U.S. patent application number 10/168297 was filed with the patent office on 2003-06-12 for modulators of dopamine neurotransmission.
Invention is credited to Andersson, Bengt, Ronnqvist, Liselott Lilja, Sonesson, Clas, Svan, Ingela Marianne, Waters, Nicholas, Waters, Susanna.
Application Number | 20030109532 10/168297 |
Document ID | / |
Family ID | 20418253 |
Filed Date | 2003-06-12 |
United States Patent
Application |
20030109532 |
Kind Code |
A1 |
Sonesson, Clas ; et
al. |
June 12, 2003 |
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 bond at the dotted line; R.sub.1 is OSO.sub.2CF.sub.3,
OSO.sub.2CH.sub.3, SOR.sub.5, SO.sub.2R.sub.5, COR.sub.5, CN,
NO.sub.2, CONHR.sub.5, CF.sub.3, 3-thiophene, 2-thiophene,
3-furane, 2-furane, F, Cl, Br, or I; R.sub.2 is a C.sub.1-C.sub.4
alkyl, an allyl, CH.sub.2SCH.sub.3, CH.sub.2CH.sub.2OCH.sub.3,
CH.sub.2CH.sub.2CH.sub.2F, CH.sub.2CF.sub.3, 3,3,3-trifluoropropyl,
4,4,4-trifluorobutyl, or --(CH.sub.2)--R.sub.6; R.sub.3 and R.sub.4
are independently selected from the group consisting of H and
C.sub.1-C.sub.4 alkyls, however both R.sub.3 and R.sub.4 cannot be
H at the same time; R.sub.5 is C.sub.1-C.sub.3 alkyls, CF.sub.3, or
N(R.sub.2).sub.2; R.sub.6 is a C.sub.3-C.sub.6 cycloalkyl,
2-tetrahydrofurane, or 3-tetra-hydrofurane, as well as
pharmaceutically acceptable salts thereof are disclosed. Also
pharmaceutical compositions comprising the above compounds and
methods wherein the above compounds are used are disclosed.
Inventors: |
Sonesson, Clas; (Billdal,
SE) ; Andersson, Bengt; (G?ouml;teborg, SE) ;
Waters, Susanna; (G?ouml;teborg, SE) ; Waters,
Nicholas; (G?ouml;teborg, SE) ; Svan, Ingela
Marianne; (G?ouml;teborg, SE) ; Ronnqvist, Liselott
Lilja; (G?ouml;teborg, SE) |
Correspondence
Address: |
BURNS DOANE SWECKER & MATHIS L L P
POST OFFICE BOX 1404
ALEXANDRIA
VA
22313-1404
US
|
Family ID: |
20418253 |
Appl. No.: |
10/168297 |
Filed: |
November 20, 2002 |
PCT Filed: |
December 22, 2000 |
PCT NO: |
PCT/SE00/02673 |
Current U.S.
Class: |
514/252.13 ;
514/254.1; 514/317; 514/326; 514/336; 544/374; 546/207; 546/212;
546/280.4; 546/283.4 |
Current CPC
Class: |
A61P 15/00 20180101;
C07D 295/096 20130101; A61P 25/18 20180101; A61P 31/18 20180101;
C07D 211/20 20130101; C07D 211/32 20130101; C07D 405/06 20130101;
A61P 25/24 20180101; A61P 25/30 20180101; A61P 25/16 20180101; A61P
15/10 20180101; A61P 43/00 20180101; C07D 295/155 20130101; A61P
25/22 20180101; C07D 211/22 20130101; A61P 25/28 20180101; A61P
1/14 20180101; A61P 3/00 20180101; A61P 25/14 20180101; A61P 25/20
20180101; A61P 29/00 20180101; C07D 211/34 20130101; C07D 295/112
20130101; A61P 25/04 20180101; A61P 25/00 20180101; C07D 295/073
20130101; C07D 211/18 20130101; C07D 211/24 20130101; A61P 25/06
20180101; A61P 39/02 20180101; C07D 211/70 20130101; A61P 3/04
20180101; A61P 25/08 20180101 |
Class at
Publication: |
514/252.13 ;
514/254.1; 514/317; 514/326; 514/336; 544/374; 546/207; 546/212;
546/280.4; 546/283.4 |
International
Class: |
C07D 49/02; C07D 45/02;
A61K 031/496; A61K 031/4436; A61K 031/443 |
Claims
1. A 3-substituted 4-(phenyl-N-alkyl)-piperazine or
4-(phenyl-N-alkyl)-piperidine compound of Formula 1: 23wherein: 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.sub.1 is selected from the group consisting of
OSO.sub.2CF.sub.3, OSO.sub.2CH.sub.3, SOR.sub.5, SO.sub.2R.sub.5,
COR.sub.5, CN, NO.sub.2, CONHR.sub.5, CF.sub.3, 3-thiophene,
2-thiophene, 3-furane, 2-furane, F, Cl, Br, and I, wherein R.sub.5
is as defined below; R.sub.2 is selected from the group consisting
of C.sub.1-C.sub.4 alkyls, allyls, CH.sub.2SCH.sub.3,
CH.sub.2CH.sub.2OCH.sub.3, CH.sub.2CH.sub.2CH.sub.2F,
CH.sub.2CF.sub.3, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and
--(CH.sub.2)--R.sub.6, wherein R.sub.6 is as defined below; R.sub.3
and R.sub.4 are independently selected from the group consisting of
H and C.sub.1-C.sub.4 alkyls, however both R.sub.3 and R.sub.4
cannot be H at the same time; R.sub.5 is selected from the group
consisting of C.sub.1-C.sub.3 alkyls, CF.sub.3, and
N(R.sub.2).sub.2, wherein R.sub.2 is as defined above; and R.sub.6
is selected from the group consisting of C.sub.3-C.sub.6
cycloalkyls, 2-tetrahydrofurane, and 3-tetra-hydrofurane, or a
pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein X is CH or C.
