Pharmaceutically active morpholinol

Details Pharmaceutically active morpholinol Pharmaceutically active morpholinol

1999-01-20

2001-08-14

Jones, Dwayne C. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06274579

ABSTRACT:

This invention relates to an optically pure morpholinol, pharmaceutical formulations containing it and processes for their preparation and use.
BACKGROUND OF THE INVENTION
Bupropion hydrochloride, (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)-amino]-1-propanone hydrochloride, is the active ingredient of Wellbutrin® which is marketed in the United States for the treatment of depression. It is also the active ingredient of Zyban® which is marketed in the United States as an aid to smoking cessation. Bupropion is a relatively weak inhibitor of the neuronal uptake of noradrenaline (NA), serotonin and dopamine (DA), and does not inhibit monoamine oxidase. While the mechanism of action of bupropion, as with other antidepressants, is unknown, it is presumed that this action is mediated by noradrenergic and/or dopaminergic mechanisms. Available evidence suggests that Wellbutrin® is a selective inhibitor of noradrenaline (NA) at doses that are predictive of antidepressant activity in animal models. See Ascher, J. A., et al., Bupropion: A Review of its Mechanism of Antidepressant Activity.
Journal of Clinical Psychiatry
, 56: p.395-401,1995.
Bupropion is extensively metabolized in man as well as laboratory animals. Urinary and plasma metabolites include biotransformation products formed via hydroxylation of the tert-butyl group and/or reduction of the carbonyl group of bupropion. Four basic metabolites have been identified. They are the erythro- and threo-amino alcohols of bupropion, the erythro-amino diol of bupropion, and a morpholinol metabolite. These metabolites of bupropion are pharmacologically active, but their potency and toxicity relative to bupropion have not been fully characterized. Because the plasma concentrations of the metabolites are higher than those of bupropion, they may be of clinical importance.
The morpholinol metabolite (+/−)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morphohlnol hydrochloride is believed to be formed from hydroxylation of the tert-butyl group of bupropion.
SUMMARY OF THE INVENTION
It has now been discovered that despite the (−) form of the morpholinol metabolite predominating in human plasma samples, it is the (+) enantiomer, (+)-(2S, 3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol in which the activity resides.
Thus the present invention provides, in one aspect, a compound of formula (I), (+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol or pharmaceutically acceptable salts and solvates thereof.
Another aspect of the invention is pharmaceutical compositions comprising a compound of formula (I) or pharmaceutically acceptable salts and solvates thereof together with one or more pharmaceutically acceptable carriers, diluents or excipients.
A further aspect of the present invention is the use of a compound of formula (I) or pharmaceutically acceptable salts and solvates thereof in therapy.
Yet another aspect of the invention provides methods of treating depression, attention deficit hyperactivity disorder (ADHD), obesity, migraine, pain, sexual dysfunction, Parkinson's disease, Alzheimer's disease, or addiction to cocaine or tobacco products in a human or animal subject comprising the administration to said subject of an effective amount of a compound of formula (I) or pharmaceutically acceptable salts and solvates thereof or pharmaceutical compositions thereof
Yet another aspect of the present invention is the use of the compound of formula (I) or pharmaceutically acceptable salts and solvates thereof or pharmaceutical compositions thereof in the preparation of a medicament for the treatment of depression, attention deficit hyperactivity disorder (ADHD), obesity, migraine, pain, sexual dysfunction, Parkinson's disease, Alzheimer's disease, addiction to cocaine or tobacco products.


