WO2001068661A9 - Crystalline alkycycline derivative - Google Patents

Crystalline alkycycline derivative

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Publication number
WO2001068661A9
WO2001068661A9 PCT/EP2001/002783 EP0102783W WO0168661A9 WO 2001068661 A9 WO2001068661 A9 WO 2001068661A9 EP 0102783 W EP0102783 W EP 0102783W WO 0168661 A9 WO0168661 A9 WO 0168661A9
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WO
WIPO (PCT)
Prior art keywords
alkycycline
aziridine
crystalline
solvent
temperature
Prior art date
Application number
PCT/EP2001/002783
Other languages
French (fr)
Other versions
WO2001068661A2 (en
WO2001068661A3 (en
Inventor
Attilio Tomasi
Mario Ungari
Mauro Galli
Paolo Fumagalli
Original Assignee
Pharmacia Italia Spa
Attilio Tomasi
Mario Ungari
Mauro Galli
Paolo Fumagalli
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmacia Italia Spa, Attilio Tomasi, Mario Ungari, Mauro Galli, Paolo Fumagalli filed Critical Pharmacia Italia Spa
Priority to AU2001263789A priority Critical patent/AU2001263789A1/en
Publication of WO2001068661A2 publication Critical patent/WO2001068661A2/en
Publication of WO2001068661A3 publication Critical patent/WO2001068661A3/en
Publication of WO2001068661A9 publication Critical patent/WO2001068661A9/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom

