Process for production of crystals of 11μ-benzaldoxim-estra-4,9-diene derivatives, crystals obtained thereby and pharmaceutical preparations containing them

1. A process for making crystals of a 11β-benzaldoxim-estra-4,9-diene derivative, said crystals having an average particle size of from 3 μm to 25 μm and a maximum particle size of 100 μm, said process comprising subjecting a supersaturated solution containing said 11β-benzaldoxim-estra-4,9-diene derivative to a wet milling by a wet milling apparatus while crystallizing, in order to obtain a primary particle suspension;

wherein said 11β-benzaldoxim-estra-4,9-diene derivative is a compound of formula (I), or a pharmacologically acceptable salt thereof:

wherein R 1 represents hydrogen or an alkyl group with 1 to 6 carbon atoms;

R 2 represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms, an acyl group with 1 to 10 carbon atoms or a —CONHR 4 group,

R 3 represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms, or a —(CH 2 ) n —CH 2 X, an —OR 5 group, a —(CH 2 ) o —CH=CH(CH 2 ) p —R 6 group or —(CH 2 ) q C=CR 7 ;

wherein n is 0, 1 or 2, o is 0, 1, 2 or 3, p is 0, 1 or 2 and q is 0, 1 or 2;

wherein X represents hydrogen, a fluoro group, a chloro group, a bromo group, an iodo group, a cyano group, an azido group, a rhodano group, an —OR 5 group or an —SR 5 group;

wherein Z represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms, an acyl group with 1 to 10 carbon atoms, a —CONHR 4 group, a —COOR 4 group, an alkali metal atom or an alkaline earth metal atom;

wherein R 4 represents an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms or an alkylaryl group with 1 to 10 carbon atoms;

wherein R 5 represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an awl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms or an acyl group with 1 to 10 carbon atoms;

wherein R 6 represents a hydrogen, a hydroxy group, an alkyl group with 1 to 10 carbon atoms, an alkoxy group with 1 to 10 carbon atoms, an awl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms, an acyl group with 1 to 10 carbon atoms or an acyloxy group with 1 to 10 carbon atoms; and

wherein R 7 represents a hydrogen, a fluoro group, a chloro group, a bromo group, an iodo group, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms or an acyl group with 1 to 10 carbon atoms.

2. The process as defined in claim 1 , wherein said 11β-benzaldoxim-estra-4,9-diene derivative is 11β-{4-[(ethylaminocarbonyl)oximinomethyl]phenyl}-7β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one.

3. The process as defined in claim 1 , wherein said supersaturated solution contains from 10 to 30 percent by weight of said compound of said formula (I), based on said supersaturated solution.

4. The process as defined in claim 3 , wherein said supersaturated solution comprises a solvent and said solvent is ethyl acetate.

5. The process as defined in claim 1 , further comprising preparing said supersaturated solution by dissolving said compound of formula (I) in a solvent at a temperature below a boiling point of said solvent to form a resulting solution and subsequently cooling said resulting solution to a temperature above a freezing point of the resulting solution.

6. The process as defined in claim 1 , wherein said crystallizing is performed in a vessel or container having a stirring device.

7. The process as defined in claim 1 , wherein said wet milling apparatus is a rotor-stator apparatus, a stirring mill, a roller mill or a colloid mill.

8. The process as defined in claim 1 , further comprising heating said primary particle suspension to a temperature (T max ) below a solubility limit of primary particles of the primary particle suspension and subsequently cooling to a temperature above a freezing point (T min ) of the primary particle suspension.

9. The process as defined in claim 8 , wherein said supersaturated solution comprises a solvent and said temperature (T max ) below said solubility limit is selected so that from 10 to 90 percent by weight of said primary particles dissolve in said solvent.

10. The process as defined in claim 8 , wherein said temperature above said freezing point (T min ) is selected so that dissolved primary particles are substantially re-crystallized.

11. The process as defined in claim 8 , wherein said cooling from said temperature (T max ) below said solubility limit to said temperature above said freezing point (T min ) occurs during a time interval of 1 minute to 10 hours.

12. The process as defined in claim 8 , wherein said heating to said temperature (T max ) below said solubility limit and said cooling to said temperature above said freezing point is performed from 1 to 10 times.

13. Crystals of a 11β-benzaldoxim-estra-4,9-diene derivative having an average particle size at from 3 μm to 25 μm and a maximum particle size of 100 μm, wherein said crystals are made by a process comprising subjecting a supersaturated solution containing said 11β-benzald-oxim-estra-4,9-diene derivative to a wet milling by a wet milling apparatus while crystallizing, in order to obtain a primary particle suspension;

wherein said 11β-benzaldoxim-estra-4.9-diene derivative is a compound of formula (I), or a pharmacologically acceptable salt thereof:

wherein R 1 represents hydrogen or an alkyl group with 1 to 6 carbon atoms;

R 2 represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms, an acyl group with 1 to 10 carbon atoms or a —CONHR 4 group,

R 3 represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms or a —(CH 2 ) n —CH 2 X, an—OR 5 group, a —(CH 2 ) o —CH=CH(CH 2 ) p —R 6 group or —(CH 2 ) q C=CR 7 ;

wherein n is 0, 1 or 2, o is 0, 1, 2 or 3, p is 0, 1 or 2 and q is 0, 1 or 2;

wherein X represents hydrogen, a fluoro group, a chloro group, a bromo group, an iodo group, a cyano group, an azido group, a rhodano group, an —OR 5 group or an —SR 5 group;

wherein Z represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms, an acyl group with 1 to 10 carbon atoms, a —CONHR 4 group, a —COOR 4 group, an alkali metal atom or an alkaline earth metal atom;

wherein R 4 represents an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms or an alkylaryl group with 1 to 10 carbon atoms;

wherein R 5 represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms or an acyl group with 1 to 10 carbon atoms;

wherein R 6 represents a hydrogen, a hydroxy group, an alkyl group with 1 to 10 carbon atoms, an alkoxy group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms, an acyl group with 1 to 10 carbon atoms or an acyloxy group with 1 to 10 carbon atoms; and

wherein R 7 represents a hydrogen, a fluoro group, a chloro group, a bromo group, an iodo group, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms or an acyl group with 1 to 10 carbon atoms.

