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Buproprion Metabolites for Treating Dementia and Other

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Buproprion Metabolites for Treating Dementia and Other (19) & (11) EP 1 759 701 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/5375 (2006.01) A61K 31/137 (2006.01) 22.12.2010 Bulletin 2010/51 A61P 25/24 (2006.01) A61P 25/34 (2006.01) A61P 25/20 (2006.01) (21) Application number: 06120882.3 (22) Date of filing: 29.02.2000 (54) Buproprion Metabolites for treating dementia and other cerebrovascular disorders Bupropinmetaboliten zur Behandlung von Dementia und anderen zerebrovasckulären Erkrankungen Métabolites du bupropion pour traiter la démence et d’autres maladies cérébrovasculaires (84) Designated Contracting States: • MUSSO ET AL: "Synthesis and evaluation of the AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU antidepressant activity of the enentiomers of MC NL PT SE bupropion" CHIRALITY, WILEY-LISS, NEW YORK, US, vol. 5, no. 7, 1993, pages 495-500, (30) Priority: 01.03.1999 US 122277 P XP002107656 ISSN: 0899-0042 11.08.1999 US 148324 P • KELLEY JAMES L ET AL: "-2-(3,5- 22.02.2000 US 510241 P difluorophenyl)-3,5-dimethyl-2-mo rpholinol: A novel antidepressant agent and selective (43) Date of publication of application: inhibitorof norepinephrine uptake" JOURNAL OF 07.03.2007 Bulletin 2007/10 MEDICINALCHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 39, no. 2, 1996, (62) Document number(s) of the earlier application(s) in pages 347-349, XP002164358 ISSN: 0022-2623 accordance with Art. 76 EPC: • SNYDER A M ET AL: "STRESS-INDUCED 00913649.0 / 1 165 086 NEUROLOGICAL IMPAIRMENTS IN AN ANIMAL MODEL OF PARKINSONISM" ANNALS OF (73) Proprietor: SEPRACOR, INC. NEUROLOGY, BOSTON, US, vol. 18, no. 5, Marlborough, MA 01752 (US) November 1985 (1985-11), pages 544-551, XP008070507 ISSN: 0364-5134 (72) Inventors: • MCNULTY M ET AL: "ANTICONVULSANT AND • Jerussi, Thomas, P. PROCONVULSANT EFFECTS OF BUPROPION Charleston, SC 29412 (US) AND FENCAMFAMIN IN THE GENETICALLY • McCullough, John, R. EPILEPSY-PRONE RAT" FEDERATION Bolton, MA 01740 (US) PROCEEDINGS, vol. 44, no. 4, 1985, page 1107, • Senanayake, Chrisantha, H. XP008070452 & 69TH ANNUAL MEETING OF THE Shrewsbury, MA 01545 (US) FEDERATION OF AMERICAN SOCIETIES FOR • Fang, Qun, K. EXPERIMENTAL BIOLOGY, ANAHEIM, CALIF Wellesley, MA 02181 (US) ISSN: 0014-9446 • GOETZ C G ET AL: "BUPROPION IN (74) Representative: Killin, Stephen James et al PARKINSONS DISEASE" NEUROLOGY, vol. 34, Venner Shipley LLP no. 8, 1984, pages 1092-1094, XP008070505 ISSN: 20 Little Britain 0028-3878 London EC1A 7DH (GB) (56) References cited: WO-A-99/37305 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 759 701 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 1 759 701 B1 • HANSARD M J ET AL: "The antiparkinsonian • "Practice guideline for the greatment of patients ability of bupropion in MPTP-treated common with Alzheimer’s disease and other dementias of marmosets" BRITISH JOURNAL OF late life" AMERICAN JOURNAL OF PSYCHIATRY PHARMACOLOGY, vol. 125, no. PROC. SUPPL., 1997 UNITED STATES, vol. 154, no. 5 SUPPL., December 1998 (1998-12), page 66P, 1997, pages 1-39, XP008070457 ISSN: 0002-953X XP008070506& JOINT MEETING OF THE BRITISH • TUNE L E: "Depression and Alzheimer’s disease" PHARMACOLOGICAL SOCIETY AND THE DEPRESSION AND ANXIETY 1998 UNITED PHYSIOLOGICAL SOCIETY; SOUTHAMPTON, STATES, vol. 8, no. SUPPL. 1, 1998, pages 91-95, ENGLAND, UK; SEPTEMBER 8-11, 1998 ISSN: XP008070454 ISSN: 1091-4269 0007-1188 • SHRETHRA M ET AL: "Status epilepticus • MUSSO D L ET AL: "Synthesis and evaluation of secondary to bupropion overdose" JOURNAL OF the anticonvulsant activity of a series of 2-amino- TOXICOLOGY CLINICAL TOXICOLOGY, vol. 37, 1-phenyl-1-propanols derived from the no. 5, August 1999 (1999-08), pages 634-635, metabolites of the antidepressant bupropion" XP008070453 & ANNUAL MEETING OF THE BIOORGANIC & MEDICINAL CHEMISTRY NORTH AMERICAN CONGRESS OF CLINICAL LETTERS, OXFORD, GB, vol. 7, no. 1, 7 January TOXICOLOGY; LA JOLLA, CALIFORNIA, USA; 1997 (1997-01-07), pages 1-6, XP004135955 ISSN: SEPTEMBER 28-OCTOBER 4, 1999 ISSN: 0960-894X 0731-3810 2 EP 1 759 701 B1 Description [0001] This invention relates to the use of bupropion metabolites and isomers thereof in therapy. [0002] Bupropion, a racemic mixture of (+)- and (-)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone, is 5 an antidepressant of the aminoketone class, and is described in U.S. Patent Nos. 3,819,706 and 3,885,046. The hydro- chloride salt of bupropion is sold under the trade names WELLBUTRIN® and WELLBUTRIN SR® for the treatment of depression. Bupropion is also sold under the trade name ZYBAN® as a drug useful to achieve smoking cessation. Additional benefits of bupropion maleate are