Definitions

  • the present invention relates to a crystalline form of a useful drug that is an alkycycline derivative.
  • US-A-5, 532,218 discloses 4-demethoxy-3' -deamino-3' - aziridinyl-4' -methansulfonyl daunorubicin, its preparation and its usage as an anticancer agent, which is referred to as "aziridino alkycycline" hereinafter and is represented from the formula la
  • the compound la intercalates into DNA via the chromophore and alkylates guanine at N 7 position in DNA minor groove via its reactive moiety on position 3' of the amino sugar.
  • Compound la is able to circumvent ' the resistance to all major classes of citotoxics, indicating that the compound belongs to a new class of anticancer drugs, and was described and claimed in US-A-5, 532, 218.
  • the present invention is relating to a crystalline aziridine alkycycline having excellent stability, to its preparation, to the pharmaceutical compositions containing it and to their use in cancer treatment.
  • Another aspect relates to samples crystalline aziridine alkycycline having a % purity > 85%, preferably >96%. Description of figures
  • Figure 1 shows the powder X-ray diffraction spectrum of crystalline aziridine alkycycline' according to the present invention, with peak intensity (counts) as the vertical axis and angle (°2 ⁇ ) as the horizontal axis.
  • X-RAY Powder Diffraction Powder X-ray diffraction was performed using a Philips analytical X-ray diffractometer type PW1800, operating under PC-APD diffraction software.
  • the system used a copper X-ray source maintained at 50 kV and 30 mA to provide CuKoi emission of 1.5406 angstroms and CuKc. 2 emission of 1.5444 angstroms, intensity ratio c_ ⁇ /a 2 0.500, irradiated length 10mm.
  • Crystalline aziridine alkycycline of the present invention can be produced by crystallizing aziridine alkycycline from an aprotic organic solvent or from a mixture of aprotic organic solvents.
  • crystalline aziridine alkycycline can be produced by dissolving amorphous aziridine alkycycline in an aprotic organic solvent solution, partially removing the solvent from the solution at a temperature of up to 45°C (external bath temp.) under vacuum and crystallizing aziridine alkycycline at a temperature of from 0° to 20°C.
  • the solution of aziridine alkycycline is kept under inert atmosphere, more preferably under nitrogen.
  • Suitable aprotic organic solvents include ketones, cyclic and linear ether, esters and a mixture thereof.
  • an anti-solvent can be added, for example n- hexane .
  • Ketones and esters include straight or branched
  • C 3 -C 6 ketones such as acetone, 2-butanone, 3-pentanone, 4- methyl-2-pentanone, and C 2 -C 4 esters such as ethyl acetate, i-butyl acetate and t-butyl acetate.
  • Ether solvents include straight or branched C 4 -C 6 ethers such as diethyl ether, methyl t-butyl ether and cyclic ethers having 5 or 6 embered ring such as tetrahydrofurane and 1,4-dioxane.
  • Preferred solvents are tetrahydrofurane and ethyl acetate.
  • the amount of the solvent dissolving aziridine alkycycline is, for example, 10 to 1000 parts by weight per part of aziridine alkycycline.
  • the amount of the aprotic organic solvent may be 10 to 100 parts by weight, more preferably 10 to 50 parts by weight, still more preferably 10 to 20 parts by weight per part of aziridine alkycycline.
  • the temperature of the solution of aziridine alkycycline at which the solvent is removed (external bath temp.) under vacuum may be, for example, up to 45°C, more preferably of from 25°to 35°C.
  • the solution from which the aziridine alkycycline is crystallized is held at a temperature of 0°to 20°C during the crystallization.
  • the period of time for crystallizing the aziridine alkycycline is not limited, but preferably it is in the range of 30 minutes to 1 day.
  • Seed crystals of crystalline aziridine alkycycline may be added into the solution to accelerate crystallization.
  • the thus obtained crystals may be recovered by common procedures, for example by filtration under reduced pressure of by centrifugal filtration, followed by drying the crystals, to obtain the crystalline aziridine alkycycline of the present invention.
  • the crystalline aziridine alkycycline bears the aprotic organic solvent used for the crystallization. In that case, the solvent may be removed by drying the crystals .
  • the drying treatment can be carried out in a conventional manner, for example by subjecting the crystals to a reduced pressure at a temperature of from 0° to 50°C, preferably from 20 to 40°C.
  • the pressure in drying may be, for example, less than 200 mmHg, preferably 1 to 50 mHg.
  • the drying treatment can be monitored by measuring the amount of solvent in the crystals. Usually, the drying will be completed in 24 to 72 hours.
  • a further aspect of the present invention is to provide a method of treating a mammal including humans, suffering from a neo-plastic disease state comprising administering to said mammal a pharmaceutical composition obtained starting from the crystalline aziridine alkycycline of formula la as defined above in amounts effective to produce a anti-cancer effect.
  • X administered ⁇ or "administering" as used herein is meant parenteral and /or oral administration. It will be appreciated that the actual preferred method and order of administration will vary according to, inter alia, the particular formulation of the aziridine alkycycline of formula la being utilized, the particular tumors being treated, and the particular host being treated.
  • the course of therapy generally employed is from about 0.1 to about 200 mg/m 2 of body surface area. More preferably, the course therapy employed is from about 1 to about 50 mg/m 2 of body surface area.
  • the anti-neoplastic therapy of the present invention is in particular suitable for treating breast, ovary, lung, colon, kidney and brain tumors in mammals, including humans .
  • the present invention will be described in detail below, referring to Examples, which are not limitative of the present invention.
  • Crystalline aziridine alkycycline 500 mg of amorphous aziridine alkycycline were dissolved in tetrahydrofurane (10 ml), the solution was cooled at 0°-2°C and 40 ml of hexane were added in, half an hour. After 90 minutes stirring, the precipitated crystals were collected by filtration and dried at 20°C for 24 hours under vacuum. The obtained crystals (390 mg) showed the same x-ray powder diffraction pattern of those prepared in Example 1.
  • Example 3 Crystalline aziridine alkycycline a) Operating as described in Example 2, but starting from 100 mg of amorphous aziridine alkycycline dissolved in ethylacetate (11 ml) and adding 33 ml of hexane, there were obtained 70 mg of crystals with the same x-ray powder diffraction pattern of those prepared in Example 1. b) Operating in the same way, but starting from 500 mg of amorphous aziridine alkycycline dissolved in ethylacetate (55 ml) and adding 165 ml of hexane, there were obtained 330 mg of crystals.
  • Example 4 Example 4
  • Example 5 Crystalline aziridine alkycycline
  • Example 6 Operating as described in Example 4, but employing 6 ml ethylacetate and stirring at a temperature of 4°C for three hours without adding hexane, there were obtained 120 mg of crystals with the same x-ray powder diffraction pattern of those prepared in Example 1.
  • Example 6

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

There is provided the crystalline form of 4-demethoxy-3'-deamino-3'-aziridinyl-4'-methansulfonyl daunorubicin, the preparation thereof and its use in the preparation of pharmaceutical composition for the treatment of tumors.

