U.S. patent number RE41,315 [Application Number 11/904,013] was granted by the patent office on 2010-05-04 for modulators of dopamine neurotransmission.
This patent grant is currently assigned to NSAB, Filial af NeuroSearch Sweden AB. Invention is credited to Bengt Andersson, Clas Sonesson, Ingela Marianne Svan, Joakim Tedroff, Nicholas Waters, Susanna Waters.
United States Patent |
RE41,315 |
Sonesson , et al. |
May 4, 2010 |
**Please see images for:
( Certificate of Correction ) ** |
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; R.sub.1 is CF.sub.3,
OSO.sub.2CF.sub.3, OSO.sub.2CH.sub.3, SOR.sub.7, SO.sub.2R.sub.7,
COR.sub.7, CN, OR.sub.3, NO.sub.2, CONHR.sub.3, 3-thiophene,
2-thiophene, 3-furane, 2-furane, F, Cl, Br, or I; R.sub.2 is F, Cl,
Br, I, CN, CF.sub.3, CH.sub.3, OCH.sub.3, OH, and NH.sub.2; R.sub.3
and R.sub.4 are independently H or a C.sub.1-C.sub.4 alkyl; R.sub.5
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.6 is a C.sub.3-C.sub.6 cycloalkyl,
2-tetrahydrofurane, or 3-tetra-hydrofurane; R.sub.7 is a
C.sub.1-C.sub.3 alkyl, CF.sub.3, or N(R.sub.4).sub.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.
##STR00001##
Inventors: |
Sonesson; Clas (Billdal,
SE), Andersson; Bengt (Goteborg, SE), Svan;
Ingela Marianne (Goteborg, SE), Waters; Susanna
(Goteborg, SE), Waters; Nicholas (Goteborg,
SE), Tedroff; Joakim (Danderyd, SE) |
Assignee: |
NSAB, Filial af NeuroSearch Sweden
AB (Sveringe Ballerup, DE)
|
Family
ID: |
20418252 |
Appl.
No.: |
11/904,013 |
Filed: |
December 22, 2000 |
PCT
Filed: |
December 22, 2000 |
PCT No.: |
PCT/SE00/02675 |
371(c)(1),(2),(4) Date: |
June 18, 2002 |
PCT
Pub. No.: |
WO01/46146 |
PCT
Pub. Date: |
June 28, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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Reissue of: |
10168019 |
Jun 18, 2002 |
06924374 |
Aug 2, 2005 |
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Foreign Application Priority Data
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Dec 22, 1999 [SE] |
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9904723 |
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Current U.S.
Class: |
546/192 |
Current CPC
Class: |
A61P
25/18 (20180101); A61P 25/30 (20180101); A61P
15/10 (20180101); A61P 25/20 (20180101); A61P
25/00 (20180101); C07D 295/096 (20130101); A61P
25/06 (20180101); A61P 21/02 (20180101); A61P
25/22 (20180101); A61P 25/14 (20180101); A61P
25/28 (20180101); A61P 43/00 (20180101); A61P
25/16 (20180101); C07D 295/073 (20130101); C07D
241/04 (20130101); A61P 3/04 (20180101); A61P
25/24 (20180101); A61P 25/04 (20180101); C07D
211/18 (20130101) |
Current International
Class: |
C07D
211/04 (20060101); A61K 31/445 (20060101) |
Field of
Search: |
;546/192 ;514/317 |
References Cited
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WO |
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|
Primary Examiner: Desai; Rita J
Attorney, Agent or Firm: Buchanan Ingersoll & Rooney
PC
Claims
What is claimed is:
1. A substituted 4-(phenyl-N-alkyl)-piperidine compound of Formula
1: ##STR00024## wherein: R.sub.1 is selected from the group
consisting of CF.sub.3, .[.OSO.sub.2CF.sub.3, OSO.sub.2CH.sub.3,
SOR.sub.7, SO.sub.2R.sub.7, COR.sub.7,.]. CN, .[.OR.sub.3,
NO.sub.2, CONHR.sub.3, F, Cl, Br, and I, wherein R.sub.7 is as
defined below.]. .Iadd.and SO.sub.2CH.sub.3.Iaddend.; R.sub.2 is
selected from the group consisting of F.[.,.]. .Iadd.and
.Iaddend.Cl.[., Br, I, CN, CF.sub.3, CH.sub.3, OCH.sub.3, OH, and
NH.sub.2.]. ; R.sub.3 is H; R.sub.4 is H; .Iadd.and .Iaddend.
R.sub.5 is .[.selected from the group consisting of.].
C.sub.1-C.sub.4 alkyl.[., 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, and 4,4,4-trifluorobutyl;
R.sub.7 is selected from the group consisting of C.sub.1-C.sub.3
alkyls, CF.sub.3, NH.sub.2 and N(C1-C4 alkyl)2,.]. .Iadd.;
.Iaddend. or a pharmaceutically acceptable salt thereof.
.[.2. A compound or pharmaceutically acceptable salt according to
claims 1, wherein R.sub.2 is CH.sub.3, F or Cl..].
.[.3. A compound according to claim 1, wherein R.sub.1 is CF.sub.3,
R.sub.2 is Cl, R.sub.3 is H, R.sub.4 is H, and R.sub.5 is
n-propyl..].
.[.4. A compound according to claim 1, wherein said compound is
4-(4-chloro-3-trifluoromethyl-phenyl)-1-propyl-piperidine..].
5. A pharmaceutical composition comprising a compound or
pharmaceutically acceptable salt .[.according to.]. .Iadd.thereof
of .Iaddend.claim 1 and one or more pharmaceutically acceptable
carriers.Iadd., .Iaddend..[.or.]. diluents.Iadd., or combinations
thereof.Iaddend..
.[.6. A compound according to claim 1, wherein R.sub.5 is selected
from the group consisting of n-propyl and ethyl..].
.[.7. A compound or pharmaceutically acceptable salt according to
claim 1, wherein R.sub.1 is SO.sub.2CH.sub.3, SO.sub.2CF.sub.3,
COCH.sub.3, CN or CF.sub.3..].
.Iadd.8. The compound or pharmaceutically acceptable salt of claim
1, wherein R.sub.1 is CF.sub.3..Iaddend.
.Iadd.9. The compound or pharmaceutically acceptable salt of claim
1, wherein R.sub.1 is CN..Iaddend.
.Iadd.10. The compound or pharmaceutically acceptable salt of claim
1, wherein R.sub.1 is SO.sub.2CH.sub.3..Iaddend.
.Iadd.11. The compound or pharmaceutically acceptable salt of claim
1, wherein R.sub.2 is F..Iaddend.
.Iadd.12. The compound or pharmaceutically acceptable salt of claim
1, wherein R.sub.2 is Cl..Iaddend.
.Iadd.13. The compound or pharmaceutically acceptable salt thereof
of claim 1, wherein R.sub.5 is selected from the group consisting
of butyl, n-propyl and ethyl..Iaddend.
.Iadd.14. The compound or pharmaceutically acceptable salt thereof
of claim 1, wherein R.sub.5 is selected from the group consisting
of n-propyl and ethyl..Iaddend.
.Iadd.15. The compound or pharmaceutically acceptable salt thereof
of claim 1, wherein R.sub.5 is butyl..Iaddend.
.Iadd.16. The compound or pharmaceutically acceptable salt thereof
of claim 1, wherein R.sub.5 is n-propyl..Iaddend.
