Title of Invention	"PROCESS FOR THE PRODUCTION OF A 11ß-[4E-(HYDROXYIMINOMETHYL)PHENYL]-17α-METHOXY-METHYL-17ß-METHOXY-ESTRA-4, 9-DIEN-3-ONE ANSOLVATE AND THE PRODUCTS THEREOF"
Abstract	Process for the production of a llp-[4E-(hydroxyiminomethyl)phenyl]- 17a-methoxymethyl- 17ß-methoxy-estra-4,9-dien-3-one ansolvate conducting as a first step the production of a solvate of 11ß-[4E- (hydroxyimino-rnethyl)phenyl]- 17a-methoxymethyl- 17p-methoxy- estra-4,9-dien-3-one, characterized in that the process comprises the following steps: a) Dissolution of the solvate above the saturation solubility in toluene in which the solvate-crystal structure is unstable, b) The optional addition of methanol or ethyl acetate as a recrystallization inhibitor, and c) The addition of a solvating agent-solvent, namely methyl tertiar butyl ether solvate, a acetone solvate or ethanol solvate and crystallization of the solvate d) drying of the crystalline solvate below the glass transition point of the amorphous substance, whereby drying of the solvate is carried out during the desolvation phase with a heating rate in the product of at least 0.5°C/minute or from a solution of the solvate by spray-drying, or e) suspension of the solvate in water at temperature of 50 to 100°C.

Title of Invention

"PROCESS FOR THE PRODUCTION OF A 11ß-[4E-(HYDROXYIMINOMETHYL)PHENYL]-17α-METHOXY-METHYL-17ß-METHOXY-ESTRA-4, 9-DIEN-3-ONE ANSOLVATE AND THE PRODUCTS THEREOF"

Abstract

Process for the production of a llp-[4E-(hydroxyiminomethyl)phenyl]- 17a-methoxymethyl- 17ß-methoxy-estra-4,9-dien-3-one ansolvate conducting as a first step the production of a solvate of 11ß-[4E- (hydroxyimino-rnethyl)phenyl]- 17a-methoxymethyl- 17p-methoxy- estra-4,9-dien-3-one, characterized in that the process comprises the following steps: a) Dissolution of the solvate above the saturation solubility in toluene in which the solvate-crystal structure is unstable, b) The optional addition of methanol or ethyl acetate as a recrystallization inhibitor, and c) The addition of a solvating agent-solvent, namely methyl tertiar butyl ether solvate, a acetone solvate or ethanol solvate and crystallization of the solvate d) drying of the crystalline solvate below the glass transition point of the amorphous substance, whereby drying of the solvate is carried out during the desolvation phase with a heating rate in the product of at least 0.5°C/minute or from a solution of the solvate by spray-drying, or e) suspension of the solvate in water at temperature of 50 to 100°C.

