MXPA01002946A - Pharmaceutical agents for the treatment of parkinson's disease, adhd and microadenomas - Google Patents

Abstract

The present invention is directed to the use of certain pyrido[1,2-a]-pyrazine derivatives, also described as bis-azabicyclic compounds and defined by the formula (I) herein, in the treatment of Parkinson's disease, attention deficit hyperactivity disorder and microadenomas in mammals, and to related compositions.

Description

PHARMACEUTICAL AGENTS FOR THE TREATMENT OF THE PARKINSON DISEASE, HYPERACTIVITY DISORDER WITH ATTENTION DEFICIT AND MICROADENOMAS FIELD OF THE INVENTION The present invention relates 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 also relates to the use of a dopamine-2 (D2) agonist in combination with a serotonin-1A receptor agonist (5HTIA) for the treatment of Parkinson's disease. It also relates to the use of an alpha-2 (a2) adrenergic receptor ligand in combination with a D2 receptor agonist or a 5HT? A receptor agonist for the treatment of ADHD. It also relates to the use of a D2 receptor agonist in combination with a 5HT-? A receptor agonist for the treatment of ADHD. It also relates to the use of an alpha-2 (a2) adrenergic receptor ligand in combination with both a D2 receptor agonist and a 5HTIA 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 Modulators of the Serotonin Receptor (5HT) IA" ("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 v. Col. Druq Development Research, 40, 1997, pp. 17-34.). Serotonin also plays a role in both positive and negative symptoms of schizophrenia. (See Sharma et al., Psychiatric Annals., 26 (2), February, 1996, pp. 88-92). It has been shown that serotonin 1A receptor agonists increase the release of dopamine (DA) in the prefrontal cortex. See Wedzony et al., Eur. J. Pharmacol .. 305: 73-78 (1996). It has been shown that buspirone, a 5HT.A receptor agonist, is effective in the treatment of a variety of symptoms associated with ADHD. It has also been shown that serotonin 1A receptor agonists reverse neuroleptic-induced dystonia in non-human primates, a condition with symptoms similar to those of human Parkinson's disease. See Casey, D.E., Neuropsvchopharmacol .. 10.370S (1994).

It has been shown that the symptoms associated with e! ADHD by drugs that release catecholamine such as methylphenidate, and by agonists of postsynaptic a2 adrenergic receptors such as clonidine. In addition, antagonists of a2 presynaptic adrenergic receptors have been shown to increase norepinephrine (NE) release. Several 1- (2-pyrimidinyl) -4- [4-cyclic] butyl] pyridine derivatives have been described as ansiliotics which generally lack sedative activity. Among these are buspirone, in which the cyclic imide group is 4,4-tetramethylene-piperidine-2,6-dione-1-yl (Wu et al., U.S. Patents 3,717,634 and 3,907,801); Casten et al., Patent of E.U.A. 4,182,763); gepirone, where the group is 4,4-dimethylpiperidine-2,6-dion-1-yl (Temple, Jr., U.S. Patent 4,423,049); and ipsapirone, wherein 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. Patents. 4,507,303 and 4,543.55; Freed et al., Patent of E.U.A. 4,562,255; Stack et al., Patent of E.U.A. 4,732,983; and New et al., U.S. Patent. 4,524,026; and Stack, patent of E.U.A. 4,788,290. The compounds of the formula (I) shown below are described in the patent of US Pat. 5,122,525 as useful agents for the treatment of anxiety and depression. The use of such compounds for the treatment of addiction is described in the patent of E.U.A. 5,616,885.

