Title of Invention

HEXA- AND OCTAHYDRO-PYRIDO[1,2-A]PYRAZINE DERIVATIVES WITH NK1 ANTAGONISTIC ACTIVITY

Abstract

The invention relates to hexahydro-pyrido[ 1,2-a]pyrazine derivatives having interesting neurokinin-NKl receptor antagonistic activity. The invention also relates to methods for the preparation of these compounds, to pharmaceutical compositions containing a pharmacologically active amount of at least one of these compounds as an active ingredient, as well as to the use of these compositions for the treatment of disorders in which neurokinin receptors are involved. The invention relates to compounds represented by the general formula (1) wherein the symbols have the meanings as given in the description.

Full Text

HEXA- AND 0CTAHYDR0-PYRlD0[1,2-a]PYRAZINE DERIVATIVES WITH NK1 ANTAGONISTIC ACTIVITY The present invention relates to hexa- and octahydro-pyrido[1,2-a]pyrazine derivatives having interesting neurokinin-NKi receptor antagonistic activity. The invention also relates to methods for the preparation of these compounds, to pharmaceutical compositions containing a pharmacologically active amount of at least one of these compounds as an active ingredient, as well as to the use of these compositions for the treatment of disorders in which neurokinin receptors are involved. From the European patent application EP 0655442 piperazine derivatives with neurokinin antagonistic activity are known. Piperazine derivatives sharing this biological activity were also disclosed in EP 0899270 which describes a series of 2-(3-indolylmethyl)-1-benzoyI-4-[(2-(benzylamino)ethyl)aminocarbonyl)] piperazine derivatives having NKi antagonistic activity. Surprisingly, it has now been found that piperazine derivatives are also NK, antagonists when the piperazine ring and it’s N-4 substituent are fused to yield hexa-or octahydro-pyrido[1,2-a]pyrazine derivatives. The invention relates to compounds of the general formula (1) wherein: R1 represents phenyl, 2-indolyl, 3-indolyl, 3-indazolyl or benzo[b]thiophen-3-yl, which groups may be substituted with halogen or alkyl (1-3C), R2 and R3 independently represent halogen, H, OCH3, CH3 and CF3t Q represents an optionally substituted aromatic or heteroaromatic five- or six-membered ring, connected by a carbon-carbon bond, the pyrido[1,2-a]pyrazine moiety may or may not contain a double bond between either carbon atoms 6 and 7 or between carbon atoms 7 and 8, and pharmacologically acceptable salts and prodrugs thereof. All compounds having formula (1) in which the asymmetrical carbon atoms 3 and 9a, as well as the potentially asymmetrical carbon atom 7 , are in either the reconfiguration or the S-configuration belong to the invention. Also prodrugs, i.e. compounds which when administered to humans by any known route, are metabolised to compounds having formula (1), belong to the invention. In particular this relates to compounds with primary or secondary amino or hydroxy groups. Such compounds can be reacted with organic acids to yield compounds having formula (I) wherein an additional group is present which is easily removed after administration, for instance, but not limited to amidine, enamine, a Mannich base, a hydroxyl-methylene derivative, an 0-(acyloxymethylene carbarnate) derivative, carbamate, ester, amide or enaminone. A prodrug is an inactive compound, which when absorbed is converted into an active form (Medicinal Chemistry: Principles and Practice, 1994, ISBN 0-85186-494-5, Ed.: F. D. King, p. 216). Suitable acid addition salts can be formed with inorganic acids or with organic acids. The invention particularly relates to compounds having formula (1) in which Q is an optionally substituted six-membered nitrogen containing heteroaromatic ring, and in which the other symbols have the meanings as given above, and including all possible stereo-isomers as outlined above. Even more preferred are compounds having formula (1) wherein R1 is 3-indolyl, R2 and R3 are CF3 groups in the 3- and 5-positions, and Q is an optionally substituted six-membered nitrogen containing heteroaromatic ring, and including all possible stereo-isomers as outlined above. In the description of the