AU2004281998A1 - Crystalline forms of 3-beta-amino 17-methylene androstane-6-alpha 7-beta-diol hydrochloride - Google Patents

Crystalline forms of 3-beta-amino 17-methylene androstane-6-alpha 7-beta-diol hydrochloride Download PDF

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Publication number
AU2004281998A1
AU2004281998A1 AU2004281998A AU2004281998A AU2004281998A1 AU 2004281998 A1 AU2004281998 A1 AU 2004281998A1 AU 2004281998 A AU2004281998 A AU 2004281998A AU 2004281998 A AU2004281998 A AU 2004281998A AU 2004281998 A1 AU2004281998 A1 AU 2004281998A1
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AU
Australia
Prior art keywords
beta
alpha
amino
diol hydrochloride
fact
Prior art date
Legal status (The legal status 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 status listed.)
Abandoned
Application number
AU2004281998A
Inventor
Pascal Billot
Colette Colladant
Hagit Elmaleh
Alexandre Giuliani
Marc-Antoine Perrin
Denis Prat
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Inflazyme Pharmaceuticals Ltd
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Inflazyme Pharmaceuticals Ltd
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Filing date
Publication date
Priority claimed from FR0312257A external-priority patent/FR2861077B1/en
Application filed by Inflazyme Pharmaceuticals Ltd filed Critical Inflazyme Pharmaceuticals Ltd
Publication of AU2004281998A1 publication Critical patent/AU2004281998A1/en
Abandoned legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
    • C07J41/0011—Unsubstituted amino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Description

'Rout_1@848M814ffue001 1 umen(s and etswnvXo~ et~~e. pf-MrItre~a~L~~ueg~~ytf 1e 2of1 13-04-ZOOO 13:12 FROM- T-04T P. 002/002 F-290 CERTIFICATE OF VERIFICATION of ar r ~ 5 =t that Mhe aWached docment Is a true and com~plete tram~aton to the beat of my knowledge of Intemnatlons) Patent Application No. 1'CT/1B 00403426. 08td hi 1 7 dayof Ap;j2006 Sigznat=r of translator: DAVIES COLLiSON CAvE 0098 WO 2005/037851 PCT/IB2004/003426 CRYSTALLINE FORMS OF 3-BETA-AMINO, 17-METHYLENE, ANDROSTANE-6-ALPHA, 7 BETA-DIOL HYDROCHLORIDE The present invention has as its object three crystalline forms of 3-beta-amino 17 methylene androstane-6-alpha 7-beta-diol hydrochloride (composed of 1 formula), represented by the structure: H2N OH S, HCI OH Patent application W00183512 describes 3-beta-amino,17-methylene, androstane-6-alpha, 7-beta-diol, as well as its pharmaceutically acceptable salts for the treatment of inflammatory illnesses and, especially, asthma: The compound 3-beta-amino,17-methylene, androstane-6-alpha, 7-beta-diol as described and prepared in the W00183512 request is notably an acetate salt. This salt in acetate form is hygroscopic, which is a major inconvenience for industrial development. This invention has the objective of finding one or more new crystalline forms that do not present the inconveniences of the form previously described. The solid forms, and notably the pharmaceutical products, can present more of a crystalline form. This is what is called polymorphism. By polymorphous form one means all asolvated forms of a crystallized molecule and by pseudo-polymorphous all solvated forms. The polymorphous and pseudo-polymorphous forms of the same molecule show different physical properties in general such as the solubility, hygroscopicity and stability. It is necessary to note that methods that permit recognizing (experimental sifting) or predicting (theoretical sifting by molecular modeling) the polymorphous or pseudopolymorphous existence of such and such or predicting their physical properties do not exist with certainty at present. Obtaining new polymorphous or pseudopolymorphous forms of molecules