3. A compound according to claim 1 or claim 2, wherein R.sub.1 is
selected from the group consisting of OSO.sub.2CF.sub.3,
OSO.sub.2CH.sub.3, SO.sub.2Me, SO.sub.2CF.sub.3, COCH.sub.3, CN,
CF.sub.3, CON(CH.sub.3).sub.2 and SO.sub.2N(CH.sub.3).sub.2.
4. A compound according to any one of the claims 1-3, wherein
R.sub.3 and R.sub.4 both are CH.sub.3.
5. A compound according to any one of the claims 1-4, wherein
R.sub.1 is selected from the group consisting of SO.sub.2CF.sub.3,
SO.sub.2CH.sub.3, COCH.sub.3, CF.sub.3, and CN, and X is CH.
6. A compound according to any one of the claims 1-5, wherein
R.sub.2 is selected from the group consisting of n-propyl and
ethyl.
7. A pharmaceutical composition comprising a compound or
pharmaceutically acceptable salt according to any one of the claims
1-6.
8. A pharmaceutical composition according to claim 7, for treatment
of a disorder in the central nervous system.
9. A pharmaceutical composition according to claim 7 or claim 8,
for treatment of a dopamine mediated disorder.
10. A pharmaceutical composition according to any one of the claims
7-9, for treatment of a condition selected from the group
consisting of movement disorders, such as iatrogenic and
non-iatrogenic Parkinsonism, dyskinesias and dystonias, tics,
tremor, Tourette's disease, stuttering and other speech
disorders.
11. A pharmaceutical composition according to any one of the claims
7-9, for treatment of a condition selected from the group
consisting of iatrogenic and non-iatrogenic psychoses and
hallucinoses, including schizophrenia and schizophreniform
disorders.
12. A pharmaceutical composition according to any one of the claims
7-9, for treatment of a condition selected from the group
consisting of mood and anxiety disorders, including manodepressive
illness, depression and obsessive-compulsive disease.
13. A pharmaceutical composition according to any one of the claims
7-9, for treatment of a condition selected from the group
consisting of neurodevelopmental and age-related disorders,
including attention-deficit disorders, autism disorders,
bradykinesia and bradyphrenia and cognitive dysfunctions.
14. A pharmaceutical composition according to any one of the claims
7-9, for treatment of a condition selected from the group
consisting of sleep disorders, sexual disorders, eating disorders,
obesitas, and headaches and other pains.
15. A pharmaceutical composition according to any one of the claims
7-9, for improvement of motor functions, cognitive functions and
related emotional disturbances in neurodegenerative and
developmental disorders, and after brain injury induced by
traumatic, toxic, inflammatory, infectious, neoplastic, vascular,
hypoxic or metabolic causes treatment of a condition selected from
the group consisting of schizophrenia and schizophreniform
disorders.
16. A pharmaceutical composition according to any one of the claims
7-9, for treatment of a substance related disorder.
17. Use of compound according to any one of the claims 1-6 for the
manufacture of a pharmaceutical composition for treatment of a
disorder in the central nervous system.
18. Use according to claim 17, wherein said pharmaceutical
composition is for treatment of a dopamine mediated disorder.
19. Use according to claim 17 or claim 18, wherein said
pharmaceutical composition is for treatment of a condition selected
from the group consisting of movement disorders, such as iatrogenic
and non-iatrogenic Parkinsonism, dyskinesias and dystonias, tics,
tremor, Tourette's disease, stuttering and other speech
disorders.
20. Use according to claim 17 or claim 18, wherein said
pharmaceutical composition is for treatment of a condition selected
from the group consisting of iatrogenic and non-iatrogenic
psychoses and hallucinoses, including schizophrenia and
schizophreniform disorders.
21. Use according to claim 17 or claim 18, wherein said
pharmaceutical composition is for treatment of a condition selected
from the group consisting of mood and anxiety disorders, including
manodepressive illness, depression and obsessive-compulsive
disease.
22. Use according to claim 17 or claim 18, wherein said
pharmaceutical composition is for treatment of a condition selected
from the group consisting of neurodevelopmental and age-related
disorders, including attention-deficit disorders, autism disorders,
bradykinesia and bradyphrenia and cognitive dysfunctions.
23. Use according to claim 17 or claim 18, wherein said
pharmaceutical composition is for treatment of a condition selected
from the group consisting of sleep disorders, sexual disorders,
eating disorders, obesitas, and headaches and other pains.
24. Use according to claim 17 or claim 18, wherein said
pharmaceutical composition is for improvement of motor functions,
cognitive functions and related emotional disturbances in
neurodegenerative and developmental disorders, and after brain
injury induced by traumatic, toxic, inflammatory, infectious,
neoplastic, vascular, hypoxic or metabolic causes treatment of a
condition selected from the group consisting of schizophrenia and
schizophreniform disorders.
25. Use according to claim 17 or claim 18, wherein said
pharmaceutical composition is for treatment of a substance related
disorder.
26. A method for treatment of a disorder in the central nervous
system of a patient, wherein a pharmaceutically active amount of a
compound or a pharmaceutically acceptable salt according to any one
of the claims 1-6 is administered to said patient.
27. A method according to claim 26, for treatment of a dopamine
mediated disorder.
28. A method according to claim 26 or claim 27, for treatment of a
condition selected from the group consisting of movement disorders,
such as iatrogenic and non-iatrogenic Parkinsonism, dyskinesias and
dystonias, tics, tremor, Tourette's disease, stuttering and other
speech disorders.
