US20030109532A1 - Modulators of dopamine neurotransmission - Google Patents

Modulators of dopamine neurotransmission Download PDF

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US20030109532A1
US20030109532A1 US10/168,297 US16829702A US2003109532A1 US 20030109532 A1 US20030109532 A1 US 20030109532A1 US 16829702 A US16829702 A US 16829702A US 2003109532 A1 US2003109532 A1 US 2003109532A1
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Clas Sonesson
Bengt Andersson
Susanna Waters
Nicholas Waters
Ingela Svan
Liselott Ronnqvist
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Neurosearch Sweden AB
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Assigned to A. CARLSSON RESEARCH AB reassignment A. CARLSSON RESEARCH AB ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: WATERS, NICHOLAS, CARLBERG, JENNA MARIA, AS LEGAL REPRESENTATIVE, TEDROFF, JOAKIM, ANDERSSON, BENGT (DECEASED) BY SVAN, INGELA MARIANNA, RONNQUIST, LISELOTT LILJA, SONESSON, CLAS, WATERS, SUSANNA
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Definitions

  • the present invention relates to new modulators of dopamine neurotransmission, and more specifically to new substituted 4-(phenyl N-alkyl)-piperazines and 4-(phenyl N-alkyl)-piperidines, and use thereof.
  • Dopamine is a neurotransmitter in the brain. Since this discovery, made in the 1950s, the function of dopamine in the brain has been intensely explored. To date, it is well established that dopamine is essential in several aspects of brain function including motor, cognitive, sensory, emotional and autonomous (e.g. regulation of appetite, body temperature, sleep) functions. Thus, modulation of dopaminergic function may be beneficial in the treatment of a wide range of disorders affecting brain functions. In fact, both neurologic and psychiatric disorders are treated with medications based on interactions with dopamine systems and dopamine receptors in the brain.
  • Drugs that act, directly or indirectly, at central dopamine receptors are commonly used in the treatment of neurologic and psychiatric disorders, e.g. Parkinson's disease and schizophrenia.
  • dopaminergic pharmaceuticals have severe side effects, such as extrapyramidal side effects and tardive dyskinesia in dopaminergic antagonists used as antipsychotic agents, and dyskinesias and psychoses in dopaminergic agonists used as anti-Parkinson's agents.
  • Therapeutic effects are unsatisfactory in many respects.
  • novel dopamine receptor ligands with selectivity at specific dopamine receptor subtypes or regional selectivity are sought for.
  • dopamine receptor agonists i.e. dopamine receptor ligands with some but not full intrinsic activity at dopamine receptors, are being developed to achieve an optimal degree of stimulation at dopamine receptors, avoiding excessive dopamine receptor blockade or excessive stimulation.
  • Boissier J. et al Chem Abstr. 61:10691c disclose disubstituted piperazines.
  • the compounds are reportedly adrenolytics, antihypertensives, potentiators of barbiturates, and depressants of the central nervous system.
  • the object of the present invention is to provide new pharmaceutically active compounds, especially useful in treatment of disorders in the central nervous system, which do not have the disadvantages of the above described substances.
  • the substances according to the present invention act preferentially on dopaminergic systems in the brain, and they have effects on biochemical indices in the brain with the characteristic features of dopamine antagonists.
  • the substances according to the invention show no, or only limited, inhibitory effects on spontaneous locomotion unlike ordinary dopamine receptor antagonists that suppress behavioral activity and induce catalepsy.
  • the substances according to the invention may even induce a slight behavioral activation with concomitant increases in small-scale movements, e.g. stops in the center of the behavior recording arena, similar to that induced by dopaminergic agonists.
  • the present invention thus relates to new 3-substituted 4-(phenyl-N-alkyl)piperazines and 3-substituted 4-(phenyl-N-alkyl)piperidines in the form of free base or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing said compounds and use of said compounds in therapy.
  • One subject of the invention is to provide new compounds for therapeutic use, and more precisely compounds for modulation of dopaminergic systems in the mammalian brain, including human brain.
  • Another subject of the invention is to provide compounds with therapeutic effects after oral administration.
  • the present invention relates to 3-substituted 4-(phenyl-N-alkyl)-piperazine or 4-(phenyl-N-alkyl)-piperidine compounds of Formula 1:
  • X is selected from the group consisting of N, CH, and C, however X may only be C when the compound comprises a double bond at the dotted line;
  • R 1 is selected from the group consisting of OSO 2 CF 3 , OSO 2 CH 3 , SOR 5 , SO 2 R 5 , COR 5 , CN, NO 2 , CONHR 5 , CF 3 , 3-thiophene, 2-thiophene, 3-furane, 2-furane, F, Cl, Br, and I, wherein R 5 is as defined below;
  • R 2 is selected from the group consisting of C 1 -C 4 alkyls, allyls, CH 2 SCH 3 , CH 2 CH 2 OCH 3 , CH 2 CH 2 CH 2 F, CH 2 CF 3 , 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and —(CH 2 )—R 6 , wherein R 6 is as defined below;
  • R 3 and R 4 are independently selected from the group consisting of H and C 1 -C 4 alkyls, however both R 3 and R 4 cannot be H at the same time;
  • R 5 is selected from the group consisting of C 1 -C 3 alkyls, CF 3 , and N(R 2 )2, wherein R 2 is as defined above;
  • R 6 is selected from the group consisting of C 3 -C 6 cycloalkyls, 2-tetrahydrofurane, and 3-tetra-hydrofurane, and pharmaceutically acceptable salts thereof.
  • the compounds according to the present invention possess dopamine-modulating properties and are useful in treating numerous central nervous system disorders including both psychiatric and neurological symptoms.
  • Diseases in which compounds with modulating effects on dopaminergic systems may be beneficial are in disorders related to ageing, for preventing bradykinesia and depression and for the improvement of mental functions. They may also be used to improve cognitive functions and related emotional disturbances in neurodegenerative and developmental disorders as well as after brain damage.
  • the compounds according to the invention can be used to improve all symptoms of psychosis, including schizophrenia and schizophreniform disorders as well as drug induced psychotic disorders.