Full Text	This invention relates to new forms of solids of the mesoprogestin 110-[4E- (hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17p-methoxy-estra-4,9-dien-3-one (oxime J 867), especially a highly pure and stable amorphous or highly crystalline form / (ansolvate/anhydrate) of the compound J 867, process for their production as well as their use in pharmaceutical compositions. 11 p-[4E-(Hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17p-methoxy-estra-4,9-dien-3-one is known, for example, from EP-A-0 648 778 Qr DE-A-43 32 283. The form that is obtained there after recrystallization from methylene chloride/isopropanol melts at 113°C. The crystal form that is described is an isopropanol solvate with 14% isopropanol (see XRPD: Table 2/Figure 4d). A characteristic feature of the oxime is its strong tendency to crystallize from solvents as a solvate. The solvate form, however, is not very suitable for' pharmaceutical applications. The solvent binding to the substance is very secure and is dissolved only at elevated temperatures. The oxime solvates completely cleave the solvent in general only above 100°C. In this case, depending on the heating rate, inhomogeneous amorphous-crystalline mixed forms are produced. The purification of the oxime from by-products of the oxiniization reaction (dioximes, Z-oxirne) is carried out by expensive column chromatography with toluene/acetone gradients. A purification by a crystallization process is hampered by the generally poor solubilities in the solvents that are suitable in this respect. A limiting factor is the fact that an isomerization of the E-isomer of the compound into Z-isomer occurs at elevated temperatures in solution. The object of the invention is therefore to replace the expensive column chromatography by a suitable process and to provide a homogeneous, solvent-free and stable This objecl is achieved by amorphous 1 lp-[4E-(hydroxyiminomethyl)phenyl]-17ct-methoxymethyl-17p-methoxy-estra-4,9-dien-3-one, which is characterized in that no crystalline reflexes can be seen in the x-ray-powder diffractogram (XRPD, Figure la/b) or its modification is characterized by the IR spectrum that is depicted in Figure 2. In addition, this object is achieved by highly crystalline 11 p-[4E-(hydroxyimino-methyl)phenyl]-17o-methoxymethyl-17p-methoxy-estra-4,9-dien-3-one ansolvate. The crystal form of the ansolvate is characterized by the x-ray-powder diffractogram that is depicted in Figure Ic or by the IR-spectrum that is depicted in Figure 3. Crystalline solvates of 1 lp-[4E-(hydroxyiminomethyl)phenyl]17a-rnethoxymethyl-17p-methoxy-estni-4,9-dien-3-one can be produced by a process that comprises the following steps: a) Production of a solvate of 11 p-[4E-(hydroxyiminomethyi)phenyl]-17a- methoxymethyl-17)3-methoxy-estra-4,9-dien-3-one and dissolving of the solvate above the saturation solubility in a solvent, especially toluene, which is different from the solvate-solvent and in which the solvate-crystal structure is unstable, b) The optional addition of another solvent as a recrystallization inhibitor, especially methanol or ethyl acetate, and c) The addition of a solvating agent-solvent, especially ethanol, acetone and methyl-tert- butyl ether (MtBE) and crystallization of the solvate. The crystalline solvates of 1 l(3-[4E-(hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17p-methoxy-estra-4,9-dien-3-one, namely the methyl-tert-butyl ether solvate, the acetone solvate and the ethanol solvate, whereby the highly crystalline forms are characterized by the x-ray-powder diffractograms depicted in Figures 4a/b/c and Table 2, are new and represent intermediate stages toward amorphous 1 lp-[4E-, (hydroxyirninomethyl)phenyl]-17a-methoxymethyl-17p-methoxy-estra-4,9-dien-3-one !or toward highly crystalline 1 lp-[4E-(hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17p-methoxy-estra-4,9-dien-3-one ansolvate. By drying the crystalline solvates of 1 lp-[4E-(hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17p-methoxy-estra-4,9-dien-3-one that are obtained above, especially by thermal desolvation preferably under vacuum and at a heating rate in the product of at least 0.5°C/minute or from a solution of the solvate by spray-drying (XRPD; Figure 1) below the glass transition point of the amorphous structure, the amorphous form of 11 (3-[4E-(hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17p-methoxy-estra-4,9-dien-3-one is then obtained. The highly crystalline form of 1 lp~[4E-(hydroxyiminomethyi)phenyl]-17a-methoxymethyl-r/p-methoxy-estra-4,9-dien-3-one can be produced by heating the solvate form or the amorphous solid form, optionally in aqueous suspension. Subjects of this invention are also pharmaceutical compositions, especially solid pharmaceutical compositions, that comprise the above-described amorphous and/or highly crystalline 1 lp-[4E-(hydroxyiminomethyl)phenyl]-l 7a-methoxymethyl-l 7(3-methoxy-estra-4,9-dien-3-one in combination with a pharmaceutically compatible vehicle and/or diluent. The pharmaceutical compositions of this invention are produced with the commonly used solid or liquid vehicles or diluents and the commonly used pharmaceutically technical adjuvants that correspond to the desired type of administration with a suitable dosage in a way that is known in the art. The term '"highly crystalline" according to the invention defines a state from which no further measurable increase of crystallinity (XRPD, DSC) can be determined by conditions that promote the recrystallization of the amorphous structure, such as, e.g., prolonged boiling of the suspended substance in water. The highly crystalline state is characterized in that no exothermic recrystallization peak can be detected between 110°C and 160°C in the DSC at a slower heating rate (IK/minute). Only the endothermic melting peak exists at 194.7°C + 2K (heating rate 5K/minute). In Figures la to c, the x-ray-powder diffractogram of amorphous 11(3-[4E-(hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17p-methoxy-estra-4,9-dien-3-oneor highly crystalline 1 lp-[4E-(hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17p-methoxy-estra-4,9-dien-3-one ansolvate (cf. Table 1) are depicted. In Figures 2 and 3, IR-spectra of amorphous 1 lp-[4E-(hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17p-methoxy-estra-4,9-dien-3-one or highly crystalline 1 lp-[4E-(hydroxyiminomethyl)phenyl] -17a-methoxymethyl-17 (3 -methoxy-estra-4,9-dien-3 -one ansolvate are depicted. In Figure 4 (Table 2), x-ray-powder diffractograms of the methyl-tert-butyl ether v- solvate, the acetone solvate, the ethanol solvate and the isopropanol solvate (cf. Table 2) from 11 p-[4E-(hydroxyiminomethyl)phenyl]-l 7a-methoxymethyl-17p-methoxy-estra-4,9-dien-3-one are depicted. In Figure 5, an x-ray-powder diffractogram of amorphous 1lp-[4E-(hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17p-methoxy-estra-4,9-dien-3-one is depicted at time 0 (start), after 12 months at 25°C and after 12 months at 40°C. In Figure 6, the solubility of highly crystalline 1 lp-[4E-(hydroxyiminomethyI)phenyl]-17a-rnethoxymethyl-17p-methoxy-estra-4,9-dien-3-one ansolvate or amorphous 1 lp-[4E-(hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17p-methoxy-estra-4,9-dien-3-onein water is shown with and without surfactant. Table 1: XRPD Data of Highly Crystalline Oxiine J867 - d-values (dobs), relative intensities Oobs) and hkl values of the highest peaks (Table Removed) Both hkl values are possible, since the peak separation is limited to 2@ = 0.08C (angular resolution of the detector). Table 2: XRPD Data of the Solvates