MXPA01005230A - Crystal modification a 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 - Google Patents
Crystal modification a 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 acidInfo
- Publication number
- MXPA01005230A MXPA01005230A MXPA/A/2001/005230A MXPA01005230A MXPA01005230A MX PA01005230 A MXPA01005230 A MX PA01005230A MX PA01005230 A MXPA01005230 A MX PA01005230A MX PA01005230 A MXPA01005230 A MX PA01005230A
- Authority
- MX
- Mexico
- Prior art keywords
- ccdc
- modification
- oxo
- cyano
- cyclopropyl
- Prior art date
Links
- 230000004048 modification Effects 0.000 title claims abstract description 41
- 238000006011 modification reaction Methods 0.000 title claims abstract description 41
- BKIMMITUMNQMOS-UHFFFAOYSA-N Nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 title abstract 2
- 238000010586 diagram Methods 0.000 claims abstract description 11
- 239000000843 powder Substances 0.000 claims abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 7
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- -1 nonane-8-yl Chemical group 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000002844 melting Methods 0.000 claims description 3
- 229940079593 drugs Drugs 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims 1
- 239000003242 anti bacterial agent Substances 0.000 claims 1
- 238000004090 dissolution Methods 0.000 claims 1
- 238000001556 precipitation Methods 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000012265 solid product Substances 0.000 description 11
- 238000004455 differential thermal analysis Methods 0.000 description 6
- IMNIMPAHZVJRPE-UHFFFAOYSA-N DABCO Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000009835 boiling Methods 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- KSCPLKVBWDOSAI-NKWVEPMBSA-N (4aS,7aS)-2,3,4,4a,5,6,7,7a-octahydro-1H-pyrrolo[3,4-b]pyridine Chemical compound N1CCC[C@H]2CNC[C@H]21 KSCPLKVBWDOSAI-NKWVEPMBSA-N 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-K Disodium phosphate Chemical compound [Na+].[Na+].[O-]P([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-K 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 238000010192 crystallographic characterization Methods 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 235000019800 disodium phosphate Nutrition 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Inorganic materials [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 102100017221 PSD2 Human genes 0.000 description 1
- 101700033940 PSD2 Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000011068 load Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000001717 pathogenic Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
Abstract
The invention relates to a defined crystal modification 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 of formula (I), to methods for producing the same, and to its use in pharmaceutical preparations. The crystal modification can be distinguished from other crystal modifications 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 of formula (I) by its characteristic X-ray powder diffractogram and its differential thermal diagram.
Description
- CRYSTALLINE MODIFICATION OF THE ACID 8-CYANO-1-CICLOPROPIL-7- (lS.6S-2,8-DIAZABICICL? R4.3.01-NONAN-8-IL) -6-FLUOR-1.4-DIHYDRO-4- OXO-3-OUINOLINCARBOXILICO. FIELD OF THE INVENTION The present invention relates to a defined crystal modification of the acid
8-cyano-l-cyclopropyl-7- (lS, 6S, 2,8-diazabicyclo [4.3.0] nonan-8-yl) -6-fluoro-l, 4-dihi-dro-4-oxo-3- quinolinecarboxylic, to processes for its preparation and to its use in pharmaceutical preparations. Description of the Prior Art Acid 8-cyano-l-cyclopropyl-7- (lS, 6S, 2,8-di-azabicyclo- [4.3.0] nonan-8-yl) -6-fluoro-l, 4- Dihydro-4-oxo-3-quinoline-carboxylic acid of the formula (I) will be referred to below as CCDC.