29. A method according to claim 26 or claim 27, for treatment of a
condition selected from the group consisting of iatrogenic and
non-iatrogenic psychoses and hallucinoses, including schizophrenia
and schizophreniform disorders.
30. A method according to claim 26 or claim 27, for treatment of a
condition selected from the group consisting of mood and anxiety
disorders, including manodepressive illness, depression and
obsessive-compulsive disease.
31. A method according to claim 26 or claim 27, for treatment of a
condition selected from the group consisting of neurodevelopmental
and age-related disorders, including attention-deficit disorders,
autism disorders, bradykinesia and bradyphrenia and cognitive
dysfunctions.
32. A method according to claim 26 or claim 27, for treatment of a
condition selected from the group consisting of sleep disorders,
sexual disorders, eating disorders, obesitas, and headaches and
other pains.
33. A method according to claim 26 or claim 27, for improvement of
motor functions, cognitive functions and related emotional
disturbances in neurodegenerative and developmental disorders, and
after brain injury induced by traumatic, toxic, inflammatory,
infectious, neoplastic, vascular, hypoxic or metabolic causes
treatment of a condition selected from the group consisting of
schizophrenia and schizophreniform disorders.
34. A method according to claim 26 or claim 27, for treatment of a
substance related disorder.
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 dopamine
receptors are commonly used in the treatment of neurologic and
psychiatric disorders, e.g. Parkinson's disease and schizophrenia.
Currently available 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. To improve efficacy and reduce side effects of
dopaminergic pharmaceuticals, novel dopamine receptor ligands with
selectivity at specific dopamine receptor subtypes or regional
selectivity are sought for. In this context, also partial 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.
[0004] Compounds belonging to the class of substituted
4-(phenyl-N-alkyl)-piperazine and substituted
4-(phenyl-N-alkyl)-piperidi- nes have been previously reported.
Among these compounds, some are inactive in the CNS, some display
serotonergic or mixed serotonergic/dopaminergic pharmacological
profiles while some are full or partial dopamine receptor agonists
or antagonists with high affinity for dopamine receptors.
[0005] A number of 4-phenylpiperazines and 4-phenylpiperidine
derivatives are known and described, for example Costall et al.
European J. Pharm. 31, 94, (1975), Mewshaw et al. Bioorg. Med.
Chem. Lett., 8, 295, (1998). The reported compounds are substituted
4-phenylpiperazine's, most of them being 2-, 3- or 4-OH phenyl
substituted and displaying DA autoreceptor agonist properties.
[0006] Fuller R. W. et al, J. Pharmacol. Exp. Therapeut. 218, 636,
(1981) disclose substituted piperazines (e.g.
1-(m-trifluoro-methylphenyl)pipera- zine) which reportedly act as
serotonin agonists and inhibit serotonin uptake. Fuller R. W. et
al, Res. Commun. Chem. Pathol. Pharmacol. 17, 551, (1977) disclose
the comparative effects on the 3,4-dihydroxy-phenylacetic acid and
Res. Commun. Chem. Pathol. Pharmacol. 29, 201, (1980) disclose the
comparative effects on the 5-hydroxyindole acetic acid
concentration in rat brain by 1-(p-chlorophenol)-piperazine.
[0007] 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.
[0008] A number of different substituted piperazines have been
published as ligands at 5-HT.sub.1A receptors, for example Glennon
R. A. et al J. Med. Chem., 31, 1968, (1988), Mokrosz, J. et al
Arch. Pharm. (Weinheim) 328, 143-148 (1995), and van Steen B. J.,
J. Med. Chem., 36, 2751, (1993), Dukat M.-L., J. Med. Chem., 39,
4017, (1996). Glennon R. A. discloses, in international patent
applications WO 93/00313 and WO 91/09594 various amines, among them
substituted piperazines, as sigma receptor ligands. Clinical
studies investigating the properties of sigma receptor ligands in
schizophrenic patients have not generated evidence of antipsychotic
activity, or activity in any other CNS disorder. Two of the most
extensively studied selective sigma receptor antagonists, BW234U
(rimcazole) and BMY14802, have both failed in clinical studies in
schizophrenic patients (Borison et al, 1991, Psychopharmacol Bull
27(2): 103-106; Gewirtz et al, 1994, Neuropsychopharmacology
10:37-40).
SUMMARY OF THE INVENTION
[0009] 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.
[0010] In the work leading to the present invention, it was found
that it is desired to provide substances with specific
pharmacological properties, namely substances that have modulating
effects on dopamine neurotransmission. These properties have not
been described earlier, and they are not possible to obtain with
the earlier known compounds. 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. However,
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.
[0011] The present invention thus relates to new 3-substituted
4-(phenyl-N-alkyl)piperazines and 3-substituted
4-(phenyl-N-alkyl)piperid- ines in the form of free base or
pharmaceutically acceptable salts thereof, pharmaceutical
compositions containing said compounds and use of said compounds in
therapy.
[0012] 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.
[0013] Another subject of the invention is to provide compounds
with therapeutic effects after oral administration.