Description

CRYSTALLINE ALKYCYCLINE DERIVATIVE
The present invention relates to a crystalline form of a useful drug that is an alkycycline derivative. US-A-5, 532,218 discloses 4-demethoxy-3' -deamino-3' - aziridinyl-4' -methansulfonyl daunorubicin, its preparation and its usage as an anticancer agent, which is referred to as "aziridino alkycycline" hereinafter and is represented from the formula la
Figure imgf000002_0001
The compound la intercalates into DNA via the chromophore and alkylates guanine at N7 position in DNA minor groove via its reactive moiety on position 3' of the amino sugar. Compound la is able to circumvent ' the resistance to all major classes of citotoxics, indicating that the compound belongs to a new class of anticancer drugs, and was described and claimed in US-A-5, 532, 218. We have now surprisingly found a crystalline form of aziridine alkycycline useful as bulk drug, particularly stable and suitable for pharmaceutical preparations . The present invention is relating to a crystalline aziridine alkycycline having excellent stability, to its preparation, to the pharmaceutical compositions containing it and to their use in cancer treatment. Another aspect relates to samples crystalline aziridine alkycycline having a % purity > 85%, preferably >96%. Description of figures
Figure 1. shows the powder X-ray diffraction spectrum of crystalline aziridine alkycycline' according to the present invention, with peak intensity (counts) as the vertical axis and angle (°2Θ) as the horizontal axis. X-RAY Powder Diffraction Powder X-ray diffraction was performed using a Philips analytical X-ray diffractometer type PW1800, operating under PC-APD diffraction software. The system used a copper X-ray source maintained at 50 kV and 30 mA to provide CuKoi emission of 1.5406 angstroms and CuKc.2 emission of 1.5444 angstroms, intensity ratio c_ι /a20.500, irradiated length 10mm. Data were collected from 2 to 40° 2Θ using a step scan of 0.02°/point with a one second/point counting time. The x-ray powder diffraction pattern for crystalline aziridine alkycycline (Figure 1) shows a crystalline structure with distinctive peaks shown in the following table I:
TABLE I
Figure imgf000003_0001
Crystalline aziridine alkycycline of the present invention can be produced by crystallizing aziridine alkycycline from an aprotic organic solvent or from a mixture of aprotic organic solvents. Specifically, crystalline aziridine alkycycline can be produced by dissolving amorphous aziridine alkycycline in an aprotic organic solvent solution, partially removing the solvent from the solution at a temperature of up to 45°C (external bath temp.) under vacuum and crystallizing aziridine alkycycline at a temperature of from 0° to 20°C.
Preferably the solution of aziridine alkycycline is kept under inert atmosphere, more preferably under nitrogen. Suitable aprotic organic solvents include ketones, cyclic and linear ether, esters and a mixture thereof.
Optionally an anti-solvent can be added, for example n- hexane .
Ketones and esters include straight or branched
C3-C6 ketones, such as acetone, 2-butanone, 3-pentanone, 4- methyl-2-pentanone, and C2-C4 esters such as ethyl acetate, i-butyl acetate and t-butyl acetate.
Ether solvents include straight or branched C4-C6 ethers such as diethyl ether, methyl t-butyl ether and cyclic ethers having 5 or 6 embered ring such as tetrahydrofurane and 1,4-dioxane.
Preferred solvents are tetrahydrofurane and ethyl acetate. The amount of the solvent dissolving aziridine alkycycline is, for example, 10 to 1000 parts by weight per part of aziridine alkycycline. Preferably, the amount of the aprotic organic solvent may be 10 to 100 parts by weight, more preferably 10 to 50 parts by weight, still more preferably 10 to 20 parts by weight per part of aziridine alkycycline. The temperature of the solution of aziridine alkycycline at which the solvent is removed (external bath temp.) under vacuum may be, for example, up to 45°C, more preferably of from 25°to 35°C. The solution from which the aziridine alkycycline is crystallized is held at a temperature of 0°to 20°C during the crystallization. The period of time for crystallizing the aziridine alkycycline is not limited, but preferably it is in the range of 30 minutes to 1 day.
Seed crystals of crystalline aziridine alkycycline may be added into the solution to accelerate crystallization. The thus obtained crystals may be recovered by common procedures, for example by filtration under reduced pressure of by centrifugal filtration, followed by drying the crystals, to obtain the crystalline aziridine alkycycline of the present invention. Occasionally, the crystalline aziridine alkycycline bears the aprotic organic solvent used for the crystallization. In that case, the solvent may be removed by drying the crystals .
The drying treatment can be carried out in a conventional manner, for example by subjecting the crystals to a reduced pressure at a temperature of from 0° to 50°C, preferably from 20 to 40°C. The pressure in drying may be, for example, less than 200 mmHg, preferably 1 to 50 mHg. The drying treatment can be monitored by measuring the amount of solvent in the crystals. Usually, the drying will be completed in 24 to 72 hours.