The CCDC is known from DE-A 19 633 805 or from PCT application No. 97 903 260.4. It is prepared by the reaction of 7-halogeno-8-cyano-l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid with (1S, 6S) -2, 8-diazabi- Cyclo [4.3.0] nonane in a mixture consisting of dimethylformamide and acetonitrile in the presence of an auxiliary base. After combining with water, the CCDC is extracted from the water with dichloromethane and isolated by removal of the extraction agent. In this case a powder is obtained, which does not show a clear crystalline modification. On the contrary, the powder is mostly amorphous and may contain mixtures of various
Ref: 129088
crystal modifications. If a unitary crystalline modification were formed by chance, it is not clear how it could be extracted and obtained in a definite way. For the obtaining of medicines is, however, a precondition that is clearly indicated, for an active product, which can be presented in various crystalline modifications, which is the crystalline modification that is used for the manufacture of the agent. The powder, partly amorphous, which is obtained accng to the preparation procedure outlined above, is also hygroscopic. The amorphous solid products, and especially the hygroscopic solid products, are difficult to handle in galenic processing since they can have, for example, low bulk weights and defective yield properties. In addition, special work techniques and facilities are required for the handling of hygroscopic solid products, in r to achieve reproducible results, for example as regards the content of active product or stability in the solid formulations produced. DETAILED DESCRIPTION OF THE INVENTION Thus, the invention has as its task the preparation of a crystalline form of defined modification of the CCDC, which is perfectly manipulable due to its physical properties, especially its crystalline properties and its behavior against water, in formulations galenicas. This task is solved accng to the invention by means of a new crystalline form of the CCDC, which is designated below as modification A. Thus the object of the invention is the crystalline modification A of the CCDC, characterized in that it has a powder diffraction diagram to the X-rays, with the reflection layers (2 Theta) indicated in Table 1 below of high and medium intensity (relative intensity> 30%).
Table 1; X-ray powder diffraction diagram of modification A of the CCDC
An X-ray powder diffraction pattern characteristic of modification A in FIG. 1 has also been given. Modification A of the CCDC accng to the invention is further distinguished by a series of other properties of the other forms of CCDC. Properties lists can serve, individually or jointly, with the other parameters for the characterization of modification A of the CCDC accng to the invention. Modification A of the CCDC is characterized, among other things, because it has a melting point of 249 ° C to 252 ° C, determined with the aid of differential thermal analysis (DTA). Figure 2 shows a characteristic differential thermal analysis diagram. Modification A of the CCDC is characterized, moreover, because it has an in-red spectrum, measured in KBr, like the one shown in figure 3.
Modification A of the CCDC is also characterized because it can be obtained according to the obtaining procedure indicated below. The crystalline modification A of CCDC is obtained if hot dissolved CCDC or amorphous CCDC is dissolved in water or in an alcohol-water mixture, then an alcohol is added and, after cooling to room temperature, the precipitated solid product is isolated. As the alcohol, ethanol and isopropanol will be used in a preferred embodiment. The CCDC of the crystalline modification A is surprisingly stable and does not change, on the occasion of prolonged storage, into another different crystalline modification or into the amorphous form. In addition, modification A has a much lower tendency, compared to amorphous CCDC, to the absorption of water from the air. For these reasons it is excellent for obtaining tablets or other solid formulations. Through its stability, it provides these formulations with storage stability that is long-lasting and desirable. Thus, with crystalline modification A, defined and specifically stable solid CCDC preparations can be manufactured. Crystal modification A of CCDC is excellently active against pathogenic bacteria in the field of human and veterinary medicine. Its broad field of application corresponds to that of the CCDC. The X-ray powder diffraction diagram for the characterization of crystal modification A of CCDC was obtained with a STADI-P transmission diffractometer with locally sensitive detector (PSD2) from Stoe. The melting point of the differential thermal analysis was obtained with the DSC 820 device from Mettler-Toledo. In this case, the sample of the
CCDC of crystalline modification A in an aluminum crucible with 10 K / minute. The IR spectrum was obtained with the FTS 60 A device from Biorad in
KBr. The following examples illustrate the invention without limiting it in any way. The diluents / base systems described in the following examples are especially preferred. COMPARATIVE EXAMPLE A mixture constituted by the mixture is stirred for 16 hours at room temperature.
3.07 g of 7-chloro-8-cyano-l-cyclopropyl-6-fluoro-l, 4-dihydro-4-oxo-3-quino-liboxylic acid, 1.39 g of (lS, 6S) -2 , 8-diazabicyclo [4.3.0] nonane, 2.24 g of 1,4-diazabicyclo [2.2.2] octane (DABCO), 29.5 ml of dimethylformamide and 29.5 ml of acetonitrile. The reaction mixture is concentrated by evaporation at 60 ° C bath temperature on the rotary evaporator and the residue is taken up in 10 ml of water.
The resulting solution is adjusted to pH 7 with dilute hydrochloric acid and the solid product is separated by filtration. The filtrate is shaken three times with 20 ml of dichloromethane each time. The organic phase is dried over sodium sulfate, filtered and the filtrate is concentrated by evaporation in a rotary evaporator at 60 ° C bath temperature.