of Oxime J867 - d-values (dobs) and relative intensities Oobs) of the highest peaks (Table Removed) The invention relates to a new highly pure and stable, amorphous or highly crystalline form of the mesoprogestin llp-[4E-(hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17(3-methoxy-estra-4,9-dien-3-one (J 867): (Figere Removed) and solvate forms of J867, which represent intermediate products for the production of the amorphous or highly crystalline form. It has proven to be a problem in the production of the amorphous or highly crystalline form that in the stage of desolvation, the substance passes through an amorphous intermediate stage, from which the ansolvate/anhydrate form recrystallizes more or less completely depending on the heating rate, final temperature and drying period. The degree of crystallinity, however, is difficult to control, so that inhomogeneous mixed forms that consist of amorphous and crystalline portions are produced. In addition, the thermal stress of the chemical structure that tends toward Z-isomerization and oxime-cleavage results in a deterioration of purity. The production of the solvate form that is suitable for the solid final form of the oxime can be associated, according to the invention, with the separation of the Z-isomer and the dioximes. By a specific use of the thermodynamic instability of suitable solvates, preferably the solvate of methyl-tert-butyl ether (MTBE) in a solvent environment that is suitable for this purpose, complete dissolution of the solvate lattice is possible far above the solubility limit and even close to room temperature. In contact with toluene in a mass ratio of 1:2 to 1:1, the crystal form of the MTBE solvate dissolves quickly and completely, despite the only slight solubility in toluene of only 3.3% by weight, even at 20-35°C. A so-called cold melting is carried out. This state can be kept stable by adding suitable solvents as recrystallization inhibitors for technical applications. The supersaturation state can be stabilized for hours in toluene solution by adding only 5% by volume of methanol. Then, by adding solvating agent-solvent (MTBE) at suitable concentration (e.g., 100-130% by volume of MTBE, relative to the toluene that is used), the solvate lattice is built up again, whereby the contaminants remain in solution for the most part. By an especially quick drying process, preferably spray-drying, below the glass transition point directly from the solution of oxime solvate J867 in an organic solvent, preferably ethanol, a stable, completely amorphous, solvent-free structure can be obtained. To this end, oxime that is dissolved in ethanol to a level of 3 to 13% by weight is sprayed using a suitable spraying unit (binary nozzle or centrifugal sprayer) in hot nitrogen and is dried in an extremely short time to form amorphous, microfine particles. The starting temperature of the nitrogen in this case is 120°C to 200°C, preferably 150°C-180°C. The ratio of oxime solution to drying gas in this case should be 0.01 to 0.3 kg of solution/m"' of Ni, preferably 0.08 to 0.12 kg of solution/mJ of ISb. The drying process is controlled such that in the dryer outlet, a temperature of 55°C to 95°C, preferably 75 to 85°C, is set. This temperature is significantly below the glass transition temperature of the amorphous oxime (105°C), where the substance assumes a gel/glass-like consistency and above which a more or less quick or spontaneous recrystallization can take place. By applying spray-drying, a solvent-free, homogeneous or microfine solid form of oxime J 867 is obtained in one process step. The advantage of using the amorphous form of oxime J867 according to the invention for the production of pharmaceutical agents lies in the fact that in addition to the good solubility properties, this amorphous structure, surprisingly enough, has a very good shelf life. Also, after 12 months in the accelerated ICH-stability test (40°C, 75% relative humidity), the amorphous structure does not show any signs of a recrystallization and/or chemical decomposition (see Figure 5). Also, during the pharmaceutical processing (wet granulation, pelletizing), the physical structure of the oxime remains stable. This means that a conversion of the amorphous into the highly crystalline form or an E/Z isomerization does not occur. By the stability, negative influences of such conversions on the bio-availability of the active ingredient are avoided. Relative to the shelf life, the same correspondingly holds true for the use of the highly crystalline form of oxime J 867 according to the invention, whereby as expected, the chemical stability, especially under stress (high temperatures and humidities) is higher than that of the amorphous form. In addition, the arnqrp_hous..fiarni has excellent solubilitv orooerties. The saturation solubility in water and injhe^sujfactant solution (025% sodium lauryl sulfate) is approximately 7 to 8x higher than that of the highly crystalline form, whereby this high supersaturation level remains stable for several hours, as in the case of water for over 24 hours (see Figure 6). The production of the highly crystalline form can be carried out starting from one of the solvate forms of oxime J867. In this respect, the solvate form can be suspended in water at a temperature of from 50 to 100°C; in this case, the solvent is cleaved far below the desolvation temperature of the dry solvate form. In the case of the MTBE solvate, an only short-term treatment (10 to 30 minutes) with water at a temperature of 65 to 75°C for complete conversion into the highly crystalline form already results. With the process according to the invention, especially the thermal desolvation, it is basically possible, depending on the process conditions, to produce amorphous-crystalline mixed forms that can pose considerable problems that cannot be reproduced, but can hinder the development of a validated production process for quality control, further pharmaceutical processing and official approval. Oxime J867 is a substance that has an antigestagenic action according to EP-A-0 648 778 or DE-A-43 32 283 and that with the same activity as RU 486 (mifepristone) on the progesterone receptor has an antiglucocorticoidal activity that is significantly reduced in comparison to RU 8486. In U.S. Applications Nos. 09/386,141, 09/386,140 and 09/386,133, oxime J 867 is referred to as mesoprogestin. In this connection, mesoprogestins are defined as compounds that have in vivo both agonistic and antagonistic activity on the progesterone receptor (PR). Corresponding functional conditions cannot be achieved with gestagen and antigestagen. Oxime J 867 is suitable in particular for the following uses: a) Oxime J 867 can be used according to U.S. Application No. 09/386,133, optionally together with an estrogen, for the production of a pharmaceutical agent for female contraception. b) Oxime J867 can be used according to U.S. Application No. 09/386,141 for treating and preventing benign hormone-dependent gynecological disorders; such as — for treating gynecological disorders, such as endometriosis, uterine fibroids, post operative peritoneal adhesions, dysfunctional bleeding (metrorrhagia, menorrhagia) and dysmenorrhea; — for preventing gynecological disorders; such as postoperative, peritoneal adhesions, dysfunctional uterine bleeding (metrorrhagia, menorrhagia) and dysmenorrhea. The daily dose of the mesoprogestin is 0.5 to 100 mg, preferably 5.0 to 50 mg and a maximum of preferably 10 to 25 mg. c) Oxime J867 according to U.S. Application No. 09/386,140 can also be used