Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-03-12
2004-06-08
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S253040, C514S253060, C514S254020, C514S255030, C514S316000, C514S426000
Reexamination Certificate
active
06747029
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to the role of dopamine D
4
receptors in behavioral hyperactivity. In particular, it relates to treatments and therapies for inhibiting motor hyperactivity and attentional dysfunction associated with attention deficit-hyperactivity disorder (ADHD).
Attention deficit-hyperactivity disorder (ADHD) is a prevalent neuropsychiatric syndrome that affects 2%-5% of school-aged boys, an uncertain proportion of girls, and some adults. See R. A. Barkley,
Attention Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment
(Guilford Press, New York, 1990). ADHD is characterized by excesses of hyperactive, inattentive and impulsive behavior. For several decades, the primary treatment available has been with psychostimulants for dopamine-enhancing effects, such as methylphenidate (Ritalin®) and amphetamines. Clinical use of these drugs is unsatisfactory owing to their short-lived benefits, risk of impaired sleep and appetite, of abnormal movements, and of abuse and illicit trade. See Goldman et al.,
JAMA,
279:1100 (1998).
An important action of stimulants is to enhance the functional activation of the amine neurotransmitter dopamine in the brain. See B. B. Hoffman and R. J. Lefkowitz in
The harmacological Basis of Therapeutics
, Chapter 10, Eds. Goodman and Gilman, McGraw-Hill, New York (1996). Dopamine (DA) is an important neurotransmitter involved in motor control, endocrine function, reward cognition and emotion. Dopamine modulates physiological processes though activation of five G-protein coupled receptors of the D
1
-like (D
1
and D
5
) and the D
2
-like (D
2
, D3, and D
4
) receptor families. See K. A. Neve and R. L. Neve, in
The Dopamine Receptors
, K. A. Neve, R. L. Neve, Eds.; Humana Press, Totawa, N.J., 1997; pp. 27-76. D
4
receptors have received much attention, in part, because some atypical antipsychotics, notably clozapine, bind to D
4
receptors with higher affinity than to the more prevalent D
2
receptors. See H. H. M. Van Tol et al.,
Nature
350:614 (1991); and Seeman et al.
Neuropsychopharmacology
16:93 (1997).
Human D
4
receptors occur in multiple forms with 2-11 copies of a 16-amino acid (48 base pair) sequence in the putative third intracellular loop of the peptide sequence. See Neve and Neve, supra. Several recent genetic studies suggest associations between polymorphic variants of the D
4
receptor gene (D4DR) and ADHD. These studies are inconclusive, with various studies producing evidence for and against such an association, but converging evidence suggests that the D
4
receptor has a role in exploratory behavior and as a genetic susceptibility factor for attention deficit disorder.
Tarazi et al., in “Dopamine D
4
receptors: significance for psychiatry at the millennium”,
Molecular Psychiatry,
4:529 (November 1999), identify a number of D
4
receptor-selective antagonists and report on the behavioral effects of these agents in animal models for psychosis. Tarazi et al. report mixed results, with some antagonists showing an antipsychotic-like effect, while others did not.
Numerous investigations into the effects of selective D
4
receptor agonists and antagonists on a variety of physiological and neurological functions have drawn a complex picture of the effects of D
4
receptor-selective drugs and no clear picture has emerged as to the role of the D
4
receptor in these processes. See Tarazi et al., supra; Patel et al.,
J. Pharmacol. Exp. Ther.,
283(2):636 (November 1997); Bristow et al.,
J. Pharmacol. Exp. Ther.,
283(3):1256 (December 1997); Feldpausch et al.,
J. Pharmacol. Exp. Ther.,
286(1):497 (July 1998; P. A. Broderick and M. F. Piercey,
J. Neuro. Transm.,
105(6-7):749 (1998); Sanner et al.,
Bioorg. Med. Chem. Lett.,
8(7):725 (April 1998); Jentsch et al.,
Psychopharmacology
(
Berl),
142(1):78 (Feb 1999); Belliotti et al.,
J. Med. Chem.,
42(25):5181 (December 1999); and Okuyama et al.,
Life Sci.,
65(20):2109 (1999).
SUMMARY OF THE INVENTION
The present invention is based on the discovery that motor hyperactivity can be dose-dependently reversed by D
4
receptor-selective antagonists.
The invention features a method of inhibiting motor hyperactivity in a mammal exhibiting the symptoms of attention deficit-hyperactivity disorder (ADHD). The method includes administering to a mammal a dopamine D
4
receptor-selective antagonist.
