Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
  • C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
  • C07J73/005—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by nitrogen as hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/08—Drugs for disorders of the urinary system of the prostate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/10—Anti-acne agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
  • A61P5/28—Antiandrogens

Definitions

• the polymorphic form of 17- ⁇ -(N-ter. butyl carbamoyl)-4-aza-5- ⁇ - androst-l-en-3-one (5-alpha reductase inhibitor) is useful in treating acne, female hirsutism and particularly benign prostatic hyperplasia.
• Polymorphism can be defined as the ability of the same chemical substance to exist in different crystalline structures.
• the different structures are are referred to as polymorphs, polymorphic modification or form.
• the polymorphic form-I is characterized by a differential scanning calorimetry (DSC) curve, at heating rate of 20°C/min and in a closed cup, exhibiting a minor endotherm with a peak temperature of about 232°C; an extrapolated onset temperature of about 223°C with an associated heat of about 11 joules / gm and by a major melting endotherm with a peak temperature of about of 261°C; an extrapolated onset temperature of about 258°C with an associated heat of about 89 J / gm.
• the X-ray powder diffraction pattern is characterized by d-spacings of 6.44, 5.69, 5.36, 4.89, 4.55,
• the polymorphic form-II is characterized by a differential scanning calorimetry (DSC) curve, at heating rate of 20°C / min and in a closed cup, exhibiting a single melting endotherm with a peak temperature of about 261°C; an extrapolated onset temperature of about 258°C, with an associated heat of about 89 J/g.
• the X-ray powder diffraction pattern is characterized by d-spacings of 14.09, 10.36, 7.92, 7.18, 6.40, 5.93, 5.66, 5.31, 4.68, 3.90, 3.60 and 3.25.
• the FT-IR spectrum (in KBr) shows bands at 3441, 3215, 1678, 1654, 1597, 1476 and 752 cm-1.
• the two polymorphic forms referred as 1 and 2 are same as the Form-I and Form- II mentioned above.
• the lattice contains one molecule of acetic acid. It decomposes losing acetic acid and recrystallizes in the range 170-174°C having melting point 255-257°C.
• the lattice contains one molecule of ethyl acetate for two molecules of Finasteride.
• the melting point of form lb is reported as 252-255°C. While doing process development to optimize the yield and quality of 17- ⁇ -(N-ter. butyl carbamoyl)-4-aza-5- ⁇ -androst-l-en-3-one, different crystallization and isolation methods were used with different combinations of organic solvents and by varying the various parameters like temperature and volume etc.
• Form-V which are different from Form-I and Form-II disclosed in the prior art.
• Fig-1 Differential scanning calorimetry of Form-Ill.
• Fig-2 X-Ray powder diffractogram of Form-Ill.
• the present invention provides a novel polymorphic form
• DSC exhibits a melting endotherm with a peak temperature of about 262°C and preceded by another minor endotherm at about 245°C and an exotherm at about 253°C.
• DSC exhibits a melting endotherm with a peak temperature of about
• Form -IN of 17- ⁇ -( ⁇ -ter. butyl carbamoyl)-4-aza-5- ⁇ -androst-l-en-3-one can be prepared by a process, which comprises: (i) preparing a slurry of 17- ⁇ -(N-ter. butyl carbamoyl)-4-aza-5- - androst-l-en-3-one in ethyl acetate, tetrahydrofuran and water mixture such that the ratio of ethyl acetate:tetrahydrofuran : water is 1:1: ⁇ 0.1 and the ratio of this solvent mixture used is 1-3 volume/weight of 17- ⁇ -(N-ter. butyl carbamoyl)-4-aza-5- -androst-l-en-3- one;
• Form-N of 17- ⁇ -( ⁇ -ter. butyl carbamoyl)-4-aza-5- ⁇ -androst-l-en-3-one of formula (I), can be prepared by a process which comprises:
• the water immiscible organic solvent used in the process of preparing Form-Ill of 17- ⁇ -(N-ter. butyl carbamoyl)-4-aza-5- ⁇ -androst-l-en-3-one include any solvents such as halogenated solvent selected from dichloromethane or chloroform or aromatic hydrocarbon solvent preferably toluene or organic solvents selected from alkyl acetates preferably ethyl acetate.
• the amount of aromatic hydrocarbon solvent is 25-50 volume/weight of 17- ⁇ -(N- ter. butyl carbamoyl)-4-aza-5- ⁇ -androst-l-en-3-one.
• the alkyl acetate solvent is 10-20 volume/weight of 17- ⁇ -(N-ter. butyl carbamoyl)-4-aza- 5- ⁇ -androst-l-en-3-one.
• the solvent selected are those in which 17- ⁇ -(N-ter. butyl carbamoyl)-4- aza-5- ⁇ -androst-l-en-3-one can be dissolved at room temperature (25-35° C) as in the case of halogenated solvents or else at elevated temperatures preferably at 40-50°C, as in case of aromatic hydrocarbon solvent or organic solvents selected from alkyl acetates, until dissolution is achieved.
• polar organic solvents as used herein are meant to include solvents selected from C5-C10 aliphatic hydrocarbons either straight chain or branched, preferably hexane or heptane or petroleum ether, which precipitate 17- ⁇ -(N-ter. butyl carbamoyl)-4- aza-5- ⁇ -androst-l-en-3-one from the solution.
• the step of saturating with a less polar organic solvent is carried out at a temperature in the range of 25-60 °C.
• Trifluoroacetamide (2.5 gm) in toluene (25 ml) medium at 80-110°C. After completion of reaction, toluene layer was washed with 5-10% aqueous sodium sulphite solution (80 ml), and then with water (200ml). The toluene is stripped under vacuum to yield residual solid that is crude Finasteride.

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• Health & Medical Sciences (AREA)
• Organic Chemistry (AREA)
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• General Health & Medical Sciences (AREA)
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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Medicinal Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Engineering & Computer Science (AREA)
• Public Health (AREA)
• Dermatology (AREA)
• Urology & Nephrology (AREA)
• Endocrinology (AREA)
• Diabetes (AREA)
• Steroid Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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Cited By (3)

Citations (5)

• 2001
  • 2001-06-19 JP JP2002525173A patent/JP2004508380A/ja not_active Withdrawn
  • 2001-06-19 BR BR0113732-8A patent/BR0113732A/pt not_active Application Discontinuation
  • 2001-06-19 WO PCT/US2001/019546 patent/WO2002020553A1/en not_active Application Discontinuation
  • 2001-06-19 CA CA002422159A patent/CA2422159A1/en not_active Abandoned
  • 2001-06-19 HU HU0300937A patent/HUP0300937A3/hu unknown
  • 2001-06-19 PL PL01361014A patent/PL361014A1/xx not_active Application Discontinuation
  • 2001-06-19 IL IL15478501A patent/IL154785A0/xx unknown
  • 2001-06-19 EP EP01948467A patent/EP1322663A1/en not_active Ceased
  • 2001-06-19 NZ NZ525116A patent/NZ525116A/en unknown
  • 2001-06-19 AU AU6991101A patent/AU6991101A/xx active Pending
• 2003
  • 2003-03-06 NO NO20031045A patent/NO20031045L/no not_active Application Discontinuation
  • 2003-04-01 ZA ZA200302554A patent/ZA200302554B/en unknown

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