U.S. patent application number 17/078055 was filed with the patent office on 2021-09-09 for phenyl-piperazine derivatives as serotonin reuptake inhibitors.
The applicant listed for this patent is H. Lundbeck A/S. Invention is credited to Kim Andersen, Benny Bang-Andersen, Ejner Knud Moltzen, Ask Puschl, Thomas Ruhland, Garrick Paul Smith.
Application Number | 20210276966 17/078055 |
Document ID | / |
Family ID | 1000005608747 |
Filed Date | 2021-09-09 |
United States Patent
Application |
20210276966 |
Kind Code |
A1 |
Ruhland; Thomas ; et
al. |
September 9, 2021 |
Phenyl-Piperazine Derivatives As Serotonin Reuptake Inhibitors
Abstract
The invention provides compounds represented by the general
formula I ##STR00001## wherein the substituents are defined in the
application. The compounds are useful in the treatment of an
affective disorder, including depression, anxiety disorders
including general anxiety disorder and panic disorder and obsessive
compulsive disorder.
Inventors: |
Ruhland; Thomas; (Roskilde,
DK) ; Smith; Garrick Paul; (Valby, DK) ;
Bang-Andersen; Benny; (Copenhagen S, DK) ; Puschl;
Ask; (Frederiksberg, DK) ; Moltzen; Ejner Knud;
(Gentofte, DK) ; Andersen; Kim; (Ridgewood,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
H. Lundbeck A/S |
Valby |
|
DK |
|
|
Family ID: |
1000005608747 |
Appl. No.: |
17/078055 |
Filed: |
October 22, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15624417 |
Jun 15, 2017 |
10844029 |
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17078055 |
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14744197 |
Jun 19, 2015 |
9708280 |
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15624417 |
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13927678 |
Jun 26, 2013 |
9090575 |
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14744197 |
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13367065 |
Feb 6, 2012 |
8476279 |
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13927678 |
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12700521 |
Feb 4, 2010 |
8110567 |
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13367065 |
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11551188 |
Oct 19, 2006 |
7683053 |
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12700521 |
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10488280 |
Jun 15, 2004 |
7144884 |
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PCT/DK2002/000659 |
Oct 2, 2002 |
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11551188 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 211/20 20130101;
C07D 295/096 20130101; C07D 211/70 20130101; C07D 295/033 20130101;
C07D 295/145 20130101; C07D 243/08 20130101 |
International
Class: |
C07D 295/145 20060101
C07D295/145; C07D 211/20 20060101 C07D211/20; C07D 211/70 20060101
C07D211/70; C07D 243/08 20060101 C07D243/08; C07D 295/096 20060101
C07D295/096; C07D 295/033 20060101 C07D295/033 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 4, 2001 |
DK |
PA200101466 |
Claims
1-15. (canceled)
16. A pharmaceutical composition, comprising:
1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine or a hydrobromic
acid addition salt thereof, and at least one pharmaceutically
acceptable carrier or diluent.
17. The composition of claim 16, wherein the composition comprises
a hydrobromic acid addition salt of
1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine.
18. The composition of claim 17, wherein the composition is a
tablet.
19. The composition of claim 18, wherein the composition comprises
1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine in an amount of
from 0.01 mg to 100 mg.
20. A method for the treatment of an affective disorder in a human
in need thereof, comprising administering to the human an amount of
the composition of claim 1 comprising a therapeutically effective
amount of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine or a
hydrobromic acid addition salt thereof.
21. The method of claim 20, wherein the affective disorder is
depression.
22. The method of claim 20, wherein the affective disorder is an
anxiety disorder.
23. The method of claim 22, wherein the anxiety disorder is general
anxiety disorder or panic disorder.
24. The method of claim 20, wherein the affective disorder is
obsessive compulsive disorder.
25. The method of claim 20, wherein the composition comprises a
therapeutically effective amount of a hydrobromic acid addition
salt of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine.
26. The method of claim 25, wherein the affective disorder is
depression.
27. The method of claim 25, wherein the affective disorder is an
anxiety disorder.
28. The method of claim 27, wherein the anxiety disorder is general
anxiety disorder or panic disorder.
29. The method of claim 25, wherein the affective disorder is
obsessive compulsive disorder.
30. The method of claim 25, wherein the composition is a
tablet.
31. The method of claim 30, wherein the affective disorder is
depression.
32. The method of claim 30, wherein the affective disorder is an
anxiety disorder.
33. The method of claim 32, wherein the anxiety disorder is general
anxiety disorder or panic disorder.
34. The method of claim 33, wherein the affective disorder is
obsessive compulsive disorder.
35. The method of claim 30, wherein the composition comprises
1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine in an amount of
from 0.01 mg to 100 mg.
36. The method of claim 35, wherein the affective disorder is
depression.
37. The method of claim 35, wherein the affective disorder is an
anxiety disorder.
38. The method of claim 37, wherein the anxiety disorder is general
anxiety disorder or panic disorder.
39. The method of claim 35, wherein the affective disorder is
obsessive compulsive disorder.
Description
[0001] The present invention relates to novel compounds which are
serotonin reuptake inhibitors and as such effective in the
treatment of for example depression and anxiety.
BACKGROUND OF THE INVENTION
[0002] Selective serotonin reuptake inhibitors (hereinafter
referred to as SSRIs) have become first choice therapeutics in the
treatment of depression, certain forms of anxiety and social
phobias, because they are effective, well tolerated and have a
favourable safety profile compared to the classic tricyclic
antidepressants.
[0003] However, clinical studies on depression indicate that
non-response to SSRIs is substantial, up to 30%. Another, often
neglected, factor in antidepressant treatment is compliance, which
has a rather profound effect on the patient's motivation to
continue pharmacotherapy.
[0004] First of all, there is the delay in therapeutic effect of
SSRIs. Sometimes symptoms even worsen during the first weeks of
treatment. Secondly, sexual dysfunction is a side effect common to
all SSRIs. Without addressing these problems, real progress in the
pharmacotherapy of depression and anxiety disorders is not likely
to happen.
[0005] In order to cope with non-response, psychiatrists sometimes
make use of augmentation strategies. Augmentation of antidepressant
therapy may be accomplished through the co-administration of mood
stabilizers such as lithium carbonate or triiodothyronin or by the
use of electroshock.
[0006] The effect of combined administration of a compound that
inhibits serotonin reuptake and a 5-HT.sub.1A receptor antagonist
has been evaluated in several studies (Innis et al. Eur. J.
Pharmacol. 1987, 143, 1095-204 and Gartside Br. J. Pharmacol. 1995,
115, 1064-1070, Blier et al. Trends in Pharmacol. Science 1994, 15,
220). In these studies, it was found that 5-HT.sub.1A receptor
antagonists would abolish the initial brake on 5-HT
neurotransmission induced by the serotonin reuptake inhibitors and
thus produce an immediate boost of 5-HT transmission and a rapid
onset of therapeutic action.
[0007] Several patent applications have been filed, which cover the
use of a combination of a 5-HT.sub.1A antagonist and a serotonin
reuptake inhibitor for the treatment of depression (see e.g.
EP-A2-687472 and EP-A2-714663).
