Modulators of dopamine neurotransmission

Abstract

New 3-substituted 4-(phenyl-N-alkyl)-piperazine and 4-(phenyl-N-alkyl)-piperidine compounds of Formula (1) wherein X is N, CH, or C, however X may only be C when the compound comprises a double bind at the dotted line; R1 is CF3, OSO2CF3, OSO2CH3, SOR7, SO2R7, COR7, CN, OR3, NO2, CONHR3, 3-thiophene, 2-thiophene, 3-furane, 2-furane, F, Cl, Br, or I; R2 is F, Cl, Br, I, CN, CF3, CH3, OCH3, OH, and NH2; R3 and R4 are independently H or a C1-C4 alkyl; R5 is a C1-C4 alkyl, an allyl, CH2SCH3, CH2CH2OCH3, CH2CH2CH2F, CH2CF3, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, or —(CH2)R6; R6 is a C3-C6 cycloalkyl, 2-tetrahydrofurane, or 3-tetra-hydrofurane; R7 is a C1-C3 alkyl, CF3, or N(R4)2, and pharmaceutically acceptable salts thereof are disclosed. Also pharmaceutical compositions comprising the above compounds and methods wherein the above compounds are used for treatment of disorders in the central nervous system are disclosed.

Description

FIELD OF THE INVENTION[0001]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.BACKGROUND OF THE INVENTION[0002]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.[0003]Drugs that act, directly or indirectly, at central dopami...

AI Technical Summary

Benefits of technology

[0012]The compounds of 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.

[0013]Yet, dopamine receptor antagonists characteristically suppress behavioral activity across a variety of experimental settings including spontaneous locomotion, amphetamine induced hyperactivity. They are also known to induce catalepsy in rodents. In contrast, the compounds of this invention show no or limited inhibitory effects on locomotor activity. Although some of the compounds can reduce locomotion, they do not induce the profound behavioral inhibition, characteristic of dopamine D2 receptor antagonists. The compounds of this invention either lack inhibitory effects on locomotor activity, or exert milder inhibitory effects on locomotor activity than what would be expected from dopaminergic antagonists. Further, they can even be mild stimulants on behavior. Despite their behavioral stimulant properties some of the compounds can reduce d-amphetamine induced hyperactivity.

[0016]Some compounds of this invention have been found to have surprisingly good pharmacokinetic properties including high oral bioavailability. They are thus suitable for the preparation of orally administered pharmaceuticals. There is no guidance in the prior art how to obtain compounds with this effect on dopamine systems in the brain.

[0026]The compounds according to this 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 aging, for preventing bradykinesia and depression and for the improvement of mental functions. They may also be used to ameliorate symptoms of mood disorders. They may be used in obesitas as an anorectic agent and in other eating disorders. They may be used to improve cognitive functions and related emotional disturbances in neurodegenerative disorders as well as after brain damage induced by vascular or traumatic insults. Likewise, cognitive and motor dysfunctions associated with developmental disorders appearing in infancy, childhood, or adolescence may improve. They can be used to improve all symptoms of schizophrenia and schizophreniform disorders, to improve ongoing symptoms as well as to prevent the occurrence of new psychotic episodes. Other psychotic disorders not characterized as schizophrenia, schizoaffective syndromes as well as psychotic symptoms, delusions and hallucinations induced by other drugs may also improve. Disruptive behavior disorders such as attention deficit hyper activity disorder (ADHD), conduct disorder and oppositional defiant disorder may also improve. They can also be used in tic disorders such as Gilles de la Tourette's syndrome and other tic disorders. Also, speech disorders such as stuttering may improve. They may also be for regulating pathological disorders of food, coffee, tea, tobacco, alcohol and addictive drug intake and also to improve mental disorders associated with psychoactive substance overuse (including alcohol) including hallucinations, withdrawal symptoms, delusions, mood disorders, sexual and cognitive disturbances.

[0028]Neurological indications include the treatment of Huntington's disease, movement disorders such as dyskinesias including other choreas as well as primary, secondary and paroxysmal dystonias, tardive movement disorders such as tardive dyskinesia and tardive dystonia as well as other drug induced movement disorders. Restless legs, periodic leg movements and narcolepsy may also be treated with compounds included in the invention. They may also improve mental and motor function in Parkinson's disease, and in related parkinsonian syndromes such as multiple system atrophies, progressive supranuclear palsy, diffuse Lewy body disorder and vascular parkinsonism. They may also be used to ameliorate tremor of different origins.

[0029]The compounds in the invention can also be used for the treatment of vascular headaches such as migraine and cluster headache, both as acute and prophylactic treatment. They may improve rehabilitation following vascular or traumatic brain injury. Moreover, they may be used to relieve pain in conditions characterized by increased muscle tone.

Problems solved by technology

These properties have not been described earlier, and they are not possible to obtain with the earlier known compounds.

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