Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-05-03
2003-08-19
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S288000, C514S213010, C514S339000, C514S250000, C514S866000, C514S909000, C514S878000, C514S879000, C514S810000, C514S811000, C514S812000, C514S813000
Reexamination Certificate
active
06608064
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to the use of certain pyrido[1,2-a]-pyrazine derivatives, also described as bis-azabicyclic compounds, in the treatment of Parkinson's disease, attention deficit hyperactivity disorder (“ADHD”) and microadenomas in mammals, including humans. It is also directed to the use of a dopamine-2 (D2) receptor agonist in combination with a serotonin-1A (5HT
1A
) receptor agonist for the treatment for Parkinson's Disease. It is also directed to the use of an alpha-2 (&agr;
2
) adrenergic receptor ligand in combination with either a D2 receptor agonist or a 5HT
1A
receptor agonist for the treatment of ADHD. It is also directed to the use of a D2 receptor agonist in combination with a 5HT
1A
receptor agonist for the treatment of ADHD. It is also directed to the use of an alpha-2 (&agr;
2
) adrenergic receptor ligand in combination with both a D2 receptor agonist and a 5HT
1A
receptor agonist for the treatment of ADHD.
BACKGROUND OF THE INVENTION
Serotonin plays a role in several psychiatric disorders, including anxiety, Alzheimer's disease, depression, nausea and vomiting, eating disorders, and migraine. (See Rasmussen et al., “Chapter 1. Recent Progress in Serotonin (5HT)
1A
Receptor Modulators”, in
Annual Reports in Medicinal Chemistry, Section I,
30, pp. 1-9, 1995, Academic Press, Inc.; Antigas et al.,
Trends Neurosci.,
19 (9), 1996, pp. 378-383; and Wolf et al.,
Drug Development Research,
40, 1997, pp. 17-34.) Serotonin also plays a role in both the positive and negative symptoms of schizophrenia. (See Sharma et al.,
Psychiatric Annals.,
26 (2), February, 1996, pp. 88-92.) Serotonin 1A receptor agonists have been shown to increase prefrontal cortex dopamine (DA) release. See Wedzony et al.,
Eur. J. Pharmacol.,
305: 73-78 (1996). Buspirone, a 5HT
1A
receptor agonist, has been shown to be efficacious in treating a variety of symptoms associated with ADHD. Serotonin 1A receptor agonists have also been shown to reverse neuroleptic induced dystonia in nonhuman primates, a condition that mimics symptoms of human Parkinson's disease. See Casey, D. E.,
Neuropsychopharmacol.,
10:370S (1994).
Symptoms associated with ADHD have been shown to be relieved by catecholamine releasing drugs such as methylphenidate, and by postsynaptic &agr;2 adrenergic receptor agonists such as clonidine. Also, presynaptic &agr;2 adrenergic receptor antagonists have been shown to increase norepinephrine (NE) release.
A number of 1-(2-pyrimidinyl)-4-[4-(cyclic-imido)butyl]piperidine derivatives have been disclosed as anxiolytic agents which are generally lacking sedative activity. Among these are buspirone, where the cyclic-imido group is 4,4-tetramethylene-piperidine-2,6-dion-1-yl (Wu et al., U.S. Pat. Nos. 3,717,634 and 3,907,801); Casten et al., U.S. Pat. No. 4,182,763); gepirone, where the group is 4,4-dimethylpiperidine-2,6-dion-1-yl (Temple, Jr., U.S. Pat. No. 4,423,049); and ipsapirone, where the group is 1,1-dioxobenzo[d]isothiazol-3(2H)-on-yl (Dompert et al., German patent publication 3,321,969-A1). See also Ishizumi et al., U.S. Pat. Nos. 4,507,303 and 4,543,55; Freed et al., U.S. Pat. No. 4,562,255; Stack et al., U.S. Pat. No. 4,732,983; New et al., U.S. Pat. No. 4,524,026; and Stack, U.S. Pat. No. 4,788,290.
Compounds of the formula (I) below are disclosed in U.S. Pat. No. 5,122,525 as useful for the treatment of anxiety and depression. The use of such compounds for the treatment of addiction is described in U.S. Pat. No. 5,616,885.
SUMMARY OF THE INVENTION
This invention relates to a method of treating a disorder selected from Parkinson's disease, ADHD, and microadenomas in a mammal, including a human, comprising administering to a mammal in need of such treatment an amount of a compound of the formula:
or a pharmaceutically acceptable acid addition salt thereof, wherein
X is N or CH;
Y is:
SCH
2
, OCH
2
, Y
1
(CH
2
)
n
or Y
1
(CH
2
)
n
substituted on carbon with up to 2 methyl groups;
n is 1 or 2; and
Y
1
is CH
2
, NH or NCH
3
;
that is effective in treating such disorder.
In the compounds of the formula (1), Y is preferably
A particularly preferred compound is that wherein Z is Y
1
(CH
2
)
n
, Y
1
is CH
2
, n is 1 and X is N.
The compounds of formula I are D2 receptor agonists and useful in the treatment of Parkinson's disease. They also exhibit 5HT
1A
receptor agonist activity.
The compounds of formula I also exhibit activity as &agr;
2
adrenergic receptor antagonists and are useful in treatment of ADHD. The compounds increase hippocampal NE release and also increase prefrontal cortex DA release.
The compounds of the formula I that are basic can form acid addition salts with a variety of organic and inorganic acids. The acids that can be used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of the formula I are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.
The term “treating” as used herein, refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term “treatment”, as used herein, refers to the act of treating, as “treating” is defined immediately above.
This invention also relates to a method for treating Parkinson's Disease in a mammal, including a human, comprising administering to a mammal in need of such treatment a D2 receptor agonizing agent in combination with a 5HT
1A
receptor agonizing agent, wherein the two foregoing active agents are present in amounts such that the combination of such agents is effective in treating Parkinson's Disease.
This invention also relates to a pharmaceutical composition for treating Parkinson's disease in a mammal, including a human, comprising: (a) a D2 receptor agonizing agent or a pharmaceutically acceptable salt thereof; (b) a 5HT
1A
receptor agonizing agent or pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier; wherein the foregoing two active agents are in the composition in amounts such that the combination of such agents is effective in treating Parkinson's disease.
This invention also relates to a method of treating ADHD in a mammal, including a human, comprising administering to a mammal in need of such treatment an &agr;
2
adrenergic receptor ligand, or pharmaceutically acceptable salt thereof, in combination with either a D2 receptor agonizing agent or a 5HT
1A
receptor agonizing agent, or pharmaceutically acceptable salt thereof, wherein the foregoing two active agents are present in amounts such that the combination of such active agents is effective in treating ADHD.
This invention also relates to a pharmaceutical composition for treating ADHD in a mammal, including a human, comprising: (a) an &agr;
2
adrenergic receptor ligand or a pharmaceutically acceptable salt thereof; (b) a D2 receptor agonizing agent or a 5HT
1A
receptor agonizing agent, or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier, wherein the two foregoing active agents are present in the composition in amounts such that the combination of such agents is effective in treating ADHD.
This invention also relates to a method of treating ADHD in a mammal, including a human, comprising administering to a mammal in need of such treatment a D2 receptor agonizing agent, or pharmaceutically acceptable salt thereof, in combination with a 5HT
1A
receptor agonizing agent, or pharmaceutically acceptable salt thereof, wherein t
Jackson Elisa R.
McLean Stafford
Zorn Stevin H.
Ginsburg Paul H.
Krass Frederick
Nissenbaum Israel
Ostrup Clinton
Pfizer Inc
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