[0008] Another approach to increase terminal 5-HT would be through
blockade of the 5-HT.sub.1B autoreceptor. Microdialysis experiments
in rats have indeed shown that increase of hippocampal 5-HT by
citalopram is potentiated by GMC 2-29, an experimental 5-HT.sub.1B
receptor antagonist.
[0009] Several patent applications covering the combination of an
SSRI and a 5-HT.sub.1B antagonist or partial agonist have also been
filed (WO 97/28141, WO 96/03400, EP-A-701819 and WO 99/13877).
[0010] It has previously been found that the combination of a
serotonin reuptake inhibitor with a compound having 5-HT.sub.2C
antagonistic or inverse agonistic effect (compounds having a
negative efficacy at the 5-HT.sub.2C receptor) provides a
considerable increase in the level of 5-HT in terminal areas, as
measured in microdialysis experiments (WO 01/41701). This would
imply a shorter onset of antidepressant effect in the clinic and an
augmentation or potentiation of the therapeutic effect of the
serotonin reuptake inhibitor (SRI).
[0011] The present invention provides compounds which are serotonin
reuptake inhibitors for the treatment of affective disorders such
as depression, anxiety disorders including general anxiety disorder
and panic disorder and obsessive compulsive disorder. Some of the
compounds also have a combined effect of serotonin reuptake
inhibition and 5-HT.sub.2c receptor modulation, which according to
WO01/41701 would imply a faster onset of anti-depressant
activity.
[0012] A few of the compounds embraced by the present invention
have previously been described in WO 01/49681 and in WO02/59108
However, the compounds of WO01/49681 are not disclosed as having
any therapeutic or biological activity. The compounds of WO02/59108
are disclosed as intermediates in the synthesis of compounds
different from the compounds of the present invention with a
therapeutic activity as melanocortin receptor agonists. One
compound, 1-(2-phenoxyphenyl)-piperazine, embraced by the present
invention, is disclosed in U.S. Pat. No. 4,064,245 as being useful
in the treatment of metabolic disorders.
SUMMARY OF THE INVENTION
[0013] The present invention provides compounds of the general
formula I
##STR00002##
[0014] wherein
[0015] Y is N, C or CH;
[0016] X represent O or S;
[0017] m is 1 or 2;
[0018] p is 0, 1, 2, 3, 4, 5, 6, 7 or 8;
[0019] q is 0, 1, 2, 3 or 4;
[0020] s is 0, 1, 2, 3, 4 or 5;
[0021] The dotted line represents an optional bond;
[0022] Each R.sup.1 is independently selected from the group
represented by C.sub.1-6-alkyl, or two R.sup.1 attached to the same
carbon atom may form a 3-6-membered spiro-attached cyclo-alkyl;
[0023] Each R.sup.2 is independently selected from the groups
represented by halogen, cyano, nitro, C.sub.1-6-alk(en/yn)yl,
C.sub.1-6-alk(en/yn)yloxy, C.sub.1-6-alk(en/yn)ylsulfanyl, hydroxy,
hydroxy-C.sub.1-6-alk(en/yn)yl, halo-C.sub.1-6-alk(en/yn)yl,
halo-C.sub.1-6-alk(en/yn)yloxy, C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl, acyl,
C.sub.1-6-alk(en/yn)yloxycarbonyl, C.sub.1-6-alk(en/yn)ylsulfonyl,
or --NR.sup.xR.sup.y;
[0024] Each R.sup.3 is independently selected from a group
represented by halogen, cyano, nitro, C.sub.1-6-alk(en/yn)yl,
C.sub.1-6-alk(en/yn)yloxy, C.sub.1-6-alk(en/yn)ylsulfanyl, hydroxy,
hydroxy-C.sub.1-6-alk(en/yn)yl, halo-C.sub.1-6-alk(en/yn)yl,
halo-C.sub.1-6-alk(en/yn)yloxy, C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.1-6-alk(en/yn)ylsulfonyl, aryl,
C.sub.1-6-alk(en/yn)yloxycarbonyl, acyl,
--NR.sup.xCO--C.sub.1-6-alk(en/yn)yl, CONR.sup.xR.sup.y or
NR.sup.xR.sup.y;
[0025] or two adjacent R.sup.3 substituents together form a
heterocycle fused to the phenyl ring selected from the group
consisting of
##STR00003##
[0026] wherein W is O or S, and R' and R'' are hydrogen or
C.sub.1-6-alkyl:
[0027] or two adjacent R.sup.3 substituents together form a fused
heteroaromatic system containing one, two or three heteroatoms,
[0028] wherein each Rx and R.sup.y is independently selected from
the group represented by hydrogen, C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl, or aryl; or RX and
R.sup.y together with the nitrogen to which they are attached form
a 3-7-membered ring which optionally contains one further
heteroatom;
[0029] or an acid addition salt thereof.
[0030] The invention also provides compounds as above provided that
the compound is not 1-(2-phenoxyphenyl)-piperazine;
[0031] The invention also provides compounds as above provided that
the compound is not 1-[2-(2-Methoxyphenoxy)phenyl]piperazine,
1-[2-(2,6-dimethoxyphenoxy)phenyl]-[1,4]-diazepane,
1-{2-[3-(dimethylamino)phenoxy]phenyl}piperazine,
1-[2-(4-methylphenoxy)phenyl]piperazine,
1-[2-(3-methylphenoxy)phenyl]piperazine,
1-[2-(3-chlorophenoxy)phenyl]piperazine,
1-[2-(3-methoxyphenoxy)phenyl]piperazine and
1-(2-phenoxyphenyl)-piperazine;
[0032] The invention provides a compound according to the above for
use as a medicament.
[0033] The invention provides a pharmaceutical composition
comprising a compound according to the above or a pharmaceutically
acceptable acid addition salt thereof and at least one
pharmaceutically acceptable carrier or diluent.
[0034] The invention provides the use of a compound according to
the above or a pharmaceutically acceptable acid addition salt
thereof for the preparation of a medicament for the treatment of
affective disorders, such as depression, anxiety disorders
including general anxiety disorder and panic disorder and obsessive
compulsive disorder.