BRIEF DESCRIPTION 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, which comprises 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; And it is Ze SCH2, OCH2 Y1 (CH2) n or Y1 (CH2) n substituted on the carbon with up to 2 methyl groups; N is 1 or 2; and Y1 is CH2, NH or NCH3; which is effective in the treatment of such a disorder. In the compounds of the formula (I), preferably Y is A particularly preferred compound is one in which Z is Y1 (CH2) n, Y1 is CH2, n is 1 and X is N. The compounds of formula I are D2 receptor agonists and are useful in the treatment of Parkinson's disease. . They also show 5HTIA receptor agonist activity. The compounds of formula I also exhibit activity as a2 adrenergic receptor antagonists and are useful in the treatment of ADHD. The compounds increase the release of NE in the hippocampus and also increase the release of DA in the prefrontal cortex. The compounds of the formula I which are basic can form acid addition salts with a variety of organic and inorganic acids. The acids that can be used to prepare the addition salts of pharmaceutically acceptable acids of the aforementioned basic compounds of the formula I are those which form non-toxic acid addition salts, ie, salts containing pharmaceutically acceptable anions such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate salts, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [ie, 1, 1 '-methylene-bis- (2-hydroxy-3-naphthoate)]. The term "treat", as used herein, refers to the reversal, alleviation, inhibition of progress or prevention of the disorder or condition to which such term applies, or of one or more symptoms of such disorder or condition. The term "treatment", as used herein, refers to the act of treating, as "treating" has just been defined. This invention also relates to a method for the treatment of Parkinson's disease in a mammal, including a human, which comprises administering to a mammal in need of such treatment a D2 receptor agonist in combination with a receptor agonist agent. 5HTIA, where the two above active agents are present in such amounts that the combination of such agents is effective in the treatment of Parkinson's disease. The invention also relates to a pharmaceutical composition for the treatment of Parkinson's disease in a mammal, including a human being, comprising: (a) a D2 receptor agonist agent or a pharmaceutically acceptable salt thereof; (b) a 5HT? A receptor agonist agent or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier; wherein the two above active agents are present in the composition in such amounts that the combination of such agents is effective in the treatment of Parkinson's disease. This invention also relates to a method for the treatment of ADHD in a mammal, including a human, which comprises administering to a mammal in need of such treatment a ligand of a 0-2 adrenergic receptor or a pharmaceutically acceptable salt thereof, in combination with a D2 receptor agonist agent or a 5HT? A receptor agonist agent, or a pharmaceutically acceptable salt thereof, wherein the two above active agents are present in such amounts that the combination of such active agents is effective in the ADHD treatment. The invention also relates to a pharmaceutical composition for the treatment of ADHD in a mammal, including a human being comprising: (a) a ligand of a c-2 adrenergic receptor or a pharmaceutically acceptable salt thereof; (b) a D2 receptor agonist agent or a 5HT? A receptor agonist agent, or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier, wherein the two above active agents are present in the composition in such amounts that the combination of such agents is effective in the treatment of 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 agonist agent, or a pharmaceutically acceptable salt thereof, in combination with a 5HT-IA receptor agonist agent, or a pharmaceutically salt acceptable thereof, wherein the two above active agents are present in such amounts that the combination of such active agents is effective in the treatment of ADHD. This invention also relates to a pharmaceutical composition for the treatment of ADHD in a mammal, including a human, comprising: (a) a D2 receptor agonist agent or a pharmaceutically acceptable salt thereof; (b) a 5HTIA receptor agonist agent or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier, wherein the two above active agents are present in the composition in such amounts that the combination of such agents is effective in the treatment of ADHD. The invention also relates to a method of treating ADHD in a mammal, including a human, which comprises administering to a mammal in need of such treatment a ligand of a 0-2 adrenergic receptor, or a pharmaceutically acceptable salt thereof, in combination with a D2 receptor agonist agent, or a pharmaceutically acceptable salt thereof, and also a 5HTIA receptor agonist agent, or a pharmaceutically acceptable salt thereof, wherein the three above active agents are present in such amounts that the combination of such active agents is effective in the treatment of ADHD. This invention also relates to a pharmaceutical composition for the treatment of ADHD in a mammal, including a human, comprising: (a) a ligand of an a2 adrenergic receptor or a pharmaceutically acceptable salt thereof; (b) a D2 receptor agonist agent or a pharmaceutically acceptable salt thereof; (c) a 5HT-IA receptor agonist agent or a pharmaceutically acceptable salt thereof; and (d) a pharmaceutically acceptable carrier, wherein the three above active agents are present in the composition in such amounts that the combination of such agents is effective in the treatment of ADHD. The compounds of formula I may contain chiral centers and, therefore, may exist in different enantiomeric and diastereomeric forms. The term "compounds of the formula I", as used herein, refers to all optical isomers and all other stereoisomers of the compounds of the formula I, as defined above, to all racemic forms and other mixtures thereof, and to all pharmaceutical compositions and methods of treatment defined above that contain or employ such isomers or mixtures.