  • the compounds according to the invention may also be used in behavioral disorders usually first diagnosed in infancy, childhood, or adolescence as well as in impulse control disorders.
  • speech disorders such as stuttering may improve. They may also be used for treating substance abuse disorders as well as disorders characterized by misuse of food.
  • Mood and anxiety disorders, personality disorders, and conversion hysteria may also be treated with the compounds according to the invention.
  • Neurological indications include the treatment of Huntington's disease and other movement disorders as well as movement disorders induced by drugs. Restless legs and related disorders as well as narcolepsy may also be treated with compounds included according to the invention. They may also improve mental and motor function in Parkinson's disease, and in related parkinsonian syndromes. They may also be used to ameliorate tremor of different origins. They may be used in the treatment of headaches and used to improve brain function following vascular or traumatic brain injury. Moreover, they may be used to relieve pain in conditions characterized by increased muscle tone.
  • the compounds according to the present invention have unexpectedly been found to act preferentially on dopaminergic systems in the brain. They have effects on biochemical indices in the brain with the characteristic features of dopamine antagonists, e.g. producing increases in concentrations of dopamine metabolites.
  • dopamine receptor antagonists characteristically suppress behavioral activity and induce catalepsy, while the compounds of this invention show no, or only limited, inhibitory effects on spontaneous locomotion. In contrast they can induce a slight behavioral activation with concomitant increases in small-scale movements, e.g. stops in the center of the behavior recording arena, similar to that induced by dopaminergic agonists. The behavioral activation is limited, not reaching the profound increases in activity induced by direct or indirect dopaminergic agonists. On the other hand, the preferred substances reduce the increase in activity induced by direct or indirect dopaminergic agonists, i.e. d-amphetamine and congeners.
  • the compounds of this invention surprisingly show an interesting dualistic dopaminergic action profile with antagonist like effects on brain neurochemistry and mild agonist like effects on normal behavior, but inhibition of behavior in states of hyperactivity.
  • the action profile suggests modulatory effects on dopaminergic functions, clearly different from known compounds belonging to these chemical classes or effects anticipated of typical dopamine receptor antagonists or agonists from these or other chemical classes.
  • the novel class of dopaminergic modulators presented in this invention may prove superior to presently known dopaminergic compounds in the treatment of several disorders related to dysfunctions of the CNS, in terms of efficacy as well as side effects.
  • the present invention offers another principle for novel therapeutics based on interactions with dopamine systems.
  • the compounds according to the invention have effects on brain neurochemistry similar to antagonists at dopamine D2 receptors.
  • the compounds according to the invention show no, or only limited inhibitory, effects on spontaneous locomotion. They can induce a slight behavioral activation with concomitant increases in small-scale movements, e.g. stops in the center of the behavior recording arena, similar to that induced by dopaminergic agonists.
  • the behavioral activation is limited, not reaching the profound increases in activity induced by direct or indirect dopamine receptor agonists.
  • the preferred substances can actually reduce the increase in activity induced by direct or indirect dopaminergic agonists, i.e. d-amphetamine and congeners.
  • the preferred structures are substituted in the meta position on the aromatic ring.
  • the compounds according to the invention can thus be used to treat symptoms in e.g.:
  • schizophrenia and other psychotic disorders such as catatonic, disorganized, paranoid, residual or differentiated schizophrenia; schizophreniform disorder; schizo-affective disorder; delusional disorder; brief psychotic disorder; shared psychotic disorder; psychotic disorder due to a general medical condition with delusions and/or hallucinations;
  • mood disorders such as depressive disorders, e.g., dysthymic disorder or major depressive disorder; bipolar disorders, e.g., bipolar I disorder, bipolar II disorder, and cyclothymic disorder; mood disorder due to a general medical condition with depressive, and/or manic features; and substance-induced mood disorder;
  • anxiety disorders such as acute stress disorder, agoraphobia without history of panic disorder, anxiety disorder due to general medical condition, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, specific phobia, social phobia, and substance-induced anxiety disorder;
  • eating disorders such as anorexia nervosa, bulimia nervosa, and obesitas
  • sleep disorders such as dyssomnias, e.g., breathing-related sleep disorder, circadian rhythm sleep disorder, hypersomnia, insomnia, narcolepsy, and “jet lag”;
  • impulse-control disorders not elsewhere classified such as intermittent explosive disorder, kleptomania, pathological gambling, pyromania, and trichotillomania;
  • personality disorders such as paranoid, schizoid or schizotypal disorder; antisocial, borderline, histrionic, and narcissistic disorder; and avoidant, dependent, obsessive-compulsive disorder;
  • medication-induced movement disorders such as neuroleptic induced parkinsonism, neuroleptic malignant syndrome, neuroleptic induced acute and tardive dystonia, neuroleptic induced akathisia, neuroleptic induced tardive dyskinesia, medication induced tremor, and medication induced dyskinesias;
  • substance-related disorders such as abuse, dependence, anxiety disorder, intoxication, intoxication delirium, psychotic disorder, psychotic disorder with delusions, mood disorder, persisting amnestic disorder, persisting dementia, persisting perception disorder, sexual dysfunction, sleep disorder, withdrawal, and withdrawal delirium due to use ore misuse of alcohol, amphetamine (or amphetamine-like substances), caffeine, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine (or phencyclidine-like substances), sedative substances, hypnotic substances, and/or anxiolytic substances;
  • substance-related disorders such as abuse, dependence, anxiety disorder, intoxication, intoxication delirium, psychotic disorder, psychotic disorder with delusions, mood disorder, persisting amnestic disorder, persisting dementia, persisting perception disorder, sexual dysfunction, sleep disorder, withdrawal, and withdrawal delirium due to use ore misuse of alcohol, amphetamine (or amphetamine-like substances), caffeine, cannabis, cocaine, hallucinogens, inhal
  • disorders usually first diagnosed in infancy, childhood, or adolescence, such as mental retardation; learning disorders; motor skills disorders, e.g. developmental coordination disorder; communication disorders, e.g. expressive language disorder, phonological disorder, receptive-expressive language disorder and stuttering; pervasive developmental disorders, e.g. Asperger's disorder, autistic disorder, childhood disintegrative disorder, and Rett's disorder; attention-deficit and disruptive behavior disorders, e.g. attention-deficit/hyperactivity disorder, conduct disorder, and oppositional defiant disorder; feeding and eating disorders of infancy or early childhood, e.g.