2.4 g of light brown solid product are obtained, which has the X-ray powder diffraction diagram shown in FIG. 4 and which, therefore, is mostly amorphous. The solid product, obtained according to this routine, absorbs approximately 17 percent by weight of water in the course of a day with a relative air humidity of 95% (adjusted by means of a saturated solution with deposit at the bottom of
Na2HPO4 x 12 H2O in water). Example 1
617 g of CCDC are dissolved from any modification in 6170 ml of chloroform. Add 100 g of sodium sulfate, stir for 5 minutes and then filter through 50 g of kieselguhr, which is further washed with 100 ml of chloroform. The solvent is removed by distillation in the rotary evaporator to a residual pressure of 10 mbar, resulting in a glassy residue. To this residue is added 740 ml of water and 740 ml of ethanol and is heated to 60 ° C until the whole has dissolved. This solution is then poured into 17 liters of boiling ethanol. The boiling is continued for another 5 minutes and it is cooled in one hour at 35 ° C. The precipitated crystals are separated by suction filtration and dried approximately for 16 hours at 20 ° C and then at 30 ° C in vacuo until constancy of weight. 530 g of solid product are obtained, which shows the X-ray powder diffraction diagram shown in Figure 1, the differential thermal analysis diagram shown in Figure 2 and the IR spectrum shown in Figure 3. The solid product obtained according to this routine absorbs approximately 3 percent by weight of water over the course of a day with a relative humidity of 95% (adjusted by means of a saturated solution with a deposit at the bottom of Na2HPO4 x 12 H2O in water). Example 2 2 g of CCDC of unknown modification are dissolved in 4 ml of water. Add 4 ml of isopropanol, start to heat the reaction mixture, stirring slowly, and then add another 32 ml of isopropanol. The resulting clear solution is heated to boiling. In this case the solution becomes cloudy and crystals are separated in the course of a short lapse of time. After three minutes of reflux, the heating is removed and the load is allowed to rest, without agitation,
for 3 to 4 hours. It is then separated by filtration by suction and the solid product is finally washed with isopropanol. It dries in the air until constant weight. 1.54 g of solid product is obtained which has an X-ray powder diffraction pattern identical to that shown in Figure 1, a differential thermal analysis diagram identical to that shown in Figure 2 and a IR spectrum identical to that shown in Figure 3. It is noted that, in relation to this date, the best method known to the applicant, to implement said invention, is that which is clear from the present description of the invention.
Claims (8)
-
- Having described the invention as above, the content of the following claims is claimed as property: 1. - 8-Cyano-1-cyclopropyl-7- (1S, 6S-2, 8-di-azabicyclo [4.3.0] acid. nonane-8-yl) -6-fluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid (CCDC) with the crystal-lino modification A, characterized in that it presents a powder diffraction diagram to the X-rays with the The following reflection layers (2 Theta) of high and medium intensity , 20 2. - 8-Cyano-1-cyclopropyl-7- (1 S, 6S-2, 8-di-azabicyclo [4.3.0] nonane-8-yl) - 6-fluoro-l, 4-dihydro acid -4-oxo-3-quinolinecarboxylic acid (CCDC) with the crystal-lino modification A, characterized in that it presents an X-ray powder diffraction diagram with the following reflection layers (2 Theta) of high and average intensity. and a melting point, determined by DTA, from 249 ° C to 252 ° C. 3. - 8-Cyano-1-cyclopropyl-7- (1 S, 6S-2, 8-di-azabicyclo [4.
- 3.0] nonane-8-yl) -6-fluoro-l, 4-dihydro-4 acid -oxo-3-quinolinecarboxylic acid (CCDC) with the crystal-lino A modification, characterized in that it is obtained by dissolution of the CCDC of unknown modification or amorphous CCDC in water or in a mixture of water-alcohol and hot precipitation after addition of alcohol .
- 4. Process for obtaining CCDC of modification A according to claim 1, characterized in that it is dissolved in water or in a water-alcohol mixture CCDC of unknown modification or amorphous CCDC and precipitated in warmer after addition of alcohol.
- 5.- Procedure for obtaining CCDC from modification A according to the claim 4, characterized in that this alcohol is ethanol or isopropanol.
- 6. Medicament characterized in that they contain, in addition to the usual auxiliary agents and excipients, CCDC of modification A according to one of claims 1 to 3.
- 7. Use of the CCDC of modification A according to one of claims 1 to 3. for the manufacture of medicines.
- 8. Use of the CCDC of modification A according to one of claims 1 to 3 in antibacterial agents.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19854356.5 | 1998-11-25 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA01005230A true MXPA01005230A (en) | 2003-11-07 |
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