The D
4
receptor-selective antagonists are selected from the group consisting of PNU-101958, RBI-257, NGD-94-1, L-745,870, L-750,667, PD-172,938, PNU-101387G, S-18126, NRA-0045, CP-293,019, YM-43611 AND YM-50001, the structures of which are shown in Table 1. Preferred D
4
receptor-selective antagonist are CP-293,019 (7R,S-(4-fluoro-phenoxymethyl)-2-(5-fluoro-pyrimidin-2-yl)-octahydropyrido[1,2-&agr;]pyrazine) and L-745,870(3-{[4-(4-chlorophenyl)piperazin-1-yl]methyl}-1H-pyrrolo[2,3-b]pyridine, based on their high selectivity for D
4
over D
2
receptors.
The D
4
receptor antagonist is administered intramuscularly, intravenously or subcutaneously to the mammal, and may be administered together with a pharmaceutically acceptable carrier. Preferred mammals include humans.
D
4
receptor-selective antagonists are expected to be superior to the conventional therapies using psychostimulants in that they do not stimulate dopamine release or block its inactivation by reuptake or transport. This expectation is supported by the observation that D
4
receptor-selective antagonists do not affect motor activity in healthy rats. See Bristow et al., supra; and Okuyama et al., supra. Furthermore, selectivity for D
4
receptors over D
2
receptors is desirable because interaction with D
2
receptors causes unwanted extrapyramidal and neuroendrocrine side effects.
By “D
4
receptor-selective antagonist” is meant an antagonist having more than 100, 200, 300, 500, 700, or 1,000 fold greater affinity for D
4
receptors than for D
2
receptors. Affinities for D
4
and D
2
receptors are determined using standard in vitro assays. See, for example, Den Hartog et al., U.S. Pat. No. 6,335,326, Patel et al.,
J. Pharmacol. Exp. Ther.
283:636-647 (1997), and Sanner et al.,
Bioorg. Med. Chem. Lett.,
8(7):725 (April 1998).
REFERENCES:
patent: 5576319 (1996-11-01), Baker et al.
patent: 6335326 (2002-01-01), Den Hartog et al.
Belliotti et al., “A Series of 6- and 7-Piperazinyl-and -Piperidinylmethylbenzoxazinones With Dopamine D4Antagonist Activity: Discovery of a Potential Atypical Antipsychotic Agent” J. Med. Chem., 42(25):5181-5187 (1999).
Bristow et al., “L-745,870, A Subtype Selective Dopamine D4Receptor Antagonist, Does Not Exhibit A Neuroleptic-Like Profile in Rodent Behavioral Tests” J. Pharmacol. Exp. Ther., 283(3):1256-1263 (1997).
Broderick et al., “Clozapine, Haloperidol, and The D4Antagonist PNU-101387G: in vivo Effects on Mesocortical, Mesolimbic, and Nigrostriatal Dopamine and Serotonin Release” J. Neuro. Transm., 105:749-767 (1998).
Feldpausch et al., “The Role of Dopamine D4Receptor in The Induction of Behavioral Sensitization to Amphetamine and Accompanying Biochemical and Molecular Adaptations” J. Pharmacol. Exp. Ther., 286(1):497-508 (1998).
Goldman et al., “Diagnosis and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents” JAMA, 279:1100-1107 (1998).
Jentsch et al., “Dopamine D4Receptor Antagonist Reversal of Subchronic Phencyclidine-Induced Object Retrieval/Detour Deficits in Monkeys” Psychopharmacology 142(1):78-84 (1999).
Leung et al., “Vascular Endothelial Growth Factor is a Secreted Angiogenic Mitogen” Science 246:1306-1309 (1989).
Okuyama et al., “A Selective Dopamine D4Receptor Antagonist, NRA0160: A Preclinical Neuropharmacological Profile” Life Sci., 65(20):2109-2125 (1999).
Patel et al., “Biological Profile of L-745,870, A Selective Antagonist with High Affinity for The Dopamine D4Receptor” J. Pharmacol. Exp. Ther. 283:636-647 (1997).
Sanner et al., “Synthesis, SAR and Pharmacology of CP-293,019: a Potent, Selective Dopamine D4Receptor Antagonist” Bioorg. Med. Chem. L
Baldessarini Ross J.
Tarazi Frank I.
Zhang Kehong
Clark & Elbing LLP
Jones Dwayne C.
The McLean Hospital Corporation
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