  • feeding disorder of infancy or early childhood pica, rumination disorder
  • tic disorders e.g. chronic motor or vocal tic disorder, and Tourette's disorder
  • other disorders of infancy, childhood or adolescence, e.g. selective mutism, and stereotypic movement disorder
  • delirium dementia
  • amnestic and other cognitive disorders such as Alzheimer's, Creutzfeldt-Jakob disease, dead trauma, Huntington's disease, HIV disease, Pick's disease, and diffuse Lewy body dementia;
  • Parkinson's Disease and related disorders such as multiple system atrophies, e.g. striatonigral degeneration, olivopontocerebellar atrophy, and shydrager syndrome; progressive supranuclear palsy; corticobasal degeneration; and vascular parkinsonism;
  • tremors such as essential, orthostatic, rest, cerebellar, and secondary tremor
  • headaches such as migraine, cluster headache, tension type headache, and paroxysmal headache
  • movement disorders such as dyskinesias, e.g. in deneral medicine condition, secondary to trauma or vascular insult, hemiballism, athetosis, Sydenham's chorea, and paroxysmal; dystonias; Ekbom's syndrome (restless legs); Wilson's Disease; Hallerworden-Spatz disease;
  • rehabilitation medicine e.g. to improve rehabilitation after vascular or traumatic brain injury
  • the synthesis of the present compounds is carried out by methods that are conventional for the synthesis of related known compounds.
  • the syntheses of compounds in Formula 1, in general, comprise the reaction of an intermediate that supplies the alkyl group with an intermediate piperidine or piperazine that supplies the amine group of Formula 2:
  • a convenient method of synthesis of the present compounds is by use of an alkyl iodide (e.g. 1-propyl-iodide).
  • alkyl iodide e.g. 1-propyl-iodide
  • other leaving groups besides iodide may be used on the alkyl group, of course, such as sulfonates, particularly methanesulfonate or toluenesulfonate, bromo and the like.
  • the alkyl intermediate is reacted with the appropriate amine in the presence of any convenient acid scavenger.
  • the usual bases such as alkali metal or alkaline earth metal carbonates, bicarbonates and hydroxides are useful acid scavengers, as are some organic bases such as trialkylamines and trialkanolamines.
  • the reaction medium for such reactions may be any convenient organic solvent which is inert to the basic conditions; acetonitrile, esters such as ethyl-acetate and the like and halogenated alkane solvents are useful. Usually the reactions will be carried out at elevated temperatures such as from ambient temperature to the reflux temperature of the reaction mixture, particularly from 50° C. to about 100° C.
  • Z is a leaving group like iodide.
  • Other leaving groups besides iodide may be used on the alkyl group, of course, such as sulfonates, particularly methanesulfonate or toluenesulfonate, bromo and the like.
  • the alkyl intermediate is reacted with the appropriate amine in the presence of any convenient acid scavenger.
  • the usual bases such as alkali metal or alkaline earth metal carbonates, bicarbonates and hydroxides are useful acid scavengers, as are some organic bases such as trialkylamines and trialkanolamines.
  • the reaction is performed in a suitable solvent such as n-butanol by heating at about 50-150° C.
  • Z is halide e.g. chloro, bromo, iodo, or sulfonate e.g. —OSO 2 CF 3 , or —OSO 2 F, in the presence of a base and a zerovalent transition metal catalyst such as Pd or Ni, according to known method (Tetrahedron Letters, vol 37, 1996, 4463-4466, J. Org. Chem., vol. 61, 1996, 1133-1135).
  • the catalyst preferably Pd will have the ability to form ligand complex and undergo oxidative addition.
  • Typical Pd catalysts will be Pd 2 (dba) 3 (wherein dba refers to di-benzylidene acetone), Pd(PPh 3 ) 4 , Pd(OAc) 2 , or PdCl 2 [P(o-tol) 3 ] 2 and typical phosphine ligands will be BINAP, P(o-tol) 3 , dppf, or the like.
  • the usual bases such as alkali metal or alkaline earth metal carbonates, bicarbonates and alkyloxides are useful acid scavengers, as are some organic bases such as trialkylamines and trialkanolamines.
  • the reaction medium for such reactions may be any convenient organic solvents, which are inert to the basic conditions; acetonitrile, toluene, dioxane, NMP (N-methyl-2-pyrrolidone), DME (dimethoxyethane), DMF (N,N-dimethylformamide), DMSO (dimethylsulfoxide) and THF (tetrahydrofuran) solvents are useful.
  • the reactions will be carried out at elevated temperatures such as from ambient temperature to the reflux temperature of the reaction mixture, particularly from 50° C. to about 120° C.
  • Y is, for example, a dialkylborane, dialkenylborane or boronic acid (e.g. BEt 2 , B(OH) 2 ) or a trialkyltin (e.g. SnMe 3 , SnBu3), and an aryl substituted with a leaving group of Formula 7:
  • Y can also be a zink- or magnesium-halide group (e.g. ZnCl 2 , ZnBr 2 , ZnI 2 , MgBr 2 , MgI 2 ) according to known methods (Tetrahedron Lett., vol. 33, 1992, 5373-5374, Tetrahedron Lett., vol. 37, 1996, 5491-5494).
  • the catalyst preferably Pd will have the ability to form ligand complex and undergo oxidative addition.
  • the definition of ligands, bases and solvents, is mentioned above.
  • transition metal catalyzed cross-coupling reaction can be performed with the opposite substitution pattern:
  • [0083] can be prepared by catalytic hydrogenation of the tetra-hydropyridine or pyridine from the previous paragraph, using standard methods known in the art, generally with palladium on carbon, PtO 2 , or Raney nickel as the catalyst.
  • the reaction is performed in an inert solvent, such as ethanol or ethyl acetate, either with or without a protic acid, such as acetic acid or HCl.
  • an inert solvent such as ethanol or ethyl acetate
  • protic acid such as acetic acid or HCl.
