| 摘要 |
<p>#CMT# #/CMT# Production of crystalline forms (specifically polymorphic forms or solvates) of enantiomers of modafinil (A) involves dissolving an enantiomer of (A) (preferably the levorotatory isomer, (-)-(A)) in a solvent other than ethanol, crystallizing the enantiomer and recovering the obtained crystalline form. Some polymorphic forms and solvates of (-)-(A) are new. #CMT# : #/CMT# Independent claims are included for: (a) the following new polymorphic forms of (-)-(A): (i) Form II, having an X-ray diffraction pattern with maxima corresponding to interplanar spacings of 8.54Å, 7.57Å, 7.44Å, 4.56Å, 3.78Å and 3.71Å; (ii) Form III, having an X-ray diffraction pattern with maxima corresponding to interplanar spacings of 12.58Å, 8.54Å, 5.01Å, 4.10Å, 3.97Å and 3.20Å; and (iii) Form IV, having an X-ray diffraction pattern with maxima corresponding to interplanar spacings of 12.38Å, 8.58Å, 7.34Å, 5.00Å and 4.09Å; (b) a new dimethyl carbonate solvate of (-)-(A), having an X-ray diffraction pattern with maxima corresponding to interplanar spacings of 12.31Å, 9.69Å, 9.09Å, 8.54Å, 7.27Å, 6.21Å, 5.45Å, 5.10Å, 5.00Å, 4.83Å, 4.63Å, 4.46Å, 4.22Å, 4.21Å, 4.09Å, 3.78Å, 3.62Å, 3.53Å, 3.42Å, 3.32Å, 3.24Å, 3.21Å and 3.10Å; (c) a method for converting a first crystalline form of an enantiomer of (A) (specifically Form I of (-)-(A)) into another crystalline form, involving suspending the first crystalline form in a suitable solvent and recovering the second form (the solvate specifically being acetonitrile, with the product being recovered as acetonitrile solvate); (d) a new acetonitrile solvate of (-)-(A), having an X-ray diffraction pattern with maxima corresponding to interplanar spacings of 16.17Å, 14.14Å, 12.32Å, 10.66Å, 9.79Å, 9.29Å, 8.54Å, 8.15Å, 7.80Å, 7.09Å, 6.31Å, 5.83Å, 5.62Å, 5.41Å, 5.10Å, 4.90Å, 4.66Å, 4.58Å, 4.46Å, 4.33Å, 4.20Å, 4.02Å, 3.92Å, 3.835Å, 3.72Å, 3.60Å, 3.57Å, 3.45Å, 3.33Å, 3.24Å, 3.19Å, 3.0Å and 3.03Å; (e) the preparation of optically active (A) from modafinic acid (B) by: (i) optically resolving (+-)-(B) and recovering at least one of the enantiomers; (ii) contacting one of the enantiomers with a lower alkyl haloformate in presence of alcohol and organic base; and (iii) converting the obtained ester into the amide; and (f) the preparation of an enantiomer of (A) by optically resolving (+-)-(B) (or its salt) by preferential crystallization and converting the obtained enantiomer into (A) (optionally via a lower alkyl ester). #CMT#ACTIVITY : #/CMT# Nootropic; Antiparkinsonian; Cerebroprotective; Nootropic; Tranquilizer; Neuroprotective; Antidepressant; Neuroleptic; #CMT#MECHANISM OF ACTION : #/CMT# None given in the source material. #CMT#USE : #/CMT# (A), i.e. 2-(benzhydrylsulfinyl)-acetamide, is a known CNS stimulant (see and ), (-)-(A) being the preferred enantiomer for medicinal use as antidepressant, stimulant for treating hypersomnia or agent for treating Alzheimer's disease. In particular the use of the new Forms II, III and IV of (-)-(A) is claimed for stimulating cognitive function and for the treatment or prevention of: (1) hypersomnia (specifically idiopathic hypersomnia or hypersomnia in cancer patients treated with morphine-type analgesics), obstructive or other sleep apnea, sleepiness (including excessive sleeping due to disease or narcolepsy) or narcolepsy; (2) CNS disorders such as Parkinson's disease; (3) ischemia-induced cerebral tissue damage; (4) vigilance disorders (especially associated with Steinert's disease) and attention disorders (e.g. attention deficiency-hyperactivity syndrome); (5) fatigue conditions, especially due to multiple sclerosis and other degenerative diseases; (6) depression (including depressive states associated with lack of sunshine, schizophrenia, shift work or jet lag); and (7) eating disorders (since (A) stimulates appetite). #CMT#ADVANTAGE : #/CMT# The present processes allow the preparation of various different polymorphic forms of enantiomers of (A), potentially having different pharmaceutical, physiological and biological properties. Production of enantiomers of (A) from (+-)-(B) by preferential crystallization gives higher yields and optical purities than the methods described in , and is suitable for large-scale use. #CMT#ORGANIC CHEMISTRY : #/CMT# Preferred Crystallization: Crystallization is carried out under kinetic or thermodynamic conditions, specifically by precipitation (optionally in presence of seed crystals of the required crystalline form) or by slowly or rapidly cooling the solution. Preferably the solvent is: (1) acetone, 1,4-dioxan, ethyl acetate or o-, m- and/or p-xylene, in which case (A) is obtained in polymorphic form I; (2) methanol and/or water, giving polymorphic form I; (3) isopropanol (preferred), n-propanol, ethyl acetate or ethanol denatured with toluene, giving polymorphic form II; (4) acetone, giving polymorphic form III; or (5) tetrahydrofuran, chloroform or methyl-ethyl ketone, giving polymorphic form IV. Alternatively (A) is obtained as solvate, specifically a dimethyl carbonate solvate obtained using dimethyl carbonate as the solvent. Preferred Production: In the production of enantiomers of (A) from (B), the chloroformate is methyl chloroformate, the base is diisopropylamine, diethyl-methylamine or DBU and the alcohol is methanol; and amidation is carried out in a lower aliphatic alcohol, preferably methanol. Optical resolution of (+-)-(B) is carried out by preferential crystallization; two preferred multi-stage, seeding-based preferential crystallization procedures are described in the claims. #CMT#ADMINISTRATION : #/CMT# The new polymorphic forms of (-)-(A) are administered orally, transmucosally or parenterally #CMT#EXAMPLE : #/CMT# Polymorphic form I of (-)-modafinil ((-)-(A)) (5 g) was dissolved in 90 ml of acetone at reflux. The solution was rapidly cooled in an ice-water bath. After 30 minutes the crystalline product was filtered off, dried at 35[deg]C and identified by X-ray diffraction as being Form III of (-)-(A). The yield was 61%.</p> |