as a pharmaceutical component for the production of a pharmaceutical agent optionally together with an estrogen in hormone replacement therapy (HRT) and for treating hormone deficiency and symptoms of hormonal irregularity. Measuring Process X-Rav-Powder Diffractometry (X-Rav Powder Diffraction: XRPD): The data were determined with an STOE powder diffractometer STADIP with germanium-monochromatic CuKai radiation (A. - 1.540598 A) - between 3° 1R Spectroscopy: A NICOEJBT 20 SXB with a photoacoustic detector MTEC (KBr, 8t, 90 seconds) was used. Solubility Studies: 200 mg of substance was added at 25°C into 50 ml of water (without and with 0.25% SDS (sodium lauryl sulfate)). Samples were taken after 0.5 hour, 2 hours, 5 hours and 24 hours. Sampling: 0.45 ^m filter attachment, dilution 1:1 with MeOH, HPLC. HPLC: The determination of purity is carried out according to the following method: Column: Superspher Si 60, 250 x 4mm, 4\|j.m Eluant: Chloroform (3% ethanol)/water such as 96.9/0.1 Flow: 1 ml/minute Detection: UV (299 nm) Evaluation: 100% surface normalization Headspace for Residual Solvent: GC-Auto system with HS40 Perkin Elmer, DB-Wax column, 30 m x 0.23 mm, FID. Grain Size Distribution: Sympatec HELOS (H0445), dry dispersing system (RODOS), pressure 2 bar. DSC: Perkin Elmer DSC 7 and NETZSCH DSC 200/1/F in Pan-Al, pierced lid, nitrogen. The invention is explained in more detail by the examples that now follow. Examples Example 1 2 kg of oxime J867 (MtBE solvate with 20 to 24% MtBE; unless otherwise indicated, the percent of solvent contained in the solvates is % by weight) is dissolved in 20 1 of ethanol at 50°C while being stirred. The solution is spray-dried in a co-current process in a spray-dryer that is operated under inert conditions (nitrogen). The drying chamber of the spray dryer is coated with 60 mJ/h of nitrogen, which is preheated to 175°C. Then, the solution is sprayed into the drying chamber via a flow inducer with 6.4 1/h with a binary nozzle that is operated with 3 bar of nitrogen as a propellant. The drying gas outlet temperature is 79°C-83°C. The oxime J867 that is dried into microfme particles is completely collected in a Oxime J867 has the following quality parameters: (Table Removed)Example 2 50 ml of toluene is added to 20 g of oxime J867 (MTBE solvate with 20%-24% MtBEi). The substance dissolves veiy quickly and completely at 25°C. 2.7 ml of methanol is added to the solution, and the solution is then mixed with 65 ml of MtBE. After about 1 minute, the recrystallization of the MtBE solvate begins. The entire process is carried out at room temperature. The suspension is stirred for 1 hour at 5°C, then filtered, and the filter cake is washed with 30 ml of cold MtBE. After drying, the yield is 84% by weight of the charging material The product that is obtained is in turn an MTBE solvate with 22.3% MtBE. The purification effect relative to the main contaminants can be seen in the table below: (Table Removed)Example 3 30 g of MtBE solvate of oxime J867 (MtBE solvate with 20 to 24 % MtBE) is suspended in 600 ml water and heated to 70°C and suspended for 30 minutes. The suspension is filtered and suctioned off in the dry state in a stream of air. Then, the crystallizate is dried in a vacuum for 3 hours at 70°C and 24 g of highly crystalline oxime J867 is obtained. The phase conversion in hot water and the drying do not result in any significant increase of the Z-isomer and the aldehyde. (Table Removed)In XRPD, with respect to the intensity and the locations of the reflexes and in the DSC with respect to the melting heat, a similarity to the data of the highly crystalline ansolvate form of oxime J867 was detected. WE CLAIM: 1. Process for the production of a 11ß-[4E- (hydroxyiminornethyl)phenyl]- 17α-rnethoxyrnethyl-17ß- methoxy-estra-4,9-dien-3-one ansolvate conducting as a first step the production of a solvate of llß-[4E-(hydroxyimino- methyl)phenyl]-17a-methoxymethyl-17ß-methoxy-estra-4,9- dien-3-one, characterized in that the process comprises the following steps: a) Dissolution of the solvate above the saturation solubility in toluene in which the solvate-crystal structure is unstable, b) The optional addition of methanol or ethyl acetate as a recrystallization inhibitor, and c) The addition of a solvating agent-solvent, namely methyl tertiar butyl ether solvate, a acetone solvate or ethanol solvate and crystallization of the solvate. d) Drying of the crystalline solvate below the glass transition point of the amorphous substance, whereby drying of the solvate is carried out during the desolvation phase with a heating rate in the product of at least 0.5°C/minute or from a solution of the solvate by spray-drying, or e) suspension of the solvate in water at temperature of 50 to 100°C. 2. 1 lp-[4E-(hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17p- methoxy-estra-4,9-dien-3-one, ansolvate obtained according to claim 1. 3. A solvent free llp-[4E-(hydroxyiminomethyl)phenyl]-17a- methoxymethyl-17p-methoxy-estra-4,9-dien-3-one as claimed in claim 2, wherein it is in amorphous form. 4. Amorphous llp-[4E-(hydroxyiminomethyl)phenyl]-17a- methoxymethyl-17p-methoxy-estra-4,9-dien-3-one, as claimed in claim 3, wherein no crystalline reflexes can be seen in the x-ray-powder diffractogram (XRPD). 5. Amorphous llß-[4E-(hydroxyiminomethyl)phenyl]- 17a- methoxymethyl-17ß-methoxy-estra-4,9-dien-3-one as claimed in claim 3, wherein the modification is characterized by the IR spectrum that is depicted in Figure 2. 6. A solvent free llß-[4E-(hydroxyiminomethyl)phenyl]-17a- methoxymethyl-17p-methoxy-estra-4,9-dien-3-one) as claimed in claim 2, wherein it is in Highly crystalline form. 7. Highly crystalline llß-[4E-(hydroxyiminomethyl)phenyl]-17α- methoxymethyl-17ß-methoxy-estra-4,9-dien-3 -one ansolvate as claimed in claim 6, wherein the crystal form is characterized by the IR spectrum that is depicted in Figure 3. 8. Highly crystalline llß-[4E-(hydroxyiminomethyl)phenyl]-17α- methoxymethyl-17ß-methoxy-estra-4,9-dien-3-one ansolvate as claimed in claim 6, wherein the crystal form is characterized by the x-ray-powder diffractogram that is depicted in Figure Ic (Table 1). 9. Pharmaceutical composition that comprises amorphous 11ß- [4E-(hydroxyiminomethyl)phenyl]-17α-methoxymethyl-17ß- methoxy-estra-4,9-dien-3-one and/or highly crystalline llß- [4E-(hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17ß- methoxy-estra-4,9-dien-3-one ansolvate obtained according to claim 1, wherein the amorphous or the crystalline form is in preferably in range of 0.5 to 100 mg, more preferably 5.0 to 50.0 mg and most preferably between 10.0 to 15.0 mg in combination with a pharmaceutically compatible vehicle and/or diluent. 10. Amorphous llß-[4E-(hydroxyiminomethyl)phenyl]- 17α- methoxymethyl- 17ß-methoxy-estra-4,9-dien-3-one and/or highly crystalline llß-[4E-(hydroxyirninornethyl)phenyl] -17α- methoxymethyl- 17ß-methoxy-estra-4,9-dien-3-one ansolvate as claimed in any one of claims 2 to 8 for use as pharmaceutical agents. 11. Pharmaceutical agent for female birth control, for treating hormone-dependent gynecological disorders and for hormone replacement therapy whenever produced by amorphous 11ß- [4E-(hydroxyiminomethyl)phenyl] -17α-methoxymethyl-17ß- methoxy-estra-4,9-dien-3-one and/or highly crystalline llß- [4E-(hydroxyiminomethyl)phenyl] -17α-methoxymethyl- 170- methoxy-estra-4, 9-dien-3 -one ansolvate as claimed in any one of claims 2 to 8, wherein the amorphous or the crystalline form is in range of 0.5 to 100 mg, more preferably 5.0 to 50.0 mg and most preferably between 10.0 to 15.0 mg.