[0014] More precisely, the present invention relates to
3-substituted 4-(phenyl-N-alkyl)-piperazine or
4-(phenyl-N-alkyl)-piperidine compounds of Formula 1: 1
[0015] wherein:
[0016] 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;
[0017] R.sub.1 is selected from the group consisting of
OSO.sub.2CF.sub.3, OSO.sub.2CH.sub.3, SOR.sub.5, SO.sub.2R.sub.5,
COR.sub.5, CN, NO.sub.2, CONHR.sub.5, CF.sub.3, 3-thiophene,
2-thiophene, 3-furane, 2-furane, F, Cl, Br, and I, wherein R.sub.5
is as defined below;
[0018] R.sub.2 is selected from the group consisting of
C.sub.1-C.sub.4 alkyls, allyls, CH.sub.2SCH.sub.3,
CH.sub.2CH.sub.2OCH.sub.3, CH.sub.2CH.sub.2CH.sub.2F,
CH.sub.2CF.sub.3, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and
--(CH.sub.2)--R.sub.6, wherein R.sub.6 is as defined below;
[0019] R.sub.3 and R.sub.4 are independently selected from the
group consisting of H and C.sub.1-C.sub.4 alkyls, however both
R.sub.3 and R.sub.4 cannot be H at the same time;
[0020] R.sub.5 is selected from the group consisting of
C.sub.1-C.sub.3 alkyls, CF.sub.3, and N(R.sub.2)2, wherein R.sub.2
is as defined above; and
[0021] R.sub.6 is selected from the group consisting of
C.sub.3-C.sub.6 cycloalkyls, 2-tetrahydrofurane, and
3-tetra-hydrofurane, and pharmaceutically acceptable salts
thereof.
[0022] 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.
[0023] 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.
[0024] 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.
Also, 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.
[0025] Mood and anxiety disorders, personality disorders, and
conversion hysteria may also be treated with the compounds
according to the invention.
[0026] 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.
[0027] 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.
[0028] Yet, 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.
[0029] Thus, 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.
[0030] Given the involvement of dopamine in a large variety of CNS
functions and the clinical shortcomings of presently available
pharmaceuticals acting on dopamine systems, 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.
[0031] These compounds 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 behavior and
dopamine systems in the brain.
DETAILED DESCRIPTION OF THE INVENTION
[0032] Pharmacology
[0033] Evidence is available that neurotransmission in the CNS is
disturbed in psychiatric and neurologic diseases. In many
instances, for example in schizophrenia or Parkinson's disease,
pharmacotherapies based on antagonism or agonism at dopamine
receptors are useful, but not optimal. In recent years much efforts
have been put on finding novel and selective ligands for dopamine
receptor subtypes (D1, D2, D3, D4, D5) with the aim to improve
efficacy and reduce side effects.
[0034] 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. In
contrast to currently used dopamine receptor antagonists 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. Surprisingly, the preferred substances can
actually reduce the increase in activity induced by direct or
indirect dopaminergic agonists, i.e. d-amphetamine and
congeners.
[0035] The preferred structures are substituted in the meta
position on the aromatic ring. This is exemplified by
cis-4-(3-methanesulfonyl-phenyl-
)-2,6-dimethyl-1-propyl-piperazine, which is the compound of
Example 3, which increases 3,4-dihydroxy-phenylacetic acid in the
striatum from 1247.+-.65 (for controls) to 3140.+-.169 ng/g tissue
at 100 .mu.mol/kg s.c., p<0.05, n=4. This increase in dopamine
turnover is accompanied by an increase in motor activity from
27.+-.11 cm/30 min (for the controls), to 253.+-.73 cm/30 min
p<0.05, n=4, at 100 .mu.mol/kg, 30-60 min post injection.
Surprisingly, although cis-4-(3-methane-sulfony-
l-phenyl)-2,6-dimethyl-1-propyl-piperazine is stimulant in itself
it reduces d-amphetamine induced hyperactivity from 21140.+-.4656
cm/60 min to 2492.+-.530 cm/60 min, p<0.05, n=4, at 100
.mu.mol/kg s.c.
[0036] Furthermore, it is important that both R3 and R4 are not H
at the same time. This is further exemplified by
cis-2,6-dimethyl-1-propyl-4-(3--
trifluoro-methyl-phenyl)-piperazine, which is the compound of
Example 2. Similar to
cis-4-(3-methanesulfonyl-phenyl)-2,6-dimethyl-1-propyl-piperaz-
ine, which is the compound of Example 3,
cis-2,6-dimethyl-1-propyl-4-(3-tr-
ifluoro-methyl-phenyl)-piperazine increases
3,4-dihydroxy-phenylacetic acid in the striatum from 996.+-.18 (for
controls) to 1388.+-.60 ng/g tissue at 100 .mu.mol/kg-s.c.,
p<0.05, n=4. Furthermore,
cis-2,6-dimethyl-1-propyl-4-(3-trifluoro-methyl-phenyl)-piperazine
does not inhibit motoractivity in the behavioral assay; 3239.+-.194
cm/60 min (for the controls) to 3619.+-.483 cm/60 min, p>0.05,
n=4, at 100 .mu.mol/kg s.c. This is very surprising since the
similar substance
1-propyl-4-(3-triflouro-methyl-phenyl)-piperazine, which
corresponds to
cis-2,6-dimethyl-1-propyl-4-(3-trifluoro-methyl-phenyl)-piperazine
wherein R3 and R4 have been substituted by H, does inhibit
motoractivity in the behavioral assay.
1-propyl-4-(3-triflouro-methyl-phenyl)-piperazin- e increases
3,4-dihydroxyphenyl-acetic acid in the striatum from 1066.+-.46
(for controls) ng/g tissue to 3358.+-.162 ng/g tissue at 50
.mu.mol/kg s.c., p<0.05, n=4, followed by strong behavioral
inhibition from 1244.+-.341 cm/60 min (for the controls) to
271.+-.137 at 50 .mu.mol/kg s.c., p<0.05, n=4, thus, lacking the
properties sought for in the present invention. Further,
1-propyl-4-(3-triflouro-methyl-phenyl)- -piperazine reduces
serotonin in the striatum from 395.+-.11 (controls) ng/g tissue to
308.+-.18 ng/g tissue at 50 .mu.mol/kg s.c., p<0.05, n=4. An
effect not seen for the compound of Example 2
[cis-2,6-dimethyl-1-propyl-4-(3-trifluoro-methyl-phenyl)-piperazine];
427.+-.5 (controls) ng/g tissue to 419.+-.23 ng/g tissue at 100
.mu.mol/kg s.c., p>0.05, n=4.