.Iadd.17. The compound or pharmaceutically acceptable salt thereof
of claim 1, wherein R.sub.5 is ethyl..Iaddend.
Description
FIELD OF THE INVENTION
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
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.
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.
Compounds belonging to the class of substituted
4-phenyl-N-alkyl)piperazine and substituted
4-(phenyl-N-alkyl)piperidines 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
antagonists or agonists with high affinity for dopamine
receptors.
A number of 4-phenylpiperazines and 4-phenyl-piperidine derivatives
are known and described, for example Costall et al. European J.
Pharm. 31, 94, (1975), and Mewshaw et al. Bioorg. Med. Chem. Lett.,
8, 295, (1998). The reported compounds are substituted
4-phenyl-piperazines, most of them being 2-, 3- or 4-OH phenyl
substituted and displaying DA autoreceptor agonist properties.
Fuller R. W. et al., J. Pharmacol. Exp. Therapeut. 218, 636, (1981)
disclose substituted piperazines (e.g.
1-(m-trifluoromethylphenyl)piperazine) 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-dihydroxyphenylacetic 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.
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. In addition, Akasaka et al (EP 0675118)
disclose bifenylderivatives of piperazines, which exhibits dopamine
D.sub.2 receptor antagonism and/or 5-HT.sub.2 receptor
antagonism.
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) 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
Among the compounds belonging to the class of substituted
4-(phenyl-N-alkyl)piperazine and substituted
4-phenyl-N-alkyl)piperidines previously reported some are inactive
in the CNS, some display serotonergic or mixed
serotonergic/dopaminergic pharmacological profiles while some are
full or partial dopamine receptor antagonists with high affinity
for dopamine receptors.
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.
In the work leading to the present invention, it was found that it
is desired to provide substances with specific pharmacological
properties, namely 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 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.
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 D.sub.2 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.
Thus, the compounds of this invention surprisingly show a
dopaminergic action profile with clear antagonist like effects on
brain neurochemistry but no, or mild, antagonist like effects, on
normal behavior, they can activate animals with a low baseline
activity, but can also inhibit 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.
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.
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.
The present invention relates to new di-substituted
4-(phenyl-N-alkyl)-piperazines and di-substituted
4-(phenyl-N-alkyl)-piperidines in the form of free base or
pharmaceutically acceptable salts thereof, process for their
preparation, pharmaceutical compositions containing said
therapeutically active compound and to the use of said active
compound in therapy. An objective of the invention is to provide a
compound for therapeutic use, and more precisely a compound for
modulation of dopaminergic systems in the mammalian brain including
man. It is also an objective of the invention to provide a compound
with therapeutic effects after oral administration.
More precisely, the present invention is directed toward
substituted 4-(phenyl N-alkyl)-piperazine or
4-(phenyl-N-alkyl)-piperidine compounds of Formula 1: ##STR00002##
wherein: X is selected from the group consisting of N, CH, and C,
however X may only be C when the compound comprises a double bind
at the dotted line; R.sub.1 is selected from the group consisting
of CF.sub.3, OSO.sub.2CF.sub.3, OSO.sub.2CH.sub.3, SOR.sub.7,
SO.sub.2R.sub.7, COR.sub.7, CN, OR.sub.3, NO.sub.2, CONHR.sub.3,
3-thiophene, 2-thiophene, 3-furane, 2-furane, F, Cl, Br, and I,
wherein R.sub.7 is as defined below; R.sub.2 is selected from the
group consisting of F, Cl, Br, I, CN, CF.sub.3, CH.sub.3,
OCH.sub.3, OH, and NH.sub.2; R.sub.3 and R.sub.4 are independently
selected from the group consisting of H and C.sub.1-C.sub.4 alkyls;
R.sub.5 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.6 is selected from the group consisting of
C.sub.3-C.sub.6 cycloalkyls, 2-tetrahydrofurane, and
3-tetrahydrofurane; R.sub.7 is selected from the group consisting
of C.sub.1-C.sub.3 alkyls, CF.sub.3, and N(R.sub.4).sub.2, wherein
R.sub.4 is as defined above, and pharmaceutically acceptable salts
thereof.
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.
Anxiety disorders, obsessive-compulsive disorder and other impulse
control disorders, post traumatic stress syndrome, personality
disorders, and conversion hysteria may also be treated with the
compounds in the invention. Other indications include sleep
disorders, "jet lag" and disorders of sexual functions.
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.
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.
DETAILED DESCRIPTION OF THE INVENTION
Pharmacology
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 (D.sub.1, D.sub.2, D.sub.3, D.sub.4, D.sub.5)
with the aim to improve efficacy and reduce side effects.
The present invention offers another principle for novel
therapeutics based on interactions with dopamine systems. The
compounds of this invention have effects on brain neurochemistry
similar to antagonists at dopamine D.sub.2 receptors. In contrast
to currently used dopamine receptor antagonists the compounds of
this invention show no, or limited inhibitory effects on
locomotion. They can even be mildly activating. Surprisingly, the
compounds of the invention can actually also reduce the increase in
activity induced by direct or indirect dopaminergic agonists, i.e.
d-amphetamine and congeners. Furthermore, some of the compounds
display a high oral bioavalability.
Below, some examples of preferred compounds according to the
invention are discussed more in detail.
One preferred compound is
4-(4-chloro-3-trifluoromethyl-phenyl)-1-propyl-piperidine, further
illustrated in Example 9. In rat,
4-(4-chloro-3-trifluoromethyl-phenyl)-1-propyl-piperidine increases
3,4-dihydroxyphenyl-acetic acid in the striatum from 1089.+-.102
(controls) to 1680.+-.136 ng/g tissue, p<0.05, n=4, at 50
.mu.mol/kg s.c. Surprisingly, it has no significant inhibition on
spontaneous behavior; 1287.+-.272 cm/30 min (for controls) vs.
944.+-.114 cm/30 min at 50 .mu.mol/kg s.c. Nor did it affect the
locomotor activity of habituated rats, from 1381.+-.877 cm/60 min
(for the controls) to 1300.+-.761 cm/60 min at 50 .mu.mol/kg
s.c.
d-Amphetamine induced hyperactivity was significantly reduced from
8376.+-.2188 cm/30 min, to 3399.+-.1247 cm/30 min, at 50 .mu.mol/kg
s.c., p<0.05, n=4, Fischer PLSD. Surprisingly,
4-(4-chloro-3-trifluoromethyl-phenyl)-1-propyl-piperidine has an
oral availability (F) of 55% in rat.
Similar to
4-(4-chloro-3-trifluoromethyl-phenyl)-1-propyl-piperidine,
4-(4-fluoro-3-trifluoromethylphenyl)-1-propyl-piperidine, which the
compound according to Example 43, increases
3,4-dihydroxyphenyl-acetic acid in the striatum from 974.+-.39 (for
controls) to 1895.+-.100 ng/g tissue, p<0.05, n=4, at 100
.mu.mol/kg s.c. According to the behavioral assay in nonpretreated
rats it mildly increases locmotoractivity from 14.+-.4 cm/30 min
(for the controls) to 540.+-.128 cm/30 min, 30-60 min, p<0.05,
n=4, at 100 .mu.mol/kg s.c. Thus,
4-(4-fluoro-3-trifluoromethylphenyl)-1-propyl-piperidine displays
the properties desired according to the present invention.