Formula I above includes compounds identical to those represented except for the fact that one or more hydrogen or carbon atoms have been replaced by isotopes thereof. Such compounds are useful as research and diagnostic tools in pharmacokinetic studies of metabolism and in binding assays. Specific applications in research include radioligand binding assays, autoradiography studies and in vivo binding studies. Examples of D2 receptor agonist agents that can be used in the methods of this invention include, but are not limited to, compounds of formula I and pharmaceutically acceptable salts, pergoiide, bromocripthane, ropinerol and pramipexole. Examples of 5HTIA receptor agonist agents that can be used in the methods of this invention include, but are not limited to: (a) compounds of formula I and their pharmaceutically acceptable salts, (b) buspirone (US Pat. No. 3,717,638; 3,907,801 and 4,182J63); (c) gepirone (U.S. Patent 4,423,049); (d) ipsapirone (German Patent Publication 3,321, 969-A1); and (d) flexinoxan. Examples of α2 adrenergic receptor antagonist agents that can be used in the methods of this invention include, but are not limited to, compounds of formula I and their pharmaceutically acceptable salts, yohimbine and idaxozan. Examples of more specific embodiments of this invention are the above methods of treatment of ADHD and compositions Pharmaceuticals for the treatment of ADHD employing a ligand of an a2 adrenergic receptor, wherein such a ligand is an antagonist of a presynaptic a2 adrenergic receptor or an agonist of a postsynaptic adrenergic a2 receptor. A preferred method of this invention is a method of treating Parkinson's disease in a mammal, including a human, which comprises administering to a mammal in need of such treatment an amount of the following compound of the formula I shown below: that is, where X is nitrogen, where Y is a group of the formula ("sunipetron") or a pharmaceutically acceptable salt thereof, which is effective in the treatment of Parkinson's disease.

Another preferred embodiment of this invention is a method for the treatment of ADHD in a mammal, including a human, which comprises administering to a mammal in need of such treatment an amount of sunipetron, or a pharmaceutically acceptable salt thereof, which is effective in the treatment of ADHD. Another preferred method of this invention is a method for the treatment of microadenomas in a mammal, including a human, which comprises administering to a mammal in need of such treatment an amount of sunipetron, or a pharmaceutically acceptable salt thereof, which is effective in the treatment of microadenomas.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows Parkinson's scores obtained in monkeys treated with 0.5 mg / kg or with 1.0 mg / kg of a compound of formula I.

DETAILED DESCRIPTION OF THE INVENTION All patents, patent applications and articles indicated in this document are incorporated by reference in their entirety. The compounds of formula I and their pharmaceutically acceptable salts can be prepared as described in the United States patent.

No. 5,122,525, in U.S. Patent 5,185,449, U.S. Patent 5,455,350, U.S. Patent Application 08 / 470,377, filed June 6, 1995, and in the PCT / PCT patent application. IB97 / 00704, which designates the United States and which was filed on June 16, 1997. The compounds of the formula I are capable of forming a wide variety of different salts with various inorganic and organic acids. The acids that can be used to prepare the pharmaceutically acceptable acid addition salts of the basic compounds of this invention, are those that form non-toxic acid addition salts, ie, salts that contain pharmacologically acceptable anions such as the hydrochloride salts, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or phosphate acid, acetate, lactate, citrate or citrate acid, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [ie, 1, 1 '-methylene-bis- (2-hydroxy-3-naphthoate)]. Although such salts have to be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of formula I from the reaction mixture in the form of a pharmaceutically unacceptable salt, then simply convert the latter into the compound of free base by treatment with an alkaline reagent and then converting the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of this invention are easily prepared by the treating the basic compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. After careful evaporation of the solvent, the desired solid salt is obtained. For use in the treatment of Parkinson's disease, the ADHD or microadenomas in a human, a compound of formula I or a pharmaceutically acceptable salt thereof is administered in an amount of about 2-300 mg / day, in a single dose or in divided doses throughout the day. In particular cases, doses outside this range are prescribed at the discretion of the corresponding physician. The preferred route of administration is generally oral administration, but in special cases parenteral administration (eg, intramuscular, intravenous or intradermal) will be preferred, for example, when oral absorption is reduced by disease or when the patient can not swallow. . In one embodiment, the compound of formula I is administered in a single dose of about 1.0 mg / kg at a frequency of about three times a day. A controlled release formulation can be used in place of the one administered once a day. In another embodiment, the compound is administered in a quantity required by the particular administration route to achieve a plasma concentration comprised between 100 and 500 ng / ml, preferably 200 ng / ml, in a range between 2 and 3 hours following the administration.