[0037]
cis-2,6-Dimethyl-1-propyl-4-(3-trifluoro-methyl-phenyl)-piperazine
thus has the propertied desired according to the present invention,
whereas 1-propyl-4-(3-triflouro-methyl-phenyl)-piperazine is not a
substance according to the present invention.
[0038]
cis-4-(3-Methanesulfonyl-phenyl)-3-methyl-1-propyl-piperidine,
which is the compound of Example 4, has the ability to increase
3,4-dihydroxyphenyl-acetic acid in the striatum from 1111.+-.13
(for controls) ng/g tissue to 1884.+-.98 ng/g tissue at 100
.mu.mol/kg s.c., p<0.05, n=4. Further, it increases spontaneous
motoractivity in the behavioral assay; from 3275.+-.290 cm/60 min
(for the controls) to 4948.+-.577 cm/60 min, p<0.05, n=4, 0-60
min, at 100 .mu.mol/kg s.c.
cis-4-(3-Methanesulfonyl-phenyl)-3-methyl-1-propyl-piperidine thus
displays the properties desired according to the invention.
[0039] The compounds according to the invention can thus be used to
treat symptoms in e.g.:
[0040] 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;
[0041] 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;
[0042] 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;
[0043] eating disorders, such as anorexia nervosa, bulimia nervosa,
and obesitas;
[0044] sleep disorders, such as dyssomnias, e.g., breathing-related
sleep disorder, circadian rhythm sleep disorder, hypersomnia,
insomnia, narcolepsy, and "jet lag";
[0045] impulse-control disorders not elsewhere classified, such as
intermittent explosive disorder, kleptomania, pathological
gambling, pyromania, and trichotillomania;
[0046] personality disorders, such as paranoid, schizoid or
schizotypal disorder; antisocial, borderline, histrionic, and
narcissistic disorder; and avoidant, dependent,
obsessive-compulsive disorder;
[0047] 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;
[0048] 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;
[0049] 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;
[0050] 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;
[0051] conversion hysteria;
[0052] conditions connected to normal aging, such as disturbances
in motor functions and mental functions;
[0053] 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;
[0054] tremors, such as essential, orthostatic, rest, cerebellar,
and secondary tremor
[0055] headaches, such as migraine, cluster headache, tension type
headache, and paroxysmal headache;
[0056] 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;
[0057] rehabilitation medicine, e.g. to improve rehabilitation
after vascular or traumatic brain injury;
[0058] pain in conditions characterized by increased muscular tone,
such as fibromyalgia, myofascial syndrome, dystonia, and
parkinsonism; as well as
[0059] conditions related to the above that fall within the larger
categories but does not meet the criteria of any specific disorder
within those categories.
[0060] Synthesis
[0061] 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: 2
[0062] A convenient method of synthesis of the present compounds is
by use of an alkyl iodide (e.g. 1-propyl-iodide). Alternatively,
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.degree. C. to about 100.degree.
C.
[0063] Another convenient method of synthesis of the present
compounds involves reductive amination with an amine of Formula 2:
3
[0064] with an aldehyde or ketone, either in the presence of a
reducing agent such as sodium cyanoborohydride or sodium
triacetoxyborohydride or followed by reduction, e.g. using
catalytic hydrogenation, to give a corresponding compound of
Formula 1.
[0065] Compounds of Fomula 3 4
[0066] wherein X=N is accomplished by reacting compounds of Formula
4: 5
[0067] with compounds of Formula 5: 6
[0068] where 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.degree. C.
[0069] Compounds of the Formula 1 wherein X=N is also accomplished
by reacting compounds of Formula 6: 7
[0070] with an aryl substituted with a leaving group of Formula 7:
8
[0071] where Z is halide e.g. chloro, bromo, iodo, or sulfonate
e.g. --OSO.sub.2CF.sub.3, or --OSO.sub.2F, 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).
[0072] The catalyst, preferably Pd will have the ability to form
ligand complex and undergo oxidative addition. Typical Pd catalysts
will be Pd.sub.2(dba).sub.3 (wherein dba refers to di-benzylidene
acetone), Pd(PPh.sub.3).sub.4, Pd(OAc).sub.2, or
PdCl.sub.2[P(o-tol).sub.3].sub.2 and typical phosphine ligands will
be BINAP, P(o-tol).sub.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. 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.degree. C. to about 120.degree. C.
[0073] Compounds of the Formula 1 wherein X=N is also accomplished
by reacting compounds of Formula 6 with an aryl substituted with a
leaving group (e.g. F or Cl) via nucleophilic aromatic displacement
reactions in the presence of a base as explained above.
[0074] Compounds of the Formula 1 wherein X=CH is also accomplished
by transition metal catalyzed cross-coupling reaction, known as,
for example, Suzuki and Stille reactions, to those skilled in the
art.
[0075] The reaction may be carried out between compounds of Formula
8: 9
[0076] wherein Y is, for example, a dialkylborane, dialkenylborane
or boronic acid (e.g. BEt.sub.2, B(OH).sub.2) or a trialkyltin
(e.g. SnMe.sub.3, SnBu3), and an aryl substituted with a leaving
group of Formula 7: 10
[0077] (for definition of Z, see above) in the presence of a base
and a zerovalent transition metal catalyst such as Pd or Ni,
according to known methods (Chem. Pharm. Bull., vol 33, 1985,
4755-4763, J. Am. Chem. Soc., vol. 109, 1987, 5478-5486.,
Tetrahedron Lett., vol. 33, 1992, 2199-2202). In addition, Y can
also be a zink- or magnesium-halide group (e.g. ZnCl.sub.2,
ZnBr.sub.2, ZnI.sub.2, MgBr.sub.2, MgI.sub.2) according to known
methods (Tetrahedron Lett., vol. 33, 1992, 5373-5374, Tetrahedron
Lett., vol. 37, 1996, 5491-5494).