reported in European Patent Application No. 118036. [0003] Although its mechanism of action is poorly understood, bupropion is reportedly a weak but selective inhibitor 10 of dopamine. Its potency as an inhibitor of norepinephrine reuptake is reportedly only half of that for dopamine, and it shows little affinity for the serotonergic transport system. Ascher, J. A., et al., J. Clin. Psychiatry, 56:395-401 (1995). [0004] Bupropion is extensively metabolized in man and animal. Three metabolites found in the plasma of healthy humans to which it has been administered are shown in Scheme 1: 15 20 25 30 35 Posner, J., et al., Eur. J. Clin Pharmacal., 29:97-103 (1985); Suckow, R.F., et al., Biomedical Chromatography, 11: 174-179 (1997). Referring to Scheme 1, metabolite 1 has the chemical name 2-(3-chlorophenyl)-3,5,5- trimethyl-2-mor- pholinol; metabolite 2 has the chemical name 1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanol; and metab- olite 3 has the chemical name 1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone. Because bupropion is 40 racemic and its metabolites are chiral enantiomers of each of the metabolites 1, 2, and 3 likely exist in human plasma following its administration. [0005] The bupropion metabolite, 1, often referred to as "hydroxybupropion," has two chiral carbon atoms and can thus exist as two pairs of enantiomers. These are shown in Scheme 2: 45 50 55 Pair 1a is reportedly the most active human metabolite bupropion. Kelley, J.L., et al., J, Med. Chem., 39: 347-349 (1996). 3 EP 1 759 701 B1 The mixture 1a has been isolated from human plasma and allegedly separated into its (S,S) and (R,R) components. Suckow, R.F., et al., Biomedical Chromatography, 11:174-179 (1997). [0006] The amino alcohol metabolite. 2 can also exist as two pairs of enantiomers. The pair wherein the alcohol and amine moieties are cis each other is commonly referred to as the erythro-amino alcohol metabolite; the pair wherein the 5 two moieties are trans to each other is referred to as the threo- amino alcohol metabolite. [0007] The tert-butyl alcohol metabolite 3 can exist as one of two enantiomers. This metabolite, the accumulation of which in human plasma coincides with the elimination of a single dose of bupropion, is believed by some to be a precursor to hydroxybupropion. Posner, J., et al., Eur. J. Clin. Pharmacol., 29:97-103 (1985); Suckow, R.F., et al., Biomedical Chromatography, 11:174-179 (1997). 10 [0008] Clearly, the metabolism of bupropion, which is complicated and poorly understood, results in a complex array of optically active compounds. The structures of these molecules and their chirality provides the skilled artisan with difficult issues of asymmetric synthesis, chiral resolution, and pharmacological activity. [0009] Bupropion is widely used to treat affective disorders in patients who do not respond to, or cannot tolerate, other antidepressants such as tricyclic agents or monoamine oxidase inhibitors. Examples of affective disorders are depression 15 and bipolar manic-depression. Bupropion is also useful in the treatment of other diseases or conditions associated with the reuptake of neuronal monoamines such as serotonin and norepinephrine. These reportedly include: schizophrenia (U.S. Patent No. 5,447,948); attention-deficit disorder; psycho-sexual dysfunction (U.S. Patent No. 4,507,323); bulimia and other eating disorders; Parkinson’s disease; migraine (U.S. Patent No. 5,753,712); and chronic pain. Bupropion also reportedly increases success rates in some smoking cessation treatments. Rose, J.E., Annu. Rev. Med:, 47: 493-507 20 (1996); Ferry, L.H. et al., J. Addict. Dis., 13:A9 (1994); and Lief, H.I., Am. J. Psychiatry, 153(3):442 (1996). [0010] Further uses of bupropion reportedly include the treatment of: the effects of ethanol (U.S. Patent No. 4,393,078); tardive dyskinesia (U.S. Patent No. 4,425,363); drowsiness (U.S. Patent Nos. 4,571,395 and 4,798,826); minimal brain dysfunction (U:S. Patent No. 4,435,449); psychosexual dysfunction (U.S. Patent No. 4,507,323); prostate hypertrophy and sexual dysfunction (U.S. Patent No. 4,835,147); psychostimulant addiction (U.S. Patent No. 4,935,429); substance 25 abuse (U.S. Patent No. 5,217,987); high cholesterol (U.S. Patent No. 4,438,138); and weight gain (U.S. Patent No. 4,895,845). [0011] Certain advantages exist in using bupropion for the treatment of diseases and conditions such as those provided above. For example, it does not inhibit monoamine oxidase or block the reuptake of serotonin, unlike other neuronal monoamine reuptake inhibitors. Administration of bupropion can thus avoid or lessen many of the adverse side effects 30 commonly associated with other antidepressants such as tricyclic agents and monoamine oxidase inhibitors.
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