The compounds used in the present invention are generally administered in the form of pharmaceutical compositions comprising at least one of the compounds of the formula (I), or a salt thereof, together with a pharmaceutically acceptable carrier or diluent. Such compositions are generally formulated in a conventional manner using solid or liquid carriers or diluents as appropriate to the desired mode of administration: for oral administration, in the form of tablets, hard or soft gelatin capsules, suspension, granules, powders and the like; and for parenteral administration, in the form of injectable solutions or suspensions, and the like. The binding of a compound to the D2 receptor can be determined using the fwing D2 receptor binding assay. LTK cells expressing the human long D2 receptor (D2L) (in T-175 flasks) are developed in minimal essential medium containing D-glucose (DMEM, Gibco) supplemented with 10% fetal bovine serum (FBS). Cells are shed with 5 mM EDTA in PBS and homogenized in 50 mM Tris HCl (pH 7.4) with 5 mM MgSO 4, using a Polytron Brinkman in position 6 for 20 seconds. The membranes are recovered after multiple spinnings of separation by centrifugation and resuspension in ice-cold clean buffer. The tissue (~ 2 mg of tissue, wet weight) is added to test tubes containing incubation buffer (50 mM Tris HCl, 120 mM NaCl, 2 mM MgCl 2, 5 mM KCl, 5 mM CaCl 2, pH 7.2) , various concentrations of test drug and [3 H] -spiperone (final concentration 0.06 nM, Amersham, Arlington Heights, IL). The non-specific binding is determined in the presence of 2 μM (+) - butaclamol. After 45 minutes at 30 ° C, the incubations are terminated by rapid filtration through Whatman GF / B filters using a Brandel cell harvester. The membranes are washed using 3 x 4 ml of ice-cold buffer and the membrane bound ligand is determined by liquid scintillation counting of the filters in a Ready-Safe scintillation mixture (for tritiated ligands). The Kd (0.06 nM) for the radioligand is previously determined by saturation analysis and is used to calculate the Apparent Kl values by means of the Cheng-Prusoff equation. The agonist or antagonist activity of a compound at the D2 receptor can be determined using the fwing three assays. (1) Modulation with the human D2 receptor of cAMP formation in GH4C1 cells GH4C1 cells, derived from rat pituitary, expressing the long or short forms of the human D2 receptor, are developed in confluence in Nutrient Blend F-10 ( HAM) (Gibco) supplemented with 10% FBS and 1-glutamine 2 mM, and 10 U / ml penicillin-streptomycin, in T-175 flasks. The cells are detached with 5 mM ethylenediamine tetraacetic acid (EDTA) in phosphate buffered saline (PBS) and resuspended in PBS containing 5 mM MgCl 2, 30 mM hydroxyethylpiperizine-N-ethanesulfonic acid (HEPES) and 50 mM isobutyl methyl xanthine. (IBMX). The cells (~ 200,000 / tube) are exposed to 5 mM forskolin, 100 nM quinpirol or forskolin plus quinpyrol plus antagonist for 11 minutes. In experiments with antagonists, the cells are exposed to the antagonists 11 minutes before exposure to quinpirole. To judge the agonist activity, the effect of a compound on the cAMP accumulation stimulated by forskolin in the absence of the quinpirole agonist is tested. The reaction is terminated with the addition of 6 N perchloric acid and the samples are neutralized with 5 N potassium hydroxide and 2 M Tris buffer. Cyclic AMP levels are measured using commercially available competitive binding equipment (Amersham). The IC 50 values are calculated by a linear regression analysis of the concentration-response curves. Apparent Kl values are calculated using the equation: Ki = CI5o / (1+ [agonist] / [CE5o of agonist]). (2) Electrophysiology in Rat Brain Cuts Male Sprague-Dawley rats (200-250 g, Charles River Laboratories, Wilmington, MA) are lightly anesthetized with halothane, decapitated and the brains are rapidly removed and placed in oxygenated and cooled medium. with ice (95% O2 / 5% CO2); 124 mM NaCl, 2 mM KCl, 1.25 mM NaH2P04, 26 mM NaHCO3, 10 mM d-glucose, 2 mM MgSO47H2O and 2 mM CaC-2; pH 7.4). The ventral tegmental area is blocked and glued using cyanoacrylate on the slide of a Vibratome Lancer (1000 Series) to which an ice-cooled medium has been applied. Cuts of the crown (350 μm) and placed in oxygenated medium (22 ° C) for 1 hour before recording. For the record, the cuts are placed in a nylon net in a recording chamber in which they are completely immersed in a medium that continuously flows at 35 ° C (~ 1 ml / min). All drugs are applied by changing the perfusion medium to a solution containing the drug. Spontaneous extracellular action potentials are recorded using glass pipettes filled with 0.9% saline solution (6-8 MW). Activation rates are plotted in series at 10 or 20 second intervals and changes in the activation rate are calculated using average speeds during 2 minute intervals before and after drug application. Concentration-response curves are constructed and analyzed by linear regression. (3) Microdialysis Concentric microdialysis probes are constructed in the form of I of dialysis fiber (molecular weight limit of 18,000, external diameter 300 μm, Hospal, The Netherlands) clogged at one end with epoxy resin and bound to fused silica microtubes. The probes, 9 mm long with 2 mm length of exposed dialysis membrane are implanted in the acoustic core (AP 1.7, ML 1.2, DV -8.0) of male Sprague Dawley rats (300-350 g) anesthetized with ketamine ( 75 mg / kg) and xylazine (10 mg / kg). After surgery, the rats are placed in methyl acrylate cages inside isolation boxes and the inlet ports of the probes are connected by PEEK flexible tubes, through a double channel fluid rotating system, to a CMA / 100 microinfusion pump (CMA / Microdialysis, Acton, MA). The probe is perfused overnight with artificial cerebrospinal fluid (147 mM NaCl2, 2.7 mM KCl, 1.3 mM CaCl2, 1.0 mM MgCl2 and 0.1 mM ascorbic acid) at 0.5 ml / min. The next day, an experiment is started increasing the flow to 1.5 ml / min and connecting the probe outlet with a PEEK tube to a 30 ml sample loop in a DECADE electrochemical detector (ANTEC, Leiden, The Netherlands). The microdialysis samples (30 ml) are collected online and injected automatically into the column every 20 or 25 minutes. The analytes are separated at 35 ° C on a 3 m C? 8 3 m BDS Hypersil column (150 x 3 mm) by reverse phase HPLC using a mobile phase of 75 mM potassium phosphate pH 5.0, containing 0.8 mM octanesulfonate, methanol 8% and 3 mM triethylamine, and are released at a flow