Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-08-20
2004-04-20
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S123000
Reexamination Certificate
active
06723734
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a salt and associated hydrates of racemic 7-(3-aminomethyl-4-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, processes for their preparation, pharmaceutical compositions comprising them, and their use in antibacterial therapy.
BACKGROUND ART
EP 688772 (corresponding to Korean Patent Laid open Publication No 96-874) discloses novel quinoline(naphthyridine)carboxylic acid derivatives, including anhydrous 7-(3-aminomethyl-4-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid of formula I, having antibacterial activity.
DISCLOSURE OF INVENTION
According to the invention there is provided 7-(3-aminomethyl-4-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate.
7-(3-aminomethyl-4-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate (hereinafter referred to as ‘the methanesulfonate’) may be obtained as an anhydrate or a hydrate (i.e., methanesulfonate.nH
2
O).
Hydrates of the methanesulfonate wherein n is in the range of from 1 to 4 are preferred. Particular hydrates of the methanesulfonate, which may be mentioned, are those in which n is 1, 1.5, 2, 2.5, 3, 3.5, and 4. Particularly preferred compounds are those in which n is 1.5 or 3, with n=1.5 being most preferred.
The moisture content of the methanesulfonate hydrates varies with the hydration number (n) of the hydrated molecule. The methanesulfonate has a molecular weight of 485.5. Thus the calculated moisture content of hydrates where n is 1, 1.5, 2, 2.5, 3, 3.5, and 4 is 3.6%, 5.0%, 6.9%, 8.5%, 10.0%, 11.5%, and 12.9%, respectively. However, the actual moisture content of the methanesulfonate hydrates may differ from the calculated value depending on various factors including recrystallization conditions and drying conditions. The observed moisture content for the methanesulfonate hydrates where n is 1, 1.5, 2, 2.5, 3, 3.5, and 4 is shown in Table 1:
TABLE 1
Hydration Number (n)
Moisture Content (% w/w)
1
2~4
1.5
4~6
2
6~8
2.5
8~9
3
9~11
3.5
11~12
4
12~13
It is possible to mix methanesulfonate hydrates having different moisture contents together to give materials having intermediate moisture contents.
Preferred methanesulfonate hydrates have a moisture content of from 4 to 6% or from 9 to 11%, especially a moisture content of from 4 to 6%.
The methanesulfonate has been observed to exist as a stable hydrate over a range of hydration numbers (n). Stability of the hydrate refers to its resistance to loss or gain of water molecules contained in the compound. The methanesulfonate hydrates maintain a constant moisture content over an extended relative humidity range. The n=3 hydrate has a constant moisture content at a relative humidity of from at least 23 to 75%, and the n=1.5 hydrate has a constant moisture content at a relative humidity of from 23 to 64% (see FIGS.
3
and
4
). In contrast, moisture absorption by the anhydrate varies greatly with relative humidity.
Both the methanesulfonate anhydrate and n=3 hydrate undergo transition to the n=1.5 hydrate in aqueous suspension indicating that the latter is thermodynamically more stable. The n=1.5 hydrate is a sesquihydrate at 11 to 64% of relative humidity. Above 75% relative humidity, it takes up water over 10% and its X-ray diffraction pattern changes. The hydrate (another form of n3 having different physicochemical properties from the n=3 hydrate of Example 2) obtained from n1.5 hydrate at 93% relative humidity is not stable at lower relative humidity, and it converts back to n=1.5 hydrate at a relative humidity below 75%.
Since the moisture content of the anhydrate changes readily depending on the environment (e.g., relative humidity, formulation additives, etc.), it may require careful handling during storage or formulation, with operations, such as quantifying procedures, being performed in a dry room. The hydrates do not change in moisture content easily and hence products, which are stable under prolonged storage and formulation may be obtained. The hydrate can be tableted without the addition of a binder since the water contained in the compound itself acts as a binder, whereas it may not be possible to tablet the anhydrate at a similar pressure.
The present invention also provides a process for the preparation of 7-(3-aminomethyl-4-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate and hydrates thereof which comprises reacting 7-(3-aminomethyl-4-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid with methanesulfonic acid and crystallizing the resulting methanesulfonate from solution, and where desired or necessary adjusting the hydration of the compound.
The methanesulfonate and its hydrates may be prepared by the addition of methanesulfonic acid to the free base which may be prepared as described in EP 688772. Preferably, 0.95 to 1.5 molar equivalents of methanesulfonic acid are added to the free base, or 1 molar equivalent of methanesulfonic acid dissolved in a suitable solvent is added to the free base. Suitable solvents for the preparation of the methanesulfonate and its hydrates include any solvent in which the methanesulfonate is substantially insoluble, and the suitable solvents include C
1
-C
4
haloalkanes, C
1
-C
8
alcohols and water, or mixtures thereof. Dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol, propanol and water, or mixtures thereof, are preferred solvents. If necessary, the free base may be heated in the solvent to facilitate solution before methanesulfonic acid is added, and alternatively the methanesulfonic acid may be added to a suspension, or partial suspension, of the free base in the solvent. Following addition of the methanesulfonic acid, the reaction mixture is preferably allowed to stand or is stirred for 1 to 24 hours at a temperature of from about −10 to 40° C. The resulting methanesulfonate is obtained as a solid, which can be isolated by filtration or by removal of the solvent under reduced pressure.
Different hydrates may be obtained by altering the recrystallization conditions used in the preparation of the methanesulfonate, and such conditions may be ascertained by conventional methods known to those skilled in the art.
The present invention also provides a process for the preparation of a hydrate of 7-(3-aminomethyl-4-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate comprising exposing the methanesulfonate anhydrate or a solvate thereof to a high relative humidity.
The methanesulfonate anhydrate or solvate thereof is preferably exposed to a relative humidity of at least 75%.
The methanesulfonate anhydrate or solvate thereof may be exposed to high relative humidity by passing humidified nitrogen gas through the methanesulfonate anhydrate or solvate thereof or by standing the methanesulfonate anhydrate or solvates thereof under a high relative humidity.
The humidified nitrogen gas used in this process, for example nitrogen gas having a humidity of at least 75%, may be made by conventional methods. In this process it is desirable to maintain the temperature in the range above which moisture condensation could occur. Also, particularly in large scale production, it is preferable to stir the sample thoroughly while the humidified nitrogen gas is passed through. When the hydrate is prepared by standing the methanesulfonate anhydrate or solvate thereof under a high relative humidity, for example a relative humidity of at least 75%, it is preferable to spread the sample as thinly as possible in order to raise the conversion efficiency.
The solvates of methanesulfonate anhydrate which may be used in the process according to this aspect of the present invention
Chang Jay Hyok
Choi Hoon
Choi Jong Ryoo
Kim Ae Ri
Lee Jin Hwa
Davis Zinna Northington
LG Life Sciences Ltd.
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