[0035] The invention provides a method for the treatment of an
affective disorder, including depression, anxiety disorders
including general anxiety disorder and panic disorder and obsessive
compulsive disorder in a living animal body, including a human,
comprising administering a therapeutically effective amount of a
compound according to the above or a pharmaceutically acceptable
acid addition salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0036] Preferred embodiments of the invention are wherein p is
0;
[0037] Preferred embodiments of the invention are wherein m is 1 or
2;
[0038] Preferred embodiments of the invention are R.sup.2 is
trifluoromethyl, or C.sub.1-6-alkyl;
[0039] Preferred embodiments of the invention are wherein R.sup.3
is selected from the group consisting of halogen, C.sub.1-6-alkoxy,
C.sub.1-6-sulfanyl, C.sub.1-6-alkyl, hydroxy or
trifluoromethyl;
[0040] Particularly preferred embodiments of the invention are
wherein the compound of the invention is any of the following:
[0041] 1-[2-(2-Trifluoromethylphenylsulfanyl)phenyl]piperazine,
[0042] 1-[2-(4-Bromophenylsulfanyl)phenyl]piperazine, [0043]
1-{2-[4-(Methylsulfanyl)phenylsulfanyl]phenyl}piperazine, [0044]
1-[2-(4-Hydroxyphenylsulfanyl]phenyl}piperazine, [0045]
1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine, [0046]
1-[2-(3,5-Dimethylphenylsulfanyl)phenyl]piperazine, [0047]
1-[2-(2,6-Dimethylphenylsulfanyl)phenyl]piperazine, [0048]
1-[2-(2,5-Dimethylphenylsulfanyl)phenyl]piperazine, [0049]
1-[2-(2-Trifluoromethylphenylsulfanyl)phenyl][1,4]diazepane, [0050]
1-[2-(3-Methylphenylsulfanyl)phenyl]-[1,4]-diazepane, [0051]
1-[2-(4-Butylphenoxy)phenyl]piperazine, [0052]
1-[2-(4-Methoxyphenoxy)phenyl]piperazine, [0053]
2-(4-Methylphenylsulfanyl)phenyl-1-piperazine, [0054]
1-[2-(4-Chlorophenylsulfanyl)phenyl]-piperazine, [0055]
1-[2-(4-Methoxyphenylsulfanyl)-4-chlorophenyl]piperazine, [0056]
1-[2-(4-Methoxyphenylsulfanyl)-4-methylphenyl]piperazine, [0057]
1-[2-(4-Methoxyphenylsulfanyl)-5-methylphenyl]piperazine, [0058]
1-[2-(4-Fluorophenylsulfanyl)-5-methylphenyl]piperazine, [0059]
1-[2-(4-Methoxyphenylsulfanyl)-5-trifluoromethylphenyl]piperazine,
[0060] 1-[2-(4-Chlorophenylsulfanyl)phenyl]-3-methylpiperazine,
[0061] 1-[2-(4-Chlorophenylsulfanyl)phenyl]-3,5-dimethylpiperazine,
[0062]
4-[2-(4-Methylphenylsulfanyl)phenyl]-3,6-dihydro-2H-pyridine,
[0063]
4-[2-(4-Methoxyphenylsulfanyl)phenyl]-3,6-dihydro-2H-pyridine or
[0064] 4-[2-(4-Methylphenylsulfanyl)phenyl]piperidine
[0065] or a pharmaceutically acceptable acid addition salt
thereof.
Definition of Substituents
[0066] Halogen means fluoro, chloro, bromo or iodo.
[0067] The expression C.sub.1-6-alk(en/yn)yl means a
C.sub.1-6-alkyl, C.sub.2-6-alkenyl or a C.sub.2-6-alkynyl group.
The expression C.sub.3-8-cycloalk(en)yl means a
C.sub.3-8-cycloalkyl- or cycloalkenyl group.
[0068] The term C.sub.1-6 alkyl refers to a branched or unbranched
alkyl group having from one to six carbon atoms inclusive,
including but not limited to methyl, ethyl, 1-propyl, 2-propyl,
1-butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl-1-propyl.
[0069] Similarly, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl,
respectively, designate such groups having from two to six carbon
atoms, including one double bond and one triple bond respectively,
including but not limited to ethenyl, propenyl, butenyl, ethynyl,
propynyl and butynyl.
[0070] The term C.sub.3-8 cycloalkyl designates a monocyclic or
bicyclic carbocycle having three to eight C-atoms, including but
not limited to cyclopropyl, cyclopentyl, cyclohexyl, etc.
[0071] The term C.sub.3-8 cycloalkenyl designates a monocyclic or
bicyclic carbocycle having three to eight C-atoms and including one
double bond.
[0072] In the term C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-cycloalk(en)yl and C.sub.1-6-alk(en/yn)yl are as defined
above.
[0073] The terms C.sub.1-6-alk(en/yn)yloxy, C.sub.1-6
alk(en/yn)ylsulfanyl, hydroxy-C.sub.1-6-alk(en/yn)yl,
halo-C.sub.1-6-alk(en/yn)yl, halo-C.sub.1-6-alk(en/yn)yloxy,
C.sub.1-6-alk(en/yn)ylsulfonyl etc. designate such groups in which
the C.sub.1-6-alk(en/yn)yl are as defined above.
[0074] As used herein, the term C.sub.1-6-alk(en/yn)yloxycarbonyl
refers to groups of the formula C.sub.1-6-alk(en/yn)yl --O--CO--,
wherein C.sub.1-6-alk(en/yn)yl are as defined above.
[0075] As used herein, the term acyl refers to formyl,
C.sub.1-6-alk(en/yn)ylcarbonyl, arylcarbonyl,
aryl-C.sub.1-6-alk(en/yn)ylcarbonyl,
C.sub.3-8-cycloalk(en)ylcarbonyl or a
C.sub.3-s-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl-carbonyl group.
[0076] The term 3-7-membered ring optionally containing one further
heteroatom as used herein refers to ring systems such as
1-morpholinyl, 1-piperidinyl, 1-azepinyl, 1-piperazinyl,
1-homopiperazinyl, 1-imidazolyl, 1-pyrrolyl or pyrazolyl, all of
which may be further substituted with C.sub.1-6-alkyl.
[0077] The heterocycles formed by two adjacent R.sup.3 substituents
and fused to the parent ring may together form rings such as
5-membered monocyclic rings such as 3H-1,2,3-oxathiazole,
1,3,2-oxathiazole, 1,3,2-dioxazole, 3H-1,2,3-dithiazole,
1,3,2-dithiazole, 1,2,3-oxadiazole, 1,2,3-thiadiazole,
1H-1,2,3-triazole, isoxazole, oxazole, isothiazole, thiazole,
1H-imidazole, 1H-pyrazole, 1H-pyrrole, furan or thiophene and
6-membered monocyclic rings such as 1,2,3-oxathiazine,
1,2,4-oxathiazine, 1,2,5-oxathiazine, 1,4,2-oxathiazine,
1,4,3-oxathiazine, 1,2,3-dioxazine, 1,2,4-dioxazine,
4H-1,3,2-dioxazine, 1,4,2-dioxazine, 2H-1,5,2-dioxazine,
1,2,3-dithiazine, 1,2,4-dithiazine, 4H-1,3,2-dithiazine,
1,4,2-dithiazine, 2H-1,5,2-dithiazine, 2H-1,2,3-oxadiazine,
2H-1,2,4-oxadiazine, 2H-1,2,5-oxadiazine, 2H-1,2,6-oxadiazine,
2H-1,3,4-oxadiazine, 2H-1,2,3-thiadiazine, 2H-1,2,4-thiadiazine,
2H-1,2,5-thiadiazine, 2H-1,2,6-thiadiazine, 2H-1,3,4-thiadiazine,
1,2,3-triazine, 1,2,4-triazine, 2H-1,2-oxazine, 2H-1,3-oxazine,
2H-1,4-oxazine, 2H-1,2-thiazine, 2H-1,3-thiazine, 2H-1,4-thiazine,
pyrazine, pyridazine, pyrimidine, 4H-1,3-oxathiin, 1,4-oxathiin,
4H-1,3-dioxin, 1,4-dioxin, 4H-1,3-dithiin, 1,4-dithiin, pyridine,
2H-pyran or 2H-thiin.
[0078] The term aryl refers to carbocyclic, aromatic systems such
as phenyl and naphtyl.