rate of 0.35 ml / minute by means of an ESA 580 pump. The amperometric detection of dopamine is performed using a vitreous carbon electrode from the DECADE detector set at 550 mV against Ag / AgCl . Extracellular dopamine levels are quantified by comparing peak heights with those of the standards. After obtaining a stable initial value (5-7 samples collected every 20 or 25 minutes), the drugs are administered and the release of DA is controlled for 4 to 7 hours. Dialysate concentrations are expressed as a percentage of the initial values. The concentrations of DA in the dialysate are not corrected for recovery through the fiber of dialysis. To determine whether each dose of drug has a significant effect on the release of DA in the acoustic nucleus, a multivariate analysis of variance is performed with repeated measurements over time, using SuperAnova software (Abacus Concepts, Inc. Berkeley CA). The ability of a particular compound to exhibit an effect against Parkinson's in non-human primates can be determined using the procedures described by Greenemyre et al., Ann. Neurol., 35: 655-661, 1994, and Klockgether et al., Ann. Neurol .. 30 .. 717-723, 1991. The agonist and antagonist activities of a particular compound of the invention at the 5-HTIA receptors can be determined using a single saturation concentration according to the following procedure. Male Hartley guinea pigs are decapitated and removed 5-HTIA receptors of the hippocampus by dissection. The individual tissues are homogenized in 5 mM HEPES buffer containing 1 mM EGTA (pH 7.5) using a manual glass-Teflon® homogenizer and centrifuged at 35,000 x g for 10 minutes at 4 ° C. The pellets are resuspended in 100 mM HEPES buffer containing 1 mM EGTA (pH 7.5) to a final protein concentration of 20 mg (hippocampus) or 5 mg (substance nigra) of protein per tube. The following agents are added so that the reaction mixture in each tube contains 2.0 mM MgCl2., 0.5 mM ATP, 1.0 mM cAMP, 0.5 mM IBMX, 10 mM phosphocreatinin, 0.31 mg / ml creatinine phosphokinase, 100 mM GTP and 0.5-1 microcuries of [32 P] -ATP (30 Ci / mmol: NEG-003 - New England Nuclear). Incubation is started by adding of tissue to siliconized microcentrifuge tubes (in triplicate) at 30 ° C for 15 minutes. Each tube receives 20 ml of tissue, 100 ml of drug or buffer (at a final concentration of 10X), 10 ml of 32 nM agonist or buffer (at a final concentration of 10X), 20 ml of forskolin (final concentration 3 mM) and 40 ml of the above reaction mixture. Incubation is terminated by the addition of 100 ml of 2% SDS solution, 1.3 mM cAMP and 45 mM ATP containing 40,000 dmp of [3 H] -AMPc (30 Ci / mmol: NET-275 -New England Nuclear) for control the cAMP recovery of the columns. The separation of [32 P] -ATP and [32 P] -AMPc is performed using the procedure of Solomon et al., Analytical Biochemistry, 1974, 58, 541-548. The radioactivity is quantified by liquid scintillation counting. Maximum inhibition is defined by 10 mM (R) -d-OH-DPAT for 5-HT-IA receptors. The percent inhibition by the test compound is then calculated in relation to the inhibitory effect of (R) -8-OH-DPAT. The reversal of the inhibition induced by the agonist of the adenylate cyclase activity stimulated by forskolin is calculated in relation to the effect of the 32 nM agonist. This invention relates to methods for treating Parkinson's disease and ADHD, wherein the two or three active agents employed are co-administered as part of the same pharmaceutical composition, as well as to processes in which these active agents are separately administered as part of an appropriate dosing regimen designed to obtain the benefits of the therapy of combination. The appropriate dosage regimen, the amount of each dose administered and the specific intervals between doses of each active agent will depend on the subject to be treated, on how the drug is tolerated and on the severity of the condition. In general, to perform the above combination procedures of this invention, the 5HT1A receptor antagonist will be administered in an amount ranging from about 5 to 90 mg per day, in a single dose or in divided doses, the a2 adrenergic receptor ligand it will be administered in an amount ranging from approximately 1.0 to 100 per day, in a single dose or in divided doses, in the case of an adrenergic receptor 2 antagonist, and in an amount ranging from approximately 0.1 to 100 mg per day, in a single dose or in divided doses, in the case of an a2 adrenergic receptor agonist, in a single dose or in divided doses, and the D2 receptor agonist will be administered in an amount ranging between approximately 0.5 and 25 mg per day , in a single dose or in divided doses. (For FDA-approved drugs that are used in the combination procedures of this invention, physicians will be guided by the dosage intervals for such drugs that are specified in the Physician's Work Reference.) However, variations may occur depending on the species of animal to be treated and its individual response to said medicament, as well as the type of pharmaceutical formulation chosen and the period of time and interval at which such administration is performed. In some cases, lower dosage levels than the lower limit of the aforementioned range may be more suitable. previously, while in other cases even higher doses may be used without causing any harmful side effects, provided that such larger doses are first divided into several small doses to be administered throughout the day. The combination methods of this invention include methods in which the desired combined activities are presented in a compound or pharmaceutically acceptable salt. Pharmaceutical compositions of this invention that exhibit more than one pharmaceutical activity (e.g., 5HT-IA agonism and D2 agonism) include pharmaceutical compositions in which all desired pharmaceutical activities are present in a compound or pharmaceutically acceptable salt. D2 receptor agonists, 5HTIA receptor agonists and a2 receptor antagonists that are employed in the pharmaceutical compositions and methods of this invention are also referred to as "therapeutic agents". The therapeutic agents can be administered orally or parenterally. Compositions that contain both a D2 receptor agonist and a 5HTIA receptor agonist, or a D2 receptor agonist, a 5HT? A receptor agonist and an a2 adrenergic receptor antagonist, will generally be administered orally or parenterally daily, in a single dose or in divided doses, so that the total amount of each active agent administered is within the above guidelines.