The importance of the substitution in the para position is
demonstrated by 1-propyl-4-(3-triflouromethyl-phenyl) piperazine,
which is not a compound according to the present invention, which
carries the same substituent as
4-(4-chloro-3-trifluoromethyl-phenyl)-1-propyl-piperidene (the
compound of Example 9) in the meta position but lacks substitution
in the para position. With this change the neurochemical effects
are retained but the effects on behavior are significantly altered.
Thus, 1-propyl-4-(3-trifluoromethyl-phenyl)-piperazine increases
3,4-dihydroxyphenyl-acetic acid in the striatum from 1066.+-.46
(controls) ng/g tissue to 3358.+-.162 ng/g tissue at 50 .mu.mol/kg
s.c., p<0.05, n=4, followed by behavioral inhibition from
1244.+-.341 cm/60 min (controls) to 271.+-.137 at 50 .mu.mol/kg
s.c., p<0.05, n=4. These properties are not desired according to
the present invention, and accordingly
1-propyl-4-(3-trifluoromethyl-phenyl)-piperazine is not a substance
according to the present invention.
1-propyl-4-(3-trifluoromethyl-phenyl)-piperazine has an oral
availability (F) of 9,5% in rat.
1-(4-Chloro-3-nitro-phenyl)-4-propyl-piperazine, which is the
compound of Example 19, increases 3,4-dihydroxyphenyl-acetic acid
in the striatum from 1074.+-.42 (for controls) to 1693.+-.104 ng/g
tissue, p<0.05, n=4, at 100 .mu.mol/kg s.c. According to the
behavioral assay it mildly increases locomotoractivity from
56.+-.25 cm/30 min (for the controls) to 266.+-.89 cm/30 min, 30-60
min, p=0.06, n=4, at 100 .mu.mol/kg s.c.
1-(4-Chloro-3-nitro-phenyl)-4-propyl-piperazine reduces
d-amphetamine induced hyperactivity from 29792.+-.3212 cm/60 min
(d-amphetamine controls) to 3767.+-.2332 cm/60min, p<0.05, n=4,
at 100 .mu.mol/kg s.c. Thus,
1-(4-Chloro-3-nitro-phenyl)-4-propyl-piperazine shows the desired
properties.
cis-4-(4-Fluoro-3-trifluoromethyl-phenyl)-2,6-dimethyl-1-propyl-piperazin-
e, which is the compound according to Example 34, has the ability
to increase spontaneous behavior in the habituated rat; from
415.+-.214 cm/60 min (for controls) to 919.+-.143 cm/60 min,
p=0.056, n=4, at 33 .mu.mol/kg s.c. in combination with a slight
increase in 3,4-dihydroxyphenyl-acetic acid in the striatum from
1015.+-.61 (for controls) to 1278.+-.143 ng/g tissue, p=0.13, n=4,
at 33 .mu.mol/kg s.c.
The ability to inhibit d-amphetamine induced hyperactivity is
demonstrated by
cis-4-(3,4-dichloro-phenyl)-2,6-dimethyl-1-propyl-piperazine, which
is the compound of Example 35. d-Amphetamine induced hyperactivity
is reduced from 19595.+-.2999 cm/60 min (for d-amphetamine
controls) to 6514.+-.3374 cm/60 min, p<0.05, n=4, at 100
.mu.mol/kg s.c.
The compounds according to the invention are especially suitable
for treatment of disorders in the central nervous system, and
particularly for treatment of dopamine mediated disorders. They
may, e.g. used to ameliorate symptoms of mood disorders, in
obesitas as an anorectic agent and in other eating disorders, to
improve cognitive functions and related emotional disturbances, to
improve cognitive and motor dysfunctions associated with
developmental disorders, to improve all symptoms of psychosis,
including schizophrenia and schizophreniform disorders, to improve
ongoing symptoms as well as to prevent vent the occurrence of new
psychotic episodes, to regulate pathological disorders due to
intake of food, coffee, tea, tobacco, alcohol and addictive drugs
etc.
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; schizoaffective 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,
post-traumatic 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;
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, Creutzfeidt-Jakob disease, dead trauma, Huntington's
disease, HIV disease, Pick's disease, and diffuse Lewy body
dementia; conversion hysteria; conditions connected to normal
aging, such as disturbances in motor functions and mental
functions; 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; pain in conditions
characterized by increased muscular tone, such as fibromyalgia,
myofascial syndrome, dystonia, and parkinsonism; as well as
conditions related to the above that fall within the larger
categories but does not meet the criteria of any specific disorder
within those categories. Synthesis
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: ##STR00003##
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 ethylacetate 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.
Another convenient method of synthesis of the present compounds
involves reductive amination with an amine of Formula 2:
##STR00004## 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.
Compounds of Formula 3: ##STR00005## wherein X.dbd.N is
accomplished by reacting compounds of Formula 4: ##STR00006## with
compounds of Formula 5: ##STR00007## where Z is a leaving group
like iodide. Other leaving groups besides iodide may be used on the
alkylgroup, 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.
Compounds of the Formula 1 wherein X.dbd.N is also accomplished by
reacting compounds of Formula 6: ##STR00008## with an aryl
substituted with a leaving group of Formula 7: ##STR00009## 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).
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.
Compounds of the Formula 1 wherein X.dbd.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.
Compounds of the Formula 1 wherein X.dbd.CH or C is also
accomplished by transition metal catalyzed cross-coupling reaction,
known as, for example, Suzuki and Stille reactions, to those
skilled in the art.
The reaction may be carried out between compounds of Formula 8:
##STR00010## 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: ##STR00011## (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, MgI) 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.
Alternatively, the transition metal catalyzed cross-coupling
coupling reaction can be performed with the opposite substitution
pattern: ##STR00012## with an heteroaryl/alkenyl substituted with
an leaving group of Formula 10: ##STR00013## 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.
Compounds of Formula 11: ##STR00014## can be prepared by catalytic
hydrogenation of the tetrahydropyridine 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 tetrahydropyridine analog which can
further be reduced with catalytic hydrogenation.
Another convenient method of syntheses of compounds of the Formula
1, wherein X.dbd.CH or C is also accomplished by treating
arylhalides of Formula 7: ##STR00015## wherein Z is Cl, Br, or I,
with alkyllithium reagents, for example, butyllithium,
sec-butyllithium or tert-butyl-lithium, 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 0.degree. C. The intermediate lithium
anions or magnesium anions thus formed may then be further reacted
with a suitable electrophile of Formula 12: ##STR00016## wherein A
is defined as a protecting group like t-Boc (tert-butoxycarbonyl),
Fmoc (fluorenylmethoxycarbonyl), Cbz (benzyloxycarbonyl) or an
alkylgroup like benzyl. The intermediates of formula 13:
##STR00017## which are formed require that the hydroky group be
removed so as to result in compounds of Formula 1 (X.dbd.CH or C).
This step may be accomplished by one of several standard methods
known in the art. For example, a thiocarbonyl 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.
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. 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
.alpha.-chloroethyl chloroformate (J. Org. Chem., vol 49, 1984,
2081-2082).
It is further possible to convert a radical R1 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.
