Salt of 7-([1
,5,6]-6-amino-3-azabicyclo [3.1.0] gex-3-yl)- 6-fluoro-1-(2,4-differenl)-1,4 - dihydro-4-oxo-1,8 - naphthiridine-3-carboxylic and methanesulfonic acid and its preparation
(57) Abstract:
Salt of 7-([1,5,6]-6-amino-3-azabicyclo[3.1.0] Gex-3-yl)-6-fluoro-1-(2,4-differenl)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic and methanesulfonic acid is favorable for the finished form of the drug stability as antibacterial means. Its preparation is that the specified salt or its monohydrate with other than the target product main peaks in the x-ray powder diffraction is boiled or heated to a temperature of 80 - 85oWith the presence of alcohol or its mixture with the aprotic co-solvent. 2 S. p. f-crystals, 5 PL. The invention relates to a new form of the anhydrous salt methanesulfonic acid and 7-([1,5,6]-6-amino-3-azabicyclo[3.1.0] Gex-3-yl)-6-fluoro-1-(2,4-differenl)- 1,4-dihydro - 4-oxo-1,8-naphthiridine-3-carboxylic acid, to a method of use of the compounds in the treatment of bacterial infections in mammals, especially humans, and to pharmaceutical compositions useful for him.In U.S. patent N 5229396, which is reproduced here for the information disclosed 7-([1,5,6]-6-amino-3-azabicyclo-[3.1.0]Gex-3-yl)-6-fluoro-1-(2,4-differenl)- 1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid, salt methansulfonate kidsthese Oh,p-differenl and R2is< / BR>having antibacterial activity
The essence of the invention.This invention relates to a new crystalline form of anhydrous 7-([1,5,6]-6-amino-3-azabicyclo[3.1.0] Gex-3-yl)-6-fluoro-1-(2,4-differenl)- 1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid, salt methanesulfonic acid, which possesses valuable and non-obvious properties. Because anhydrate is almost stable hydrophobic, problems making ready preparative forms of the active ingredient during operations tabletting or encapsulation easier.Detailed description of the invention.7-([1,5,6]-6-amino-3-azabicyclo[3.1.0] Gex-3-yl)-6-fluoro-1-(2,4 - differenl)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid, salt methanesulfonic acid disclosed in U.S. Pat. USA N 5229396 and characterized by the main peaks in the x-ray powder diffraction (PL.1), is essentially hygroscopic and can absorb water from the atmosphere, forming the monohydrate. Monohydrate is characterized by the main peaks in the x-ray powder diffraction (PL.2).A new crystal form.7-([1,5,6]-6-amino-3-azabicyclo[3.1.0] Gex-3-yl-6-fluoro-1-(2,4 - differenl)-1,) hydrophobic stable and is characterized by the main peaks in the following x-ray powder diffraction (PL.3).Anhydrate can be obtained by heating
7-([1,5,6]-6-amino-3-azabicyclo[3.1.0] Gex-3-yl)-6-fluoro-1-(2,4-differenl)- 1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid, salt methanesulfonic acid or its derivative monohydrate in an organic solvent or a mixture of it with the aprotic co-solvent, such as isopropanol, dimethyl sulfoxide, n-propanol, tetrahydrofuran or n-butanol, preferably n-butanol or tetrahydrofuran/n-butanol, to the temperature of reflux distilled or to a temperature between approximately 70oC and 90oC, preferably about 85oC. depending on the reaction temperature and other conditions, the reaction time usually varies from about 1 to 20 hours, preferably from about 2 to 16 hours.The resulting suspension of crystals is cooled to a temperature between about 20oC and 30oC, preferably about 25oC, during the period of time between about 2 and 24 hours, preferably from about 2 to 12 hours. The crystalline product is then filtered from the mother liquor and dried under vacuum until the solvent is removed.Anhydrate you can assign to accept as antibacterial means, as described in videoskim media selected taking into account the proposed route of administration and generally accepted pharmaceutical practice. For example, it may be assigned to receive orally or in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in a mixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. In the case of animals, it mainly include animal feed.The invention is also pharmaceutical compositions comprising proteobacterial effective amount of anhydrate instead with a pharmaceutically acceptable diluent or carrier.Anhydrate you can enter people for the treatment of bacterial diseases either oral or