substituents the abbreviation ‘ alkyl(Ci.3)’ means ‘methyl, ethyl, n-propyl or isopropyl’. ‘Optionally substituted’ means that a group may or may not be further substituted by one or more groups selected from alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxyl, alkyloxy, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, oxo, nitro, acyl, amido, alkylamido, dialkylamido, carboxyl, or two optional substituents may together with the carbon atoms to which they are attached form a 5- or 6-membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or sulphur. Within the context of the explanation of ‘optionally substituted1, ‘alkyP means C1-3-alkyl, ‘alkenyl’ means Cv3-alkenyl, ‘alkynyP means C1-3-alkynyl, ‘acyf means C1-3-acy! and ‘aryl’ means furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazynyI, phenyl, indazolyl, indolyl, indolizinyl, isoindolyl, benzi[b]furanyl, benzo[b]thiophenyl, benzimidazolyl, benzthiazolyl, purinyl, quinolynyl, isochinolyl, chinolyl, phtalazinyl, quinazolinyl, quinoxalinyl, 1,8 -naphthyridinyl, pteridinyl, naphthyl or azulenyl, preferably phenyl, pyridyl of naphthyl. Optional substituents may themselves bear additional optional substituents. Preferred optional substituents include C1-3 alkyl such as for example methyl, ethyl, and trifluoromethyl, fluoro, chloro, bromo, hydroxyl, C1-3 alkyloxy such as for example methoxy, ethoxy and trifluoromethoxy, and amino. Heteroaromatic’ means containing at least one hetero atom such as N, O or S. ‘Five- or six-membered rings’ are for example: furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, 1,2,3-oxadiazole, 1,2,3-triazole, 1,3,4-thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine rings The compounds of the invention of the general formula (1), as well as the salts thereof, have NK-, antagonistic activity and show a good bioavailability. They are useful in the treatment of disorders in which neurokinins which interact with NKi receptors, e.g. neurokinin-1 (= Substance P) are involved, or that can be treated via manipulation of those systems. For instance in acute and chronic pain, emesis, inflammatory diseases such as meningitis, arthritis, asthma, psoriasis and (sun)burns; gastro-intestinal disorders, in particular irritable bowel syndrome, inflammatory bowel disease (Crohn’s disease), ulcerative colitis; bladder or Gl tract hypermotility disorders, urinary tract inflammation; allergic responses such as eczema and rhinitis; cardio-vascular disorders such as hypertension, atherosclerosis, edema, angina, cluster headache and migraine; cutaneous diseases such as urticaria, lupus erythematosus and pruritus; respiratory disorders including chronic obstructive pulmonary disease, bronchospams, bronchopneumonia, bronchitis, respiratory distress syndrome and cystic fibrosis; various neoplastic diseases; psychiatric and/or neurological disorders such as schizophrenia and other psychotic disorders; mood disorders such as bipolar I disorders, bipolar II disorders and unipolar depressive disorders like minor depression, seasonal affective disorder, postnatal depression dysthymia and major depression; anxiety disorders including panic disorder (with or without agoraphobia), social phobia, obsessive compulsive disorder (with or without co-morbid chronic tic or schizotypal disorder), posttraumatic stress disorder and generalized anxiety disorder; substance related disorders, including substance use disorders (like dependence and abuse) and substance induced disorders (like substance withdrawal); pervasive development disorders including autistic disorder and Rett’s disorder; attention deficit and disruptive behavior disorders such as attention deficit hyperactivity disorder; impulse control disorders like agression, pathological gambling; eating disorders like anorexia nervosa and bulimia nervosa, obesity; sleep disorders like insomnia; tic disorders like Tourette’s disorder; restless legs syndrome; disorders characterized by impairment of cognition and memory such as Alzheimer’s disease, Creutzfeldt-Jacob disease, Huntington’s disease, Parkinson’s disease and neurorehabilitation (post-traumatic brain lesions) The NK1 antagonistic properties