[0079] The acid addition salts of the invention are preferably
pharmaceutically acceptable salts of the compounds of the invention
formed with non-toxic acids. Exemplary of such organic salts are
those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic,
bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic,
propionic, tartaric, salicylic, citric, gluconic, lactic, malic,
mandelic, cinnamic, citraconic, aspartic, stearic, palmitic,
itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and
theophylline acetic acids, as well as the 8-halotheophyllines, for
example 8-bromotheophylline. Exemplary of such inorganic salts are
those with hydrochloric, hydrobromic, sulfuric, sulfamic,
phosphoric and nitric acids.
[0080] Further, the compounds of this invention may exist in
unsolvated as well as in solvated forms with pharmaceutically
acceptable solvents such as water, ethanol and the like. In
general, the solvated forms are considered equivalent to the
unsolvated forms for the purposes of this invention.
[0081] Some of the compounds of the present invention contain
chiral centres and such compounds exist in the form of isomers
(i.e. enantiomers). The invention includes all such isomers and any
mixtures thereof including racemic mixtures.
[0082] Racemic forms can be resolved into the optical antipodes by
known methods, for example, by separation of diastereomeric salts
thereof with an optically active acid, and liberating the optically
active amine compound by treatment with a base. Another method for
resolving racemates into the optical antipodes is based upon
chromatography on an optically active matrix. Racemic compounds of
the present invention can also be resolved into their optical
antipodes, e.g. by fractional crystallization of d- or l-
(tartrates, mandelates or camphorsulphonate) salts. The compounds
of the present invention may also be resolved by the formation of
diastereomeric derivatives.
[0083] Additional methods for the resolution of optical isomers,
known to those skilled in the art, may be used. Such methods
include those discussed by J. Jaques, A. Collet and S. Wilen in
"Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New
York (1981).
[0084] Optically active compounds can also be prepared from
optically active starting materials.
[0085] Pharmaceutical Compositions
[0086] The pharmaceutical formulations of the invention may be
prepared by conventional methods in the art. For example: Tablets
may be prepared by mixing the active ingredient with ordinary
adjuvants and/or diluents and subsequently compressing the mixture
in a conventional tabletting machine. Examples of adjuvants or
diluents comprise: corn starch, potato starch, talcum, magnesium
stearate, gelatine, lactose, gums, and the like. Any other
adjuvants or additives usually used for such purposes such as
colourings, flavourings, preservatives etc. may be used provided
that they are compatible with the active ingredients.
[0087] Solutions for injections may be prepared by dissolving the
active ingredient and possible additives in a part of the solvent
for injection, preferably sterile water, adjusting the solution to
desired volume, sterilising the solution and filling it in suitable
ampules or vials. Any suitable additive conventionally used in the
art may be added, such as tonicity agents, preservatives,
antioxidants, etc.
[0088] The pharmaceutical compositions of this invention or those
which are manufactured in accordance with this invention may be
administered by any suitable route, for example orally in the form
of tablets, capsules, powders, syrups, etc., or parenterally in the
form of solutions for injection. For preparing such compositions,
methods well known in the art may be used, and any pharmaceutically
acceptable carriers, diluents, excipients or other additives
normally used in the art may be used.
[0089] Conveniently, the compounds of the invention are
administered in unit dosage form containing said compounds in an
amount of about 0.01 to 100 mg. The total daily dose is usually in
the range of about 0.05-500 mg, and most preferably about 0.1 to 50
mg of the active compound of the invention.
[0090] The compounds of the invention are prepared by the following
general methods:
[0091] a) Deprotection or cleavage from a polymer support of a
compound with formula II
##STR00004##
[0092] wherein Z represents
##STR00005##
[0093] and R.sup.1, R.sup.2, R.sup.3, m, p, q, s, X, Y and the
dotted line are as described above, and R is a tert-butyl, methyl,
ethyl, allyl or benzyl group or R'''OCO.sub.2 is a solid supported
carbamate group, such as the Wang resin-based carbamate linker.
[0094] b) Chemical transformation of a compound with formula
III
##STR00006##
[0095] wherein R.sup.1, R.sup.2, m, p, q, Y and the dotted line are
as described above, to the corresponding diazonium compound, and
subsequently reacting with a compound HXZ, wherein X and Z are as
defined above.
[0096] c) Reacting a compound with formula IV
##STR00007##
[0097] wherein R.sup.2, R.sup.3, X, s and q are as described above
with an alkylating agent of formula
(Cl--(CH.sub.2).sub.m+1)NH(CH.sub.2).sub.2Cl or
(Br--(CH.sub.2).sub.m+1)NH(CH.sub.2).sub.2Br wherein m are as
defined above.
[0098] d) Reacting a compound with formula V
##STR00008##
[0099] wherein R.sup.2, R.sup.3, X, s and q are as described above
and G is a bromine or iodine atom with a compound of formula VI
##STR00009##
[0100] wherein R.sup.1, m and p are as defined above.
[0101] e) Dehydrating and optionally simultaneously deprotecting a
compound of formula
##STR00010##
[0102] wherein R.sup.1, R.sup.2, R.sup.3, X, m, p, q and s are as
described above and R is either a hydrogen atom or a BOC group.
[0103] f) Hydrogenate the double bond in a compound of formula
VIII
##STR00011##
[0104] wherein R.sup.1, R.sup.2, R.sup.3, X, m, p, q and s are as
described above.
[0105] The deprotection according to method a) was performed by
standard techniques, known to the persons skilled in the art and
detailed in the textbook Protective Groups in Organic Synthesis T.
W. Greene and P. G. M. Wuts, Wiley Interscience, (1991) ISBN
0471623016.
[0106] Starting materials of formula II wherein R'''=tert-Bu were
prepared according to the procedure as outlined below.
Fluoronitrobenzene derivatives were reacted with phenols or
thiophenols according to the procedure of Sawyer et al. J. Org.
Chem. 1998, 63, 6338 followed by reduction using standard
procedures known to the persons skilled in the art. This includes
reduction to the corresponding aniline using a metal hydride salt
such as sodium borohydride in conjunction with palladium on carbon
catalyst in an alcoholic solvent or reduction using a metal
chloride salt such as zinc chloride or tin chloride. The resulting
aniline was then converted to a properly substituted
3,5-diketopiperazine in a modification of the procedure of Kruse et
al. Recl. Trav. Chim. Pays-Bas 1998, 107, 303 using
N-butyloxycarbonyliminodiacetic acid. The 3,5-diketopiperazine
derivative was then reduced with for example borane to the
corresponding BOC protected piperazine, which was then deprotected
to the piperazine in situ.
##STR00012##
[0107] The compounds shown in formula II, wherein Y=CH and the
optional double bond is reduced, were prepared from their tertiary
alcohol precursors VII wherein R is a BOC group, by a modified
Barton reduction in a similar manner as described in Hansen et al.
Synthesis 1999, 1925-1930. The intermediate tertiary alcohols were
prepared from the corresponding properly substituted
1-bromo-phenylsulfanylbenzenes or their corresponding ethers by
metal-halogen exchange followed by addition of an appropriate
electrophile of the formula IX in a similar manner as described in
Palmer et al. J. Med. Chem. 1997, 40, 1982-1989. The properly
substituted 1-bromo-phenylsulfanylbenzenes were prepared in a
similar manner as described in the literature by reaction of
properly substituted thiophenols with properly substituted
aryliodides according to Schopfer and Schlapbach Tetrahedron 2001,
57, 3069-3073 Bates et al., Org. Lett. 2002, 4, 2803-2806 and Kwong
et al. Org. Lett. 2002, 4, (in press). The corresponding
substituted 1-bromo-phenoxybenzenes may be prepared as described by
Buck et al. Org. Lett. 2002, 4, 1623-1626.