  • Z is Cl, Br, or I
  • alkyllithium reagents for example, butyllithium, sec-butyllithium or tert-butyllithium, preferably butyllitium or Mg (grignard reaction) in an inert solvent.
  • Suitable solvents include, for example ether or tetrahydrofuran, preferably tetrahydrofuran. Reaction temperatures range from about ⁇ 110° C. to about 60° C.
  • the intermediate lithium anions or magnesium anions thus formed may then be further reacted with a suitable electrophile of Formula 12:
  • A is defined as a protecting group like t-Boc (tert-butoxycarbonyl), Fmoc (fluorenylmethoxycarbonyl), Cbz (benzyloxycarbonyl) or a an alkylgroup like benzyl.
  • t-Boc tert-butoxycarbonyl
  • Fmoc fluorenylmethoxycarbonyl
  • Cbz benzyloxycarbonyl
  • This step may be accomplished by one of several standard methods known in the art.
  • a thio-carbonyl derivative for example a xanthate
  • the hydroxyl group may be removed by reduction with a hydride source such as triethylsilane under acidic conditions, using such as, for example, trifluoroacetic acid or boron trifluoride.
  • the reduction reaction can be performed neat or in a solvent, such as methylene chloride.
  • a further alternative would be to first convert the hydroxyl group to a suitable leaving group, such as tosylate or chloride, using standard methods.
  • the leaving group is then removed with a nucleophilic hydride, such as, for example, lithium aluminium hydride.
  • This last reaction is performed typically in an inert solvent, such as, ether or tetrahydrofuran.
  • Another alternative method for removing the hydroxyl group is to first dehydrate the alcohol to an olefin with a reagent such as Burgess salt (J. Org. Chem., vol 38, 1973, 26) followed by catalytic hydrogenation of the double bond under standard conditions with a catalyst such as palladium on carbon.
  • the alcohol may also be dehydrated to the olefin by treatment with acid such as p-toluenesulfonic acid or trifluoroacetic acid.
  • the protecting group, A is removed under standard conditions known by those skilled in the art.
  • t-Boc cleavages are conveniently carried out with trifluoroacetic acid either neat or in combination with methylene chloride.
  • F-moc is conveniently cleaved off with simple bases such as, ammonia, piperidine, or morpholine, usually in polar solvents such as DMF and acetonitrile.
  • A is Cbz or benzyl
  • these are conveniently cleaved off under catalytic hydrogenation conditions.
  • the benzyl group can also be cleaved off under N-dealkylation conditions such as treatment with a-chloroethyl chloroformate (J. Org. Chem., vol 49, 1984, 2081-2082).
  • a radical R 1 in a compound of the Formula 1 into another radical R1, e.g. by oxidizing methylsulfide to methylsulfone (for example by m-chloroperoxybenzoic acid), substitution of a triflate or halide group with a cyano group (for example palladium catalyzed cyanation), substitution of triflate or halide group with a ketone (for example palladium catalyzed Heck reaction with butyl vinyl ether), substitution of a triflate or halide group with a carboxamide (for example, palladium catalyzed carbonylation), or cleaving an ether by, for example, converting a methoxy group into the corresponding hydroxyl derivate, which can further be converted into the corresponding mesylate or triflate.
  • the terms mesylate and triflate refers to OSO 2 CH 3 , CH 3 SO 3 or OSO 2 CF 3 ,
  • C 1 -C 4 alkyl refers to an alkyl containing 1-4 carbon atoms in any isomeric form.
  • the various carbon moieties are defined as follows:
  • Alkyl refers to an aliphatic hydrocarbon radical and includes branched or unbranched forms such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl.
  • cycloalkyl refers to a radical of a saturated cyclic hydrocarbon such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • patient refers to an individual in need of the treatment according to the invention.
  • treatment used herein relates to both treatment in order to cure or alleviate a disease or a condition, and to treatment in order to prevent the development of a disease or a condition.
  • the treatment may either be performed in an acute or in a chronic way.
  • Both organic and inorganic acids can be employed to form non-toxic pharmaceutically acceptable acid addition salts of the compounds according to the invention.
  • Illustrative acids are sulfuric, nitric, phosphoric, hydrochloric, citric, acetic, lactic, tartaric, palmoic, ethane disulfonic, sulfamic, succinic, cyclohexylsulfamic, fumaric, maleic, and benzoic acid.
  • These salts are readily prepared by methods known in the art.
  • the pharmaceutical composition containing a compound according to the invention may also comprise substances used to facilitate the production of the pharmaceutical preparation or the administration of the preparations.
  • substances are well known to people skilled in the art and may for example be pharmaceutically acceptable adjuvants, carriers and preservatives.
  • the compounds used according to the present invention will normally be administered orally, rectally, or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic, acid addition salt, such as the hydrochloride, lactate, acetate, sulfamate salt, in association with a pharmaceutically acceptable carrier.
  • the carrier may be a solid, semisolid or liquid preparation.
  • the active substance will constitute between 0.1 and 99% by weight of the preparation, more specifically between 0.5 and 20% by a weight for preparations intended for injection and between 0.2 and 50% by weight for preparations suitable for oral administration.
  • the selected compound may be mixed with a solid excipient, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinyl-pyrrolidine, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets.
  • a concentrated sugar solution which may contain e.g.
  • the tablet can be coated with a polymer known to the man skilled in the art, dissolved in a readily volatile organic solvent or mixture of organic solvents. Dyestuffs may be added to these coatings in order to readily distinguish between tablets containing different active substances or different amounts of the active compound.
  • the active substance may be admixed with e.g. a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the active substance using either the mentioned excipients for tablets e.g. lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatine.
  • liquids or semisolids of the drug can be filled into hard gelatine capsules.
  • Dosage units for rectal application can be solutions or suspensions or can be prepared in the form of suppositories comprising the active substance in a mixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with vegetable oil or paraffin oil.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing from about 0.2% to about 20% by weight of the active substance herein described, the balance being sugar and mixture of ethanol, water, glycerol and propylene glycol.
  • Such liquid preparations may contain coloring agents, flavoring agents, saccharine and carboxymethylcellulose as a thickening agent or other excipients known to the man in the art.