Full Text

This invention relates to new forms of solids of the mesoprogestin 110-[4E-
(hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17p-methoxy-estra-4,9-dien-3-one (oxime
J 867), especially a highly pure and stable amorphous or highly crystalline form /
(ansolvate/anhydrate) of the compound J 867, process for their production as well as their use in pharmaceutical compositions.
11 p-[4E-(Hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17p-methoxy-estra-4,9-dien-3-one is known, for example, from EP-A-0 648 778 Qr DE-A-43 32 283. The form that is obtained there after recrystallization from methylene chloride/isopropanol melts at 113°C. The crystal form that is described is an isopropanol solvate with 14% isopropanol (see XRPD: Table 2/Figure 4d). A characteristic feature of the oxime is its strong tendency to crystallize from solvents as a solvate. The solvate form, however, is not very suitable for' pharmaceutical applications. The solvent binding to the substance is very secure and is dissolved only at elevated temperatures. The oxime solvates completely cleave the solvent in general only above 100°C. In this case, depending on the heating rate, inhomogeneous amorphous-crystalline mixed forms are produced.
The purification of the oxime from by-products of the oxiniization reaction (dioximes, Z-oxirne) is carried out by expensive column chromatography with toluene/acetone gradients. A purification by a crystallization process is hampered by the generally poor solubilities in the solvents that are suitable in this respect. A limiting factor is the fact that an isomerization of the E-isomer of the compound into Z-isomer occurs at elevated temperatures in solution.
The object of the invention is therefore to replace the expensive column chromatography by a suitable process and to provide a homogeneous, solvent-free and stable
This objecl is achieved by amorphous 1 lp-[4E-(hydroxyiminomethyl)phenyl]-17ct-methoxymethyl-17p-methoxy-estra-4,9-dien-3-one, which is characterized in that no crystalline reflexes can be seen in the x-ray-powder diffractogram (XRPD, Figure la/b) or its modification is characterized by the IR spectrum that is depicted in Figure 2.
In addition, this object is achieved by highly crystalline 11 p-[4E-(hydroxyimino-methyl)phenyl]-17o-methoxymethyl-17p-methoxy-estra-4,9-dien-3-one ansolvate. The crystal form of the ansolvate is characterized by the x-ray-powder diffractogram that is depicted in Figure Ic or by the IR-spectrum that is depicted in Figure 3.
Crystalline solvates of 1 lp-[4E-(hydroxyiminomethyl)phenyl]17a-rnethoxymethyl-17p-methoxy-estni-4,9-dien-3-one can be produced by a process that comprises the following steps:
a) Production of a solvate of 11 p-[4E-(hydroxyiminomethyi)phenyl]-17a-
methoxymethyl-17)3-methoxy-estra-4,9-dien-3-one and dissolving of the solvate above
the saturation solubility in a solvent, especially toluene, which is different from the
solvate-solvent and in which the solvate-crystal structure is unstable,
b) The optional addition of another solvent as a recrystallization inhibitor, especially
methanol or ethyl acetate, and
c) The addition of a solvating agent-solvent, especially ethanol, acetone and methyl-tert-
butyl ether (MtBE) and crystallization of the solvate.
The crystalline solvates of 1 l(3-[4E-(hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17p-methoxy-estra-4,9-dien-3-one, namely the methyl-tert-butyl ether solvate, the acetone solvate and the ethanol solvate, whereby the highly crystalline forms are characterized by the x-ray-powder diffractograms depicted in Figures 4a/b/c and Table 2, are new and represent intermediate stages toward amorphous 1 lp-[4E-, (hydroxyirninomethyl)phenyl]-17a-methoxymethyl-17p-methoxy-estra-4,9-dien-3-one !or toward highly crystalline 1 lp-[4E-(hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17p-methoxy-estra-4,9-dien-3-one ansolvate.
By drying the crystalline solvates of 1 lp-[4E-(hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17p-methoxy-estra-4,9-dien-3-one that are obtained above, especially by thermal desolvation preferably under vacuum and at a heating rate in the product of at least 0.5°C/minute or from a solution of the solvate by spray-drying (XRPD; Figure 1) below the glass transition point of the amorphous structure, the amorphous form of 11 (3-[4E-(hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17p-methoxy-estra-4,9-dien-3-one is then obtained. The highly crystalline form of 1 lp~[4E-(hydroxyiminomethyi)phenyl]-17a-methoxymethyl-r/p-methoxy-estra-4,9-dien-3-one can be produced by heating the solvate form or the amorphous solid form, optionally in aqueous suspension.
Subjects of this invention are also pharmaceutical compositions, especially solid pharmaceutical compositions, that comprise the above-described amorphous and/or highly crystalline 1 lp-[4E-(hydroxyiminomethyl)phenyl]-l 7a-methoxymethyl-l 7(3-methoxy-estra-4,9-dien-3-one in combination with a pharmaceutically compatible vehicle and/or diluent.
The pharmaceutical compositions of this invention are produced with the commonly used solid or liquid vehicles or diluents and the commonly used pharmaceutically technical adjuvants that correspond to the desired type of administration with a suitable dosage in a way that is known in the art.
The term '"highly crystalline" according to the invention defines a state from which no further measurable increase of crystallinity (XRPD, DSC) can be determined by conditions that promote the recrystallization of the amorphous structure, such as, e.g., prolonged boiling of the suspended substance in water. The highly crystalline state is characterized in that no exothermic recrystallization peak can be detected between 110°C and 160°C in the DSC at a slower heating rate (IK/minute). Only the endothermic melting peak exists at 194.7°C + 2K (heating rate 5K/minute).
In Figures la to c, the x-ray-powder diffractogram of amorphous 11(3-[4E-(hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17p-methoxy-estra-4,9-dien-3-oneor highly crystalline 1 lp-[4E-(hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17p-methoxy-estra-4,9-dien-3-one ansolvate (cf. Table 1) are depicted.
In Figures 2 and 3, IR-spectra of amorphous 1 lp-[4E-(hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17p-methoxy-estra-4,9-dien-3-one or highly crystalline 1 lp-[4E-(hydroxyiminomethyl)phenyl] -17a-methoxymethyl-17 (3 -methoxy-estra-4,9-dien-3 -one ansolvate are depicted.
In Figure 4 (Table 2), x-ray-powder diffractograms of the methyl-tert-butyl ether
v-
solvate, the acetone solvate, the ethanol solvate and the isopropanol solvate (cf. Table 2) from 11 p-[4E-(hydroxyiminomethyl)phenyl]-l 7a-methoxymethyl-17p-methoxy-estra-4,9-dien-3-one are depicted.
In Figure 5, an x-ray-powder diffractogram of amorphous 1lp-[4E-(hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17p-methoxy-estra-4,9-dien-3-one is depicted at time 0 (start), after 12 months at 25°C and after 12 months at 40°C.
In Figure 6, the solubility of highly crystalline 1 lp-[4E-(hydroxyiminomethyI)phenyl]-17a-rnethoxymethyl-17p-methoxy-estra-4,9-dien-3-one ansolvate or amorphous 1 lp-[4E-(hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17p-methoxy-estra-4,9-dien-3-onein water is shown with and without surfactant.
Table 1: XRPD Data of Highly Crystalline Oxiine J867 - d-values (dobs), relative intensities Oobs) and hkl values of the highest peaks