The therapeutic agents can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the routes indicated previously, and such administration can be carried out in a single dose or in multiple doses. More particularly, the therapeutic agents of this invention can be administered in a wide variety of different dosage forms, that is, they can be combined with various inert pharmaceutically acceptable carriers in the form of tablets, capsules, dragees, troches, hard candies, suppositories, aqueous suspensions. , injectable solutions, elixirs, syrups and the like. Such vehicles include solid diluents or fillers, sterile aqueous media, various non-toxic organic solvents, etc. In addition, oral pharmaceutical compositions can be conveniently adulterated and / or flavored. In general, the therapeutic compounds of this invention, when administered separately (ie, not in the same pharmaceutical composition) are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% in weight. For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, together with various disintegrants such as starch (and preferably corn starch, potato or tapioca), alginic acid and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic.

In addition, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for forming tablets. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; Preferred materials in this regard also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring materials or dyes and, if desired, also emulsifying and / or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and various similar combinations thereof. For parenteral administration, solutions of a therapeutic agent may be employed in sesame or peanut oil, or in aqueous propylene glycol. Aqueous solutions should be suitably buffered if necessary and the liquid diluent should first be made isotonic. These aqueous solutions are suitable for intravenous injection. Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection. The preparation of all these solutions under sterile conditions is easily accomplished by conventional pharmaceutical techniques well known to those skilled in the art. The following example is only intended to illustrate the invention and should not be construed as limiting its scope.

