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

Definitions

• the subject of the present invention is three crystalline forms of 3-beta-5 amino, 17-methylene, androstane-6-alpha, 7-beta-diol hydrochloride (compound of formula I), represented by the structure:
• Patent application WO0183512 describes 3-beta-amino, 17-methylene, androstane-6 alpha, 7-beta-diol and its pharmaceutically acceptable salts for the treatment of 5 inflammatory diseases and in particular asthma:
• Compound 3- beta-amino, 17-methylene, androstane-6-alpha, 7-beta-diol as described and prepared in this application WO0183512 is in particular in the form of acetate salt.
• This salt in acetate form is hygroscopic, which is a major drawback for industrial development.
• the object of the invention is to find one or more new crystalline forms which do not have the drawbacks of the form previously described.
• the solid forms, and in particular the pharmaceutical products can have more than one crystalline form. This is called polymorphism.
• polymorphic form is understood to mean all asolvated forms of a crystallized molecule and pseudo-polymorphic all solvated forms.
• the polymorphic and pseudo-polymorphic forms of the same molecule generally show different physical properties such as solubility, hygroscopicity and stability. It should be noted that for the moment there are no methods allowing to know (experimental screening) or predict (theoretical screening by molecular modeling) with certainty o the existence of such or such polymorph, such or such pseudopolymorph, nor to predict their physical properties.
• Obtaining new polymorphic or pseudopolymorphic forms of molecules having a therapeutic activity is of great interest for the pharmaceutical industry in particular from the point of view of their preparation on an industrial scale, their use in pharmaceutical compositions, the search for better stability.
• the Applicant has identified three new crystalline forms of 5 3-beta-amino, 17-methylene hydrochloride, androstane-6-alpha, 7-beta-diol (form A, form B and form C).
• Form A which is anhydrous
• form B which is dihydrated
• form C which is mono-hydrated.
• the crystalline form A has, in addition to the advantages mentioned above, an absence of hygroscopicity.
• the invention therefore firstly relates to a new crystalline form of the hydrochloride of 3-beta-amino, 17-methylene, androstane-6-alpha, anhydrous 7-beta-diol which is called form A.
• La0 crystalline form A 3-beta-amino, 17-methylene, androstane-6-alpha, 7-beta-diol hydrochloride, according to the invention, is in the form of a crystalline powder, it is stable from 0 to 90% Humidity Relative (HR) and begins to degrade chemically around 240 ° C to decompose completely above 280 ° C. It has been defined by the indexing of its X-ray diagram with the powders described below.
• HR Humidity Relative
• the invention also relates to a new crystalline form of 3-beta-amino hydrochloride, 17-methylene, androstane-6 -alpha, 7-beta-diol hydrate which is called form B. It can be used as an intermediate for the preparation of form A. It is a stable dihydrate form above 50% RH. It is also defined below by the indexing of its X-ray diagram by powders. o
• the invention also relates to a new crystalline form of the hydrochloride of 3-beta-amino, 17-methylene, androstane-6-alpha, 7-beta-diol hydrate which is called form C. Form C appeared mixed with other forms (anhydrous forms D and E).
• Form C was obtained pure thanks to an additional treatment by maintenance for a few days in a humid atmosphere at 97% RH. It is a stable mono-hydrated form from 0 to 90% RH. It transforms into anhydrous D by heating above 60 ° C. It is also defined below by the indexing of its X-ray diagram by powders.
• the crystalline forms A, B or C of the compound of formula (I) exhibit similar therapeutic activities as those described for the compound 3-beta-amino, 17-methylene, androstane-6-alpha, 7-beta-diol in the application WO0183512. o They are particularly useful in the treatment of inflammatory diseases, and asthma.
• the analyzes are carried out on a Philips X'pert Pro diffractometer having a copper anticathode tube fitted with a front monochromator (wavelength of copper: 1.54060 ⁇ ).
• the assembly is of the Bragg-Brentano type, with a Philips X'celerator detector.
• the swept angular range extends from 2 to 40 degrees in 2 ⁇ with a step of 0.02 degrees in 2 ⁇ .
• the counting time is 300 seconds per step.
• the asymmetric unit consists of a molecule of 3-beta-amino, 17-methylene hydrochloride, androstane-6-alpha, 7-beta-diol.
• the form A as obtained according to the crystallization process described in example 1 or example 2 described below, is a pure physical form.
• Form B can be used as an intermediate for the preparation of Form A.
• Form B is a di-hydrate form which crystallizes in a triclinical network (space group El,
• form B is a pure physical form.
• Form C is a mono-hydrate form which crystallizes in a triclinic network (space group
• the asymmetric unit consists of two molecules of 3-beta-amino hydrochloride, 17-methylene, androstane-6-alpha , 7-beta-diol and 2 molecules of water.
• the form C is a pure physical form.
• the subject of the invention is therefore the crystalline forms A, B or C as described above as a medicament.
• 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 in the form of simple or coated tablets, capsules, granules, suppositories, ova, injections, ointments, creams, gels, microspheres, implants, patches, which are prepared according to the usual methods.
• the crystalline forms A, B or C of 3-beta-amino, 17-methylene, androstane-6-alpha, 7-beta-diol hydrochloride can be mixed with the excipients, diluents and any vehicles known to those skilled in the art for the manufacture of pharmaceutical compositions.
• excipients usually used in these pharmaceutical compositions mention may be made of talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not, fatty substances of animal or vegetable origin, paraffmic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.
• the invention thus extends to pharmaceutical compositions containing as active ingredient at least one of the crystalline forms A, B or C of 3-beta-amino, 17-methylene hydrochloride, androstane-6-alpha, 7-beta- diol as defined above and one or more pharmaceutically acceptable excipients, diluents or carriers.
• the subject of the invention is also the application of the crystalline forms A, B or C of 3-beta-amino, 17-methylene, androstane-6-alpha, 7-beta-diol hydrochloride as defined above for the preparation of a medicament for treating inflammatory diseases, such as asthma.
• the following examples illustrate the invention without, however, limiting it.
• EXAMPLE 2 3-beta-amino hydrochloride, 17-methylene, androstane-6-alpha, 7-beta-diol, Form A. 250 mg of the product of formula I are dissolved at room temperature in the minimum amount of ethanol. Water is added until crystallization starts, the product of formula I polymorphic is obtained B. Then after evaporation under a stream of nitrogen at room temperature, the product of formula I form A is obtained.
• EXAMPLE 3 3-beta-amino hydrochloride, 17-methylene, androstane-6-alpha, 7-beta-diol, Form A.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Steroid Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (3)

Publications (1)

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Family Applications (1)

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• 2004
  • 2004-10-20 JP JP2006534854A patent/JP2007509050A/ja active Pending
  • 2004-10-20 WO PCT/IB2004/003426 patent/WO2005037851A1/fr active Application Filing
  • 2004-10-20 AU AU2004281998A patent/AU2004281998A1/en not_active Abandoned
  • 2004-10-20 MX MXPA06005679A patent/MXPA06005679A/es unknown
  • 2004-10-20 KR KR1020067009800A patent/KR20070007766A/ko not_active Application Discontinuation
  • 2004-10-20 CA CA002542821A patent/CA2542821A1/fr not_active Abandoned
  • 2004-10-20 RU RU2006117320/04A patent/RU2006117320A/ru not_active Application Discontinuation
  • 2004-10-20 EP EP04769678A patent/EP1680441A1/de not_active Withdrawn

Non-Patent Citations (1)

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