(Table Removed)
Both hkl values are possible, since the peak separation is limited to 2@ = 0.08C (angular resolution of the detector).
Table 2: XRPD Data of the Solvates of Oxime J867 - d-values (dobs) and relative intensities Oobs) of the highest peaks

(Table Removed)
The invention relates to a new highly pure and stable, amorphous or highly crystalline form of the mesoprogestin llp-[4E-(hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17(3-methoxy-estra-4,9-dien-3-one (J 867):
(Figere Removed)

and solvate forms of J867, which represent intermediate products for the production of the amorphous or highly crystalline form. It has proven to be a problem in the production of the amorphous or highly crystalline form that in the stage of desolvation, the substance passes through an amorphous intermediate stage, from which the ansolvate/anhydrate form recrystallizes more or less completely depending on the heating rate, final temperature and drying period. The degree of crystallinity, however, is difficult to control, so that inhomogeneous mixed forms that consist of amorphous and crystalline portions are produced. In addition, the thermal stress of the chemical structure that tends toward Z-isomerization and oxime-cleavage results in a deterioration of purity.
The production of the solvate form that is suitable for the solid final form of the oxime can be associated, according to the invention, with the separation of the Z-isomer and the dioximes. By a specific use of the thermodynamic instability of suitable solvates, preferably the solvate of methyl-tert-butyl ether (MTBE) in a solvent environment that is suitable for this purpose, complete dissolution of the solvate lattice is possible far above the solubility limit and even close to room temperature. In contact with toluene in a mass ratio of 1:2 to 1:1, the crystal form of the MTBE solvate dissolves quickly and completely, despite the only slight solubility in toluene of only 3.3% by weight, even at 20-35°C. A so-called cold melting is
carried out. This state can be kept stable by adding suitable solvents as recrystallization inhibitors for technical applications. The supersaturation state can be stabilized for hours in toluene solution by adding only 5% by volume of methanol. Then, by adding solvating agent-solvent (MTBE) at suitable concentration (e.g., 100-130% by volume of MTBE, relative to the toluene that is used), the solvate lattice is built up again, whereby the contaminants remain in solution for the most part.
By an especially quick drying process, preferably spray-drying, below the glass transition point directly from the solution of oxime solvate J867 in an organic solvent, preferably ethanol, a stable, completely amorphous, solvent-free structure can be obtained. To this end, oxime that is dissolved in ethanol to a level of 3 to 13% by weight is sprayed using a suitable spraying unit (binary nozzle or centrifugal sprayer) in hot nitrogen and is dried in an extremely short time to form amorphous, microfine particles. The starting temperature of the nitrogen in this case is 120°C to 200°C, preferably 150°C-180°C. The ratio of oxime solution to drying gas in this case should be 0.01 to 0.3 kg of solution/m"' of Ni, preferably 0.08 to 0.12 kg of solution/mJ of ISb. The drying process is controlled such that in the dryer outlet, a temperature of 55°C to 95°C, preferably 75 to 85°C, is set. This temperature is significantly below the glass transition temperature of the amorphous oxime (105°C), where the substance assumes a gel/glass-like consistency and above which a more or less quick or spontaneous recrystallization can take place.
By applying spray-drying, a solvent-free, homogeneous or microfine solid form of oxime J 867 is obtained in one process step.
The advantage of using the amorphous form of oxime J867 according to the invention for the production of pharmaceutical agents lies in the fact that in addition to the good solubility properties, this amorphous structure, surprisingly enough, has a very good shelf life.
Also, after 12 months in the accelerated ICH-stability test (40°C, 75% relative humidity), the amorphous structure does not show any signs of a recrystallization and/or chemical decomposition (see Figure 5). Also, during the pharmaceutical processing (wet granulation, pelletizing), the physical structure of the oxime remains stable. This means that a conversion of the amorphous into the highly crystalline form or an E/Z isomerization does not occur. By the stability, negative influences of such conversions on the bio-availability of the active ingredient are avoided.
Relative to the shelf life, the same correspondingly holds true for the use of the highly crystalline form of oxime J 867 according to the invention, whereby as expected, the chemical stability, especially under stress (high temperatures and humidities) is higher than that of the amorphous form.
In addition, the arnqrp_hous..fiarni has excellent solubilitv orooerties. The saturation solubility in water and injhe^sujfactant solution (025% sodium lauryl sulfate) is approximately 7 to 8x higher than that of the highly crystalline form, whereby this high supersaturation level remains stable for several hours, as in the case of water for over 24 hours (see Figure 6).
The production of the highly crystalline form can be carried out starting from one of the solvate forms of oxime J867. In this respect, the solvate form can be suspended in water at a temperature of from 50 to 100°C; in this case, the solvent is cleaved far below the desolvation temperature of the dry solvate form. In the case of the MTBE solvate, an only short-term treatment (10 to 30 minutes) with water at a temperature of 65 to 75°C for complete conversion into the highly crystalline form already results.
With the process according to the invention, especially the thermal desolvation, it is basically possible, depending on the process conditions, to produce amorphous-crystalline mixed forms that can pose considerable problems that cannot be reproduced, but can hinder
the development of a validated production process for quality control, further pharmaceutical processing and official approval.
Oxime J867 is a substance that has an antigestagenic action according to EP-A-0 648 778 or DE-A-43 32 283 and that with the same activity as RU 486 (mifepristone) on the progesterone receptor has an antiglucocorticoidal activity that is significantly reduced in comparison to RU 8486.
In U.S. Applications Nos. 09/386,141, 09/386,140 and 09/386,133, oxime J 867 is referred to as mesoprogestin. In this connection, mesoprogestins are defined as compounds that have in vivo both agonistic and antagonistic activity on the progesterone receptor (PR). Corresponding functional conditions cannot be achieved with gestagen and antigestagen.
Oxime J 867 is suitable in particular for the following uses:
a) Oxime J 867 can be used according to U.S. Application No. 09/386,133, optionally
together with an estrogen, for the production of a pharmaceutical agent for female
contraception.
b) Oxime J867 can be used according to U.S. Application No. 09/386,141 for treating
and preventing benign hormone-dependent gynecological disorders; such as