[0078] 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.
[0079] Alternatively, the transition metal catalyzed cross-coupling
reaction can be performed with the opposite substitution pattern:
11
[0080] with an heteroaryl/alkenyl substituted with an leaving group
of Formula 10: 12
[0081] in the presence of a base and a zerovalent transition metal
catalyst such as Pd or Ni, according known methods discussed in the
previous paragraph.
[0082] Compounds of Formula 11: 13
[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.sub.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.
When the pyridine ring is quaternized with an alkyl group the ring
can be partly reduced by NaBH.sub.4 or NaCNBH.sub.4, yielding the
tetra-hydropyridine analog which can further be reduced with
catalytic hydrogenation.
[0084] Another convenient method of syntheses of compounds of the
Formula 1, wherein X=CH is also accomplished by treating
arylhalides of Formula 7: 14
[0085] wherein Z is Cl, Br, or I, with 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.degree. C. to about 60.degree. C. The
intermediate lithium anions or magnesium anions thus formed may
then be further reacted with a suitable electrophile of Formula 12:
15
[0086] wherein A is defined as a protecting group like t-Boc
(tert-butoxycarbonyl), Fmoc (fluorenylmethoxycarbonyl), Cbz
(benzyloxycarbonyl) or a an alkylgroup like benzyl. The
intermediates of Formula 13: 16
[0087] which are formed require that the hydroxy group be removed
so as to result in compounds of Formula 1 (X=CH).
[0088] This step may be accomplished by one of several standard
methods known in the art. For example, a thio-carbonyl derivative
(for example a xanthate) may be prepared and removed by a free
radical process, of which are known to those skilled in the art.
Alternatively, 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.
[0089] 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.
[0090] The protecting group, A, is removed under standard
conditions known by those skilled in the art. For example, 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. When 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).
[0091] It is further possible to convert a radical R.sub.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.sub.2CH.sub.3, CH.sub.3SO.sub.3 or
OSO.sub.2CF.sub.3, CF.sub.3SO.sub.3, respectively.
[0092] In summary, the general process for preparing the present
compounds has six main variations, which may briefly be described
as follows: 17 18 19 20 21 22
[0093] As used herein the term C.sub.1-C.sub.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.
[0094] The term cycloalkyl refers to a radical of a saturated
cyclic hydrocarbon such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl.
[0095] The term "patient" used herein refers to an individual in
need of the treatment according to the invention.
[0096] The term "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.
[0097] 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.
[0098] 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. Such substances are well known
to people skilled in the art and may for example be
pharmaceutically acceptable adjuvants, carriers and
preservatives.
[0099] In clinical practice 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. Usually 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.
[0100] To produce pharmaceutical preparations containing the
compound according to the invention in the form of dosage units for
oral application, 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. If coated tablets are required, the cores,
prepared as described above, may be coated with a concentrated
sugar solution which may contain e.g. gum arabic, gelatine, talcum,
titanium dioxide, and the like. Alternatively, 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.
[0101] For the preparation of soft gelatine capsules, 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. Also liquids or semisolids of the drug can be filled into
hard gelatine capsules.
[0102] 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. Optionally 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.
[0103] 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.
[0104] In therapeutical treatment 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.
[0105] It is known for those skilled in the art that replacing a
hydrogen in a non-substituted position in the aromatic ring with a
fluorine atom may block the possibility for enzymatic hydroxylation
which render the compound low oral bioavailability. This type of
exchange (H to F) seldom changes the pharmacological profile. Thus,
it may be important, in some cases to introduce a fluorine atom in
any non-substituted positions in the aromatic ring of compounds of
Formula 1 to improve the oral bioavailability.
[0106] Additionally, 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.
[0107] The invention is further illustrated in the examples below,
which in no way are intended to limit the scope of the
invention.
EXAMPLE 1
3-(cis-3,5-Dimethyl-4-propyl-piperazin-1-yl)-benzonitrile
[0108] A mixture of 3-bromo-benzonitrile (0.35 g),
cis-2,6-dimethyl-1-prop- yl-piperazine (0.3 g), sodium
tert-butoxide (0.28 g) BINAP (25 mg)-and [Pd.sub.2(dba).sub.3 (20
mg) in toluene (6 ml) was heated under argon at 80.degree. C. for
24 h. After cooling to room temperature, the reaction mixture was
filtered through a pad of celite and evaporated to dryness. The
crude material was purified by flash chromatography on silica gel
using CH.sub.2Cl.sub.2:MeOH (45:1 (v/v)). MS m/z (relative
intensity, 70 eV) 257 (M+, 38), 242 (52), 228 (bp), 130 (45) 112
(74).
EXAMPLE 2
cis-2,6-Dimethyl-1-propyl-4-(3-trifluoro-methyl-phenyl)-piperazine
[0109] The titled compound was prepared in a similar manner as
described in Example 1 from 3-iodobenzotrifluoride and
cis-2,6-dimethyl-1-propyl-pi- perazine. The amine was converted
into the HCl salt and recrystallized from ethanol/diethylether:
m.p. 188.degree. C. MS m/z (relative intensity, 70 eV) 300 (M+,
26), 271 (58), 112 (bp), 70 (73), 56 (93).
EXAMPLE 3
cis-4-(3-Methanesulfonyl-phenyl)-2,6-dimethyl-1-propyl-piperazine
[0110] 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.degree. C. MS m/z (relative intensity, 70 eV) 310 (M+, 24), 281
(57), 112 (bp), 70 (55) 56 (59).