parenteral routes, and it may be administered orally at dose levels of from about 0.1 to 500 mg/kg/day, preferably 0.5 to 50 mg/kg/day, administered in a single dose or up to 3 separate doses. Intramuscular or intravenous dose of about 0.1-200 mg/kg/day, mostly 0.5 to 50 mg/kg/day. In intramuscular dose may be single or up to 3 fractional doses, intravenous administration can be a lifespan the STI on the weight and condition of the subject, subject to treatment and selected a particular method of administration.Antibacterial activity of anhydrite demonstrated by test Steer's replicating technique, which is standard in vitro test method for antibacterial activity described B. Steers et al., Antibiotics and Chemotherapy, 9,307 (1959).Hydration properties were determined gravitometric in a certain range of relative humidities, using VT1 of microbalance to use sorption moisture (Model MB 3000 W).Preparation A.7-([1,5,6]-6-amino-3-azabicyclo[3.1.0] Gex-3-yl)-6-fluoro-1-(2,4-differenl)- 1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid, salt methanesulfonic acid
Ethyl ester of 7-([1,5,6]-6-tert-butyloxycarbonyl-3-azabicyclo- [3.1.0] Gex-3-yl)-6-fluoro-1-(2,4-differenl)-1,4-dihydro-4-oxo-1,8 - naphthiridine-3-carboxylic acid (25 g) and methanesulfonyl acid (11 g) was added to a mixture of water (250 ml) and tetrahydrofuran (250 ml). The resulting suspension is heated to the temperature of reflux distilled (about 66oC) and maintained at this temperature for 20 hours, after which a clear solution is obtained. The solution is cooled to 35-40oC and concentrate when demoted is cooled to room temperature (about 20oC) and then stirred at 10oC for 2 hours. Crystalline product 7-([1,5,6]-6-amino-3-azabicyclo[3.1.0] -Gex-3-yl)-6-fluoro-1-(2,4-differenl)-1,4 - dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid, salt methanesulfonic acid, separated by filtration and washed with a mixture of tetrahydrofuran (12.5 ml) and water (12.5 ml). The crystals are dried under vacuum at 30-35oC up until the residual water content in the crystals is not less than 0.2%. The output of 21.2 g, 90%. Crystals of 7-([1,5,6]-6-amino-3-azabicyclo[3.1.0] Gex-3-yl)-6-fluoro-1-(2,4-differenl)-1,4 - dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid, salt methansulfonate acids are characterized by the main peaks in the x-ray powder diffraction (PL.4).Crystals of 7-([1,5,6]-6-amino-3-azabicyclo[3.1.0]Gex-3-yl)-6-fluorescent-1-(2,4-differenl)-1,4 - dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid, salt methanesulfonic acid, can absorb water from the atmosphere and form the monohydrate. Monohydrate is characterized by the main peaks in the x-ray powder diffraction.Example 1.7-([1,5,6]-6-amino-3-azabicyclo[3.1.0] Gex-3-yl)-6-fluoro-1-(2,4-differenl)-1,4 - dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid, salt methanesulfonic acid, anhydrous
7-([1,5,6 the ol methanesulfonate acid or its monohydrate (20 g) is stirred with isopropanol (220 ml). The suspension of crystals is refluxed for 16 hours or until the study under the microscope shows that the crystalline form has changed to a hexagonal shape. The suspension of crystals is cooled to 20-25oC and stirred at this temperature for about 1 hour. The crystalline product is filtered off with isopropanol (50 ml) and dried in vacuum at 40oC up until all solvent is removed. Exit 98%.The product is a new polymorphic form 7-([1,5,6]-6-amino-3-azabicyclo[3.1.0] Gex-3-yl)-6-fluoro-1-(2,4 - differenl)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid, salt methanesulfonic acid, anhydrous, characterized by the main peaks in the following x-ray powder diffraction.Example 2.7-([1,5,6]-6-amino-3-azabicyclo[3.1.0] Gex-3-yl)-6-fluoro-1-(2,4 - differenl)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid, salt methanesulfonic acid, anhydrous
7-([1,5,6]-6-amino-3-azabicyclo[3.1.0] Gex-3-yl)-6-fluoro-1-(2,4 - differenl)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid, salt methanesulfonic acid or its monohydrate (7 g) is dissolved in dimethylsulfoxide (DMCO, 21 ml) and heated to 80-85oC dniu crystals maintained at a temperature of about reflux distilled 85oC for 2-16 hours or until the study under the microscope shows that the crystalline form has changed to a hexagonal shape. The resulting suspension of crystals is cooled to 20-25oC. the Crystalline product was filtered from the mother liquor, washed with isopropanol (50 ml) and dried under vacuum at 50oC to completely remove all solvents. Yield 77%.The product is the same as in example 1.Example 3.7-([1,5,6]-6-amino-3-azabicyclo[3.1.0] Gex-3-yl)-6-fluoro-1- (2,4-differenl)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid, salt methanesulfonic acid, anhydrous