EXAMPLE The behavioral effects of the administration of sunipetron on the Parkinson's score in monkeys treated with MPTP- (1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine) were determined. The methods employed are described in Greenemyre et al., Supra and Klockgether et al., Supra. In summary 0.5 mg / kg or 1.0 mg / kg of sunipetron were administered to monkeys with Parkinson's disease and the severity of Parkinson's symptoms was assessed at each of 4 time points after administration of the drug compared with the administration of a control solution ("Vehicle"). The Parkinson's scores obtained in the study are shown in Figure 1. Together with the estimates shown for the plasma levels of the compound after administration, the data show that the maximum reduction in Parkinson's score was achieved at plasma levels of approximately 200 ng / ml. The minimum effective plasma level was approximately 100 ng / ml.

Claims (19)

NOVELTY OF THE INVENTION CLAIMS

1. - The use of a compound of the formula or a pharmaceutically acceptable acid addition salt thereof, wherein X is N or CH; And it is

Z is

SCH) OCH2, Y1 (CH2) n or Y1 (CH2) n substituted on the carbon with up to 2 methyl groups; n is 1 or 2; and Y1 is CH2) NH or NCH3; for the manufacture of a medicament for treatment of a disorder selected from Parkinson's disease, ADHD and microadenomas in a mammal. 2. The use as claimed in claim 1, wherein the compound of formula (I) or the pharmaceutically acceptable salt that is used is one in which Y is

Z is Y1 (CH2) n, Y1 is CH2, n is 1 and X is N. 3. The use of a D2 receptor agonist agent, or a pharmaceutically acceptable salt thereof, in combination with a 5HT receptor agonist agent. ? A > or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of Parkinson's disease in a mammal. 4. A pharmaceutical composition for the treatment of Parkinson's disease in a mammal, comprising: (a) a D2 receptor agonist agent or a pharmaceutically acceptable salt thereof; (b) a 5HT-IA receptor agonist agent or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier; where the two above active agents are present in the composition in such amounts that the combination of such agents is effective in the treatment of Parkinson's disease.

