Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-17
2002-07-23
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S183000, C514S411000, C540S456000
Reexamination Certificate
active
06423722
ABSTRACT:
The invention relates to macrolide chemistry. It concerns the compound of formula I
i.e. {[1E-(1R,3R,4S)]1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R}-12-[2-(4-chloro-3-methoxycyclohexyl)-1-methylvinyl]-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetraone, hereinafter briefly named “33-epichloro-33-desoxy-FR520” or “33-epichloro-33-desoxyascomycin”, in crystalline form.
For simplicity, formula I as referred to herein should be understood as including the compound of formula I in the various tautomeric forms with which it is in equilibrum, particularly in solution, and solvated, e.g. hydrated forms, such as the tautomeric forms of formula
and of formula
The compound of formula I is known in amorphous form, e.g. from Sandoz EP 427 680, Example 66a in the form of a colourless foamy resin [with
1
H-NMR=4.56 (m, H-33)], and from Merck EP 480 623, Example 53 (without any physicochemical characterization). Various names and carbon atom numberings are used in the literature.
Prior to the present invention, the compound of formula I had never been recovered in crystalline form.
It appears that the presence of a halogen atom, especially chlorine in the cyclohexyl moiety of the molecule, particularly in the 4 position thereof (also marked as position 33 in formulae I and Ic herein), has an unfavourable effect on the crystallization properties of this structural class of compounds. Thus in EP 427 680 none of the halogenated final products is obtained in crystalline form, they are colourless foams or foamy resins, and characterized by their NMR spectra.
Similarly, in EP 480 623, which covers exclusively macrolide end products halogenated in the cyclohexyl moiety, none of the specific compounds disclosed is characterized by data indicative of crystallinity, such as a melting point; most end products therein are not characterized by any physicochemical data at all, and those that are characterized, are characterized by their mass spectra, which are not indicative as regards physical state; and none of the 4-chloro end products disclosed is characterized at all.
Further analogous macrolides halogenated in the cyclohexyl moiety are also disclosed in e.g. Fisons WO 91/13889, specifically, as Examples 42a), 42b) and 49a): the compounds therein are also not obtained in crystalline form, but recovered as a foam or an oil.
Overall, the 23-membered tricyclomacrolides derived from FK 506 are obtainable in crystalline form only with difficulty, if at all, as appears also from e.g. Merck WO 97/8182, concerning a macrolide compound having a basic substituent capable of forming salts, which could be obtained in crystalline form, but as a tartrate salt. The compound of the present invention is devoid of such a basic substituent.
It is thus surprising that crystallization of the compound of formula I has now been successfully achieved.
The invention concerns the compound of formula I in crystalline form. The crystalline form may appear as solvated, e.g. hydrated, or anhydrous form, or be a tautomer.
While the first recovery of the compound of formula I in crystalline form occurred several years after the first synthesis of the compound, initially obtained only in amorphous form, it has turned out that subsequently to its first crystallization, the compound could be induced to crystallize from the amorphous form quite readily. The crystalline material has thus now become easily accessible, using a variety of experimental conditions extending beyond the initially used recrystallization conditions, which involved the addition of water to an ethanolic solution of the amorphous compound.
The invention also concerns a process for the preparation of the compound of formula I, or a tautomeric or solvated form thereof, in crystalline form which comprises appropriately converting amorphous compound of formula I from a solution thereof under crystallization-inducing conditions.
It also concerns the compound of formula I, or a tautomeric or solvated form thereof, in crystalline form whenever prepared by that process, and the compound of formula I in a non-crystalline, e.g. in dissolved state, or a tautomeric or solvated form thereof, whenever produced from a crystalline form.
The process of the invention is effected in conventional manner. The precise conditions under which crystals are formed may now be empirically determined and a number of methods are suitable in practice, including the initial addition of water to an ethanolic solution of the compound of formula I in amorphous form.
Crystallization-inducing conditions normally involve the use of an appropriate crystallization-inducing solvent, such as methanol, ethanol, isopropanol or water or mixtures thereof. Conveniently, the amorphous compound is dissolved in the solvent at a temperature of normally at least 10° C. The solution may be produced by dissolving in a solvent any one or more of amorphous forms of the compound, and solvates thereof, such as hydrates, methanolates, ethanolates, isopropanolates and acetonitrilates. Crystals may then be formed by conversion from solution, crystallization taking place at a temperature of between about 10° C. and the boiling point of the solvent. The dissolution and crystallization may be carried out in various conventional ways. For instance, amorphous compound may be dissolved in a solvent or a mixture of solvents in which it is readily soluble at elevated temperatures but in which it is only sparingly soluble at lower temperatures. Dissolution at elevated temperature is followed by cooling during which the desired crystals crystallize out of solution. Solvents which are suitable include esters such as methyl acetate and ethyl acetate, toluene and acetonitrile. Mixed solvents comprising a good solvent in which the compound is readily soluble, preferably, in amounts of at least 1% by weight at 30° C., and a poor solvent in which it is more sparingly soluble, preferably in amounts of not more than about 0.01% by weight at 30° C., may also be employed provided that crystallization from the mixture at a reduced temperature, of normally at least about, 10° C., is possible using the selected solvent mixture.
Alternatively, the difference in solubility of the crystals in different solvents may be used. For example, the amorphous compound may be dissolved in a good solvent in which it is highly soluble such as one in which it is soluble in amounts of at least 1% by weight at about 30° C., and the solution subsequently mixed with a poor solvent in which it is more sparingly soluble, such as one in which it is soluble in amounts of not more than about 0.01% by weight at about 30° C. Thus, the solution of the compound in the good solvent may be added to the poor solvent, while maintaining normally a temperature in excess of about 10° C., or the poor solvent may be added to the solution of the compound in the good solvent, again while normally maintaining a temperature in excess of about 10° C. Examples of good solvents include lower alcohols, such as methanol, ethanol and isopropanol, as well as acetone, tetrahydrofuran and dioxane. Examples of poor solvents are water, hexane and diethyl ether. Preferably, crystallization is effected at a temperature in the range of about 10° C. to about 60° C.
In an alternative embodiment of the process of the invention, solid amorphous compound is suspended at a temperature of normally at least about 10° C. in a solvent in which it is incompletely soluble, preferably only sparingly soluble, at that temperature. A suspension results in which particles of solid are dispersed, and remain incompletely dissolved in the solvent. Preferably the solids are maintained in a state of suspension by agitation e.g. by shaking or stirring. The suspension is kept at a temperature of normally about 10° C. or higher in order to effect a transformation of the starting solids into crystals. The amorphous solid compound suspended in a suitable solvent may be a solvate, e
Dosenbach Cornelia
Grassberger Maximilian
Hartmann Otto
Horvath Amarylla
Mutz Jean-Paul
Chang Ceila
Loeschorn Carol A.
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