A further aspect of the present invention is to provide a method of treating a mammal including humans, suffering from a neo-plastic disease state comprising administering to said mammal a pharmaceutical composition obtained starting from the crystalline aziridine alkycycline of formula la as defined above in amounts effective to produce a anti-cancer effect.
By the term X administered λ or "administering" as used herein is meant parenteral and /or oral administration. It will be appreciated that the actual preferred method and order of administration will vary according to, inter alia, the particular formulation of the aziridine alkycycline of formula la being utilized, the particular tumors being treated, and the particular host being treated. In the method of the subject invention, for the administration of the aziridine alkycycline formulation, the course of therapy generally employed is from about 0.1 to about 200 mg/m2 of body surface area. More preferably, the course therapy employed is from about 1 to about 50 mg/m2 of body surface area.
The anti-neoplastic therapy of the present invention is in particular suitable for treating breast, ovary, lung, colon, kidney and brain tumors in mammals, including humans . The present invention will be described in detail below, referring to Examples, which are not limitative of the present invention.
Example 1 J
Crystalline 4-demethoxy-3'r -deamino-3' -aziridinyl-4' - ethansulfonyl daunorubicin (aziridine alkycycline) Amorphous 4-demethoxy-3' -deamino-3' -aziridinyl-4' - methansulfonyl daunorubicin (aziridine alkycycline, prepared according to example 2 of US-A-5, 532,218) was dissolved in tetrahydrofurane (THF) or ethylacetate (AcOEt) , that were then completely removed by evaporation under different conditions. The resulting crystals were collected and analyzed, x-ray powder diffraction pattern is shown in Figure 1. The following table II summarizes the conditions of the different experiments. Table II
Figure imgf000007_0001
Example 2
Crystalline aziridine alkycycline 500 mg of amorphous aziridine alkycycline were dissolved in tetrahydrofurane (10 ml), the solution was cooled at 0°-2°C and 40 ml of hexane were added in, half an hour. After 90 minutes stirring, the precipitated crystals were collected by filtration and dried at 20°C for 24 hours under vacuum. The obtained crystals (390 mg) showed the same x-ray powder diffraction pattern of those prepared in Example 1. Example 3 Crystalline aziridine alkycycline a) Operating as described in Example 2, but starting from 100 mg of amorphous aziridine alkycycline dissolved in ethylacetate (11 ml) and adding 33 ml of hexane, there were obtained 70 mg of crystals with the same x-ray powder diffraction pattern of those prepared in Example 1. b) Operating in the same way, but starting from 500 mg of amorphous aziridine alkycycline dissolved in ethylacetate (55 ml) and adding 165 ml of hexane, there were obtained 330 mg of crystals. Example 4
Crystalline aziridine alkycycline Operating as described in Example 3 b, but keeping the solution at room temperature, there were obtained 250 mg of crystals with the same x-ray powder diffraction pattern of those prepared in Example 1. Example 5 Crystalline aziridine alkycycline
Operating as described in Example 4, but employing 6 ml ethylacetate and stirring at a temperature of 4°C for three hours without adding hexane, there were obtained 120 mg of crystals with the same x-ray powder diffraction pattern of those prepared in Example 1. Example 6
Crystalline aziridine alkycycline
1500 mg of amorphous aziridine alkycycline were dissolved in ethylacetate (100 ml) and the solvent was removed under vacuum at 27°-30°C (external bath temp.); the resulting suspension was filtered and the collected crystals were dried at 20°C for 24 hours under vacuum. The obtained crystals (1350 mg) showed the same x-ray powder diffraction pattern of those prepared in Example 1. Example 7
Crystalline aziridine alkycycline
31 g of amorphous aziridine alkycycline were dissolved in ethylacetate (3.5 1) under nitrogen atmosphere, the solvent was removed under vacuum at 28-30°C. The resulting suspension was maintained at 0°-4°C for one hour and then filtered," the collected crystals were dried at 30 °C for about 40 hours under vacuum (25-50 mmHg) . The obtained crystals (28 g, 90% yield) showed the same x-ray powder diffraction pattern of those prepared in Example 1. The crystals resulting from examples 1 to 7 were also analyzed with HSM (Hot Stage Microscopy) [THMS 600 Linka + optical microscopy Reichert] and Thermogravimetric Analysis (TGA) ; the resulting data are shown in tables III and IV. Table III -Crystalline aziridine alkycycline - TGA 2°C/min
Figure imgf000009_0001
Note: When Temp, was > 150°C, sample degradation was observed.
Table IV- Crystalline aziridine alkycycline, HSM 10°C/min ( hermornicroscopy)
Figure imgf000010_0001

