Piperidine derivatives as neurotransmitter re-uptake inhibitors

Details Piperidine derivatives as neurotransmitter re-uptake inhibitors Piperidine derivatives as neurotransmitter re-uptake inhibitors

1999-10-12

2002-04-23

Rotman, Alan L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S232000

Reexamination Certificate

active

06376673

ABSTRACT:

The present invention relates to novel piperidine-derivatives which are valuable monoamine neurotransmitter, i.e dopamine, serotonin and noradrenaline, re-uptake inhibitors and the use of the novel piperidine derivatives for the treatment of disorders or diseases responsive to the inhibition of monoamine neurotransmitter re-uptake, including diseases such as Parkinson's disease, depression, obsessive compulsive disorders, panic disorders, dementia, memory deficits, attention deficit hyperactivity disorder, obesity, anxiety, eating disorders and drug addiction or misuse, including cocaine abuse.
BACKGROUND OF THE INVENTION
The brain consists of a plurality of neurons that communicate with each other via chemical messengers. Each neuron generates neurochemicals or neurotransmitters which act at sites being referred to as receptors on the cellular membrane of neurons. One group. of neurotransmitters, referred to as the monoamine neurotransmitters, includes serotonin, dopamine and noradrenaline.
Monoamine neurotransmitters are released into the synaptic cleft between neurons in order to stimulate postsynaptic receptor activity. The removal (or inactivation) of monoamine neurotransmitters occurs mainly by a reuptake mechanism into the presynaptic terminals. By inhibiting the re-uptake an enhancement of the physiological activity of monoamine neurotransmitters occur.
The compounds of the present invention are valuable monoamine reuptake inhibitors, in particular dopamine reuptake inhibitors, and are as such considered useful for the treatment of Parkinsonism, depression, obesity, narcolepsy, drug addiction or misuse, including cocaine abuse, attention-deficit hyperactivity disorders, Gilles de la Tourettes disease and senile dementia. Dopamine re-uptake inhibitors enhances indirectly via the dopamine neurones the release of acetylcholin and are therefore also useful for the treatment of memory deficits, e.g. in Alzheimers disease, presenile dementia, memory dysfuntion in ageing, and chronic fatigue syndrome.
Compounds with noradrenaline re-uptake inhibiting activity are considered useful for enhancing attention, alertness, arousal, vigilance and for treating depression.
The serotonergic neural system of the brain have been shown to influence a variety of physiologic functions, and compounds having serotonin re-uptake inhibiting activity are predicted to have the ability to treat in mammals, including humans, a variety of disorders associated with this neural system, for example eating disorders, depression, obsessive compulsive disorders, panic disorders, alcoholism, pain, memory deficits and anxiety.
The compounds of the present invention are valuable inhibitors of serotonin reuptake and therefore predicted to be useful for the treatment of a range of disorders as mentioned above. Included among these disorders are depression and disorders related to depression, such as pseudodementia or Ganser's syndrome, migraine pain, bulimia, obesity, pre-menstrual syndrome or late luteal phase syndrome, tobacco abuse, panic disorder, post-traumatic syndrome, memory loss, dementia of ageing, memory dysfunction in ageing, social phobia, attention deficit hyperactivity disorder, chronic fatigue syndrome, premature ejaculation, erectile difficulty, anorexia nervosa, disorders of sleep, autism, mutism or trichotillomania.
OBJECTS OF THE INVENTION
It is an object of the present invention to provide novel piperidine-derivatives which are monoamine neurotransmitter re-uptake inhibitors and therefore useful for the treatment of disorders such as Parkinson's disease, depression and related diseases, obsessive compulsive disorders, panic disorders, dementia, memory deficits, attention deficit hyperactivity disorder, obesity, anxiety, eating disorders, drug addiction or misuse, including cocaine abuse.
Another object of the present invention is to provide novel pharmaceutical compositions containing the novel piperidine-derivatives.
Still another object of the invention is to provide a method of treating diseases or disorders responsive to the inhibition of monoamine neurotransmitter re-uptake, such as Parkinsonism, depression and related diseases, obsessive compulsive disorders, panic disorders, dementia, memory deficits, attention deficit hyperactivity disorder, obesity, anxiety, eating disorders, drug addiction or misuse, including cocaine abuse.
Other objects will become apparent hereinafter to one skilled in the art.
THE PRESENT INVENTION
The invention then, inter alia, comprises the following, alone or in combination:
A compound having the formula,
or a pharmaceutically acceptable salt thereof; wherein
R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl or 2-hydroxyethyl;
R
3
is —CR′═NOR″ wherein R′ and R″ each independently are hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, cycloalkylalkenyl, alkynyl, cycloalkylalkykyl, aryl or benzyl;
R
4
is
phenyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF
3
, CN, amino, nitro, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heteroaryl;
3,4-methylenedioxyphenyl;
benzyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF
3
, CN, amino, nitro, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heteroaryl;
heteroaryl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF
3
, CN, amino, nitro, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heteroaryl; or
naphthyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF
3
, CN, amino, nitro, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heteroaryl;
a compound as above which is
1-Metyl-3-methoxyiminomethyl-4-(3,4-dichlorophenyl)piperidine
or a pharmaceutically acceptable addition salt thereof;
a pharmaceutical composition, comprising a therapeutically effective amount of a compound as above, or a pharmaceutically acceptable addition salt thereof, together with at least one pharmaceutically acceptable carrier or diluent;
the use of a compound as above for the manufacture of a medicament for the treatment of a disorder or disease of a living animal body, including a human, which disorder or disease is responsive to the inhibition of monoamine neurotransmitter re-uptake in the central nervous system;
the use of a compound as above for the manufacture of a medicament for the treatment of a disorder or disease of a living animal body, including a human, which disorder or disease is responsive to the inhibition of dopamine neurotransmitter re-uptake in the central nervous system;
the use of a compound as above wherein the disorder or disease is Parkinsonism, depression, pseudodementia, obesity, narcolepsy, drug addiction and/or abuse, attention-deficit hyperactivity disorders, senile dementia, or memory dysfunction;
a method for the preparation of the compounds as above comprising the step of reacting a compound having the formula
herein R
4
, R′ and R is as defined above, with a compound having the formula NH
2
—OR″, wherein R″ is as defined above;
a method of treating a disorder or disease of a living animal body, including a human, which disorder or disease is responsive to the inhibition of monoamine neurotransmitter reuptake, comprising the step of administering to such a living animal body, including a human, in need thereof a therapeutically effective amount of a compound as above;
a method of treating a disorder or disease of a living animal body, including a human, which disorder or disease is responsive to the inhibition of dopamine neurotransmitter reuptake, comprising the step of administering to such a living animal body, including a human, in need thereof a therapeutically effective amount of a compound as above; and
the methods as above, wherein Parkinsonism, depression, pseudodementia, obesity, narcolepsy, drug a

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