— for treating gynecological disorders, such as endometriosis, uterine fibroids, post
operative peritoneal adhesions, dysfunctional bleeding (metrorrhagia, menorrhagia) and
dysmenorrhea;
— for preventing gynecological disorders; such as postoperative, peritoneal adhesions,
dysfunctional uterine bleeding (metrorrhagia, menorrhagia) and dysmenorrhea. The
daily dose of the mesoprogestin is 0.5 to 100 mg, preferably 5.0 to 50 mg and a
maximum of preferably 10 to 25 mg.
c) Oxime J867 according to U.S. Application No. 09/386,140 can also be used as a
pharmaceutical component for the production of a pharmaceutical agent optionally together with an estrogen in hormone replacement therapy (HRT) and for treating hormone deficiency and symptoms of hormonal irregularity.
Measuring Process
X-Rav-Powder Diffractometry (X-Rav Powder Diffraction: XRPD):
The data were determined with an STOE powder diffractometer STADIP with germanium-monochromatic CuKai radiation (A. - 1.540598 A) - between 3° 1R Spectroscopy:
A NICOEJBT 20 SXB with a photoacoustic detector MTEC (KBr, 8t, 90 seconds) was used.
Solubility Studies:
200 mg of substance was added at 25°C into 50 ml of water (without and with 0.25% SDS (sodium lauryl sulfate)). Samples were taken after 0.5 hour, 2 hours, 5 hours and 24 hours.
Sampling: 0.45 ^m filter attachment, dilution 1:1 with MeOH, HPLC.
HPLC:
The determination of purity is carried out according to the following method:
Column: Superspher Si 60, 250 x 4mm, 4|j.m
Eluant: Chloroform (3% ethanol)/water such as 96.9/0.1
Flow: 1 ml/minute
Detection: UV (299 nm)
Evaluation: 100% surface normalization
Headspace for Residual Solvent:
GC-Auto system with HS40 Perkin Elmer, DB-Wax column, 30 m x 0.23 mm, FID.
Grain Size Distribution:
Sympatec HELOS (H0445), dry dispersing system (RODOS), pressure 2 bar.
DSC:
Perkin Elmer DSC 7 and NETZSCH DSC 200/1/F in Pan-Al, pierced lid, nitrogen.
The invention is explained in more detail by the examples that now follow.
Examples
Example 1
2 kg of oxime J867 (MtBE solvate with 20 to 24% MtBE; unless otherwise indicated, the percent of solvent contained in the solvates is % by weight) is dissolved in 20 1 of ethanol at 50°C while being stirred. The solution is spray-dried in a co-current process in a spray-dryer that is operated under inert conditions (nitrogen). The drying chamber of the spray dryer is coated with 60 mJ/h of nitrogen, which is preheated to 175°C. Then, the solution is sprayed into the drying chamber via a flow inducer with 6.4 1/h with a binary nozzle that is operated with 3 bar of nitrogen as a propellant. The drying gas outlet temperature is 79°C-83°C. The oxime J867 that is dried into microfme particles is completely collected in a
Oxime J867 has the following quality parameters:

(Table Removed)Example 2
50 ml of toluene is added to 20 g of oxime J867 (MTBE solvate with 20%-24% MtBEi). The substance dissolves veiy quickly and completely at 25°C. 2.7 ml of methanol is added to the solution, and the solution is then mixed with 65 ml of MtBE. After about 1 minute, the recrystallization of the MtBE solvate begins. The entire process is carried out at room temperature. The suspension is stirred for 1 hour at 5°C, then filtered, and the filter cake is washed with 30 ml of cold MtBE. After drying, the yield is 84% by weight of the charging material The product that is obtained is in turn an MTBE solvate with 22.3% MtBE. The purification effect relative to the main contaminants can be seen in the table below:

(Table Removed)Example 3
30 g of MtBE solvate of oxime J867 (MtBE solvate with 20 to 24 % MtBE) is suspended in 600 ml water and heated to 70°C and suspended for 30 minutes. The suspension is filtered and suctioned off in the dry state in a stream of air. Then, the crystallizate is dried in a vacuum for 3 hours at 70°C and 24 g of highly crystalline oxime J867 is obtained.
The phase conversion in hot water and the drying do not result in any significant increase of the Z-isomer and the aldehyde.

(Table Removed)In XRPD, with respect to the intensity and the locations of the reflexes and in the DSC with respect to the melting heat, a similarity to the data of the highly crystalline ansolvate form of oxime J867 was detected.