  • Solutions for parenteral applications by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance, preferably in a concentration of from 0.5% to about 10% by weight. These solutions may also containing stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules. The use and administration to a patient to be treated in the clinic would be readily apparent to an ordinary skill in the art.
  • an effective amount or a therapeutic amount of the compounds according to the invention are from about 0.01 to about 500 mg/kg body weight daily, preferably 0.1-10 mg/kg body weight daily.
  • the compounds may be administered in any suitable way, such as orally or parenterally.
  • the daily dose will preferably be administered in individual dosages 1 to 4 times daily.
  • the present invention is also considered to include stereoisomers as well as optical isomers, e.g. mixtures of enantiomers as well as individual enantiomers and diastereomers, which arise as a cosequense of structural asymmetry in certain compounds of the instant series. Separation of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art.
  • the titled compound was prepared in a similar manner as described in Example 1 from 3-bromo-methanesulfonyl benzene and cis-2,6-dimethyl-1-propyl-piperazine.
  • the amine was converted into the HCl salt and recrystallized from ethanol/diethylether: m.p. 233° C.
  • velocity at each time point is calculated as the distance traveled since the preceding sample divided by the time elapsed since the preceding sample.
  • the number of stops is then calculated as the number of times that the velocity changes from a non-zero value to zero.
  • the number of stops in the center of the behavioral recording arena is calculated as the number of stops occurring at a position at least ten centimeters from the edges of the recording arena.

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070149542A1 (en) * 2004-06-08 2007-06-28 Clas Sonesson Disubstituted phenylpiperidines/piperazines as modulators of dopamine neurotransmission
US20070179185A1 (en) * 2004-06-08 2007-08-02 Clas Sonesson New disubstituted phenylpiperidines as modulators of dopamine and serotonin neurotransmission
US20070238879A1 (en) * 2004-10-13 2007-10-11 Gauthier Donald R Process for the synthesis of 4-(3-methanesulfonylphenyl)-1-n-propyl-piperidine
US20070238878A1 (en) * 2004-10-13 2007-10-11 Richard Desmond Process for the synthesis of 4-(3-sulfonylphenyl)-piperidines
US20070270467A1 (en) * 2004-06-08 2007-11-22 Clas Sonesson Substituted piperidines as modulators of dopamine neurotransmission
US20080132489A1 (en) * 2005-02-10 2008-06-05 Dan Peters Novel Alkyl Substituted Homopiperazine Derivatives and Their Use as Monoamine Neurotransmitter Re-Uptake Inhibitors
US20080234321A1 (en) * 2005-10-13 2008-09-25 Clas Sonesson 3,5-Disubstituted Phenyl-Piperidines as Modulators of Dopamine Neurotransmission
US20100197712A1 (en) * 2007-06-18 2010-08-05 Arvid Carlsson Use of dopamine stabilizers
US9012476B2 (en) 2011-12-08 2015-04-21 IVAX International GmbH Hydrobromide salt of pridopidine
WO2015058053A1 (en) * 2013-10-18 2015-04-23 Psyadon Pharmaceuticals, Inc. Fused benzazepines for treatment of stuttering
USRE46117E1 (en) 1999-12-22 2016-08-23 Teva Pharmaceuticals International Gmbh Modulators of dopamine neurotransmission
US11207308B2 (en) 2012-04-04 2021-12-28 Prilenia Neurotherapeutics Ltd. Pharmaceutical compositions for combination therapy
US11298361B2 (en) 2012-07-12 2022-04-12 Emalex Biosciences, Inc. Fused benzazepines for treatment of Tourette's Syndrome
WO2023049480A1 (en) * 2021-09-25 2023-03-30 Alexander Shulgin Research Institute Substituted phenylalkylamines
US12594281B2 (en) 2024-03-15 2026-04-07 Emalex Biosciences, Inc. Pharmaceutical dosage forms and methods of use

Families Citing this family (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE9904723D0 (sv) 1999-12-22 1999-12-22 Carlsson A Research Ab New modulators of dopamine neurotransmission II
SE9904724D0 (sv) * 1999-12-22 1999-12-22 Carlsson A Research Ab New modulators of dopamine neurotransmission I
PE20020690A1 (es) * 2000-11-03 2002-08-23 Upjohn Co Metodo y tratamiento y prevencion de los dolores de cabeza de migranas
IL160307A0 (en) 2001-08-31 2004-07-25 Univ Rockefeller Phosphodiesterase activity and regulation of phosphodiesterase 1-b-mediated signaling in brain
ES2346452T3 (es) 2004-06-08 2010-10-15 Nsab, Filial Af Neurosearch Sweden Ab, Sverige Nuevas fenilpiperidinas/piperazinas disustituidas utilizadas como moduladores de la neurotransmision de la dopamina.
JP2008502652A (ja) * 2004-06-18 2008-01-31 ノイロサーチ アクティーゼルスカブ モノアミン神経伝達物質再取込み阻害剤としての、新規アルキル置換ピペラジン誘導体及びその使用
US20080269286A1 (en) 2005-12-07 2008-10-30 Clas Sonesson Disubstituted Phenylpiperidines as Modulators of Cortical Catecholaminergic Neurotransmission
ATE490963T1 (de) * 2006-03-10 2010-12-15 Univ New York State Res Found Tropan-prodrugs mit aktivität auf dem zns
MX2009004552A (es) * 2006-10-27 2009-11-10 Janssen Pharmaceutica Nv Metodos de tratamiento de trastornos de comportamiento perturbador.
AU2007346591A1 (en) * 2007-02-07 2008-08-14 Gosforth Centre (Holdings) Pty Ltd Treatment of ADHD
CN101711236B (zh) * 2007-04-12 2012-10-31 Nsab神经研究瑞典公司分公司 表现出改善的心血管副作用特性的多巴胺受体稳定剂/调节剂的n-氧化物和/或二-n-氧化物衍生物
AU2008258597A1 (en) 2007-06-05 2008-12-11 Nsab, Filial Af Neurosearch Sweden Ab, Sverige New disubstituted phenylpyrrolidines as modulators of cortical catecholaminergic neurotransmission
MX2010011724A (es) * 2008-04-29 2010-11-30 Nsab Af Neurosearch Sweden Ab Moduladores de neurotransmision de dopamina.