of the compounds of the invention were tested using the methods outlined below. Pharmacological Methods Receptor Binding for human NKt Receptors Affinity of the compounds for human NKT receptors was assessed using radio-receptor binding assays. Membrane preparations were prepared from Chinese Hamster Ovarium fibroblast (CHO) cells in which the human NKi receptor was stably expressed. Membranes were incubated with [3H]-substance P in the absence or the presence of specified concentrations of the compounds, diluted in a suitable buffer in presence of peptidase inhibitor for 10 min at 25 °C. Separation of bound radioactivity from free was done by filtration over Whatman GF/B glass fiber filters with two 5 sec washings. Bound radioactivity was counted by liquid scintillation counting using a Betaplate counter. Measured radioactivity was plotted against the concentration of the displacing test compound and displacement curves were calculated by four-parameter logistic regression, resulting in IC5o values, i.e. that concentration of displacing compound by which 50% of the radioligand is displaced. Affinity pKi values were calculated by correcting the IC50 values for radioligand concentration and its affinity for the human NK-) receptor according to the Cheng-Prusoff equation: pKi=-log[ICso/(1+S/Kd)] in which the IC50 is as described above, S is the concentration [3H]-substance P used in the assay expressed in mol/l, and Kd is the equilibrium dissociation constant of [3H]-substance P for human NK1 receptors (in mol/I). cAMP measurements The effects of test compounds at formation of cyclic AMP (cAMP) was assessed using CHO fibroblast cells, stably expressing cloned human NK-, receptors. In addition to coupling to phospholipase C, human NKi receptors are also able to stimulate adenylate cyclase, which converts ATP into cAMP. For tests, cells were cultured in 24-well plates. Prior to experiments, medium was replaced by serum-free a-DMEM culture medium, containing [3H]-adenine which is taken up by the cells and converted sequentially into radiolabeled adenosine, AMP, ADP and ultimately into radiolabeled ATP. After 2 hrs, cells were rinsed twice with phosphate-buffered saline (pH 7.4) in presence of 1 mM isobutylmethylxanthine (IBMX; inhibitor of phospho-diesterases that hydrolyse cAMP into AMP). Subsequently, cells were stimulated by 10 nM substance P in absence or presence of test compounds in appropriate dilutions in PBS/IBMX for 20 min. After stimulation, medium was aspirated and cells were extracted by 5% trichloroacetic acid. Radiolabeled ATP and cAMP were recovered from the extracts using sequential column chromatography. Extracts were separated by ion-exchange chromatography over DOWEX 50WX4 columns, allowing the recovery of ATP. Columns were subsequently put on top of aluminum oxide columns and eluted with water. Recovery of cAMP was performed by eluting the aluminum oxide columns with 100 mM imidazole (pH 7.4). Both ATP and cAMP fractions were counted for radioactivity using liquid scintillation counting and conversion ratios were calculated as: v = [cAMP] * 100% / ([ATP] + [cAMP]). Concentration-response relationships were constructed by plotting cAMP conversion against compound concentration and IC5o values were calculated by four-parameter logistic regression. Antagonist potencies (pA2) values were calculated using: pA2 =ICa/(1 +[SP]/EC50) in which the IC50 of the test compound was obtained from concentration-effect relationships, [SP] is the concentration of substance P (in mol/l; typically 10 nM), and the EC50 is the potency of substance P at human cloned NK1 receptors. agonist - induced gerbil Foot-Tapping The ability of NK-, antagonists to antagonise foot-tapping induced by centrally administered NK-i agonists has been demonstrated (Rupniak and Williams, 1994 (Eur. J. Pharmacol. 265:179); Bristow and Young, 1994 (Eur. J. Pharmacol. 254: 245)). Therefore, we have used this model to assess the in vivo activity of the compounds of the invention. 