having Park Case # 2819 WO 2005/037851 PCT/IB2004/003426 -2 therapeutic activity hold a major interest for the pharmaceutical industry, especially from the viewpoint of their preparation on an industrial scale, their implementation within pharmaceutical compounds, hence the search for better stability. The requester has submitted evidence for three new crystalline forms of 3-beta-amino 17 methylene androstane-6-alpha 7-beta-diol hydrochloride (form A, form B and form C). Form A is anhydrous, form B is de-hydrated, and form C is mono-hydrated. In addition to the advantages stated above, crystalline form A shows an absence of hygroscopicity. The invention therefore initially has the objective of a new crystalline form of anhydrous 3 beta-amino 17-methylene androstane-6-alpha 7-beta-diol hydrochloride that one calls form A. The crystalline form A of 3-beta-amino 17-methylene androstane-6-alpha 7-beta-diol hydrochloride, according to the invention, presents itself as a crystalline powder that is stable from 0 to 90% Relative Humidity (RH) and begins to deteriorate chemically around 2400C, decomposing completely above 280 0 C. It has been defined by indexing its X-ray powder pattern described below. The invention also has for an objective a new crystalline form of hydrated 3-beta-amino 17 methylene androstane-6-alpha 7-beta-diol hydrochloride that is called form B. It can be used as an intermediary for preparing form A. It is a matter of a stable de-hydrated form above 50% HR. It is also defined below by indexing its X-ray powder pattern. The invention also has the objective of a new crystalline form of hydrated 3-beta-amino 17 methylene androstane-6-alpha 7-beta-diol hydrochloride that is called form C. Form C appeared in mixture with other forms (anhydrous forms D and E). Form C has been obtained pure, thanks to a complementary treatment by maintaining it for a few days in a humid atmosphere at 97% RH. It is a matter of a stable mono-hydrated form from 0 to 90% RH. It turns into anhydrous D by heating above 600C. It is also defined below by indexing its X-ray powder pattern. The crystalline forms A, B or C of the compound of formula (I) present similar therapeutic activities as those described for the compound 3 beta-amino, 17-methylene, androstane-6-alpha, 7 beta-diol in the W00183512 request. They are especially useful in the treatment of inflammatory illnesses, and of asthma. Park Case # 2819 WO 2005/037851 PCT/IB2004/003426 -3 Diffraction of the X-rays by powder patterns The analyses were done on a Philips X'pert Pro X-ray diffractometer having an anticathode copper tube equipped with a monochromator in front (wavelength of Cu Kai ray: 1.54060 A). The installation is of the Bragg-Brentano type with a Philips X'celerator detector. The swept angular surface extends from 2 to 40 degrees in 20 with a step of 0.02 degreed in 20. The counting period was 300 seconds per step. Form A Form A crystallizes in a monoclinic network (group of space P2 1 , Z=2), the mesh parameters of which are as follows at T = 295 K: a = 16.058(2) A, P3 = 90.24(2)0 b = 6.995 (1) A, V=1012.2 A 3 c = 9.011(2) A density =1.168 The asymmetric unit is composed of one molecule of 3-beta-amino 17-methylene androstane-6 alpha 7-beta-diol hydrochloride. As all rays present on the diffraction diagram are indexed, form A, as obtained according to the crystallization process described in Example 1 or Example 2 described below, is a pure physical form. The indexing of the initial 30 rays of the diffraction powder pattern of X-rays of form A of 3-beta amino 17-methylene androstane-6-alpha 7-beta-diol hydrochloride at T = 295 K, in interreticular distances, as well as in positions 2E "ACu Kamid , gives the following result: h k 1 Interreticular 2 theta distance (A) "ACu Kamid "1.54184 A 1 0 0 16.058 5.50 0 0 1 9.011 9.82 2 0 0 8.029 11.02 -1 0 1 7.872 11.24 1 0 1 7.844 11.28 1 1 0 6.413 13.81 -2 0 1 6.007 14.75 2 0 1 5.982 14.81 0 1 1 5.526 16.04 3 0 0 5.353 16.56 2 1 0 5.274 16.81 -1 1 1 5.229 16.96 1 1 1 5.221 16.98 Park Case # 2819 WO 2005/037851 PCT/I B2004/003426 -4 3 0 1 4.610 19.25 3 0 1 4.594 19.32 -2 1 1 4.557 19.48 2 1 1 4.546 19.53 0 0 2 4.506 19.70 -1 0 2 4.343 20.45. 