EP2271638B1 (de) * 2008-04-29 2011-08-31 NSAB, Filial af NeuroSearch Sweden AB, Sverige Modulatoren der dopamin-neurotransmission
JP2011519839A (ja) * 2008-04-29 2011-07-14 エヌエスエイビー、フィリアル アヴ ノイロサーチ スウェーデン エービー、スヴェーリエ ドーパミン神経伝達のモジュレーター
JP6166534B2 (ja) 2009-08-05 2017-07-19 イントラ−セルラー・セラピーズ・インコーポレイテッドＩｎｔｒａ−Ｃｅｌｌｕｌａｒ Ｔｈｅｒａｐｉｅｓ， Ｉｎｃ． 新規調節タンパク質および阻害剤
EP2539706B1 (de) 2010-02-24 2015-03-04 Research Triangle Institute Arylpiperazin-opioid-rezeptor-antagonisten
WO2011107583A1 (en) 2010-03-04 2011-09-09 Nsab, Filial Af Neurosearch Sweden Ab, Sverige Substituted 4-phenyl-n-alkyl-piperidines for preventing onset or slowing progression of neurodegenerative disorders
JP2013536825A (ja) 2010-09-03 2013-09-26 イバックス・インターナショナル・ゲーエムベーハー ドパミン作動性安定化剤として有用なプリドピジンの重水素化類似体
WO2012039660A1 (en) 2010-09-20 2012-03-29 A. Carlsson Research Ab Phenylpiperidine compounds for the treatment of neurological and psychiatric disorders
BR112014005389A8 (pt) * 2011-09-07 2018-04-03 Ivax Int Gmbh Sal cloridrato de 4- (3-metanossulfonil-fenil) -1- propil-piperidina em uma forma cristalina, composição farmacêutica compreendendo o mesmo e usos do dito sal
US20150216850A1 (en) * 2012-09-27 2015-08-06 Michael Hayden Combination of rasagiline and pridopidine for treating neurodegenerative disorders, in particular huntington's disease
US11090297B2 (en) 2013-06-21 2021-08-17 Prilenia Neurotherapeutics Ltd. Pridopidine for treating huntington's disease
HK1221646A1 (zh) 2013-06-21 2017-06-09 Teva Pharmaceuticals International Gmbh 高剂量普利多匹定用於治疗亨廷顿舞蹈症的用途
MX377576B (es) 2014-01-22 2025-03-04 Prilenia Neurotherapeutics Ltd Formulaciones de pridopidina de liberación modificada.
TW201613859A (en) 2014-06-30 2016-04-16 Teva Pharma Analogs of PRIDOPIDINE, their preparation and use
MX2017008136A (es) 2014-12-22 2018-03-06 Teva Pharmaceuticals Int Gmbh Sal de l-tartrato de pridopidina.
US11471449B2 (en) 2015-02-25 2022-10-18 Prilenia Neurotherapeutics Ltd. Use of pridopidine to improve cognitive function and for treating Alzheimer's disease
JP6887952B2 (ja) * 2015-02-25 2021-06-16 プリレニア ニューロセラピューティクス リミテッド 認知機能を改善するため、およびアルツハイマー病を治療するためのプリドピジンの使用
US10702512B2 (en) 2015-05-13 2020-07-07 A. Carlsson Research Ab Treatment of debilitating fatigue
AR105434A1 (es) 2015-07-22 2017-10-04 Teva Pharmaceuticals Int Gmbh Proceso para preparar pridopidina
JP7034488B2 (ja) * 2016-02-24 2022-03-14 プリレニア・ニューロセラピューティクス・エルティーディー プリドピジンを使用する神経変性眼疾患の治療
CA3035099C (en) * 2016-08-24 2023-01-17 Prilenia Therapeutics Development Ltd. Use of pridopidine for treating dystonias
EP4516356A3 (de) 2016-08-24 2025-05-14 Prilenia Neurotherapeutics Ltd. Verwendung von pridopidin zur behandlung von funktionalem verfall
CN109952100A (zh) 2016-09-15 2019-06-28 普瑞尼亚医疗发展有限公司 普利多匹定用于治疗焦虑和抑郁的用途
HUE058314T2 (hu) * 2016-09-16 2022-07-28 Prilenia Neurotherapeutics Ltd Pridopidin alkalmazása Rett-szindróma kezelésére
US12102627B2 (en) 2016-09-16 2024-10-01 Prilenia Neurotherapeutics Ltd. Use of pridopidine for treating rett syndrome
CA3050700C (en) * 2017-01-20 2023-10-03 Prilenia Neurotherapeutics Ltd. Use of pridopidine for the treatment of fragile x syndrome
EP3357909A1 (de) 2017-02-02 2018-08-08 Sandoz AG Kristalline 4-[3-(methylsulfonyl)phenyl]-1-propyl-piperidin
SI4154882T1 (sl) 2017-08-14 2026-01-30 Prilenia Neurotherapeutics Ltd. Zdravljenje amiotrofične lateralne skleroze s pridopidinom
CA3073568A1 (en) 2017-08-30 2019-03-07 Prilenia Neurotherapeutics Ltd. High concentration dosage forms of pridopidine
US12036213B2 (en) 2017-09-08 2024-07-16 Prilenia Neurotherapeutics Ltd. Pridopidine for treating drug induced dyskinesias
JP2020533296A (ja) 2017-09-08 2020-11-19 プリレニア ニューロセラピューティクス リミテッド 薬物誘発性ジスキネジアを治療するためのプリドピジン
CN113395964A (zh) 2019-02-04 2021-09-14 普瑞尼亚神经治疗有限公司 用于帕金森氏病和与帕金森症相关的其它疾病的低剂量普利多匹定
EP4519246A4 (de) 2022-05-03 2025-08-13 Prilenia Neurotherapeutics Ltd Verfahren und zwischenprodukte zur herstellung von pridopidin
JPWO2024172156A1 (de) * 2023-02-16 2024-08-22
IL315049A (en) 2024-08-15 2026-03-01 Prilenia Neurotherapeutics Ltd Taste-masking compounds containing pridopidine, their use and method for their preparation

Family Cites Families (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB850662A (en) 1956-10-22 1960-10-05 Parke Davis & Co Substituted piperazines and processes for their production
US3324916A (en) * 1964-04-09 1967-06-13 Saeki Susumu Rubber rolls for rubbing unhulled rice
BE662455A (de) 1964-04-14
FR1459013A (fr) 1964-08-05 1966-04-29 Allen & Hanburys Ltd Procédé de préparation de dérivés de la 4-phényl-pipéridine
GB1060160A (en) * 1964-08-05 1967-03-01 Allen & Hanburys Ltd 4-phenylpiperidine derivatives
US3539573A (en) * 1967-03-22 1970-11-10 Jean Schmutz 11-basic substituted dibenzodiazepines and dibenzothiazepines
ZA7546B (en) * 1974-01-21 1976-08-25 Parke Davis & Co New antibacterial amide compounds and methods for their production