60 min prior to anaesthesia with N2O (0.8L/min), halothane (3%) and O2 (0.8 L/min) male gerbils (40-60 g; Charles River) received an injection of vehicle or test compound (p.o.). Upon successful narcosis the anaesthetic was adjusted to N2O (0.6L/min)( halothane (1.5%) and O2 (0.6 L/min) and a midline scalp incision made. GR 73632 was infused into the cerebroventricular space (AP - 0.5mm, L -1.2 mm, and vertical -4.5mm from bregma). Following recovery from anaesthesia (about 3-4 min) the foot tapping response was recorded for 5 minutes. The predefined criterion for antagonism of this response was defined as inhibition of foot tapping for > 5 min. The compounds of the invention, as exemplified by the compounds 1 - 6, have a high affinity for NK1 receptors with pKrvalues > 7.0 in the binding assay described above. As outlined in detail in the examples given, some of these compounds have been used as intermediates in the synthesis of other compounds. The compounds of the invention are active in the cAMP assay, their pA2-values being in line with their pKj-values. Some of the compounds belonging to the invention penetrate the blood brain barrier as is evident from their activity in the neurokinin-agonist induced gerbil foot tapping assay. This property makes them useful in the treatment of CNS disorders. The compounds having formula (1) and their salts can be obtained according to at least one of the following methods known for compounds of this type. The compounds of the present invention may be prepared by the general route outlined in Scheme 1. Thus reaction of an amino acid ester with 5-oxo-piperidine-1,2-dicarboxyiic acid 1-benzyl ester (H.C. Beyerman, P. Boekee Reel. Trav. Chim. Pays-Bas, 1959, 78, 648) under standard peptide coupling procedures as described in M. Bodanszky, A. Bodanszky The Practice of Peptide Synthesis, Springer-Verlag, 1994; ISBN: 0-387-57505-7 afforded dipeptides 1, use of a chiral amino acid would result in Scheme 1 the formation of diastereomers and these can be separated at this (or a later) stage using standard chromatographic methods. Protection of the ketone in I as a cyclic or acyclic ketal, such as those described in T.W. Greene, P.G.M. Wuts Protective Groups in Organic Synthesis, John Wiley & Sons, 1999, yields compounds of formula II, in which A and B represent a cyclic or acyclic ketal. This reaction can be conducted following conventional methods that are generally known in the art. Removal of the benzyloxycarbonyl group under reductive conditions (H2, Pd/C) in a solvent such as methanol, followed by acid catalyzed cyclisation afforded diketopiperazines of formula III. Reduction of III with an active hydride reagent such as lithium aluminum hydride leads to an amine, which can be acylated with an appropriate acid chloride, under conditions that are generally known in the art, to afford IV. Hydrolysis of the ketal to form V can be done by methods as described in T.W. Greene, P.G.M. Wuts Protective Groups in Organic Synthesis, John Wiley & Sons,’1999. In cases were R1 contains an NH-group, as for example in an indolyi- or indazolyl-group, the NH is protected with a tert-butyloxycarbonyl group done by methods as described in T.W. Greene, P.G.M. Wuts Protective Groups in Organic Synthesis, John Wiley & Sons, 1999. After eventual protection of R1, compound V is converted to triflate VI by treatment with a lithium-amide base, such as lithium bis(trimethylsilyl)amide, in an ethereal solvent, such as tetrahydrofuran, at low temperature (-70°C), followed by the addition of a bis(trifluoromethanesulfonimide), such as A/-phenyl-bis(trifluoromethanesulfonimide). Triflate VI can be coupled, under palladium catalysis, with an aromatic or heteroaromatic stannane in a solvent such as 1,4-dioxane, to afford the compounds of the present invention VII. In an alternative route triflate VI is converted to stannane VIII with hexamethyld itin, under palladium catalysis, in a solvent such as tetrahydrofuran; subsequently stannane VIII can be coupled with an appropriate aromatic or heteroaromatic halide, under palladium catalysis, in a solvent such as tyA/Hdimethylformamide to afford compounds VII. The compounds VI and VIII were isolated as mixtures of double bond isomers or as a single isomer for which the position of the double bond was not determined. Compounds VII