Claims

Claims
1. A crystalline aziridine alkycycline of the formula la
Figure imgf000011_0001
2 . A crystalline aziridine alkycycline according tc claim 1 having the distinctive peaks in the powder X-ray diffraction shown in the following table I :
TABLE I
Figure imgf000011_0002
3. A crystalline aziridine alkycycline according to claim 1 having the powder X-ray diffraction spectrum of Fig.l.
4. A crystalline aziridine alkycycline according to claim 1 or 2 having a % purity > 85%.
5. A crystalline aziridine alkycycline according to claim 4 having a % purity >96%.
6. A process for preparing a crystalline aziridine alkycycline according to claim 1 or 2 comprising crystallizing aziridine alkycycline.
7. A process according to claim 6 comprising crystallizing aziridine alkycycline from an aprotic organic solvent.
8. A process according to claim 6 comprising:
(a) dissolving aziridine alkycycline in a solution of an aprotic organic solvent or a mixture thereof,
(b) partially removing the solvent from the solution at a temperature of up to 45°C (external bath temp.) and
(c) crystallizing aziridine alkycycline at a temperature of from 0° to 20°C.
9. A process according to claim 6, 7 or 8 wherein the removal of the solvent is made at a temperature of from 25° to 35°C and the crystallization temperature is of from 0° to 5°C.
10. A process according to claim 7, 8 or 9 in which the solvent is ethylacetate, tetrahydrofurane or a mixture thereof.
11. A crystalline aziridine alkycycline according to claim 1 or 2 for use in the treatment of the human or animal body by therapy.
12. Use of a crystalline aziridine alkycycline according to claim 1 or 2 in the preparation of a medicament for use in the treatment of cancer in a patient in need of such treatment.
13. A pharmaceutical composition comprising a crystalline aziridine alkycycline according to claim 1 or 2 and a pharmaceutically acceptable diluent or carrier.
14. A method of treating cancer comprising administrating to a person in need thereof, a pharmaceutical composition according to claim 13.
PCT/EP2001/002783 2000-03-17 2001-03-12 Crystalline alkycycline derivative WO2001068661A2 (en)

Priority Applications (1)

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Applications Claiming Priority (2)

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GB0006601.9 2000-03-17
GB0006601A GB0006601D0 (en) 2000-03-17 2000-03-17 Crystalline alkycycline derivative

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WO2001068661A3 WO2001068661A3 (en) 2002-03-21
WO2001068661A9 true WO2001068661A9 (en) 2003-05-22

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Publication number Priority date Publication date Assignee Title
GB0117403D0 (en) * 2001-07-17 2001-09-05 Pharmacia & Upjohn Spa Solvent-free crystalline anthracycline derivatives

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GB9325417D0 (en) * 1993-12-13 1994-02-16 Erba Carlo Spa 3'- aziridino-anthracycline derivatives
GB9808027D0 (en) * 1998-04-15 1998-06-17 Pharmacia & Upjohn Spa 13-dihydro-3' aziridino anthracyclines

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AU2001263789A1 (en) 2001-09-24
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GB0006601D0 (en) 2000-05-10

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