1 0 2 4.333 20.50 3 1 0 4.251 20.90 4 0 0 4.014 22.14 -2 0 2 3.936 222.59 2 0 2 3.9222 222.67 -3 1 1 3.850 23.11 3 1 1 3.840 23.17 0 1 2 3.788 23.49 -1 1 2 3.690 24.12 1 1 2 3.684 24.16 -4 0 1 3.673 24.23 Form B Form B can be used as a an intermediary for the preparation of form A. Form B is a de-hydrated form that crystallizes in a triclinic network (group of space P1, Z=1), the mesh parameters of which are as follows at T = 295 K: a = 8.856(2) A, a = 100.76(1)* b = 18.482(1) A, P3= 90.06(1). c = 6.904(2) A y = 78.35(1) ° V=1086.5
A
3 density = 1.198 The asymmetric unit is composed of two molecules of 3-beta-amino 17-methylene androstane-6 alpha 7-beta-diol hydrochloride and 4 molecules of water. As all rays present on the diffraction diagram are indexed, form B, as obtained according to the crystallization process described in Example 3 described below, is a pure physical form. The indexing of the initial 30 rays of the diffraction powder pattern of X-rays of form B of 3-beta amino 17-methylene androstane-6-alpha 7-beta-diol hydrochloride at T = 295 K, in interreticular distances, as well as in positions 28 "ACu Kami d , gives the following result: h k 1 Interreticular 2 theta distance (A) "ACu Kamid "1.54184 A 0 1 0 17.770 4.97 Park Case # 2819 WO 2005/037851 PCT/IB2004/003426 -5 0 2 0 8.885 9.96 1 0 0 8.667 10.21 1 1 0 8.509 10.40 -1 1 0 7.227 12.25 1 2 0 6.960 12.72 0 0 1 6.778 13.06 0 -1 1 6.777 13.06 0 1 1 5.966 14.85 0 -2 1 5.964 14.85 0 3 0 5.923 14.96 -1 2 0 5.651 15.68 -1 -1 1 5.446 16.28 1 0 1 5.441 16.29 1 3 0 5.438 16.30 -1 0 1 5.243 16.91 1 -1 1 5.238 16.93 -1 -2 1 5.172 17.15 1 1 1 5.168 17.16 0 2 1 4.953 17.91 0 -3 1 4.952 17.91 -1 1 1 4.695 18.90 1 -2 1 4.690 18.92 -1 -3 1 4.594 19.32 1 2 1 4.591 19.33 -1 3 0 4.481 19.82 0 4 0 4.443 19.99 2 1 0 4.425 20.07 2 0 0 4.334 20.49 1 4 0 4.331 20.51 Form C Form C is a mono-hydrate form that crystallizes in a triclinic network (group of space PI, Z=1), the mesh parameters of which are as follows at T = 295 K: a = 7.2328(5) A, a = 97.135(6) ° b = 21.063 (2) A, 1 = 102.653(5) ° c = 7.1563(5) A y = 91.1 7 7
(
6 )* V =1054.2 A' density = 1.178 The asymmetric unit is composed of two molecules of 3-beta-amino 17-methylene androstane-6 alpha 7-beta-diol hydrochloride and 2 molecules of water. As all present rays on the diagram of diffraction are indexed, the C form, as obtained according to the process of crystallization described in Example 4 the described below, is a pure physical form. The indexing of the initial 30 rays of the diffraction powder pattern of X-rays of form B of 3-beta Park Case # 2819 WO 2005/037851 PCT/IB2004/003426 -6 amino, 17-methylene, androstane-6-alpha, 7-beta-diol hydrochloride at T = 295 K, in interreticular distances, as well as in positions 2e "ACu Kamid , gives the following result: h k 1 Interreticular 2 theta distance (A) "ACu Kamid "1.54184 A 0 1 0 20.875 4.23 0 2 0 10.437 8.47 1 0 0 7.049 12.56 0 3 0 6.958 12.72 0 0 1 6.922 12.79 0 -1 1 6.845 12.93 -1 1 0 6.780 13.06 1 1 0 6.581 13.46 0 1 1 6.325 14.00 0 -2 1 6.155 14.39 -1 2 0 5.980 14.81 1 2 0 5.712 15.51 -1 0 1 5.604 15.81 -1 -1 1 5.506 16.10 0 2 1 5.447 16.27 -1 1 1 5.323 16.66 0 -3 1 5.267 16.83 0 4 0 5.219 16.99 -1 -2 1 5.083 17.45 -1 3 0 5.079 17.46 1 3 0 4.834 18.35 -1 2 1 4.804 18.47 0 3 1 4.612 19.24 -1 -3 