In summary, the general process for preparing the present compounds
has six main variations, which may briefly be described as follows:
##STR00018## or according to Scheme 2: ##STR00019## or according to
Scheme 3: ##STR00020## or according to Scheme 4: ##STR00021## or
according to Scheme 5: ##STR00022## or according to Scheme 6:
##STR00023##
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. The term cycloalkyl refers to a radical of a
saturated cyclic hydrocarbon such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl.
The term "patient" used herein refers to an individual in need of
the treatment and/or prevention according to the invention.
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.
Both organic and inorganic acids can be employed to form non-toxic
pharmaceutically acceptable acid addition salts of the compounds of
this 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. Such substances are well known to people
skilled in the art and may for example be pharmaceutically
acceptable adjuvants, carriers and preservatives.
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.
To produce pharmaceutical preparations containing the compound of
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 polyvinylpyrrolidine, 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.
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,
cornstarch or amylopectin), cellulose derivatives or gelatine. Also
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.
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.
Solutions for parenteral applications by injection can be prepared
in an aqueous solution of a watersoluble 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.
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.
In therapeutical treatment an effective amount or a therapeutic
amount of the compounds of 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 invention is further illustrated in the examples below, which
in no way are intended to limit the scope of the invention.
EXAMPLE 1
1-(4-Chloro-3-trifluoromethyl-phenyl)-4-propyl-piperazine
A mixture of 5-bromo-2-chlorobenzotrifluoride (0.2 g, 0.85 mmol),
n-propyl piperazine (0.15 g, 1.17 mmol), sodium tert-butoxide
(0.134 g) dppf (14 mg) and [Pd.sub.2(dba).sub.3 (10 mg) in dioxane
(5 ml) was heated under argon at 100.degree. C. for 24 h. After
cooling to room temperature, the reaction mixture was taken up in
Et.sub.2O (40-50 ml) and washed with brine (15-20 ml). The organic
fraction was dried (MgSO.sub.4), filtered and evaporated to
dryness. The crude material was purified by flash chromatography on
silica gel using CH.sub.2Cl.sub.2:MeOH (9:1 (v/v)). The amine was
converted into the HCl-salt and recrystallized from
ethanol/diethylether; m.p. 268.degree. C. (HCl); MS m/z (rel.
intensity, 70 eV)) 307 (M+, 6), 279 (33), 277 (98), 70 (bp), 56
(40). Rf=0.35 (EtOAc)
EXAMPLE 2
1-(3-Chloro-5-trifluoromethyl-phenyl)-4-propyl-piperazine
A suspension of 1-(3-Chloro-5-trifluoromethyl-phenyl)-piperazine
(100 mg) and ground K.sub.2CO.sub.3 (200 mg) was stirred in
CH.sub.3CN (30 mL) at room temperature. A solution of
1-bromo-propyl (52 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 the
title compound (85 mg). MS m/z (relative intensity, 70 eV) 306 (M+,
25), 277 (bp), 234 (23), 206 (23), 179 (23).
EXAMPLE 3
1-(3-Chloro-5-trifluoromethyl-phenyl)-4-ethyl-piperazine
Beginning with 1-(3-Chloro-5-trifluoromethyl-phenyl)-piperazine and
iodoethane, the title compound was recovered by the procedure
described in Example 2. MS m/z (rel. intensity, 70 eV)) 292 (M+,
bp), 277 (88), 234 (33), 206 (55), 179 (49).
EXAMPLE 4
1-(3-Chloro-5-trifluoromethyl-phenyl)-4-isopropyl-piperazine
Beginning with 1-(3-Chloro-5-trifluoromethyl-phenyl)-piperazine and
iso-propylbromide, the title compound was recovered by the
procedure described in Example 2. MS m/z (rel. intensity, 70 eV)
306 (M+, 30), 291 (bp), 206 (25), 193 (15), 179 (20).
EXAMPLE 5
1-(4-Chloro-3-trifluoromethyl-phenyl)-4-ethyl-piperazine
Beginning with 1-(4-Chloro-3-trifluoromethyl-phenyl)-piperazine and
bromo-ethane, the title compound was recovered by the procedure
described in Example 2. MS m/z (rel. intensity, 70 eV) 293 (M+, 6),
292 (30), 277 (29), 57 (bp), 56 (41).
EXAMPLE 6
1-(3,5-Bis-trifluoromethyl-phenyl)-4-propyl-piperazine
Beginning with 1-(3,5-Bis-trifluoromethyl-phenyl)-4-piperazine and
1-propyliodide, the title compound was recovered by the procedure
described in Example 2. m.p. 266.1 (HCl), MS m/z (rel. intensity,
70 eV) 340 (M+, 20), 311 (95), 240 (30), 70 (bp), 56 (46).
EXAMPLE 7
1-(3,5-Bis-trifluoromethyl-phenyl)-4-ethyl-piperazine
Beginning with 1-(3,5-Bis-trifluoromethyl-phenyl)-4-piperazine and
iodoethane, the title compound was recovered by the procedure
described in Example 2. MS m/z (rel. intensity, 70 eV) 326 (M+,
65), 311 (bp), 268 (35), 240 (70), 213 (65).
EXAMPLE 8
4-(4-Chloro-3-trifluoromethyl-phenyl)-1-butyl-piperidine
Beginning with 4-(4-Chloro-3-trifluoromethyl-phenyl)-piperidine and
1-butylbromide, the title compound was recovered by the procedure
described in Example 2. MS m/z (rel. intensity, 70 eV) 319 (M+, 6),
278 (31), 277 (19), 276 (bp), 70 (30).
EXAMPLE 9
4-(4-Chloro-3-trifluoromethyl-phenyl)-1-propyl-piperidine
Beginning with 4-(4-Chloro-3-trifluoromethyl-phenyl)-piperidine and
1-propyliodide, the title compound was re-covered by the procedure
described in Example 2. m.p. 218-220.degree. C. (HCl), MS m/z (rel.
intensity, 70 eV) 305 (M+, 4), 278 (35), 277 (13), 276 (bp), 70
(40).
EXAMPLE 10
4-(4-Chloro-3-trifluoromethyl-phenyl)-1-ethyl-piperidine
Beginning with 4-(4-Chloro-3-trifluoromethyl-phenyl)-piperidine and
iodoethane, the title compound was recovered by the procedure
described in Example 2. MS m/z (rel. intensity, 70 eV) 291 (M+, 6),
278 (29), 277 (11), 276 (bp), 70 (50).
EXAMPLE 11
1-(3,4-dichloro-phenyl)-4-propyl-piperazine
Beginning with 1-(3,4-dichloro-phenyl)-4-piperazine and
iodo-propane, the title compound was recovered by the procedure
described in Example 2. MS m/z (rel. intensity, 70 eV) 273 (M+, 7),
272 (37), 245 (64), 243 (bp), 70 (48).
EXAMPLE 12
1-(2-Chloro-5-trifluoromethyl-phenyl)-4-propyl-piperazine
Beginning with 1-(2-Chloro-5-trifluoromethyl-phenyl)-piperazine and
1-iodopropane, the title compound was recovered by the procedure
described in Example 2. m.p. 234.degree. C. (HCl), MS m/z (rel.
intensity, 70 eV) 306 (M+, 20), 279 (34), 277 (bp), 70 (99), 56
(48).
EXAMPLE 13
2-Fluoro-5-(4-propyl-piperazin-1-yl)-benzonitrile
Beginning with 2-fluoro-5-piperazin-1-yl-benzo-nitrile and
1-iodopropane, the title compound was recovered by the procedure
described in Example 2. MS m/z (rel. intensity, 70 eV) 247 (M+,
25), 218 (bp), 175 (28), 147 (33), 70 (65).