##STR00013##
[0108] The cleavage from a polymer support, such as from the Wang
resin based carbamate linker, according to method a) was performed
according to literature known procedures (Zaragoza Tetrahedron
Lett. 1995, 36, 8677-8678 and Conti et al. Tetrahedron Lett. 1997,
38, 2915-2918).
[0109] The starting material of formula II may also be prepared
according to the methods described in patent application WO
01/49681. The diamines were either commercially available or
synthesised by methods known to chemists skilled in the art.
Iron-complexes, like
.eta..sup.6-1,2-dichlorobenzene-.eta..sup.5-cyclopentadienyliron(II)
hexafluorophosphate and substituted analogues were synthesised
according to literature known procedures (Pearson et al. J. Org.
Chem. 1996, 61, 1297-1305) or synthesised by methods known to
chemists skilled in the art.
##STR00014##
[0110] The diazotation followed by reaction with a compound HXZ
according to the method b) was performed by addition of the
diazonium salt of the corresponding aniline to a solution of sodium
salt of a thiophenol or a phenol in an aqueous suspension of
copper. The starting material of formula III was prepared as
outlined in the following. A fluoronitrobenzene derivative was
reacted with a piperazine derivative in a solvent such as DMF, NMP
or other dipolar aprotic solvent containing an organic base such as
triethylamine to afford the orthonitophenylpiperazine derivative.
The intermediate orthonitrophenylpiperazine was subsequently
reduced using standard procedures as stated above to give the
starting material of formula III.
[0111] The reaction of a compound of formula IV with an alkylating
agent of formula (Cl--(CH.sub.2).sub.m+1)NH(CH.sub.2).sub.2Cl or
(Br--(CH.sub.2).sub.m+1)NH(CH.sub.2).sub.2Br as its hydrobromide or
hydrochloride salt, wherein m is as defined above was performed in
a similar manner as described in Sircar et al. J. Med. Chem. 1992,
35, 4442-4449. Starting materials of formula IV were prepared as
described above for starting materials of formula II.
[0112] The reaction of a compound of formula V with a diamine of
formula VI in method d) was performed in a similar manner as
described in Nishiyama et al. Tetrahedron Lett. 1998, 39, 617-620.
The starting material of formula V was prepared in a similar manner
as described in Schopfer et al. Tetrahedron 2001, 57,
3069-3073.
[0113] The dehydration reaction and optional simultaneous
deprotection of a compound of formula VII in method e) was
performed in a similar manner as described in Palmer et al J. Med.
Chem. 1997, 40, 1982-1989. The starting material of formula VII
wherein R=H was prepared from a compound of formula VII wherein R
is a BOC group (see above) by deprotection with hydrochloric acid
in methanol. Compounds of formula VII wherein R=BOC, may be
prepared as described in Palmer et al. J. Med. Chem. 1997, 40,
1982-1989.
[0114] The reduction of the double bond according to method f) was
generally performed by catalytic hydrogenation at low pressure
(<3 atm.) in a Parr apparatus, or by using reducing agents such
as diborane or hydroboric derivatives as produced in situ from
NaBH.sub.4 in trifluoroacetic acid in inert solvents such as
tetrahydrofuran (THF), dioxane, or diethyl ether. The starting
material of formula VIII was prepared from II as described in
method a).
EXAMPLES
[0115] Analytical LC-MS data were obtained on a PE Sciex API 150EX
instrument equipped with IonSpray source and Shimadzu LC-8A/SLC-10A
LC system. Column: 30.times.4.6 mm Waters Symmmetry C18 column with
3.5 .mu.m particle size; Solventsystem: A=water/trifluoroacetic
acid (100:0.05) and B=water/acetonitrile/trifluoroacetic acid
(5:95:0.03); Method: Linear gradient elution with 90% A to 100% B
in 4 min and with a flow rate of 2 mL/min. Purity was determined by
integration of the UV (254 nm) and ELSD trace. The retention times
(RT) are expressed in minutes. Preparative LC-MS-purification was
performed on the same instrument. Column: 50.times.20 mm YMC ODS-A
with 5 .mu.m particle size; Method: Linear gradient elution with
80% A to 100% B in 7 min and with a flow rate of 22.7 mL/min.
Fraction collection was performed by split-flow MS detection.
[0116] .sup.1H NMR spectra were recorded at 500.13 MHz on a Bruker
Avance DRX500 instrument or at 250.13 MHz on a Bruker AC 250
instrument. Deuterated methylenchloride (99.8% D), chloroform
(99.8% D) or dimethyl sulfoxide (99.8% D) were used as solvents.
TMS was used as internal reference standard. Chemical shift values
are expressed in ppm-values. The following abbreviations are used
for multiplicity of NMR signals: s=singlet, d=doublet, t=triplet,
q=quartet, qui=quintet, h=heptet, dd=double doublet, dt=double
triplet, dq=double quartet, tt=triplet of triplets, m=multiplet and
b=broad singlet.
[0117] For ion-exchange chromatography, the following material was
used: SCX-columns (1 g) from Varian Mega Bond Elut.RTM., Chrompack
cat. No. 220776. Prior to use, the SCX-columns were pre-conditioned
with 10% solution of acetic acid in methanol (3 mL). For
de-complexation by irradiation, a ultraviolet light source (300 W)
from Philipps was used. As starting polymer supports for solid
phase synthesis, Wang-resin (1.03 mmol/g, Rapp-Polymere, Tuebingen,
Germany) was used.
[0118] Preparation of Intermediates
[0119]
.eta..sup.6-1,2-Dichlorobenzene-.eta..sup.5-cyclopentadienyliron(II-
) hexafluorophosphate Ferrocene (167 g), anhydrous aluminium
trichloride (238 g) and powdered aluminium (24 g) were suspended in
1,2-dichlorobenzene (500 mL) and heated to 90.degree. C. in a
nitrogen atmosphere for 5 h with intensive stirring. The mixture
was cooled to room temperature and water (1000 mL) was added
carefully in small portions while cooling on an ice bath. Heptane
(500 mL) and diethylether (500 mL) were added, and the mixture was
stirred at room temperature for 30 minutes. The mixture was
extracted with diethylether (3.times.300 mL). The aqueous phase was
filtered, and aqueous ammonium hexafluorophosphate (60 g in 50 mL
water) was added in small portions under stirring. The product was
allowed to precipitate at room temperature. After 3 hours the
precipitate was filtered off, washed intensively with water and
dried in vacuo (50.degree. C.) to give 81 g (21%) of the title
compound as a light yellow powder. .sup.1H NMR (D.sub.6-DMSO): 5.29
(s, 5H); 6.48 (m, 2H); 7.07 (m, 2H).