EXAMPLE 4
cis-4-(3-Methanesulfonyl-phenyl)-3-methyl-1-propyl-piperidine
[0111] A suspension of
cis-4-(3-methanesulfonyl-phenyl)-3-methyl-piperidin- e (0.28 g) and
ground K.sub.2CO.sub.3 (300 mg) was stirred in CH.sub.3CN (30 mL)
at room temperature. A solution of 1-iodo-propane (220 mg) in
CH.sub.3CN (5 mL) was added dropwise. The mixture was stirred at
50.degree. C. overnight. The reaction mixture was filtered and the
volatiles were evaporated in vacuum. The oily residue was
chromatographed on a silica column with MeOH:CH.sub.2Cl.sub.2 (1:9
(v/v)) as eluent. Collection of the fractions containing pure
product and evaporation of the solvent afforded pure
cis-4-(3-Methanesulfonyl-phenyl)-3-methyl-1-pro- pyl-piperidine.
The amine was converted into the HCl salt and recrystallized from
ethanol/diethylether: m.p. 197.degree. C. MS m/z (relative
intensity, 70 eV) 295 (M+, 1), 266 (47), 84 (bp), 70 (49) 63 (27).
.sup.13C-NMR (75.4 MHz, CDCl.sub.3): 11.8, 12.7, 20.0, 24.7, 34.9,
44.5, 44.8, 54.7, 60.3, 60.6, 124.8, 126.2, 129.1, 132.7, 140.6,
146.7.
EXAMPLE 5
cis-2,6-Dimethyl-1-propyl-4-(3-trifluoromethane-sulfonyl-phenyl)-piperazin-
e
[0112] The titled compound was prepared in a similar manner as
described in Example 4 from
cis-2,6-dimethyl-1-(3-trifluoromethane-sulfonyl-phenyl)-
-piperazine and iodopropane. MS m/z (relative intensity, 70 eV) 364
(M+, 18), 335 (79), 112 (bp), 70 (56), 56 (60).
EXAMPLE 6
cis-1-[3-(3,5-Dimethyl-4-propyl-piperazin-1-yl)-phenyl]-ethanone
[0113] The titled compound was prepared in a similar manner as
described in Example 4 from
cis-1-[3-(3,5-dimethyl-piperazin-1-yl)-phenyl]-ethanone and
iodopropane. MS m/z (relative intensity, 70 eV) 274 (M+, 27), 259
(32), 245 (40), 132 (35) 112 (bp), Rf=0.36 (CH.sub.2Cl.sub.2:MeOH
19/1).
EXAMPLE 7
cis-2,6-Dimethyl-1-ethyl-4-(3-trifluoromethane-sulfonyl-phenyl)-piperazine
[0114] The titled compound was prepared in a similar manner as
described in Example 4 from
cis-2,6-dimethyl-1-(3-trifluoromethane-sulfonyl-phenyl)-
-piperazine and bromo-ethane. MS m/z (relative intensity, 70 eV)
350 (M+, 17), 335 (48), 98 (bp), 71 (41), 56 (76).
EXAMPLE 8
cis-2,6-Dimethyl-1-allyl-4-(3-trifluoromethane-sulfonyl-phenyl)-piperazine
[0115] The titled compound was prepared in a similar manner as
described in Example 4 from
cis-2,6-dimethyl-1-(3-trifluoromethane-sulfonyl-phenyl)-
-piperazine and allyl-bromide. MS m/z (relative intensity, 70 eV)
362 (M+, 22), 110 (bp), 83 (59), 68 (40), 56 (40).
[0116] Synthesis of intermediates used in the above Examples are
described in the preparations below.
[0117] Preparation 1:
1-Benzyl-3-methyl-4-(3-methylsulfanyl-phenyl)-piperi- din-4-ol
[0118] 3-Bromothioanisole (3 g) dissolved in dry THF (40 ml) was
added dropwise to a mixture of Mg (0.4 g) and THF under a stream of
Argon (g). The mixture was then brought to reflux for. 1 h. The
cloudy solution was cooled to 0.degree. C. and
1-benzyl-3-methyl-4-piperidone (3 g) dissolved in dry THF (30 ml)
was added dropwise. The mixture was then stirred at r.t. (30 min)
and finally refluxed for 1 h. The reaction mixture was quenched
with saturated ammonium chloride solution (30 ml). The mixture was
extracted several times with EtOAc and the combined organic phases
were dried (MgSO.sub.4), filtered and evaporated to dryness. The
oily residue was chromathographed on a silica column using
CH.sub.2Cl.sub.2:MeOH (19:1 (v/v)) as eluent, yielded 3.12 g of
1-Benzyl-3-methyl-4-(3-methylsulfanyl-phenyl)-piperidin-4-ol. MS
m/z (rel. intensity, 70 eV) 327 (M+, 11), 160 (16), 148 (11), 91
(bp), 65 (15).
[0119] Preparation 2:
1-Benzyl-3-methyl-4-(3-methylsulfanyl-phenyl)-1,2,3,-
6-tetrahydro-pyridine
[0120] 1-Benzyl-3-methyl-4-(3-methylsulfanyl-phenyl)-piperidin-4-ol
(3.12 g) was dissolved in trifluoroacetic acid (80 ml) and refluxed
for 3 days. CH.sub.2Cl.sub.2 (100 ml) was added and the mixture was
washed with two portions of 10%-Na.sub.2CO.sub.3, dried
(MgSO.sub.4), filtered and evaporated to dryness (yield 1.35 g). MS
m/z (rel. intensity, 70 eV) 309 (M+, 24), 143 (35), 128 (22), 91
(bp), 65 (23).