EXAMPLE 14
1-(4-Methyl-3-nitro-phenyl)-4-propyl-piperazine
Beginning with 1-(4-methyl-3-nitro-phenyl)-piperazine and
1-bromopropane, the title compound was recovered by the procedure
described in Example 2. MS m/z (rel. intensity, 70 eV) 263 (M+,
26), 234 (bp), 191 (19), 70 (84), 56 (40).
EXAMPLE 15
1-Ethyl-4-(4-Methyl-3-nitro-phenyl)-piperazine
Beginning with 1-(4-methyl-3-nitro-phenyl)-piperazine and
1-bromoethane, the title compound was recovered by the procedure
described in Example 2. MS m/z (rel. intensity, 70 eV) 249 (M+,
53), 234 (47), 84 (36), 57 (bp), 56 (46).
EXAMPLE 16
1-Allyl-4-(4-Methyl-3-nitro-phenyl)-piperazine
Beginning with 1-(4-methyl-3-nitro-phenyl)-piperazine and
allylbromide, the title compound was recovered by the procedure
described in Example 2. MS m/z (rel. intensity, 70 eV) 261 (M+,
60), 96 (70), 69 (bp), 68 (48), 56 (73).
EXAMPLE 17
1-Isopropyl-4-(4-Methyl-3-nitro-phenyl)-piperazine
Beginning with 1-(4-methyl-3-nitro-phenyl)-piperazine and
1-isopropylbromide, the title compound was recovered by the
procedure described in Example 2. MS m/z (rel. intensity, 70 eV)
263 (M+, 31), 249 (15), 248 (bp), 84 (15), 56 (42).
EXAMPLE 18
1-Butyl-4-(4-Methyl-3-nitro-phenyl)-piperazine
Beginning with 1-(4-methyl-3-nitro-phenyl)-piperazine and
1-butylbromide, the title compound was recovered by the procedure
described in Example 2. MS m/z (rel. intensity, 70 eV) 277 (M+,
23), 234 (bp), 191 (17), 70 (64), 56 (33).
EXAMPLE 19
1-(4-Chloro-3-nitro-phenyl)-4-propyl-piperazine
Beginning with 1-(4-Chloro-3-nitro-phenyl)-piperazine and
1-bromopropane, the title compound was recovered by the procedure
described in Example 2. m.p. 249.degree. C. (HCl); MS m/z (rel.
intensity, 70 eV) 283 (M+, 27), 254 (87), 165 (bp), 153 (78), 56
(90).
EXAMPLE 20
1-(4-Fluoro-3-trifluoromethyl-phenyl)-4-propyl-piperazine
Beginning with 1-(4-fluoro-3-trifluoromethyl-phenyl)-piperazine and
1-bromopropane, the title compound was recovered by the procedure
described in Example 2. m.p. 238.degree. C. (HCl); MS m/z (rel.
intensity, 70 eV) 290 (M+, 17), 261 (70), 190 (34), 70 (bp), 56
(44).
EXAMPLE 21
1-(3-Fluoro-5-trifluoromethyl-phenyl)-4-propyl-piperazine
Beginning with 1-(3-fluoro-5-trifluoromethyl-phenyl)-piperazine and
1-bromopropane, the title compound was recovered by the procedure
described in Example 2. m.p. 242.degree. C. (HCl); MS m/z (rel.
intensity, 70 eV) 290 (M+, 34), 261 (bp), 218 (22), 190 (20), 70
(37).
EXAMPLE 22
1-Ethyl-4-(3-fluoro-5-trifluoromethyl-phenyl)-piperazine
Beginning with 1-(3-fluoro-5-trifluoromethyl-phenyl)-piperazine and
1-iodoethane, the title compound was recovered by the procedure
described in Example 2; MS m/z (rel. intensity, 70 eV) 276 (M+,
46), 261 (41), 190 (30), 84 (30), 57 (bp).
EXAMPLE 23
1-Butyl-4-(3-fluoro-5-trifluoromethyl-phenyl)-piperazine
Beginning with 1-(3-fluoro-5-trifluoromethyl-phenyl)-piperazine and
1-bromobutane, the title compound was recovered by the procedure
described in Example 2; MS m/z (rel. intensity, 70 eV) 304 (M+,
22), 261 (bp), 218 (22), 190 (21), 70 (46).
EXAMPLE 24
1-Isopropyl-4-(3-fluoro-5-trifluoromethyl-phenyl)-piperazine
Beginning with 1-(3-fluoro-5-trifluoromethyl-phenyl)-piperazine and
isopropylbromide, the title compound was recovered by the procedure
described in Example 2; MS m/z (rel. intensity, 70 eV) 290 (M+,
30), 275 (bp), 190 (20), 84 (23), 56 (64).
EXAMPLE 25
1-(3-Methanesulfonyl-4-methoxy-phenyl)-4-propyl-piperazine
Beginning with 1-(3-Methanesulfonyl-4-methoxy-phenyl)-piperazine
and n-Pr-I, the title compound was recovered by the procedure
described in Example 2;: MS m/z (rel. intensity, 70 eV)) 312 (M+,
38), 284 (17), 283 (bp), 70 (49), 56 (17).
EXAMPLE 26
1-Butyl-4-(3-Methanesulfonyl-4-methoxy-phenyl)-piperazine
Beginning with 1-(3-Methanesulfonyl-4-methoxy-phenyl)-piperazine
and n-Bu-Br, the title compound was recovered by the procedure
described in Example 2; MS m/z (rel. intensity, 70 eV)) 326 (M+,
32), 284 (16), 283 (bp), 70 (58), 56 (23).
EXAMPLE 27
1-Ethyl-4-(3-Methanesulfonyl-4-methoxy-phenyl)-piperazine
Beginning with 1-(3-Methanesulfonyl-4-methoxy-phenyl)-piperazine
and Et-I, the title compound was recovered by the procedure
described in Example 2: MS m/z (rel. intensity, 70 eV)) 298 (M+,
81), 283 (45), 84 (36), 57 (bp), 56 (41).
EXAMPLE 28
1-Isopropyl-4-(3-Methanesulfonyl-4-methoxy-phenyl)-piperazine
Beginning with 1-(3-Methanesulfonyl-4-methoxy-phenyl)-piperazine
and isopropylbromide, the title compound was recovered by the
procedure described in Example 2: MS m/z (rel. intensity, 70 eV))
312 (M+, 43), 297 (bp), 84 (35), 71 (33), 56 (73).
EXAMPLE 29
1-Allyl-4-(3-Methanesulfonyl-4-methoxy-phenyl)-piperazine
Beginning with 1-(3-Methanesulfonyl-4-methoxy-phenyl)-piperazine
and allylbromide, the title compound was recovered by the procedure
described in Example 2: MS m/z (rel. intensity, 70 eV)) 310 (M+,
91), 214 (73), 96 (86), 69 (80), 56 (bp).