[0120] Preparation of Polystyrene-Bound Amines
4-[(Piperazin-1-yl)carbonyloxymethyl]phenoxymethyl polystyrene
[0121] 4-[(4-Nitrophenoxy)carbonyloxymethyl]phenoxymethyl
polystyrene (267 g, 235 mmol) was suspended in dry
N,N-dimethylformamide (2 L). N-Methylmorpholine (238.0 g, 2.35 mol)
and piperazine (102.0 g, 1.17 mol) were added and the mixture was
stirred at room temperature for 16 h. The resin was filtered off
and washed with N,N-dimethylformamide (2.times.1 L),
tetrahydrofuran (2.times.1 L), water (1.times.500 mL), methanol
(2.times.1 L), tetrahydrofuran (2.times.1 L) and methanol
(1.times.1 L). Finally, the resin was washed with dichloromethane
(3.times.500 mL) and dried in vacuo (25.degree. C., 36 h) to yield
an almost colourless resin (240.0 g).
[0122] The following polystyrene bound diamines were prepared
analogously: [0123]
4-[(1,4-Diazepan-1-yl)carbonyloxymethyl]phenoxymethyl
polystyrene
Preparation of Resin-Bound
.eta..sup.6-aryl-.eta..sup.5-cyclopentadienyliron(II)
hexafluorophosphates
4-({4-[.eta..sup.6-(2-Chlorophenyl)-.eta..sup.5-cyclopentadienyliron(II)]p-
iperazin-1-yl}carbonyloxymethyl)phenoxymethyl polystyrene
hexafluorophosphate (Intermediate for 1a-1h and 1k-1l)
[0124] 4-[(Piperazin-1-yl)carbonyloxymethyl]phenoxymethyl
polystyrene (115.1 g, 92 mmol) was suspended in dry tetrahydrofuran
(1.6 L), and
.eta..sup.6-1,2-dichlorobenzene-.eta..sup.5-cyclopentadienyliron(II)
hexafluorophosphate (76.0 g, 184 mmol) was added followed by
potassium carbonate (50.9 g, 368 mmol). The reaction mixture was
stirred at 60.degree. C. for 16 h. After cooling to room
temperature, the resin was filtered off and washed with
tetrahydrofuran (2.times.500 mL), water (2.times.250 mL),
tetrahydrofuran (2.times.500 mL), water (2.times.250 mL), methanol
(2.times.250 mL), dichloromethane (2.times.250 mL) and methanol
(2.times.250 mL). Finally, the resin was washed with
dichloromethane (3.times.500 mL) and dried in vacuo (25.degree. C.,
36 h) to yield a dark orange resin (142 g).
[0125] The following polystyrene bound iron-complex was prepared
analogously: [0126]
4-({4-[.eta..sup.6-(2-Chloro-phenyl)-.eta..sup.5-cyclopentadienyliron(II)-
]-[1,4]-diazepan-1-yl}carbonyloxymethyl)phenoxymethyl polystyrene
hexafluorophosphate (Intermediate for 1i and 1j)
[0127] Preparation of Further Intermediates
1-tert-Butoxycarbonyl-4-[2-(4-methylphenylsulfanyl)phenyl]piperidin-4-ol
[0128] A solution of BuLi (2.5 M in hexane, 12.0 ml, 30 mmol) was
slowly added to a stirred solution of
1-bromo-2-(4-methylphenylsulfanyl)benzene (30 mmol) in dry THF (75
ml) under Argon at -78.degree. C. The solution was stirred for 10
min before 4-oxo-piperidine-1-carboxylic acid tert-butyl ester
(5.98 g, 30 mmol) was added in one portion. The solution was
allowed to warm up to room temperature and then stirred for 3 h.
Saturated aqueous NH.sub.4Cl (150 ml) was added and the solution
was extracted with ethylacetate (150 ml). The organic phase was
washed with brine, dried (MgSO.sub.4) and the solvent was
evaporated in vacuo. Crude 1 was purified by flash chromatography
on silica gel (eluent: Ethylacetat/heptane 20:80) to produce the
target compound as a white foam. LC/MS (m/z) 399.3 (MH.sup.+);
RT=3.82; purity (UV, ELSD): 98%, 100%; yield: 5.02 g (42%).
1-tert-Butyloxycarbonyl-4-[2-(4-methylphenylsulfanyl)phenyl]-3,5-dioxopipe-
razine (Intermediate for 2a)
[0129] 2-(4-Methylphenylsulfanyl)aniline (2.9 g, 13.5 mmol) was
dissolved in dry THF (200 mL) and placed under a nitrogen
atmosphere. N-(tert-butylocycarbonyl)iminodiacetic acid (4.7 g,
20.2 mmol) and carbonyl diimidazole (4.2 g, 40.4 mmol) were added
to the solution and the reaction was refluxed for 60 hours. The
reaction mixture was cooled to room temperature and ethyl acetate
(500 mL) was added. The resulting solution was then washed with 2 N
NaHCO.sub.3 (2.times.200 mL), 2 N HCl (2.times.200 mL) and
saturated sodium chloride solution (100 mL) and the solvents
evaporated in vacuo. Yield 6.0 g, 107%, .sup.1H NMR (CDCl.sub.3)
1.5 (s, 9H); 2.32 (s, 3H); 4.4-4.6 (m, 4H); 7.02-7.18 (m, 3H);
7.2-7.45 (m, 5H).
[0130] The following 3,5 diketopiperazine derivatives were prepared
in an analogous fashion: [0131]
1-tert-Butyloxycarbonyl-4-[2-(4-chlorophenylsulfanyl)phenyl]-3,5-dioxopip-
erazine (Intermediate for 2b) [0132]
1-tert-Butyloxycarbonyl-4-[2-(4-methoxyphenylsulfanyl)-4-chlorophenyl]-3,-
5-dioxopiperazine (Intermediate for 2c) [0133]
1-tert-Butyloxycarbonyl-4-[2-(4-methoxyphenylsulfanyl)-4-methylphenyl]-3,-
5-dioxopiperazine (Intermediate for 2d) [0134]
1-tert-Butyloxycarbonyl-4-[2-(4-methoxyphenylsulfanyl)-5-methylphenyl]-3,-
5-dioxopiperazine (Intermediate for 2e) [0135]
1-tert-Butyloxycarbonyl-4-[2-(4-fluorophenylsulfanyl)-5-methylphenyl]-3,5-
-dioxopiperazine (Intermediate for 2j) [0136]
1-tert-Butyloxycarbonyl-4-[2-(4-methoxyphenylsulfanyl)-5-trifluoromethylp-
henyl]-3,5-dioxopiperazine (Intermediate for 2g)
2-(3-Methylpiperazin-1-yl)phenylamine (intermediate for 3a)
[0137] Fluoronitrobenzene (7.1 g, 50 mmol) was dissolved in DMF
(100 mL) containing triethylamine (10 g, 100 mmol) and placed under
a nitrogen atmosphere. To the solution was added
2-methyl-piperazine (5.5 g, 55 mmol). The reaction was heated to
80.degree. C. for 16 hours. The reaction was allowed to cool to
room temperature before the solvent was reduced to half volume in
vacuo. Ethyl acetate (200 mL) and ice-water (250 mL) were added to
the solution and the product was extracted with diethyether
(2.times.200 mL). The aqueous phase was saturated with sodium
chloride and extracted with ethyl acetate (2.times.200 mL). The
organic phases were combined, washed with saturated brine, dried
over magnesium sulfate, filtered and the filtrate was concentrated
in vacuo. The product (10.5 g) was dissolved in ethanol (250 mL).
