Methods of using and compositions comprising dopamine reuptake inhibitors
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A technology for solvates, pharmaceuticals, in the field of racemic and optically pure metabolites
Inactive Publication Date: 2008-09-03
SEPACOR INC
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[0009] Sibutramine has many side effects
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Embodiment 13-14
[0158] Examples 13-14 describe methods for determining the binding affinity of compounds of the invention and the binding affinities determined using these methods.
[0159] Finally, Example 15 describes oral formulations comprising compounds of the invention.
Embodiment 1
[0160] 5.1. Example 1: Synthesis of Sibutramine
[0161] Synthesis of 1-(4-Chlorophenyl)cyclobutanenitrile
[0162] To a suspension of NaH (176 g 60%, washed with hexane) in dimethyl sulfoxide (150 mL) was added chlorobenzylnitrile (303 g) over a period of 1 hour at room temperature with mechanical stirring and 1,3-dibromopropane (223 mL, 445 g). The reaction mixture was stirred for another 1 hour and isopropanol (10 ml) was slowly added to quench excess NaH. Water (150 mL) was added. The reaction mixture was extracted with tert-butyl methyl ether (MTBE) (2x200 mL), and the combined extracts were washed with water (3x200 mL), brine, and washed over MgSO 4 dry. The solvent was removed with a rotary evaporator and the final product was purified by distillation to give the title compound (22 g, 56%) as a light yellow oil, bp 110-120°C / 10 mmHg. pass the product through 1 H NMR assay.
[0163] Synthesis of 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine
[0164] A solut...
Embodiment 4
[0176] To a solution of (-)-desmethylsibutramine (0.78 g) in ethyl acetate (5 mL) was added HCl / diethyl ether (1M, 5 mL) at 0°C. The reaction mixture was stirred for 1 hour and the solid was collected by filtration. The solid was then dried to yield 068 g of a white solid. through 1 H and 13 CNMR (DMSO-d 6 ) assayed the product and determined >99% chemical purity by HPLC. [α]=-5°(c=05, H 2 O). The racemate and other enantiomers were prepared and determined in the same manner. 5.4. Example 4. (R / S)-desmethylsibutramine
[0177] Another method for the preparation of racemic desmethylsibutramine ((R / S)-DMS) is shown in Scheme 2 and described in detail below
[0178]
[0179] Process 2
[0180] Preparation of 1-(4-chlorophenyl)-1-cyclobutylcarbaldehyde
[0181] Following Scheme 2, diisobutylaluminum hydride (DIBAL-H) (87 mL, 1 M in THF, 87.0 mmol) was added to 1-(4-chlorophenyl)cyclobutyronitrile ( CCBC; 10g, 521mmol) in solution. The resulting mixture was stirred...
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Abstract
Methods are disclosed for the treatment and prevention of disorders and conditions including, but are not limited to, erectile dysfunction, affective disorders, weight gain, cerebral functional disorders, pain, obsessive-compulsive disorder, substance abuse, chronic disorders, anxiety, eating disorders, migraines, incontinence, depresson, attention deficit disorder, attention deficit disorder with hyperactivity, bipolar and manic conditions, dysthymic disorder, and cyclothymic disorder, senile dementia, Alzheimer's type dementia, memory loss, amnesia / amnestic syndrome, disturbance of consciousness, coma, lowering of attention, speech disorders, Parkinson's disease, Lennox syndrome, autism, epilepsy, hyperkinetic syndrome and schizophrenia. The methods comprise the administration of a dopamine reuptake inhibitor and optionally an additional pharmacologically active compound. Pharmaceutical compositions and dosage forms are also disclosed that comprise a dopamine reuptake inhibitor and optionally an additional pharmacologically active compound. Preferred dopamine reuptake inhibitors are racemic or optionally pure sibutramine metabolites, wherein the sibutramine metabolite is selected from the group consisting of (+)-desmethylsibutramine, (-)-desmethylsibutramine, (±)-desmethylsibutramine, (+)-didesmethylsibutramine, (-)-didesmethylsibutramine, and (±)-didesmethylsibutramine.
Description
[0001] This application claims the benefit of U.S Provisional Application No. 60 / 097,665, filed August 24, 1998, and U.S. Provisional Application No. 60 / 099,306, filed September 2, 1998, both of which are hereby incorporated by reference in their entirety middle. 1. Field of invention [0002] The present invention relates to methods of using dopamine reuptake inhibitors and compositions comprising dopamine reuptake inhibitors, especially racemic and optically pure metabolites of sibutramine. 2. Background of the invention [0003] Sibutramine, chemical name [N-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl]-N,N-dimethylamine, is a neuronal monoamine Reuptake inhibitors, which were originally disclosed in US Patent Nos. 4,746,680 and 4,806,570. Sibutramine inhibits the reuptake of norepinephrine and, to a lesser extent, serotonin and dopamine. See, eg, Buckett et al., Prog Neuro-psychopharm & Biol Psychiat, 12575-584, (1988); King et al., J Clin Pharm, 26:607-611 (1989). ...
Claims
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