1=H;
2 R=CF3, R1=H;
3 R=CN, R1=H;
4 R=R1=CN
or its pharmaceutically acceptable salt, in which R1represents a C1-C6alkyl; R2represents a C1-C6alkyl; R3represents H or halogen and
represents a substituted heterocycle, as defined in paragraph 1 of the claims; and X represents NH or O
where the values of A, B, K, T, W, X, Y, U, V, Z, R1specified in paragraph 1 of the claims
or its pharmaceutically acceptable salts, where R1- H, CH3or CH2OH; R2- CH3CH2CH3; R3- H, C1-C6alkyl, gidroksilirovanii C1-C6alkyl, halogen; R4- H, C1-C6alkyl, gidroksilirovanii C1-C6alkyl or halogen; R5- H or halogen; R6, R7are the same or different and mean H, C1-C6alkyl, gidroksilirovanii C1-C6alkyl or C1-C6alkoxy-substituted C1-C6alkyl; X represents NH or O, which inhibit exogenously or endogenously stimulated secretion of gastric acid and therefore can be used for the prevention and treatment of gastrointestinal inflammatory diseases
< / BR>where R1, R2and R3form any of a variety of quinolones and friends heterocyclic structures similar to those known socialists as having antimicrobial activity, and (2) (a) R4and R5are, independently, hydrogen, lower alkyl, cycloalkyl, heteroalkyl, or-C(=O)-X-R8where X is a covalent bond, N, O or S and R8is lower alkyl, lower alkenyl, arylalkyl, carbocyclic ring, heterocyclic ring, or (b) R4and R5together form a heterocyclic ring that includes the nitrogen to which they are attached, and their pharmaceutically acceptable salts and biokerosene esters and solvate