Palladium on charcoal catalyst (10% w/w, 2.2 g) was added to the
solution and the solution was hydrogenated in a Parr apparatus at 3
bar for 3 hours. The solution was filtered and the solvents
evaporated in vacuo to give the aniline product. Yield (8.0 g,
83%)
[0138] The following intermediates were prepared in an analogous
fashion: [0139] 2-(3,5-Dimethylpiperazin-1-yl)phenylamine
(intermediate for 3b) Compounds of the invention:
Example 1
1a, 1-[2-(2-Trifluoromethylphenylsulfanyl)phenyl]piperazine
[0140] To a solution of 2-trifluoromethylthiophenol (1.75 g, 9.8
mmol) in a 1:1 mixture of tetrahydrofuran/dimethylformamide (30
mL), sodium hydride (7.4 mmol, 60% in mineral oil) was carefully
added at room temperature (Caution: Generation of hydrogen). The
mixture was stirred for an additional 30 min after the generation
of hydrogen had ceased. Subsequently,
4-({4-[.eta..sup.6-(2-chloro-phenyl)-.eta..sup.5-cyclopentadienyliron(II)-
]piperazin-1-yl}carbonyloxymethyl)phenoxymethyl polystyrene
hexafluorophosphate (3.5 g, 2.45 mmol) was added and the mixture
was stirred at 55.degree. C. for 12 h. After cooling to room
temperature, the resin was filtered off and washed with
tetrahydrofuran (2.times.50 mL), tetrahydrofuran/water (1:1)
(2.times.50 mL), N,N-dimethylformamide (2.times.50 mL), water
(2.times.50 mL), methanol (3.times.50 mL), tetrahydrofuran
(3.times.50 mL), and subsequently with methanol and tetrahydrofuran
(each 50 mL, 5 cycles). Finally, the resin was washed with
dichloromethane (3.times.50 mL) and dried in vacuo (25.degree. C.,
12 h) to yield a dark orange resin. The thus obtained resin and a
0.5 M solution of 1,10-phenanthroline in 3:1 mixture of
pyridine/water (20 mL) was placed in light-transparent reactor
tube. The suspension was agitated by rotation under irradiation
with visible light for 12 h. The resin was filtered and washed with
methanol (2.times.25 mL), water (2.times.25 mL) and tetrahydrofuran
(3.times.25 mL) until the washing solutions were colourless
(approx. 5 cycles) and the irradiation procedure was repeated until
decomplexation was complete (approx. 5 cycles). After the
decomplexation was completed, the resin was washed with
dichlormethane (3.times.25 mL) and dried in vacuo (25.degree. C.,
12 h) to obtain a light brown resin. 100 mg (77 .mu.mol) of the
thus obtained resin were suspended in a 1:1 mixture of
trifluoroacetic acid and dichlormethane (2 mL) and stirred at room
temperature for 2 h. The resin was filtered off and washed with
methanol (1.times.0.5 mL) and dichloromethane (1.times.0.5 mL). The
filtrates were collected and the volatile solvents evaporated in
vacuo. The crude product was purified by preparative LC-MS and
subsequently by ion-exchange chromatography. LC/MS (m/z) 339
(MH.sup.+); RT=2.39; purity (UV, ELSD): 92%, 100%; overall yield: 1
mg (4%).
[0141] The following arylpiperazines and aryl[1,4]diazepanes were
prepared analogously: [0142] 1b,
1-[2-(4-Bromophenylsulfanyl)phenyl]piperazine: LC/MS (m/z) 350
(MH.sup.+); RT=2.46; purity (UV, ELSD): 75%, 92%; yield: 2 mg (7%).
[0143] 1c,
1-(2-[4-(Methylsulfanyl)phenylsulfanyl]phenyl}piperazine: LC/MS
(m/z) 317 (MH.sup.+); RT=2.39; purity (UV, ELSD): 91%, 100%; yield:
2 mg (8%). [0144] 1d,
1-[2-(4-Hydroxyphenylsulfanyl]phenyl}piperazine: LC/MS (m/z) 287
(MH.sup.+); RT=1.83; purity (UV, ELSD): 84%, 100%; yield: 3 mg
(13%). [0145] 1e,
1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine: LC/MS (m/z) 299
(MH.sup.+); RT=2.48; purity (UV, ELSD): 95%, 100%; yield: 4 mg
(17%). [0146] 1f,
1-[2-(3,5-Dimethylphenylsulfanyl)phenyl]piperazine: LC/MS (m/z) 299
(MH.sup.+); RT=2.51; purity (UV, ELSD): 96%, 100%; yield: 5 mg
(21%). [0147] 1g,
1-[2-(2,6-Dimethylphenylsulfanyl)phenyl]piperazine: LC/MS (m/z) 299
(MH.sup.+); RT=2.42; purity (UV, ELSD): 97%, 100%; yield: 4 mg
(17%). [0148] 1h,
1-[2-(2,5-Dimethylphenylsulfanyl)phenyl]piperazine: LC/MS (m/z) 299
(MH.sup.+); RT=2.46; purity (UV, ELSD): 97%, 100%; yield: 1 mg
(4%). [0149] 1i,
1-[2-(2-Trifluoromethylphenylsulfanyl)phenyl]-[1,4]-diazepane:
LC/MS (m/z) 353 (MH.sup.+); RT=2.46; purity (UV, ELSD): 70%, 96%;
yield: 1 mg (4%). [0150] 1j,
1-[2-(3-Methylphenylsulfanyl)phenyl]-[1,4]-diazepane: LC/MS (m/z)
299 (MH.sup.+); RT=2.44; purity (UV, ELSD): 76%, 93%; yield: 1 mg
(4%). [0151] 1k, 1-[2-(4-Butylphenoxy)phenyl]piperazine: LC/MS
(m/z) 311 (MH.sup.+); RT=2.77; purity (UV, ELSD): 91%, 100%; yield:
4 mg (17%). [0152] 1l, 1-[2-(4-Methoxyphenoxy)phenyl]piperazine:
LC/MS (m/z) 285 (MH.sup.+); RT=2.08; purity (UV, ELSD): 93%, 100%;
yield: 4 mg (18%)
Example 2
2a, 2-(4-Methylphenylsulfanyl)phenyl-1-piperazine hydrochloride
[0153]
1-tert-Butyloxycarbonyl-4-[2-(4-methylphenylsulfanyl)phenyl]-3,5-di-
oxo-piperazine (5.5 g, 13 mmol) was dissolved in dry THF (50 mL)
and placed under a nitrogen atmosphere. Borane tetrahydrofuran
complex (50 mmol, 1.0 M) in tetrahydrofuran was added and the
reaction was refluxed for ten minutes. Excess borane was quenched
by the addition of an excess of ethyl acetate and the reaction was
refluxed for a further 20 minutes. The reaction was allowed to cool
to room temperature before hydrogen chloride dissolved in methanol
(50 mL, 4 M) was added and the reaction was refluxed for 4.5 hours.
The reaction was allowed to cool to room temperature and the
reaction was concentrated in vacuo. The compound was crystallised
from the gum residue by the addition of ether/methanol solution.
The crystalline solid was filtered and washed with ether/methanol
(1:1) to give a white crystalline solid. Yield (2.0 g, 47%) .sup.1H
NMR (D.sub.6-DMSO) 2.35 (s, 3H); 3.18 (br s, 8H); 6.68 (d, 2H);
7.02 (m, 1H); 7.18 (m, 1H); 7.3-7.5 (m, 4H); MS (MH.sup.+) 285.