[0121] Preparation 3:
cis-1-Benzyl-3-methyl-4-(3-methylsulfanyl-phenyl)-pi- peridine
[0122]
1-Benzyl-3-methyl-4-(3-methylsulfanyl-phenyl)-1,2,3,6-tetrahydro-py-
ridine (1.35 g) was dissolved in 35 ml MeOH. Solid ammonium formate
(1.93 g) and Pd/C (0.25 g) were added. The mixture was refluxed
under a nitrogen atmosphere for 4 h. The mixture was then filtered
through a pad of Celite, and the solvent was evaporated in
vacuo.
[0123] The residue was redissolved in CH.sub.2Cl.sub.2 and purified
by flash-chromathography. Yield 0.51 g of the titled compound. MS
m/z (rel. intensity, 70 eV) 311 (M+, 48), 310 (32), 160 (19), 91
(bp), 65 (15).
[0124] Preparation 4:
cis-1-Benzyl-4-(3-methanesulfonyl-phenyl)-3-methyl-p- iperidine
[0125]
cis-1-Benzyl-3-methyl-4-(3-methyl-sulfanyl-phenyl)-piperidine (0.49
g) and CF.sub.3COOH (0.27 g) was dissolved in CH.sub.2Cl.sub.2 (40
ml) and cooled to 0.degree. C. m-Chloroperoxybenzoic acid (0.57 g)
was added portions wise and the mixture was stirred at r.t over
night. The resulting clear solution was washed with
10%-Na.sub.2CO.sub.3 solution, dried (MgSO.sub.4), filtered and
concentrated by evaporation and yielding an oily residue (0.5 g).
MS m/z (relative intensity, 70 eV) 343 (M+, bp), 342 (92), 328
(17), 266 (22), 252 (85).
[0126] Preparation 5:
cis-4-(3-Methanesulfonyl-phenyl)-3-methyl-piperidine
[0127] A solution of
cis-1-Benzyl-4-(3-methanesulfonyl-phenyl)-3-methyl-pi- peridine
(0.38 g) in 1,2-dichloroethane (10 ml) was cooled to 0.degree. C.
Then .alpha.-chloroethyl chloroformate (1.6 g) dissolved in
1,2-dichloroethane (5 ml) was added dropwise at 0.degree. C. The
reaction mixture was then brought to reflux for 2 days. The
volatiles were evaporated in vacuo and the residue triturated with
methanol. The mixture was brought to reflux for 4 hours. The
solvent was evaporated to afford the title compound as HCl salt
(0.28 g). MS m/z (relative intensity, 70 eV) 253 (M+, 15), 115
(28), 70 (65), 57 (bp), 56 (86).
[0128] Preparation 6:
cis-2,6-dimethyl-1-(3-trifluoromethane-sulfonyl-phen-
yl)-piperazine
[0129] The titled compound was prepared in a similar manner as
described in Example 1 from 3-bromo-trifluoromethan-sulfonyl
benzene and cis-2,6-dimethyl-piperazine. MS m/z (relative
intensity, 70 eV) 322 (M+, 15), 253 (12), 252 (bp), 119. (27), 70
(40).
[0130] Preparation 7:
cis-1-[3-(3,5-dimethyl-piperazin-1-yl)-phenyl]-ethan- one
[0131] The titled compound was prepared in a similar manner as
described in Example 1 from 3-bromo-acetophenone and
cis-2,6-dimethyl-piperazine. MS m/z (relative intensity, 70 eV) 232
(M+, 8), 163 (10), 162 (bp), 132 (9), 70 (12).
[0132] The following tests were used for evaluation of the
compounds according to the invention.
[0133] In vivo Test: Behavior
[0134] For behavioral testing, the animals were placed in separate
motility meter boxes 50.times.50.times.50 cm equipped with an array
of 16.times.16 photocells (Digiscan activity monitor, RXYZM (16)
TAO, Omnitech Electronics, USA), connected to an Omnitech Digiscan
analyzer and a Apple Macintosh computer equipped with a digital
interface board (NB DIO-24, National Instruments, USA). Behavioral
data from each motility meter box, representing the position
(center of gravity) of the animal at each time, were recorded at a
sampling frequency of 2.5 Hz and collected using a custom written
LABView.TM. application. The data from each recording session were
analyzed with respect to distance traveled and small-scale
movements, e.g. stops in the center of the behavior recording
arena, during the recording session. To determine stops in the
center, 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. For behavioral testing of habituated rats, the animals were
placed in the motility meter boxes 30 minutes before the
administration of test compound. Each behavioral recording session
lasted 60 or 30 minutes, starting immediately after the injection
of test compound. Similar behavioral recording procedures was
applied for non-habituated rats, habituated rats and drug
pre-treated rats. Rats pretreated with d-amphetamine are given the
dose 1.5 mg/kg s.c. 5 min before the behavioral session in the
motility meter.
[0135] In vivo Test: Neurochemistry
[0136] After the behavioral activity sessions the rats were
decapitated and their brains rapidly taken out and put on an
ice-cold petri-dish. The limbic forebrain, the striatum, the
frontal cortex and the remaining hemispheral parts of each rat were
dissected and frozen. Each brain part was subsequently analyzed
with respect to its content of monoamines and their metabolites.
The monoaminergic indices analyzed were dopamine (DA),
3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA),
3-methoxytyramine (3-MT), serotonin (5-HT), 5-hydroxyindole acetic
acid (5-HIAA), and noradrenaline (NA). All monoaminergic indices in
the dissected tissue were analyzed by means of HPLC with
electrochemical detection as described by Svensson K, et al., 1986,
NaunynSchmiedeberg's Arch Pharmacol 334: 234-245 and references
cited therein.
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