were initially formed as mixtures of double bond isomers, which could be isomerised to the most stable configuration in which the double bond is in between the carbonatoms 6 and 7. Details of compounds synthesized by this route are given in the examples below. SPECIFIC EXAMPLES OF SYNTHESES Example 1 (see scheme 1) To a solution of a mixture of (9R,2’R)- and (9S,2’R) 9-[2-(1H-lndol-3-yl)-1-methoxy- carbonyl-ethylcarbamoyl]-1,5-dioxa-8-aza-spiro[5.5]undecane-8-carboxyIic acid benzyl ester (92.8 g) in methanol (1 L) was added 10% palladium on carbon (approximately 5 g). The resulting mixture was hydrogenated with H2 (1 atm.) overnight at room temperature. The catalyst was removed by filtration over Celite and the remaining solution was concentrated in vacuo to afford a mixture of (2R,9’R) and (2R,9lS)-2-[(1,5-Dioxa-8-aza-spiro[5.5]undecane-9-carbonyl)-amino]-3-(1H-indol-3-yl)-propionic acid methyl ester (69.0 g). Rf 0.24 (SiO2, CH2CI2/MeOH/NH4OH 92:7.5:0.5). Example 4 A mixture of (2R,9’R) and (2/?,9’S)-2-[(1,5-Dioxa-8-aza-spiro[5.5]undecane-9-carbonyl)-amino]-3-(1H-indol-3-yl)-propionic acid methyl ester (69.0 g) and acetic acid (9 ml) in acetonitrile (900 ml) was heated under reflux overnight. After cooling to room temperature the mixture was concentrated to approximately one third its original volume. The formed precipitate was collected by filtration to afford (3 R,9aS)-3-(IH-indol-3-ylmethyl)-hexahydro-spiro[2H-pyrido[1,2-a]pyrazine-1,4-dione-7,2-[1,3]dioxane] (23.7 g; Rf 0.34 (Et2O/MeOH 9:1)). Concentration of the filtrate and purification of the residue by flash chromatography (SiO2, Et2O/MeOH 9:1) afforded (3R,9aR)-3-(1 H-indol-3-y!methyl)-hexahydro-spiro[2H-pyrido[1,2-a]pyrazine-1,4-dione-7f2’-[1,3]dioxane] (20.6 g; Rf 0.18 (SiO2j Et2O/MeOH 9:1). Example 5 To a suspension of lithium aluminum hydride (10.6 g) in THF (500 ml) was added drop-wise a solution of (3R,9aR)-3-(1H-indol-3-ylmethyl)-hexahydro-spiro[2H-pyrido[1,2-a]pyrazine-1,4HJione-7,241,3]dioxane] (20.6 g) in THF (100 ml), and the resulting mixture was heated under reflux for 2 days. After cooling to 5°C water (9.2 ml) 2M sodium hydroxide (aq, 18.4 ml), and again water (9.2 ml) were added drop-wise. The resulting mixture was heated under reflux for another hour, cooled to room temperature, filtered over Celite, and concentrated in vacuo to afford crude (3Rr9aR)-3-(1H-indol-3-ylmethyl)-octahydro-spiro[2H-pyrido[1,2-a]pyrazine-7,2J-[1,3]dioxane] (197 g, Rf 0.16 (SiO2t CH2CI2/MeOH/NH4OH 92:7.5:0.5)) which was used as such in the next step. Example 6 To a solution of (3R,9aR)-3-(1H-indol-3-ylmethyI)-octahydro-spiro[2H-pyrido[1,2-a]pyrazine-7,2’-[1,3]dioxane] (19.7 g) in dichloromethane was added diisopropylethylamine (9.6 ml) at room temperature and at 5°C, 3,5-bis(trifluoromethyl)benzoyl chloride (10 ml) drop-wise. The resulting mixture was stirred at room temperature overnight, concentrated in vacuo and purified by column chromatography (SiO2, CH2CI2/MeOH/NH4OH 96:3.75:0.25) to afford (3R,9aR)-2-[3,5-bis(trifluoromethyl)benzoyl]-3-(1H-indol-3-ylmethyl)-octahydro-spiro-[2H-pyrido-t1f2-a]pyra2ine-7l2l-l1l3]dioxane] (30.0 g). Rf 0.35 (SiO2, CH2CI2/MeOWNH4OH 96:3.75: 0.25). Example 7 A mixture of (3R,9af?)-2-[3,5-bis(trifluoromethy!)ben2oyl]-3-(1H-indol-3-ylmethyl)-octahydro-spiro-pH-pyricloti^-ajpyrazine-y^’-JI^Jdioxane] (30.0 g) in acetic acid (150 ml) and 6M hydrochloric acid (150 ml) was heated at 40°C for three days. After cooling to room temperature dichloromethane (750 ml) and 2M sodium hydroxide (aq., 1700 ml) were added. The layers were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with water, concentrated in vacuo, and purified by flash-chromatography (SiO2, CH2CI2/MeOH 98:2) to afford (3R,9aR)-2-[3I5-bis(trifluoromethyl)benzoyll-3-(1H-indol-3-ylmethyl)-octahydro-2H-pyrido[1,2-a]pyrazin-7-one (21.7 g). Rf 0.12 (SiO2, CH2CI2/MeOH 98:2). Example 8 To a suspension of (3R,9aR)-2-[3,5-bis(trifluorornethyl)benzoyl]-3-(1H-indol-3-ylmethyl)-octahydro-2H-pyrido[1,2-a]pyrazin-7-one (12.0 g), triethylamine (2.93 g), and 4-dimethylaminopyridine (600 mg) in acetonitrile (125 ml) was added drop wise a solution of di-tert-b utyl dicarbonate (6.4 g) in