5. The use of a ligand of an adrenergic receptor or a pharmaceutically acceptable salt thereof, in combination with a D2 receptor agonist agent, or a pharmaceutically acceptable salt thereof, and also in combination with a 5HT receptor agonist agent. - A, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of ADHD in a mammal.

6. A pharmaceutical composition for the treatment of ADHD in a mammal, comprising: (a) a ligand of an a2 adrenergic receptor or a pharmaceutically acceptable salt thereof; (b) a D2 receptor agonist agent or a pharmaceutically acceptable salt thereof; (c) a 5HT? A receptor agonist agent or a pharmaceutically acceptable salt thereof; and (d) a pharmaceutically acceptable carrier, wherein the three above active agents are present in the composition in such amounts that the combination of such active agents is effective in the treatment of ADHD.

7. The use of a ligand of an a2 adrenergic receptor or a pharmaceutically acceptable salt thereof, in combination with a D2 receptor agonist agent or a 5HT-? A receptor agonist agent, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of ADHD in a mammal.

8. - A pharmaceutical composition for the treatment of ADHD in a mammal, comprising: (a) a ligand of an a2 adrenergic receptor or a pharmaceutically acceptable salt thereof; (b) a D2 receptor agonist agent or a 5HT? A receptor agonist agent, or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier, wherein the two above active agents are present in the composition in such amounts that the combination of such agents is effective in the treatment of ADHD.

9. The use of a D2 receptor agonist agent, or a pharmaceutically acceptable salt thereof, in combination with a 5HT? A receptor agonist agent, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treatment of the ADHD in a mammal.

10. A pharmaceutical composition for the treatment of ADHD in a mammal, comprising: (a) a D2 receptor agonist agent or a pharmaceutically acceptable salt thereof; (b) a 5HTIA receptor agonist agent or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier; wherein the two above active agents are present in the composition in such amounts that the combination of such agents is effective in the treatment of ADHD.

11. The use of sunipetron, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of Parkinson's disease in a mammal.

12. The use of sunipetron, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of ADHD in a mammal.

13. The use of sunipetron, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of microadenomas in a mammal.

14. The use as claimed in claim 5, wherein the a2 adrenergic receptor ligand is an antagonist of a presynaptic adrenergic a2 receptor or an agonist of a postsynaptic a2 adrenergic receptor.

15. The use as claimed in claim 7, wherein the a2 adrenergic receptor ligand is an antagonist of a presynaptic a2 adrenergic receptor or an agonist of a postsynaptic a2 adrenergic receptor.

16. A pharmaceutical composition according to claim 6, wherein the a2 adrenergic receptor ligand used is an antagonist of a presynaptic a2 adrenergic receptor or an agonist of a postsynaptic adrenergic a2 receptor.

17. The pharmaceutical composition according to claim 8, wherein the ligand of the adrenergic receptor 2 is used in an antagonist of a presynaptic adrenergic a2 receptor or an agonist of a postsynaptic adrenergic a2 receptor.

18. - A pharmaceutical composition for the treatment of a disorder selected from Parkinson's disease, ADHD and microadenomas in a mammal, comprising an amount of a compound of the formula or a pharmaceutically acceptable acid addition salt of! same, where X is N or CH; And it is Z is SCH2, OCH2, Y1 (CH2) n or Y1 (CH2) n substituted on the carbon with up to 2 methyl groups; n is 1 or 2; and Y1 is CH2, NH or NCH3; which is effective in the treatment of such disorder, and a pharmaceutically acceptable vehicle.

19. The pharmaceutical composition according to claim 18, wherein the compound of formula (I) or the pharmaceutically acceptable salt that is used is one in which Y is Z is Y1 (CH2) n, Y1 is CH2, n is 1 and X is N.