Pharmaceutically active morpholinol

Details Pharmaceutically active morpholinol Pharmaceutically active morpholinol

2001-06-22

2002-05-21

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

06391875

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 (+/−)-(2*,3*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol 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-(3chlorophenyl)-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 (1986-02-01), None
patent: 92/18489 (1992-10-01), None
patent: 01/62257 (2001-08-01), None
Golden et al., “Bupropion in Depression,” Arch. Gen Psychiatry, vol. 45, Feb. 1988.
Laizure, et al., “Pharmacokinetics of bupropion and its major basic metabolites in normal subjects after a single dose,” Clin. Pharm. Ther., 1985 (38), pp. 586-589.
Suckow, et al., “Enantiomeric Determination of the Phenylmorpholinol Metabolite of Buproprion in Human Plasma Using Coupled Achiral-Chiral Liquid Chromatography,” Biomedical Chromatography, 1997, vol. 11, pp. 174-179.
Welch, et al., “Phmaracological significance of the species difference in bupropion metabolism,” Xenobiotica, 1987, vol. 17, No. 3, pp. 287-298.
Suckow, et al., “Pharmacokinetics of Bupropion and Metabolites in Plasma and Brain of Rats, Mice, and Guinea Pigs,” The American Society of Pharmacology and Experimental Therapeutics, 1986, vol. 14, No. 6, pp. 692-697.
Posner, J., et al., “The Disposition of Bupropion and Its Metabolites in Healthy Male Volunteers After and Multiple Doses,” Eur. J. Clin. Pharmacol., 1985, vol. 29, pp. 97-103.
Ascher, J.A., et al., “Bupropion: A Review of its Mechanism of Antidepressant Activity,” J. Cling. Psych., 1995, vol. 56, pp. 395-401.
Boswell, G. Evan, et al., “Synthesis and Anti-terrabenazine Activity of V-e Analogues of Dimethyl-2-phenylmorpholines,” J. Heterocyclic Chem., vol. 33, pp. 33-39.
Boswell, G. Evan, et al., “Synthesis, Stereochemistry and Anti-Tetrabenazine Activity of Bicyclo Analogues 2-phenylmorpholines,” J. Heterocyclic Chem., vol. 34, pp. 1813-1820.
Martin et al., “Antidepressant Profile of Bupripion and three Metabolites in Mice,” Pharmacopsychiatry, 1990, vol. 23, pp. 187-194.
Eisman, et al., “The Isolation and Identification of Some Basic Urinary Metabolites of Bupropion-HCL in Man,” Pharmacologist, 1979, vol. 21, p. 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, 1980, vol. 215, No. 1.
Ferris et al., “Some Neurochemical Properties of a New Antidepressant, Bupropion Hydrochloride (Wellbutrin),” Drug Development Research, 1981, vol. 1, pp. 21-35.
Maxwell, et al., “Bupropion,” Pharmacol & Biochem Propertics Drug Substances (M E Goldberg, Ed), Am Pharm Assoc. Pub., Washington, 1981, vol. 3, pp. 1-55.
Findlay, et al., “Pharmacokinetics of Bupropion, a Novel Antidepressant Agent, Following Oral Administration to Healthy Subjects,” European Journal of Clinical Pharmacology, 1981, vol. 21, pp. 127-135.
Butz, et al., “Radioimmunoassay and Pharmacokinetic Profile of Bupropion in the Dog,” The Journal of Pharmacology and Experimental Therapeutics, 1981, vol. 217, No. 3.
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, 1983, vol. 22, No. 11, pp. 1257-1267.
Mehta, “The Chemistry of Bupropion, ” J. Clinical Psychiatry, May 1983, 44:5 (Sec. 2).
Schroeder, David, “Metabolism and Kinetics of Bupropion,” J. Clinical Psychiatry, May 1983, 44:5 (Sec. 2).
Lai, et al., “Clinical Pharmacokinetics of Bupropian: A Review,” J. Clinical Psychiatry, May 1983, 44:5 (Sec. 2).
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, Aug. 1984, vol. 73, No. 8.
Laizure et al., “Stability of Bupropion and its Major Metabolites in Human Plasma,” Therapeuytic Drug Monitoring, 1985, vol. 7, pp. 447-450.
Cooper, et al., “Bupropion: Possible Rose of Major Metabolites in Mode of Action,” Clin. Pharmacol. Ther., Feb. 1985, vol. 37, No. 2.
DeVane, et al., “The Effect of Experimentally-Induced Renal Failure on Accumulation of Bupropion and its major basic metabolites in plasma and brian of guinea pigs,” Psychopharmacology, 1986, vol. 89, pp. 404-408.
Perumal, et al., “Effect of Plasma from Patients Contianing Bupropian and its M

Affiliated with

Also associated with

Rating

Pharmaceutically active morpholinol does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Pharmaceutically active morpholinol, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pharmaceutically active morpholinol will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2898107