EXAMPLE 30
2-Methanesulfonyl-4-(4-propyl-piperazin-1-yl)-phenol
1-(3-Methanesulfonyl-4-methoxy-phenyl)-4-propyl-piperazine (30 mg)
was dissolved in 48-% HBr (2 ml) and stirred at 120.degree. C.
under an Argon-atmosphere for 3 h. The excess of HBr was then
evaporated and absolute ethanol added and evaporated. This
procedure was repeated several times to yield an residue of
2-Methanesulfonyl-4-(4-propyl-piperazin-1-yl)-phenol.times.HBr. MS
m/z (relative intensity, 70 eV) 298 (M+, 35), 269 (bp), 226 (15),
199 (12), 70 (62).
EXAMPLE 31
4-(4-Butyl-piperazine-1-yl)-2-methanesulfonyl-phenol
Beginning with
1-butyl-4-(3-Methanesulfonyl-4-methoxy-phenyl)-piperazine, the
title compound was recovered by the procedure described in Example
30: MS m/z (rel. intensity, 70 eV)) 312 (M+, 29), 270 (15), 269
(bp), 226 (13), 70 (29).
EXAMPLE 32
4-(4-Isopropyl-piperazine-1-yl)-2-methanesulfonyl-phenol
Beginning with
1-isopropyl-4-(3-Methanesulfonyl-4-methoxy-phenyl)-piperazine, the
title compound was recovered by the procedure described in Example
30: MS m/z (rel. intensity, 70 eV)) 298 (M+, 39), 284 (18), 283
(bp), 84 (23), 56 (51).
EXAMPLE 33
cis-4-(4-Chloro-3-trifluoromethyl-phenyl)-2,6-dimethyl-1-propyl-piperazine
Beginning with 5-bromo-2-chlorobenzotrifluoride and
cis-2,6-dimethyl-1-propyl-piperazine, the title compound was
recovered by the procedure described in Preparation 9: m.p.
256.degree. C. (HCl), MS m/z (rel. intensity, 70 eV)) 335 (M+, 5),
305 (55), 112 (bp), 70 (67), 56 (82).
EXAMPLE 34
cis-4-(4-Fluoro-3-trifluoromethyl-phenyl)-2,6-dimethyl-1-propyl-piperazine
Beginning with 5-bromo-2-fluorobenzotrifluoride and
cis-2,6-dimethyl-1-propyl-piperazine, the title compound was
recovered by the procedure described in Preparation 9: m.p.
221.degree. C. (HCl), MS m/z (rel. intensity, 70 eV)) 318 (M+, 32),
289 (74), 112 (bp), 70 (71), 56 (85).
EXAMPLE 35
cis-4-(3,4-dichloro-phenyl)-2,6-dimethyl-1-propyl-piperazine
Beginning with 4-bromo-1,2-dichlorobenzene and
cis-2,6-dimethyl-1-propyl-piperazine, the title compound was
recovered by the procedure described in Preparation 9: m.p.
225.degree. C. (HCl), MS m/z (rel. intensity, 70 eV)) 301 (M+, 24),
271 (64), 112 (bp), 70 (47), 56 (53).
EXAMPLE 36
4-(4-Fluoro-3-trifluoromethylphenyl)-1-propyl-1,2,3,6-tetrahydropyridine
Beginning with
4-(4-fluoro-3-trifluoromethyl-phenyl)-1-propyl-piperidine-4-ol, the
titled compound was recovered by the procedure described in
Preparation 5: MS m/z (rel. intensity, 70 eV)) 287 (M+, 20), 259
(15), 258 (bp), 177 (17), 147 (21).
EXAMPLE 37
4-(3-Fluoro-5-trifluoromethylphenyl)-1-propyl-1,2,3,6-tetrahydropyridine
Beginning with
4-(3-fluoro-5-trifluoromethyl-phenyl)-1-propyl-piperidine-4-ol, the
titled compound was recovered by the procedure described in
Preparation 5: MS m/z (rel. intensity, 70 eV)) 287 (M+, 27), 259
(14), 258 (bp), 177 (6), 146 (7).
EXAMPLE 38
4-(2-Chloro-5-trifluoromethylphenyl)-1-propyl-1,2,3,6-tetrahydropyridine
Beginning with
4-(2-Chloro-5-trifluoromethylphenyl)-1-propyl-piperidine-4-ol, the
titled compound was recovered by the procedure described in
Preparation 5. MS m/z (rel. intensity, 70 eV) 303 (M+, 18), 276
(32), 274 (bp), 177 (6), 128 (5).
EXAMPLE 39
4-(1-Propyl-1,2,3,6-tetrahydro-pyridine-4-yl)-2-trifluoromethyl-phenylamin-
e
4-Pyridin-4-yl-2-trifluoromethyl-phenylamine (270 mg) was dissolved
in 1-iodo-propane (2 ml) and heated to 100.degree. C. for 2 h. Then
the voilatiles were evaporated and the residue redissolved in abs
EtOH (20 ml) and NaBH.sub.4 (800 mg) was added portions wise at
-20.degree. C. The mixture was then allowed to reach r.t. and
stirred over night. To the mixture was added 10% Na.sub.2CO.sub.3
solution (20 ml). The aqueous layer was extracted with
CH.sub.2Cl.sub.2 and the combined organic phases were dried
(MgSO.sub.4), filtered and evaporated to dryness. The crude product
was purified by flash chromatography (MeOH: CH.sub.2Cl.sub.2 (1:9
(v/v)). Collection of the fractions containing pure product and
evaporation of the solvent afforded pure
4-(1-Propyl-1,2,3,6-tetrahydro-pyridine-4-yl)-2-trifluoromethyl-phenylami-
ne (200 mg). MS m/z (rel. intensity, 70 eV)) 284 (M+, 53), 255
(bp), 144 (40), 127 (39), 70 (39). Rf 0.28 (MeOH)
EXAMPLE 40
2,4-Difluoro-N,N-dimethyl-5-(1-propyl-1,2,3,6-tetrahydro-pyridin-4-yl-benz-
enesulfonamide
Beginning with
2,4-difluoro-N,N-dimethyl-5-pyridin-4-yl-benzenesulfonamide, the
titled compound was recovered by the procedure described in Example
39: MS m/z (rel. intensity, 7.0 eV)) 344 (M+, 22), 316 (18), 315
(bp), 207 (10), 164 (9). Rf 0.27 (MeOH)
EXAMPLE 41
4-(3-Methanesulfonyl-4-methoxy-phenyl)-1-propyl-1,2,3,6-tetrahydro-pyridin-
e
Beginning with 4-(3-methanesulfonyl-4-methoxy-phenyl)-pyridine, the
titled compound was recovered by the procedure described in Example
39: MS m/z (rel. intensity, 70 eV)) 309 (M+, 31), 281 (12), 280
(bp), 128 (20), 115 (30).
EXAMPLE 42
2-Fluoro-5-(1-propyl-1,2,3,6-tetrahydropyridine-4-yl)-benzonitrile
Beginning with 2-Fluoro-5-pyridine-4-yl-benzonitrile, the titled
compound was recovered by the procedure described in Example 39: MS
m/z (rel. intensity, 70 eV)) 244 (M+, 24), 217 (16), 216 (bp), 158
(11), 134 (10).
EXAMPLE 43
4-(4-Fluoro-3-trifluoromethylphenyl)-1-propyl-piperidine
Beginning with
4-(4-Fluoro-3-trifluoromethylphenyl)-1-propyl-1,2,3,6-tetrahydropyridine,
the titled compound was recovered by the procedure described in
Preparation 6: m.p. 195-197.degree. C. (HCl), MS m/z (rel.
intensity, 70 eV)) 289 (M+, 4), 261 (15), 260 (bp), 177 (7), 70
(13).
