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

• US 20030225050A1
• Filed: 04/17/2003
• Published: 12/04/2003
• Est. Priority Date: 04/23/2002
• Status: Active Grant

• Current Assignee: Bayer Intellectual Property GmbH (Bayer AG)
• Original Assignee: Schering Ag (Merck & Co., Inc.)
• Inventors: Gliesing, Sabine, Grawe, Detlef, Mueller, Uwe, Hoesel, Peter, Gerecke, Hagen, Eichardt, Annette
• Granted Patent: US 7,192,942 B2
• Time in Patent Office: Days
• US Class Current: 514/179
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 5/24 of the sex hormones
• CPC Class Codes: C07J 41/0083 substituted in position 11-beta by an optionally substituted phenyl group not further condensed with other rings

Abstract

The process for making crystals of a 11β-benzaldoxim-estra-4,9-diene derivative having a predetermined average particle size in a predetermined size range and a maximum particle size that does not exceed a predetermined maximum value, includes subjecting a supersaturated solution containing a special 11β-benzaldoxim-estra-4,9-diene derivative of formula (I) to a wet milling by a wet milling apparatus while crystallizing, in order to obtain a primary particle suspension. Crystals obtained according to this process and pharmaceutical preparations containing them are also described.

Claims

1. A process for making crystals of a 11β

-benzaldoxim-estra-4,9-diene derivative, said crystals having an average particle size in a predetermined size range and a maximum particle size that does not exceed a predetermined maximum value, 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 R¹ represents hydrogen or an alkyl group with 1 to 6 carbon atoms;

R² 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 —

CONHR⁴ group,

R³ 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 —

(CH₂)_n—

CH₂X, an —

OR⁵ group, a —

(CH₂)_o—

CH═

CH(CH₂)_p—

R⁶ group or —

(CH₂)_qC═

CR⁷;

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 —

OR⁵ group or an —

SR⁵ 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 —

CONHR⁴ group, a —

COOR⁴ group, an alkali metal atom or an alkaline earth metal atom;

wherein R⁴ 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 R⁵ 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 R⁶ 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 R⁷ 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}-17β

-methoxy-17α

-methoxymethyl-estra-4,9-dien-3-one.

3. The process as defined in claim 1, wherein said average particle size of said crystals amounts to from 3 μ

m to 25 μ

m.

4. The process as defined in claim 1, wherein said predetermined maximum value is 100 μ

m.

5. 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.

6. The process as defined in claim 5, wherein said supersaturated solution comprises a solvent and said solvent is ethyl acetate.

7. 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.

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

9. 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.

10. 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.

11. The process as defined in claim 10, 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.

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

13. The process as defined in claim 10, 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.

14. The process as defined in claim 10, 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.

15. Crystals of a 11β

-benzaldoxim-estra-4,9-diene derivative having an average particle size in a predetermined size range and a maximum particle size that does not exceed a predetermined maximum value, wherein said crystals are made by a 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 R¹ represents hydrogen or an alkyl group with 1 to 6 carbon atoms;

R² 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 —

CONHR⁴ group,

R³ 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 —

(CH₂)_n—

CH₂X, an —

OR⁵ group, a —

(CH₂)_o—

CH═

CH(CH₂)_p—

R⁶ group or —

(CH₂)_qC═

CR⁷;

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 —

OR⁵ group or an —

SR⁵ 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 —

CONHR⁴ group, a —

COOR⁴ group, an alkali metal atom or an alkaline earth metal atom;

wherein R⁴ 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 R⁵ 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 R⁶ 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 R⁷ 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.

16. The crystals as defined in claim 15, wherein said 11β

-benzaldoxim-estra-4,9-diene derivative is 11β

-{4-[(ethylaminocarbonyl)oximinomethyl]phenyl}-17β

-methoxy-17 α

-methoxymethyl-estra-4,9-dien-3-one.

17. The crystals as defined in claim 15, wherein said average particle size is 3 μ

m to 25 μ

m and said predetermined maximum value is 100 μ

m.

18. The crystals as defined in claim 15, 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.

19. The crystals as defined in claim 18, wherein said supersaturated solution comprises a solvent and said solvent is ethyl acetate.

20. The crystals as defined in claim 15, 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.

21. The crystals as defined in claim 15, 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. A pharmaceutical preparation containing crystals of 11β

-benzaldoxim-estra-4,9-diene derivative, said crystals having an average particle size and a maximum particle size, wherein said crystals are made by a process comprising subjecting a supersaturated solution containing the 11 13-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 R¹ represents hydrogen or an alkyl group with 1 to 6 carbon atoms;

R² 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 —

CONHR⁴ group,

R³ 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 —

(CH₂)_n—

CH₂X, an —

OR⁵ group, a —

(CH₂)_o—

CH═

CH(CH₂)_p—

R⁶ group or —

(CH₂)_qC═

CR⁷;

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 -OR⁵ group or an —

SR⁵ 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 —

CONHR⁴ group, a —

COOR⁴ group, an alkali metal atom or an alkaline earth metal atom;

wherein R⁴ 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 R⁵ 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 R⁶ 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 R⁷ 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.

23. The pharmaceutical preparation as defined in claim 22, 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.

24. The pharmaceutical preparation as defined in claim 22, wherein said average particle size is from 3 μ

m to 25 μ

m and said maximum particle size is 100 μ

m

25. The pharmaceutical preparation as defined in claim 22, 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.

26. The pharmaceutical preparation as defined in claim 22, 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.

27. The pharmaceutical preparation as defined in claim 26, wherein said solvent is ethyl acetate.