1 4.516 19.66 1 -1 1 4.474 19.84 1 0 1 4.465 19.88 -0 -4 1 4.459 19.91 -1 4 0 4.297 20.67 1 -2 1 4.290 20.71 1 1 1 4.266 20.82 Therefore the invention has as its objective the crystalline forms A, B or C as previously described as medicine. The crystalline forms A, B or C of 3-beta-amino 17-methylene androstane-6-alpha 7-beta diol hydrochloride can be used orally, parenterally, topically by inhalation, or via implants. They can be prescribed as simple or sugar-coated tablets, capsules, granules, suppositories, ovums, injectable preparations, ointments, creams, gels, microspheres, implants, or patches, all of which may be prepared according to the usual methods. Park Case # 2819 WO 2005/037851 PCT/IB2004/003426 -7 The crystalline forms A, B or C of 3-beta-amino 17-methylene androstane-6-alpha 7-beta diol hydrochloride can be mixed with excipients, diluents and all vehicles known to professionals for the manufacture of pharmaceutical compounds. By way of example of excipients that are usually employed in these pharmaceutical compounds, one can cite talc, acacia gum, lactose, starch, magnesium stearate, cacao butter, aqueous vehicles or not, plant or animal fats, paraffinic derivatives, glycols, and the various wetting, dispersing or emulsifiers agents and preservatives. The invention thus extends to pharmaceutical compounds containing as their principal active ingredient at least one of the crystalline forms A, B or C of 3-beta-amino 17-methylene androstane-6-alpha 7-beta-diol hydrochloride as defined above and one or several pharmaceutically acceptable excipients, diluents or supports. The invention also has for its object application of the crystalline forms A, B or C of 3-beta amino 17-methylene androstane-6-alpha 7-beta-diol hydrochloride as definite above for the preparation of a medicine destined to treat inflammatory illnesses, such as asthma. The following examples illustrate the invention without, however, limiting it. EXAMPLE 1: 3-beta-amino 17-methylene androstane-6-alpha 7-beta-diol hydrochloride, Form A., 250 mg of product of formula I is dissolved at ambient temperature in the minimum amount of methanol. Some isopropylic ether is added until the onset of precipitation. After centrifuging, one obtains 195 mg of form A as the product of I. EXAMPLE 2: 3-beta-amino 17-methylene androstane-6-alpha 7-beta-diol hydrochloride, Form A. 250 mg of the product of formula I is dissolved at ambient temperature in the minimum amount of ethanol. Water is added until the onset of crystallization; one gets polymorphous B as the product of formula I. Then after evaporation under a stream of nitrogen at ambient temperature, one gets form A as the product of formula I. Park Case # 2819 WO 2005/037851 PCT/IB2004/003426 -8 EXAMPLE 3: 3-beta-amino 17-methylene androstane-6-alpha 7-beta-diol hydrochloride, Form B., After 3 days of being subjected to a relative humidity above 95%, form A as the product of formula I changes into form B. EXAMPLE 4: 3-beta-amino 17-methylene androstane-6-alpha 7-beta-diol hydrochloride, Form C., 250 mg of product of formula I is dissolved at ambient temperature in the minimum amount of methyl ethylcetone (MEC). After transfer in water by azeotropic distillation at constant volume and balancing under a relative humidity above 97%, one obtains form C as the product of formula I. Park Case # 2819

Claims (2)