EXAMPLE 44
4-(3-Fluoro-5-trifluoromethylphenyl)-1-propyl-piperidine
Beginning with
4-(3-Fluoro-5-trifluoromethylphenyl)-1-propyl-1,2,3,6-tetrahydrtpyridine,
the titled compound was recovered by the procedure described in
Preparation 6: m.p. 215.degree. C. (HCl) MS m/z (rel. intensity, 70
eV)) 289 (M+, 4), 261 (15), 260 (bp), 177 (6), 70 (11).
EXAMPLE 45
4-(2-Chloro-5-trifluoromethylphenyl)-1-propyl-piperidine
Beginning with
4-(2-Chloro-5-trifluoromethylphenyl)-1-propyl-1,2,3,6-tetrahydropyridine,
the titled compound was recovered by the procedure described in
Preparation 6: MS m/z (rel. intensity, 70 eV)) 305 (M+, 4), 290
(3), 278 (32), 277 (15), 276 (bp).
EXAMPLE 46
4-(1-Propyl-piperidin-4-yl)-2-trifluoromethyl-phenylamine
Beginning with
4-(1-Propyl-1,2,3,6-tetrahydropyridine-4-yl)-2-trifluoromethyl-phenylamin-
e, the titled compound was recovered by the procedure described in
Preparation 6: MS m/z (rel. intensity, 70 eV)) 286 (M+, 2), 257
(17), 98 (10), 96 (8), 70 (bp), Rf=0.28 (MeOH).
EXAMPLE 47
2,4-Difluoro-N,N-dimethyl-5-(1-propyl-piperidin-4-yl-benzenesulfonamide
Beginning with
2,4-difluoro-N,N-dimethyl-5-(1-propyl-1,2,3,6-tetrahydro-pyridin-4-yl-ben-
zene-sulfonamide, the titled compound was recovered by the
procedure described in Preparation 6: MS m/z (rel. intensity, 70
eV)) 346 (M+, 2), 318 (19), 317 (bp), 209 (10), 70 (13).
EXAMPLE 48
4-(3-Methanesulfonyl-4-methoxy-phenyl)-1-propyl-piperidine
Beginning with
4-(3-methanesulfonyl-4-methoxy-phenyl)-1-propyl-piperidine, the
titled compound was recovered by the procedure described in
Preparation 6: MS m/z (rel. intensity, 70 eV) 311 (M+, 6), 283
(17), 282 (bp), 280 (11), 70 (22), Rf=0.3 (MeOH).
EXAMPLE 49
1-(4-Chloro-3-methanesulfonyl-phenyl)-4-propyl-piperazine
Beginning with 1-(4-Chloro-3-methanesulfonyl-phenyl)-piperazine and
1-iodopropane, the titled compound was recovered by the procedure
described in Example 2. MS m/z (rel. intensity, 70 eV)) 316 (M+,
25), 289 (41), 287 (bp), 70 (59), 56 (23)
EXAMPLE 50
1-Allyl-4-(3-Chloro-5-trifluoromethyl-phenyl)-piperazine
Beginning with 1-(3-Chloro-5-trifluoromethyl-phenyl)-piperazine and
allylbromide, the title compound was recovered by the procedure
described in Example 2. MS m/z (rel. intensity, 70 eV)) 305 (M+,
7), 96 (57), 69 (bp), 68 (48), 56 (69).
EXAMPLE 51
2-Fluoro-5-(1-propyl-piperidin-4-yl)-benzonitrile
Beginning with
2-fluoro-5-(1-propyl-tetrahydropyridin-4-yl)-benzonitrile, the
title compound was recovered by the procedure described in
preparation 6. MS m/z (rel. intensity, 70 eV)) 246 (M+, 6), 217
(bp), 174 (5), 146 (6), 134 (7).
Syntheses of intermediates used in the above Examples are described
in the preparations below.
PREPARATION 1
1-(3-Chloro-5-trifluoromethyl-phenyl)-piperazine
Beginning with 3,5-dichlorobenzotrifluoride (500 mg, 2.32 mmol) and
piperazine (1 g, 11.6 mmol), 320 mg of the title compound was
recovered by the procedure described in Example 1.
PREPARATION 2
1-(4-Chloro-3-trifluoromethyl-phenyl)-piperazine
Beginning with 5-bromo-2-chlorobenzotrifluoride (602 mg) and
piperazine (1 g), 480 mg of the title compound was recovered by the
procedure described in Example 1.
PREPARATION 3
1-(3,5-Bis-trifluoromethyl-phenyl)-4-piperazine
Beginning with 1-iodo-3,5-bis (trifluoromethyl)-benzene and
piperazine, the title compound was recovered by the procedure
described in Example 1.
PREPARATION 4
1-Benzyl-4-(4-chloro-3-trifluoromethyl-phenyl)-piperidine-4-ol
(Prepared According to Collection Czechoslav. Chem. Commun. 1973,
38, 3879)
A solution of 5-Bromo-2-chlorobenzotrifluoride (5 g, 19.2 mmol) in
dry diethyl ether (40 ml) was added dropwise at room temperature to
a mixture of Mg (470 mg) in dry diethyl ether (20 ml) under a
stream of Argon (g). The reaction gave rise to a solution of
Grignard's reagent. A solution of 1-benzyl-4-piperidone (1.3 g,
6.88 mmol) in dry diethyl ether (30 ml) was added dropwise via
syringe at room temperature. The combined mixture was stirred for 1
hour, and finally quenched with saturated ammonium chloride
solution (40 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 EtOAc:toluene (1:1 (v/v))
as eluent affording the title compound (1.6 g, 64%). MS m/z
(relative intensity, 70 eV) 369 (M+, 23), 278 (15), 91 (bp), 65
(16), 56 (21).
PREPARATION 5
1-Benzyl-4-(4-chloro-3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine
1-Benzyl-4-(4-chloro-3-trifluoromethyl-phenyl)-piperidine-4-ol (1.5
g) was dissolved trifluoroacetic acid (35 ml) and refluxed for 24
hours and then CH.sub.2Cl.sub.2 (200 ml) was added. The phases were
separated and then the organic phase was washed with two portions
of 10%-Na.sub.2CO.sub.3, dried (MgSO.sub.4), filtered and
evaporated to dryness. Yield 1.5 g. MS m/z (relative intensity, 70
eV) 351 (M+, 27), 172 (9), 92 (11), 91 (bp), 65 (21).
PREPARATION 6
1-Benzyl-4-(4-chloro-3-trifluoromethyl-phenyl)-piperidine
1-Benzyl-4-(4-chloro-3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridin-
e (1.45 g) was dissolved in methanol (40 ml). Concentrated
hydrochloric acid (0.2 ml) and 50 mg Pd/C, were added. The
resulting mixture was hydrogenated under a hydrogen gas pressure
(40 psi) for 1 h and then filtered through a pad of celite. The
solvent was evaporated in vacuum and the residue was purified by
flash chromatography (SiO.sub.2, CH.sub.2Cl.sub.2:MeOH, 9:1 (v/v))
to give the pure title compound (1.2 g). MS m/z (relative
intensity, 70 eV) 353 (M+, 16), 262 (20), 91 (bp), 65 (18), 56
(14).