acetonitrile (50 ml), at room Claims 1. Compounds of the general formula (1) I wherein: R1 represents phenyl, 2-indolyl, 3-indolyl, 3-indazolyl or benzo[b]thiophen-3-yl, which groups may be substituted with halogen oralkyl(1-3C), R2 and R3 independently represent halogen, H, OCH3, CH3 and CF3, Q represents an optionally substituted aromatic or heteroaromaticfive- or six-membered ring, connected by a carbon-carbon bond, the pyrido[1f2-a]pyrazine moiety may or may not contain a double bond between either carbon atoms 6 and 7 or between carbon atoms 7 and 8, all stereoisomers as well as pharmacologically acceptable salts and prodrugs thereof, prodrugs being derivatives of the compounds having formula (1) wherein a group is present which is easily removed after administration, such as amidine, enamine, a Mannich base, a hydroxyl-Ynethylene derivative, an O-(acyloxymethylene carbamate) derivative, carbamate, ester, amide or enaminone. Compounds as claimed in claim 1 having formula (1) in which Q is an optionally substituted six-membered nitrogen containing heteroaromatic ring, and the other symbols have the meanings as given above, including all possible stereo-isomers. 3. Compounds as claimed in claim 1 having formula (1) wherein R1 is 3-indoIyl, R2 and R3 are CF3 groups in the 3- and 5-positions, and Q is an optionally substituted six-membered nitrogen containing heteroaromatic ring, including all possible stereo-isomers. 4. Pharmaceutical compositions containing a pharmacologically active amount of at least one compound as claimed in one of the claims 1 -3 as an active ingredient. 5. A compound as claimed in any of the claims 1 - 3, or a salt thereof, for use as a medicament 6. Use of a compound as claimed in one of the claims 1 -3 for the preparation of a pharmaceutical composition for the treatment of disorders in which neurokinins which interact with NK-, receptors, e.g. Substance P, are involved, or that can be treated via manipulation of those receptors. 7. Use as claimed in claim 5 characterized in that said disorders are acute and chronic pain, emesis, inflammatory diseases such as meningitis, arthritis, asthma, psoriasis and (sun)bums; gastro-intestinal disorders, in particular irritable bowel syndrome, inflammatory bowel disease (Crohn’s disease), ulcerative colitis; bladder or Gl tract hyperrnotility disorders, urinary tract inflammation; allergic responses such as eczema and rhinitis; cardio-vascular disorders such as hypertension, atherosclerosis, edema, angina, cluster headache and migraine; cutaneous diseases such as urticaria, lupus erythematosus and pruritus; respiratory disorders including chronic obstructive pulmonary disease, bronchospams, bronchopneumonia* bronchitis, respiratory distress syndrome and cystic fibrosis; various neoplastic diseases; psychiatric and/or neurological disorders such as schizophrenia and other psychotic disorders; mood disorders such as bipolar I disorders, bipolar II disorders and unipolar depressive disorders like minor depression, seasonal affective disorder, postnatal depression dysthymia and major depression; anxiety disorders including panic disorder (with or without agoraphobia), social phobia, obsessive compulsive disorder (with or without co-morbid chronic tic or schizotypal disorder), posttraumatic stress disorder and generalized anxiety disorder; substance related disorders, including substance use disorders (like dependence and abuse) and substance induced disorders (like substance withdrawal); pervasive development disorders including autistic disorder and Rett’s disorder; attention deficit and disruptive behavior disorders such as attention deficit hyperactivity disorder; impulse control disorders like agression, pathological gambling; eating disorders like anorexia nervosa and bulimia nervosa, obesity; sleep disorders like insomnia; tic disorders like Tourette’s disorder; restless legs syndrome; disorders characterized by impairment of cognition and memory such as Alzheimer’s disease, Creutzfeldt-Jacob disease, Huntington’s disease, Parkinson’s disease and neurorehabiiitation (post-traumatic brain lesions)

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