WE CLAIM:
1. Process for the production of a 11ß-[4E-
(hydroxyiminornethyl)phenyl]- 17α-rnethoxyrnethyl-17ß-
methoxy-estra-4,9-dien-3-one ansolvate conducting as a first
step the production of a solvate of llß-[4E-(hydroxyimino-
methyl)phenyl]-17a-methoxymethyl-17ß-methoxy-estra-4,9-
dien-3-one, characterized in that
the process comprises the following steps:
a) Dissolution of the solvate above the saturation solubility
in toluene in which the solvate-crystal structure is
unstable,
b) The optional addition of methanol or ethyl acetate as a
recrystallization inhibitor, and
c) The addition of a solvating agent-solvent, namely methyl
tertiar butyl ether solvate, a acetone solvate or ethanol
solvate and crystallization of the solvate.
d) Drying of the crystalline solvate below the glass transition
point of the amorphous substance, whereby drying of the
solvate is carried out during the desolvation phase with a
heating rate in the product of at least 0.5°C/minute or
from a solution of the solvate by spray-drying, or
e) suspension of the solvate in water at temperature of 50 to 100°C.
2. 1 lp-[4E-(hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17p-
methoxy-estra-4,9-dien-3-one, ansolvate obtained according to
claim 1.
3. A solvent free llp-[4E-(hydroxyiminomethyl)phenyl]-17a-
methoxymethyl-17p-methoxy-estra-4,9-dien-3-one as claimed
in claim 2, wherein it is in amorphous form.
4. Amorphous llp-[4E-(hydroxyiminomethyl)phenyl]-17a-
methoxymethyl-17p-methoxy-estra-4,9-dien-3-one, as claimed in claim 3, wherein no crystalline reflexes can be seen in the x-ray-powder diffractogram (XRPD).
5. Amorphous llß-[4E-(hydroxyiminomethyl)phenyl]- 17a-
methoxymethyl-17ß-methoxy-estra-4,9-dien-3-one as claimed
in claim 3, wherein the modification is characterized by the IR
spectrum that is depicted in Figure 2.
6. A solvent free llß-[4E-(hydroxyiminomethyl)phenyl]-17a-
methoxymethyl-17p-methoxy-estra-4,9-dien-3-one) as claimed
in claim 2, wherein it is in Highly crystalline form.
7. Highly crystalline llß-[4E-(hydroxyiminomethyl)phenyl]-17α-
methoxymethyl-17ß-methoxy-estra-4,9-dien-3 -one ansolvate as
claimed in claim 6, wherein the crystal form is characterized by
the IR spectrum that is depicted in Figure 3.
8. Highly crystalline llß-[4E-(hydroxyiminomethyl)phenyl]-17α-
methoxymethyl-17ß-methoxy-estra-4,9-dien-3-one ansolvate as
claimed in claim 6, wherein the crystal form is characterized by
the x-ray-powder diffractogram that is depicted in Figure Ic
(Table 1).
9. Pharmaceutical composition that comprises amorphous 11ß-
[4E-(hydroxyiminomethyl)phenyl]-17α-methoxymethyl-17ß-
methoxy-estra-4,9-dien-3-one and/or highly crystalline llß-
[4E-(hydroxyiminomethyl)phenyl]-17a-methoxymethyl-17ß-
methoxy-estra-4,9-dien-3-one ansolvate obtained according to
claim 1, wherein the amorphous or the crystalline form is in
preferably in range of 0.5 to 100 mg, more preferably 5.0 to
50.0 mg and most preferably between 10.0 to 15.0 mg in
combination with a pharmaceutically compatible vehicle and/or
diluent.
10. Amorphous llß-[4E-(hydroxyiminomethyl)phenyl]- 17α-
methoxymethyl- 17ß-methoxy-estra-4,9-dien-3-one and/or
highly crystalline llß-[4E-(hydroxyirninornethyl)phenyl] -17α-
methoxymethyl- 17ß-methoxy-estra-4,9-dien-3-one ansolvate as
claimed in any one of claims 2 to 8 for use as pharmaceutical
agents.
11. Pharmaceutical agent for female birth control, for treating
hormone-dependent gynecological disorders and for hormone
replacement therapy whenever produced by amorphous 11ß-
[4E-(hydroxyiminomethyl)phenyl] -17α-methoxymethyl-17ß-
methoxy-estra-4,9-dien-3-one and/or highly crystalline llß-
[4E-(hydroxyiminomethyl)phenyl] -17α-methoxymethyl- 170-
methoxy-estra-4, 9-dien-3 -one ansolvate as claimed in any one
of claims 2 to 8, wherein the amorphous or the crystalline form
is in range of 0.5 to 100 mg, more preferably 5.0 to 50.0 mg and
most preferably between 10.0 to 15.0 mg.

Documents:

in-pct-2002-1146-del-abstract.pdf

in-pct-2002-1146-del-claims.pdf

in-pct-2002-1146-del-complete specificaation (granted).pdf

in-pct-2002-1146-del-correspondence-others.pdf

in-pct-2002-1146-del-correspondence-po.pdf

IN-PCT-2002-1146-DEL-Description (Complete).pdf

in-pct-2002-1146-del-drawings.pdf

in-pct-2002-1146-del-form-1.pdf

in-pct-2002-1146-del-form-18.pdf

in-pct-2002-1146-del-form-2.pdf

in-pct-2002-1146-del-form-3.pdf

in-pct-2002-1146-del-form-5.pdf

in-pct-2002-1146-del-gpa.pdf

in-pct-2002-1146-del-pct-304.pdf

in-pct-2002-1146-del-pct-306.pdf

in-pct-2002-1146-del-pct-409.pdf

in-pct-2002-1146-del-petition-137.pdf

in-pct-2002-1146-del-petition-138.pdf

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Patent Number

233136

Indian Patent Application Number

IN/PCT/2002/01146/DEL

PG Journal Number

13/2009

Publication Date

27-Mar-2009

Grant Date

27-Mar-2009

Date of Filing

21-Nov-2002

Name of Patentee

SCHERING AKTIENGESELLSCHAFT,

Applicant Address

MULLERSTRASSE 178, D-13342 BERLIN, GERMANY.

Inventors:

#	Inventor's Name	Inventor's Address
1	DETLEF GRAWE	AM KOTSCHAUER WEG 10, 99510 KLEINROMSTEDT, GERMANY.
2	PETER HOSEL	SCHEIDLER STRASSE 11, 07745 JENA, GERMANY.
3	UWE MULLER	BURGERGARTEN 17, 07745 JENA, GERMANY.
4	GABRIELE WINTER	STIELEICHENSTRASSE 15, 16567 SCHONFLIESS, GERMANY.

PCT International Classification Number

C07J 41/00

PCT International Application Number

PCT/EP01/05237

PCT International Filing date

2001-05-09

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	00110887.7	2000-05-23	EPO