14. The crystals as defined in claim 13 , wherein said 11β-benzaldoxim-estra-4,9-diene derivative is 11β-{4-[(ethylaminocarbonyl)oximinomethyl]phenyl}-17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one.

15. The crystals as defined in claim 13 , wherein said supersaturated solution contains from 10 to 30 percent by weight of said 11β-benzaldoxim-estra-4.9-diene derivative, based on said supersaturated solution, and said process comprises preparing said supersaturated solution by dissolving said 11β-benzaldoxim-estra4,9-diene derivative in a solvent at a temperature below a boiling point of said solvent to form a resulting solution and subsequently cooling said resulting solution to a temperature above a freezing point of the resulting solution.

16. The crystals as defined in claim 15 , wherein said supersaturated solution comprises a solvent and said solvent is ethyl acetate.

17. The crystals as defined in claim 13 , wherein said supersaturated solution comprises a solvent; said process comprises heating said primary particle suspension to a temperature (T max ) below a solubility limit of primary particles of the primary particle suspension and subsequently cooling to a temperature above a freezing point (T min ) of the primary particle suspension and wherein said temperature (T max ) below said solubility limit is selected so that from 10 to 90 percent by weight of said primary particles dissolve in said solvent and said temperature above said freezing point (T min ) is selected so that dissolved primary particles are substantially re-crystallized, said cooling from said temperature (T max ) below said solubility limit to said temperature above said freezing point (T min ) occurs during a time interval of 1 minute to 10 hours.

18. The crystals as defined in claim 13 , wherein said crystallizing is performed in a vessel or container having a stirring device and said wet milling apparatus is a rotor-stator apparatus, a stirring mill, a roller mill or a colloid mill.

19. A pharmaceutical preparation containing crystals of 11β-benzaldoxim-estra-4,9-diene derivative, said crystals having an average particle size of from 3 μm to 25 μm and a maximum particle size of 100 μm, wherein said crystals are made by a process comprising subjecting a supersaturated solution containing the 11β-benzaldoxim-estra-4,9-diene derivative to a wet milling by a wet milling apparatus while crystallizing, in order to obtain a primary particle suspension;

wherein said 11β-benzaldoxim-estra-4,9-diene derivative is a compound of formula (I), or a pharmacologically acceptable salt thereof:

wherein R 1 represents hydrogen or an alkyl group with 1 to 6 carbon atoms;

R 2 represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms, an acyl group with 1 to 10 carbon atoms or a —CONHR 4 group,

R 3 represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms, or a —(CH 2 ) n —CH 2 X, an —OR 5 group, a —(CH 2 ) o —CH=CH(CH 2 ) p R 5 group or—(CH 2 ) q C=CR 7 ;

wherein n is 0, 1 or 2, o is 0, 1, 2 or 3, p is 0, 1 or 2 and q is 0, 1 or 2;

wherein X represents hydrogen, a fluoro group, a chloro group, a bromo group, an iodo group, a cyano group, an azido group, a rhodano group, an —OR 5 group or an —SR 5 group;

wherein Z represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms, an acyl group with 1 to 10 carbon atoms, a —CONHR 4 group, a —COOR 4 group, an alkali metal atom or an alkaline earth metal atom;

wherein R 4 represents an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms or an alkylaryl group with 1 to 10 carbon atoms;

wherein R 5 represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, art alkylaryl group with 1 to 10 carbon atoms or an acyl group with 1 to 10 carbon atoms;

wherein R 6 represents a hydrogen, a hydroxy group, an alkyl group with 1 to 10 carbon atoms, an alkoxy group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms, an acyl group with 1 to 10 carbon atoms or an acyloxy group with 1 to 10 carbon atoms; and

wherein R 7 represents a hydrogen, a fluoro group, a chloro group, a bromo group, an iodo group, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms or an acyl group with 1 to 10 carbon atoms.

20. The pharmaceutical preparation as defined in claim 19 , wherein said 11β-benzaldoxim-estra-4,9-diene derivative is 11β-{4[(ethylaminocarbonyl)-oximino-methyl]-phenyl}-17β-methoxy-17α-methoxymethyl-estra-4,9-dien-3-one.

21. The pharmaceutical preparation as defined in claim 19 , wherein said crystallizing is performed in a vessel or container having a stirring device and said wet milling apparatus is a rotor-stator apparatus, a stirring mill, a roller mill or a colloid mill.

22. The pharmaceutical preparation as defined in claim 19 , wherein said supersaturated solution contains from 10 to 30 percent by weight of said 11β-benzaldoxim-estra-4,9-diene derivative, based on said supersaturated solution, and said process comprises preparing said supersaturated solution by dissolving said 11β-benzaldoxim-estra-4,9-diene derivative in a solvent at a temperature below a boiling point of said solvent to form a resulting solution and subsequently cooling said resulting solution to a temperature above a freezing point of the resulting solution.

23. The pharmaceutical preparation as defined in claim 22 , wherein said solvent is ethyl acetate.