  1. 7-beta-diol hydrochloride, characterized by the fact that it crystallizes in a triclinic network (group of space P1 space, Z=1), the mesh parameters of which are as follows at T = 295 K: a = 8.85 6(2) A, a = 100.76(1)* b = 18.482(1) A, 13 = 90.06(1) ° c = 6.904(2) A y = 78.35(l) V = do 1086.5 A 3 density = 1.198 5) mono hydrate crystalline form C of 3-beta-amino 17-methylene androstane-6-alpha 7-beta-diol hydrochloride, characterized by the fact that the indexing of the diffraction powder pattern of X rays at 295 K gives the following results for the initial 30 rays: h k 1 Interreticular 2 theta distance (A) "ACu Kamid "1.54184 A 0 1 0 20.875 4.23 0 2 0 10.437 8.47 1 0 0 7.049 12.56 0 3 0 6.958 12.72 0 0 1 6.922 12.79 0 -1 1 6.845 12.93 -1 1 0 6.780 13.06 1 1 0 6.581 13.46 0 1 1 6.325 14.00 0 -2 1 6.155 14.39 -1 2 0 5.980 14.81 1 2 0 5.712 15.51 -1 0 1 5.604 15.81 -1 -1 1 5.506 16.10 0 2 1 5.447 16.27 -1 1 1 5.323 16.66 0 -3 1 5.267 16.83 0 4 0 5.219 16.99 -1 -2 1 5.083 17.45 -1 3 0 5.079 17.46 1 3 0 4.834 18.35 -1 2 1 4.804 18.47 0 3 1 4.612 19.24 -1 -3 1 4.516 19.66 1 -1 1 4.474 19.84 1 0 1 4.465 19.88 0 -4 1 4A59 19.91 -1 4 0 4.297 20.67 1 -2 1 4.290 20.71 1 1 1 4.266 20.82 6) mono hydrate crystalline form C of 3-beta-amino 17-methylene androstane Park Case # 2819 WO 2005/037851 PCT/IB2004/003426 -12 6-alpha 7-beta-diol hydrochloride, characterized by the fact that it crystallizes in a triclinic network (group of space P1, Z=1) the mesh parameters of which are as follows at T = 295 K: a = 7.2328(5) A, a = 97.135(6)* b = 21.063 (2) A, 13 = 102.653(5)0 c = 7.1563(5) A y = 91.177(6)* V = 1054.2 A 3 density = 1.178 7) Process of preparation of form A, according to Claims 1 or 2, characterized by the fact that crystallization takes place in a mixture of alcohol and ether and notably in an isopropylic methanol ether mixture. 8) Process of preparation of form C according to Claim 5 or 6, characterized by the fact that 250 mg of the product of formula (1) are dissolved at ambient temperature in a solvent such as methyl ethylcetone (MEC) and which are then transferred in water by azeotropic distillation at constant volume and balancing at a relative humidity above 97%. 9) As medications, crystalline forms A, B or C as defined by Claims 1 to 8. 10) Pharmaceutical compound characterized by the fact that it comprises form A of 3-beta-amino
  2. 17-methylene androstane-6-alpha 7-beta-diol hydrochloride in the pure state or possibly in combination with one and/or the other of the other crystalline forms of B or C and/or subject to a form of combination with any compatible and pharmaceutically acceptable additive or inert dilutant. 11) Application of the crystalline forms as defined by one any of the Claims 1 to 8 for the preparation of a medicine designed to treat inflammatory illnesses. Park Case # 2819
AU2004281998A 2003-10-20 2004-10-20 Crystalline forms of 3-beta-amino 17-methylene androstane-6-alpha 7-beta-diol hydrochloride Abandoned AU2004281998A1 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US51267903P 2003-10-20 2003-10-20
US60/512,679 2003-10-20
FR0312257 2003-10-20
FR0312257A FR2861077B1 (en) 2003-10-20 2003-10-20 CRYSTALLINE FORMS OF 3-BETA-AMINO CHLORYDRATE, 17-METHYLENE, ANDROSTANE-6-ALPHA, 7-BETA-DIOL
PCT/IB2004/003426 WO2005037851A1 (en) 2003-10-20 2004-10-20 Crystalline forms of 3-beta-amino 17-methylene androstane-6-alpha 7-beta-diol hydrochloride

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EP (1) EP1680441A1 (en)
JP (1) JP2007509050A (en)
KR (1) KR20070007766A (en)
AU (1) AU2004281998A1 (en)
CA (1) CA2542821A1 (en)
MX (1) MXPA06005679A (en)
RU (1) RU2006117320A (en)
WO (1) WO2005037851A1 (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU5208401A (en) * 2000-04-28 2001-11-12 Inflazyme Pharm Ltd 3-nitrogen-6,7-dioxygen steroids and uses related thereto

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CA2542821A1 (en) 2005-04-28
EP1680441A1 (en) 2006-07-19
WO2005037851A1 (en) 2005-04-28
JP2007509050A (en) 2007-04-12
MXPA06005679A (en) 2006-08-17
RU2006117320A (en) 2007-11-27

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