GB1560271A (en) 1977-01-14 1980-02-06 Joullie International Sa Therapeutically useful m-trifluoromethylphenylpiperazine derivatives
US4202898A (en) 1978-06-05 1980-05-13 Synthelabo Method of treating anxiety and depression
FR2429212A1 (fr) * 1978-06-20 1980-01-18 Synthelabo Derives de phenylpiperazine et leur application en therapeutique
FR2459797A2 (fr) * 1978-08-01 1981-01-16 Synthelabo Derives de phenyl-1 piperazine et leur application en therapeutique
US4267328A (en) * 1978-08-01 1981-05-12 Synthelabo 1-Phenylpiperazines
US4333942A (en) * 1979-08-03 1982-06-08 Byk Gulden Lomberg Chemische Fabrik Gmbh Anti-depressant and analgesic 4-phenoxypiperidines
SE446335B (sv) * 1982-03-30 1986-09-01 Astra Laekemedel Ab Ren enantiomer av en metasubstituerad 3-fenyl-1-propylpiperidin
US4518712A (en) 1980-06-30 1985-05-21 Taiho Pharmaceutical Company Limited Piperazine derivative and analgesic composition containing the same
GB2083476B (en) 1980-09-12 1984-02-08 Wyeth John & Brother Ltd Heterocyclic compounds
FR2501506A1 (fr) * 1981-03-11 1982-09-17 Sanofi Sa Compositions pharmaceutiques a action anorexigene contenant des derives de la tetrahydropyridine
US4415736A (en) * 1981-12-28 1983-11-15 E. I. Du Pont De Nemours & Co. Certain tetrahydropyridine intermediates
ATE50987T1 (de) * 1982-05-10 1990-03-15 Takeda Chemical Industries Ltd Dihydropyridinderivate, deren herstellung und verwendung.
US4504660A (en) * 1982-07-06 1985-03-12 American Home Products Corporation Process for the production of 2,6-diaminobenzonitrile derivatives
HU198454B (en) 1987-12-14 1989-10-30 Richter Gedeon Vegyeszet Process for production of new derivatives of tetrahydrospiridin and medical compositions containing these compounds
FR2639226B1 (fr) * 1988-11-18 1993-11-05 Sanofi Utilisation de trifluoromethylphenyltetrahydropyridines pour la preparation de medicaments destines a combattre les troubles anxio-depressifs
AU7162791A (en) * 1989-12-27 1991-07-24 Miroslav Radman Novel system for isolating and producing new genes, gene products and dna sequences
CA2071897A1 (en) * 1989-12-28 1991-06-29 Richard A. Glennon Sigma receptor ligands and the use thereof
WO1992018475A2 (en) 1991-04-17 1992-10-29 The Upjohn Company Substituted phenylazacycloalkanes as cns agents
AU676993B2 (en) * 1991-06-27 1997-04-10 Virginia Commonwealth University Sigma receptor ligands and the use thereof
RU2052456C1 (ru) * 1991-06-27 1996-01-20 Научно-исследовательский институт фармакологии РАМН Гидрохлорид 3-метил-n-[2-( 4′ -фенилпиперазино)этил]бензамида, обладающий нейролептической активностью, и 3-метил-n-[2-(4-фенилпиперазино)этил]бензамид в качестве исходного соединения для его синтеза
IE914218A1 (en) 1991-09-11 1993-03-24 Mcneilab Inc Novel 4-arylpiperazines and 4-arylpiperidines
PT533268E (pt) 1991-09-18 2002-02-28 Glaxo Group Ltd Derivados de benzanilida como antagonistas de 5-ht1d
GB9119932D0 (en) 1991-09-18 1991-10-30 Glaxo Group Ltd Chemical compounds
GB9119920D0 (en) 1991-09-18 1991-10-30 Glaxo Group Ltd Chemical compounds
CN1036395C (zh) * 1992-03-19 1997-11-12 约翰韦恩兄弟有限公司 哌嗪衍生物的制备方法
US5502050A (en) * 1993-11-29 1996-03-26 Cornell Research Foundation, Inc. Blocking utilization of tetrahydrobiopterin to block induction of nitric oxide synthesis
CA2144669A1 (en) * 1994-03-29 1995-09-30 Kozo Akasaka Biphenyl derivatives
AU6470096A (en) 1995-07-19 1997-02-18 Yoshitomi Pharmaceutical Industries, Ltd. Fused triazole compounds
US5892041A (en) * 1996-08-12 1999-04-06 Neurogen Corporation Fused indolecarboxamides: dopamine receptor subtype specific ligands
DE19637237A1 (de) * 1996-09-13 1998-03-19 Merck Patent Gmbh Piperazin-Derivate
EP0975614A1 (de) * 1997-04-18 2000-02-02 Smithkline Beecham Plc Ein bicyclisches aryl or einen bicyclischen heterocyclischen ring enthaltende verbindungen mit kombinierter 5ht1a, 5ht1b und 5ht1d rezeptor antagonistischer aktivität
SE9702799D0 (sv) * 1997-07-25 1997-07-25 Astra Ab New compounds
US6303627B1 (en) * 1998-06-19 2001-10-16 Eli Lilly And Company Inhibitors of serotonin reuptake
CA2336691C (en) * 1998-07-10 2009-02-10 Massachusetts Institute Of Technology Ligands for metals and metal-catalyzed processes
US6232326B1 (en) 1998-07-14 2001-05-15 Jodi A. Nelson Treatment for schizophrenia and other dopamine system dysfunctions
IL146403A0 (en) 1999-06-22 2002-07-25 Neurosearch As Novel benzimidazole derivatives and pharmaceutical compositions comprising these compounds
SE9904724D0 (sv) * 1999-12-22 1999-12-22 Carlsson A Research Ab New modulators of dopamine neurotransmission I
SE9904723D0 (sv) * 1999-12-22 1999-12-22 Carlsson A Research Ab New modulators of dopamine neurotransmission II
AU2001280599A1 (en) 2000-07-15 2002-01-30 Smith Kline Beecham Corporation Compounds and methods
ES2247298T3 (es) 2001-01-23 2006-03-01 Eli Lilly And Company Derivados de piperazina y piperidina como agonistas del receptor de melanocortina.