PREPARATION 7
4-(4-chloro-3-trifluoromethyl-phenyl)-piperidine
A solution of
1-Benzyl-4-(4-chloro-3-trifluoromethyl-phenyl)-piperidine (1.1 g)
in 1,2-dichloroethane (50 ml) was cooled to 0.degree. C. Then
.alpha.-chloroethyl chloroformate (1.5 g) dissolved in
1,2-dichloroethane (30 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
(light brown crystals, 1.0 g) MS m/z (relative intensity, 70 eV)
263 (M+, 34), 262 (22), 83 (22), 57 (60), 56 (bp).
PREPARATION 8
1-(3,4-dichloro-phenyl)-piperazine
Beginning with 4-bromo-1,2-dichlorobenzene (200 mg, 0.88 mmol) and
piperazine (91 mg, 1.06 mmol), 98 mg of the title compound was
recovered by the procedure described in Example 1.
PREPARATION 9
1-(3-Methanesulfonyl-4-methoxy-phenyl)-piperazine
A mixture of 4-bromo-2-methanesulfonyl-1-methoxy-benzene (0.65 g,),
piperazine (0.43 g,), sodium tert-butoxide (0.13 g) BINAP (19 mg)
and [Pd.sub.2(dba).sub.3 (27 mg) in dioxane (5 ml) was heated under
argon at 100.degree. C. for 24 h. After cooling to room
temperature, the reaction mixture was taken up in Et.sub.2O (40-50
ml) and washed with brine (15-20 ml). The organic fraction was
dried (MgSO.sub.4), filtered and evaporated to dryness. The crude
material was purified by flash chromatography on silica gel using
CH.sub.2Cl.sub.2:MeOH (9:1 (v/v)) Yield 0.14 g: MS m/z (rel.
intensity, 70 eV)) 270 (M+, 23), 229 (11), 228 (bp), 148 (7), 56
(17).
PREPARATION 10
4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-propyl-piperidine-2-ol.
Beginning with 4-bromo-1-fluoro-2-trifluoromethyl-benzene and
1-propyl-4-piperidone, the titled compound was recovered by the
procedure described in Preparation 4.
MS m/z (rel. intensity, 70 eV)) 305 (M+, 5), 276 (bp), 258 (50),
191 (13), 185 (33).
PREPARATION 11
4-(3-Fluoro-5-trifluoromethyl-phenyl)-1-propyl-piperidine-2-ol
Beginning with 1-bromo-3-fluoro-5-trifluoromethyl-benzene and
1-propyl-4-piperidone, the titled compound was recovered by the
procedure described in Preparation 4.
MS m/z (rel. intensity, 70 eV)) 305 (M+, 6), 276 (bp), 258 (34),
258 (34), 185 (14).
PREPARATION 12
2,4-Difluoro-N,N-dimethyl-5-pyridin-4-yl-benzenesulfonamide
5-Bromo-2,4-difluoro-N,N-dimethyl-benzenesulfonamide (400 mg) and
4-pyridine-boronic acid (165 mg) was dissolved in toluene (5 ml)
and abs EtoH (5 ml). To the mixture was then added Na2CO3 (200 mg)
and Pd(PPh.sub.3).sub.4 (79 mg) under an atmosphere of Argon. The
resulting mixture was heated to 90.degree. C. for 18 h. Then
CH.sub.2Cl.sub.2 was added and the organic phase was washed with
water and dried (MgSO.sub.4), filtered and evaporated to dryness.
The residue was then used without any further purification. (MS m/z
(rel. intensity, 70 eV) 298 (M+, 77), 256 (36), 191 (bp), 190 (98),
143 (74).
PREPARATION 13
4-Pyridin-4-yl-2-trifluoromethyl-phenylamine
Beginning with 4-bromo-2-trifluoromethyl-phenylamine, the titled
compound was recovered by the procedure described in Preparation
12; MS m/z (rel. intensity, 70 eV)) 238 (M+, 52), 218 (44), 191
(27), 75 (41), 51 (bp).
PREPARATION 14
4-(3-methanesulfonyl-4-methoxy-phenyl)-pyridine
Beginning with 4-bromo-2-methanesulfonyl-1-methoxy-benzene, the
titled compound was recovered by the procedure described in
Preparation 12; MS m/z (rel. intensity, 70 eV)) 263 (M+, bp), 182
(36), 169 (18), 154 (32), 127 (18).
PREPARATION 15
4-(2-Chloro-5-trifluoromethyl-phenyl)-1-propyl-piperidin-4-ol
Beginning with 4-chloro-3-iodobenzotrifluoride and
1-propyl-4-piperidone, the titled compound was recovered by the
procedure described in Preparation 4, MS m/z (rel. intensity, 70
eV)) 321 (M+, 8), 294 (38), 292, (bp), 274 (52), 56 (35).
PREPARATION 16
1-(4-Chloro-3-methanesulfonyl-phenyl)-piperazine
Beginning with 5-bromo-2-chloro-methanesulfonyl-benzene and
piperazine, the title compound was recovered by the procedure
described in Example 1. MS m/z (rel. intensity, 70 eV)) 274 (M+,
20), 234 (40), 232 (bp), 153 (9), 56 (12).
The following tests were uses for evaluation of the compounds
according to the invention.
In vivo Test: Behavior
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 25 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 small-scale
movements 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
pretreated 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.
In vivo Test: Neurochemistry
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-dihydroxyphenyl-acetic
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,
Naunyn-Schmiedeberg's Arch Pharmacol 334: 234-245 and references
cited therein.
In vivo Test: Pharmacokinetics in the Rat
To determine oral availability (F); and plasma half life (t1/2) of
test compounds of this invention experiments performed in the rat
were undertaken. On day one rats were implanted with one catheter
in the jugular vein and one catheter in the carotid artery under
ketamine anesthesia. On day three test compound is injected the
either orally or in the jugular vein catheter. Blood samples are
collected during 8 hours from the arterial catheter. The blood
samples were heparinized and centrifuged. Plasma is collected from
the centrifuged samples and frozen. The levels of test compound
were subsequently determined in each sample by means of gas
chromatography mass spectrometry (Hewlett-Packard 5972MSD). The
plasma samples, taken from the rats of the Sprague-Dawley strain,
(0.5 ml) were diluted with water (0.5 ml), and 30 pmol (50 .mu.l)
of ((-)-S-3-(3-Ethylsulfonylphenyl)-N-n-propyl-piperidine as
internal standard was added. The pH was adjusted to 11.0 by the
addition of 25 .mu.l saturated Na.sub.2CO.sub.3. After mixing, the
samples were extracted with 4 ml dichloromethane by shaking for 20
min. The organic layer was, after centrifugation, transferred to a
smaller tube and evaporated to dryness under a stream of nitrogen
and subsequently redissolved in 40 .mu.l toluene for GC-MS
analysis. A standard curve over the range of 1-500 pmol was
prepared by adding appropriate amounts of test compound to blank
plasma samples. GC was performed on a HP-Ultra 2 capillary column
(12 m.times.0.2 mm ID), and 2 .mu.l was injected in the splitless
mode. The GC temperature was held at 90.degree. C. for 1 minute
following injection, and was then increased by 30.degree. C./min to
the final temperature of 290.degree. C. Each sample was run in
duplicate. The lowest detectable concentration of test compound was
generally found to be 1 pmol/ml.
* * * * *