Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-09-17
2001-02-06
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S238800, C514S239500, C514S438000, C514S620000, C514S649000, C514S651000, C514S653000, C514S654000
Reexamination Certificate
active
06184222
ABSTRACT:
FIELD OF THE INVENTION
The invention belongs to the fields of pharmaceutical chemistry and psychiatric medicine, and provides a method of treatment of the psychiatric disorder known as conduct disorder.
BACKGROUND OF THE INVENTION
A significant number of children and adolescents display a behavioral disorder which suggests total disregard for the basic rights of others, far exceeding the expected idiosyncrasies of the developing individual. Children and adolescents with these conduct disorders have considerable difficulty behaving in a socially acceptable way and in following rules at school and at home. The conduct disorder patient typically exhibits aggressive behavior toward people and animals, is deceitful, lies, steals, destroys the property of others, is truant from school, runs away from home, as well as a variety of additional antisocial symptoms. When untreated, children and adolescents suffering with conduct disorders are typically very unhappy and face a difficult future. They are unable to cope with the demands of adulthood, have continuing problems maintaining relationships, are unable to hold a job, and often break the law and behave antisocially.
Current therapies for the treatment of conduct disorders are not totally satisfactory. Methylphenidate (Ritalin™), which exhibits noradrenergic and dopaminergic effects, has been reported to induce improvement in many patients' symptoms (Shah, et al.,
Journal of Child and Adolescent Psychopharmacology,
4(4), 255-261 (1994)). Some patients, however, were refractory to methylphenidate dosing, and others were unable to be maintained on the treatment for long periods of time. Furthermore, due to the high potential for substance abuse in conduct disorder patients, the use of stimulants such as methylphenidate is problematic. Shah also demonstrated that certain patients benefitted from the augmentation of methylphenidate treatment by the addition of pemoline, a dopamine reuptake inhibitor. Haloperidol and lithium carbonate have found utility in the treatment of the aggressive symptoms of conduct disorder (Platt, et al.,
Arch. Gen. Psychiatry,
41, 657-662 (1984)), but both are associated with undesirable side effects, including negative effects on cognition.
The need for a safe and effective treatment for conduct disorders, without the disadvantages of current therapies, continues to be a concern of the psychiatric community.
SUMMARY OF THE INVENTION
The present invention provides a method of treating conduct disorder comprising the administration to a patient in need of such treatment of an effective amount of a norepinephrine reuptake inhibitor.
DETAILED DESCRIPTION
Many compounds, including those discussed at length below, are norepinephrine reuptake inhibitors, and no doubt many more will be identified in the future. In the practice of the present invention, it is intended to include reuptake inhibitors which show 50% effective concentrations of about 1000 nM or less, in the protocol described by Wong et al.,
Drug Developmernt Research,
6, 397 (1985). The norepinephrine reuptake inhibitors useful for the method of the present invention are characterized in being selective for the inhibition of neurotransmitter reuptake relative to their ability to act as direct agonists or antagonists at other receptors. Norepinephrine reuptake inhibitors useful for the method of the present invention include, but are not limited to:
Tomoxetine, (R)-(−)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine, is usually administered as the hydrochloride salt. Tomoxetine was first disclosed in U.S. Pat. No. 4,314,081. The word “tomoxetine” will be used here to refer to any acid addition salt or the free base of the molecule. See, for example, Gehlert, et al.,
Neuroscience Letters,
157, 203-206 (1993), for a discussion of tomoxeline's activity as a norepinophrine reuptake inhibitor;
The compounds of formula I:
wherein X is C
1
-C
4
alkylthio, and Y is C
1
-C
2
alkyl or a pharmaceutically acceptable salt thereof. The compounds of formula I were described in U.S. Pat. No. 5,281,624, of Gehlert, Robertson, and Wong, and in Gehlert, et al.,
Life Sciences,
55(22), 1915-1920, (1995). The compounds are there taught to be inhibitors of norepinephrine reuptake in the brain. It is also explained that the compounds exist as stereoisomers, and that they accordingly include not only the racemates, but also the isolated individual isomers as well as mixtures of the individual isomers. For example, the compounds of formula I include the following exemplary species:
N-ethyl-3-phenyl-3-(2-methylthiophenoxy)propylamine benzoate;
(R)-N-methyl-3-phenyl-3-(2-propylthiophenoxy)propylamine hydrochloride;
(S)-N-ethyl-3-phenyl-3-(2-butylthiophenoxy)propylamine;
N-methyl-3-phenyl-3-(2-ethylthiophenoxy)propylamine malonate;
(S)-N-methyl-3-phenyl-3-(2-tert-bucylthiophenoxy)propylamine naphthalene-2-sulfonate;
(R)-N-methyl-3-(2-methylthiophenoxy)-3-phenylpropylamine;
Reboxetine (Edronax™), 2-[&agr;-(2-ethoxy)phenoxybeonzyl]morpholine, is usually administered as the racemate. It was first taught by U.S. Pat. No. 4,229,449, which describes its utility for the treatment of depression. Reboxetine is a selective norepinephrine reuptake inhibitor. The term “reboxetine” will be used here to refer to any acid addition salt or the free base of the molecule existing as the racemate or either enantiomer;
Duloxetine, N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, is usually administered as the hydrochloride salt and as the (+) enantiomer. It was first taught by U.S. Pat. No. 4,956,388, which shows its high potency. The word “duloxetine” will be used here to refer to any acid addition salt or the free base of the molecule;
Venlafaxine is known in the literature, and its method of synthesis and its activity as an inhibitor of serotonin and norepinephrine uptake are taught by U.S. Pat. No. 4,761,501. Venlafaxine is identified as compound A in that patent; and
Milnacipran (N,N-diethyl-2-aminomethyl-1-phenylcyclopropanecarboxamide) is taught by U.S. Pat. No. 4,478,836, which prepared milnacipran as its Example 4. The patent describes its compounds as antidepressants. Moret et al.,
Neuropharmacology
24, 1211-19 (1985), describe its pharmacological activities as an inhibitor of serotonin and norepinephrine reuptake.
All of the U.S. patents which have been mentioned above in connection with compounds used in the present invention are incorporated herein by reference.
A preferred duloxetine enteric formulation is a pellet formulation comprising a) a core consisting of duloxetine and a pharmaceutically acceptable excipient; b) an optional separating layer; c) an enteric layer comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS) and a pharmaceutically acceptable excipient; d) an optional finishing layer. The following example demonstrates the preparation of a preferred such formulation.
REFERENCES:
patent: 5441985 (1995-08-01), Foreman et al.
patent: 5532268 (1996-07-01), Wong et al.
patent: 5658590 (1997-08-01), Heiligenstein et al.
patent: 5696168 (1997-12-01), Heiligenstein et al.
patent: 0 687 472 (1995-12-01), None
patent: WO96/12485 (1996-05-01), None
Chemical Abstract 89:157222, “Comparison of Inhibition of Monoamine Uptake by Cocaine, Methylphenidate, and Amphetamine”, Apr. 1978.
POPPER, C.W.: “Antidepressants in the treatment of attention-deficit/hyperactivity disorder” THE JOURNAL OF CLINICAL PSYCHIATRY, vol. 58 , No. suppl. 13, 1997, pp. 14-29.
GREYDANUS, D.E. ET AL.: “The rebellious adolescent: Evaluation and management of oppositional and conduct disorders”PEDIATRIC CLINICS OF NORTH AMERICA, vol. 44, No. 6, pp. 1457-1485 (1997).
Eli Lilly and Company
Krass Frederick
Titus Robert D.
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