US20050004164A1 (en) 2003-04-30 2005-01-06 Caggiano Thomas J. 2-Cyanopropanoic acid amide and ester derivatives and methods of their use
US7160888B2 (en) 2003-08-22 2007-01-09 Warner Lambert Company Llc [1,8]naphthyridin-2-ones and related compounds for the treatment of schizophrenia
ES2346452T3 (es) * 2004-06-08 2010-10-15 Nsab, Filial Af Neurosearch Sweden Ab, Sverige Nuevas fenilpiperidinas/piperazinas disustituidas utilizadas como moduladores de la neurotransmision de la dopamina.
SE0401465D0 (sv) 2004-06-08 2004-06-08 Carlsson A Research Ab New substituted piperdines as modulators of dopamine neurotransmission

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE46117E1 (en) 1999-12-22 2016-08-23 Teva Pharmaceuticals International Gmbh Modulators of dopamine neurotransmission
US20070149542A1 (en) * 2004-06-08 2007-06-28 Clas Sonesson Disubstituted phenylpiperidines/piperazines as modulators of dopamine neurotransmission
US20070179185A1 (en) * 2004-06-08 2007-08-02 Clas Sonesson New disubstituted phenylpiperidines as modulators of dopamine and serotonin neurotransmission
US20070270467A1 (en) * 2004-06-08 2007-11-22 Clas Sonesson Substituted piperidines as modulators of dopamine neurotransmission
US8314126B2 (en) 2004-06-08 2012-11-20 Nsab, Filial Af Neurosearch Sweden Ab, Sverige Disubstituted phenylpiperdines/piperazines as modulators of dopamine neurotransmission
US7579474B2 (en) 2004-06-08 2009-08-25 Nsab, Filial Af Neurosearch Ab, Sverige Substituted piperidines as modulators of dopamine neurotransmission
US7763639B2 (en) 2004-06-08 2010-07-27 Nsab, Filial Af Neurosearch Sweden Ab, Sverige Disubstituted phenylpiperidines/piperazines as modulators of dopamine neurotransmission
US20100256163A1 (en) * 2004-06-08 2010-10-07 Clas Sonesson Disubstituted phenylpiperdines/piperazines as modulators of dopamine neurotransmission
US7851629B2 (en) 2004-06-08 2010-12-14 Nsab, Filial Af Neurosearch Sweden Ab, Sverige Disubstituted phenylpiperidines as modulators of dopamine and serotonin neurotransmission
US20070238879A1 (en) * 2004-10-13 2007-10-11 Gauthier Donald R Process for the synthesis of 4-(3-methanesulfonylphenyl)-1-n-propyl-piperidine
US20070238878A1 (en) * 2004-10-13 2007-10-11 Richard Desmond Process for the synthesis of 4-(3-sulfonylphenyl)-piperidines
US7923459B2 (en) 2004-10-13 2011-04-12 Nsab, Filial Af Neurosearch Sweden Ab, Sverige Process for the synthesis of 4-(3-methanesulfonylphenyl)-1-N-propyl-piperidine
US7923444B2 (en) 2005-02-10 2011-04-12 Neurosearch A/S Alkyl substituted homopiperazine derivatives and their use as monoamine neurotransmitter re-uptake inhibitors
US20080132489A1 (en) * 2005-02-10 2008-06-05 Dan Peters Novel Alkyl Substituted Homopiperazine Derivatives and Their Use as Monoamine Neurotransmitter Re-Uptake Inhibitors
US20080234321A1 (en) * 2005-10-13 2008-09-25 Clas Sonesson 3,5-Disubstituted Phenyl-Piperidines as Modulators of Dopamine Neurotransmission
US8501777B2 (en) 2005-10-13 2013-08-06 Nsab, Filial Af Neurosearch Sweden Ab, Sverige 3,5-disubstituted phenyl-piperidines as modulators of dopamine neurotransmission
US20100197712A1 (en) * 2007-06-18 2010-08-05 Arvid Carlsson Use of dopamine stabilizers
US9012476B2 (en) 2011-12-08 2015-04-21 IVAX International GmbH Hydrobromide salt of pridopidine
US9814706B2 (en) 2011-12-08 2017-11-14 Teva Pharmaceuticals International Gmbh Hydrobromide salt of pridopidine
US11207308B2 (en) 2012-04-04 2021-12-28 Prilenia Neurotherapeutics Ltd. Pharmaceutical compositions for combination therapy
US11298361B2 (en) 2012-07-12 2022-04-12 Emalex Biosciences, Inc. Fused benzazepines for treatment of Tourette's Syndrome
WO2015058053A1 (en) * 2013-10-18 2015-04-23 Psyadon Pharmaceuticals, Inc. Fused benzazepines for treatment of stuttering
WO2023049480A1 (en) * 2021-09-25 2023-03-30 Alexander Shulgin Research Institute Substituted phenylalkylamines
US12594281B2 (en) 2024-03-15 2026-04-07 Emalex Biosciences, Inc. Pharmaceutical dosage forms and methods of use

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