7-([1,5,6]-6-amino-3-azabicyclo[3.1.0] Gex-3-yl)-6-fluoro-1- (2,4-differenl)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid, salt methanesulfonic acid or its monohydrate (55,6 g) dissolved in dimethylsulfoxide (DMCO, 159 ml) and heated to 80-85oC as long, until it forms a solution. The solution is cooled to 20-25oC and stirred for 2 hours prior to the formation of a suspension of crystals. To the solution at about 25oC is added dropwise dichloromethane (1200 ml) to cause complete crystallization. The suspension of crystals incubated at room temperature for PR is eh hexagonal shape. The crystalline product is filtered from the mother liquor, washed with dichloromethane (3 119 ml) and dried under vacuum at 50oC to remove the solvent. Yield 91%.The product is the same as in example 1.Example 4.7-([1,5,6]-6-amino-3-azabicyclo[3.1.0] Gex-3-yl)-6-fluoro-1- (2,4-differenl)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid, salt methanesulfonic acid, anhydrous
7-([1,5,6]-6-amino-3-azabicyclo[3.1.0] Gex-3-yl)-6-fluoro-1- (2,4-differenl)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid, salt methanesulfonic acid or its monohydrate (1 g) was stirred with n-propanol (44 ml). The suspension of crystals is refluxed for 3 hours or until the study under the microscope shows that the crystalline form has changed to a hexagonal shape. The suspension of crystals is cooled at 20-25oC and stirred over night. The crystalline product is filtered from the mother liquor, washed with n-propanol (10 ml) and dried under vacuum at 50-55oC to remove the solvent. Yield 68%.The product is the same as in example 1.Example 5.7-([1,5,6]-6-amino-3-azabicyclo[3.1.0 of islote, anhydrous
7-([1,5,6]-6-amino-3-azabicyclo[3.1.0] Gex-3-yl)-6-fluoro-1- (2,4-differenl)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid, salt methanesulfonic acid or its monohydrate (70 g) is stirred with a mixture of tetrahydrofuran (175 ml) and n-butanol (525 ml). The suspension of crystals is heated for 16 hours or until the study under the microscope, shows that the crystalline form has changed to a hexagonal shape. The suspension of crystals is cooled to 20-25oC during the night. The crystalline product is filtered from the mother liquor, washed with a mixture of tetrahydrofuran (25 ml) and n-butanol (75 ml) and dried in vacuum at 80oC to remove solvent. Yield 95%.The product is the same as in example 1.Example 6.7-([1,5,6]-6-amino-3-azabicyclo[3.1.0]Gex-3-yl)-6-fluoro-1- (2,4-differenl)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid, salt methanesulfonic acid, anhydrous
7-([1,5,6]-6-amino-3-azabicyclo[3.1.0]Gex-3-yl)-6-fluoro-1- (2,4-differenl)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic acid, salt methanesulfonic acid or its monohydrate (5 g) mixed with n-butanol, containing up to 1% water (220 ml). The suspension of crystals is heated to Ampelisca form has changed to a hexagonal shape. The suspension of crystals is cooled to 20-25oC and stirred over night. The crystalline product is filtered from the mother liquor, washed with n-butanol (20 ml) and dried under vacuum at 50-55oC to remove the solvent. Yield 92%.The product is the same as in example 1. 1. Salt of 7-([1,5,6]-6-amino-3-azabicyclo[3.1.0] GEK-3-yl)-6-fluoro-1-(2,4-differenl)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic and methanesulfonic acids, characterized by the following main peaks in the x-ray powder diraction processes:
2. A method of obtaining a connection on p. 1, characterized in that the salt of 7-([1,5,6]-6-amino-3-azabicyclo[3.1.0] GEK-3-yl)-6-fluoro-1-(2,4-differenl)-1,4-dihydro-4-oxo-1,8-naphthiridine-3-carboxylic and methanesulfonic acid or its monohydrate is boiled or heated to a temperature of 80 - 85oC in the presence of alcohol or its mixture with the aprotic co-solvent.
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