REFERENCES:
patent: 5648347 (1997-07-01), Mehta et al.
patent: 0 170 430 A1 (1986-02-01), None
patent: 170430 (1986-05-01), None
patent: WO 92/18489 (1992-10-01), None
Ferris et al., “Mechanism of Antidepressant Activity of Bupropion”, J. Clin. Psychiatry Monograph, 11(1):2-14, 1993.*
Graham et al., Organic Chemistr, 3rd Edition, pp. 301, 319 and 322, 1984.*
Kelley et al., J. Med. Chem 39, pp. 347-349, 1996.*
Patel of Pharmacotherapy of Cognitive Impairment in Alzheimer's Disease: A Review, Journal of Geriatric Psychiatry and Neurology, vol. 8, pp. 81-95, Apr. 1995.*
Martin, et al., “Antidepressant Profile of Bupropion and three Metabolites in Mice”, Pharmacopsychiatry 23 (1990) 187-194.
Eisman, et al., “The Isolation and Identification of Some Basic Urinary Metabolites of Bupropion-HCL in Man”,Pharmacologist, 1979, 21, 191.
Cooper, et al., “Behavioral and Biochemical Effects of the Antidepressant Bupropion (Wellbutrin): Evidence for Selective Blockade of Dopamine Uptake in Vivo”,The Journal of Pharmacology and Experimental Therapeutics, vol. 215, No. 1, 1980.
Ferris, et al., Some Neurochemical Properties of a New Antidepressant, Bupropion Hydrochloride (Wellbutrin™),Drug Development Research1:21-35, 1981.
Maxwell, et al., “Bupropion”,Pharmacol & Biochem Properties Drug Substances (M E Goldberg, Ed), Am Pharm Assoc Publ, Washington, vol. 3, pp. 1-55, 1981.
Findlay, et al., “Pharmacokinetics of Bupropion, a Novel Antidepressant of Bupropion, a Novel Antidepressant Agent, Following Oral Administration to Healthy Subjects”,European Journal of Clinical Pharmacology, 21:127-135, 1981.
Butz, et al., “Radioimmunoassay and Pharmacokinetic Profile of Bupropion in the Dog”,The Journal of Pharmacology and Experimental Therapeutics, vol. 217, No. 3, 1981.
Butz, et al., “Relationship between Bupropion Disposition and Dopamine Uptake Inhibition in Rats and Mice1”,The Journal of Pharmacology and Experimental Therapeutics, vol. 221, No. 3, 1982.
Ferris, et al., “Bupropion: A New Antidepressant Drug, The Mechanism of Action of Which is Not associated with Down-Regulation of Postsynaptic &bgr;-Adrenergic, Serotonergic (5-HT2), &agr;2- Adrenergic, Imipramine and Dopaminergic Receptors in Brain”,Neuropharmacology, vol. 22, No. 11, pp. 1257-1267, 1983.
Mehta, “The Chemistry of Bupropion”,J. Clinical Psychiatry, 44:5 (Sec. 2), May, 1983.
Schroeder, David, “Metabolism and Kinetics of Bupropion”,J. Clinical Psychiatry, 44:5(Sec. 2), May, 1983.
Cooper, et al., “Determination of Bupropion and Its Major Basic Metabolites in Plasma by Liquid Chromatography With Dual-Wavelength Ultraviolet Detection”,Journal of Pharmaceutical Sciences, vol. 73, No. 8, Aug., 1984.
Cooper, et al., “Bupropion: Possible Role of Major Metabolites in Mode of Action”,Clin. Pharmacol. Ther, vol. 37, No. 2, Feb., 1985.
DeVane, et al., “The Effect of Experimentally-Induced Renal Failure on Accumulation of Bupropion and its major basic metaolites in plasma and brain of guinea pigs”,Psychopharmacology, 89: 404-408, 1986.
Perumal, et al., “Effect of Plasma From Patients Containing Bupropion and its Metabolites on the Uptake of Norepinephrine”Neuropharmacology, vol. 25, No. 22, pp. 199-202, 1986.
Perumal, et al., “Down Regulations of &bgr;-Receptors by Bupropion and its Major Metabolite in Mouse Brain”,Neuropharmacology, vol. 25, No. 12, pp. 1323-1326, 1986.
Thomas Smith, et al., “Brain regional [3H]flunitrazepam binding in rats chronically treated with bupropion or B.W.306U”,Brain Research, 367, pp. 385-389, 1986.
Golden, et al., “Bupropion in Depression”,Arch Gen Psychiatry-vol. 45, Feb., 1988.
Ferris, et al., “Mechanism of Antidepressant Activity of Bupropion”,J Clin Psychiatry Monograph, vol. 11, pp. 2-14, 1993.
Musso, et al., “Synthesis and Evaluation of the Antidepressant Activity of the Enantiomers of Bupropion”,Chirality5:495-500, 1993.
Cooper, et al., “Evidence that the Acute Behavioral and Electrophysiological Effects of Bupropion (Wellbutrin®) Are Mediated by a Noradrenergic Mechanism”,Neuropsychopharmacology, vol. 11, No. 2, 1994.
Modell, et al., “Comparative sexual side effects of bupropion, fluoxetine, paroxetine, and sertraline”,Clinical Pharmacology & Therapeutics, vol. 61, No. 4, 1996.
Hsyu, et al., “Ph

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