[0154] The following compounds were prepared in an analogous
fashion: [0155] 2b, 1-[2-(4-chlorophenylsulfanyl)phenyl]piperazine
LC-MS (m/z) 305.1 (MH.sup.+) RT=2.46 purity (UV, ELSD) 71%, 91%
yield 0.096 g, 100% [0156] 2c,
1-[2-(4-methoxyphenylsulfanyl)-4-chlorophenyl]piperazine LC-MS
(m/z) (MH.sup.+) 335.2 RT=2.38 purity (UV, ELSD) 98%, 100% yield
0.22 g, 62% [0157] 2d,
1-[2-(4-methoxyphenylsulfanyl)-4-methylphenyl]piperazine LC-MS
(m/z) (MH.sup.+) 315.1 RT=2.33 purity (UV, ELSD) 97%, 100% yield
0.21 g, 56% [0158] 2e,
1-[2-(4-methoxyphenylsulfanyl)-5-methylphenyl]piperazine LC-MS
(m/z) (MH.sup.+) 315.2 RT=2.38 (UV, ELSD) 98%, 100% yield 2.3 g,
58% [0159] 2f,
1-[2-(4-fluorophenylsulfanyl)-5-methylphenyl]piperazine LC-MS (m/z)
(MH.sup.+) 303.2 RT=2.46 (UV) 98% yield 2.1 g, 62% [0160] 2g,
1-[2-(4-Methoxyphenylsulfanyl)-5-trifluoromethylphenyl]piperazine
LC-MS (m/z) (MH.sup.+) 369 RT=2.50 (UV, ELSD) 96%, 100% yield 0.54
g, 31%
Example 3
3a, 1-[2-(4-Chlorophenylsulfanyl)phenyl]-3-methylpiperazine
[0161] 2-(3-Methylpiperazin-1-yl)phenylamine (0.96 g, 5 mmol) was
dissolved in 30 mL water containing sulfuric acid (0.28 mL, 5.2
mmol) and the solution was cooled to 0.degree. C. and sodium
nitrite (0.36 g, 5.2 mmol) was added. The reaction was stirred for
30 minutes before the pH of the reaction was adjusted to pH 7 with
sodium acetate. The diazonium salt solution was then added dropwise
to a solution of 4-chlorothiophenol in a suspension of copper (0.3
g, 5 mmol) in 2 M NaOH (4 mL). After addition, the reaction mixture
was heated to 60.degree. C. for 30 minutes before being allowed to
cool to room temperature and ethyl acetate (10 mL) was added. The
reaction mixture was filtered and the layers were separated. The
aqueous layer was extracted with ethyl acetate (2.times.10 mL). The
combined organic phases were dried (MgSO.sub.4) and volatile
solvents evaporated in vacuo. The crude product was purified by
flash chromatography using silica gel, eluting with ethyl
acetate/methanol/ammonia 96:3:1. The pure product was isolated as a
colourless oil. Yield (0.18 g, 11%) .sup.1H NMR (CDCl.sub.3, 500
MHz) 1.12 (d, 3H); 2.6-2.72 (br m, 2H); 3.0-3.15 (m, 5H); 6.9 (m,
2H); 7.08 (d, 1H); 7.15 (m, 1H); 7.25-7.35 (m, 4H); MS (MH.sup.+)
319.1.
[0162] The following compound was prepared in an analogous fashion:
[0163] 3b,
1-[2-(4-Chlorophenylsulfanyl)phenyl]-3,5-dimethylpiperazine LC-MS
(m/z) (MH)+333.1 RT=2.29 (UV, ELSD) 83%, 100% yield 0.54 g,
31%.
Example 4
4a,
4-[2-(4-Methylphenylsulfanyl)phenyl]-3,6-dihydro-2H-pyridine
[0164] Concentrated aq hydrochloric acid (10 ml) was added to a
stirred solution of
1-tert-butoxycarbonyl-4-[2-(4-methylphenylsulfanyl)phenyl]piperidin-4-ol
(0.84 g, 2.1 mmol) in acetic acid (30 mL). The solution was boiled
under reflux overnight, cooled to room temperature and then stirred
in an ice bath. An aqueous solution of NaOH (9.1 M, 40 mL) was
slowly added and the unclear solution was extracted with ethyl
acetate (2.times.40 ml). The combined organic phases were dried
(MgSO.sub.4) and the solvents evaporated in vacuo. The crude
material (0.48 g) was dissolved in ethyl acetate (3.2 mL) at
50.degree. C. and a solution of oxalic acid (0.11 g) in EtOH (3.2
mL) was slowly added. The target compound was collected as a white
oxalic salt. .sup.1H (DMSO-d) .delta. 7.3-7.2 (m, 711); 7.15 (m,
1H); 7.00 (m, 111); 5.6 (d, 1H); 3.7 (d, 2H); 3.25 (t, 211); 2.6
(m, 2H); 2.3 (s, 3H). LC/MS (m/z) 282.2 (MH); RT=2.24; purity (UV,
ELSD): 99%, 100%; yield: 0.31 g (40%).
[0165] The following derivative was prepared analogously: [0166]
4b, 4-[2-(4-Methoxyphenylsulfanyl)phenyl]-3,6-dihydro-2H-pyridine
LC/MS (m/z) 298 (MH.sup.+); RT=2.00; purity (UV, ELSD): 97%, 100%;
yield: 0.28 g (30%).
Example 5
5a, 4-[2-(4-Methylphenylsulfanyl)phenyl]piperidine
[0167] Methyl Chloro-oxo-acetate (1.37 g, 11.25 mmol) was added to
a stirred solution of
1-tert-butoxycarbonyl-4-[2-(4-methylphenylsulfanyl)phenyl]piperidin-4-ol
(3.00 g, 7.5 mmol) and 4-(dimethylamino)pyridine (1.65 g, 13.5
mmol) in a mixture of dry CH.sub.3CN (24 ml) and CHCl.sub.3 (12 mL)
at 0.degree. C. under argon. The reaction mixture was allowed to
reach room temperature and then stirred 2 h. Ethyl acetate (140 mL)
was added and some salts were removed by filtration through celite.
The organic phase was washed with sat. NaHCO.sub.3 (140 ml), brine
(140 mL) and dried (MgSO.sub.4). The solvents were evaporated in
vacuo and the crude material was dried in vacuo. This material was
dissolved in dry toluen (48 mL) under argon. Bu.sub.3SnH (3.27 g,
11.25 mmol) and AIBN (0.31 g, 1.88 mmol) were added. The solution
was stirred under argon at 90.degree. C. for 2.5 h. The solvent was
evaporated in vacuo, and the crude material was purified by flash
chromatography on silica gel (eluent: a stepwise gradient of
ethylacetat in heptane from 10:90 to 20:80) to produce
4-(2-(4-methylphenylsulfanyl)phenyl)-piperidine-1-carboxylic acid
tert-butyl ester as a clear oil (1.94 g, 67%). This oil was
dissolved in MeOH (9.2 mL) and HCl in diethylether (2.0 M) was
added at 0.degree. C. The reaction mixture was allowed to warm to
room temperature and stirred overnight. The target compound was
collected as its hydrochloride. M.p 229-231.degree. C. Calculated
for C.sub.18H.sub.21NS.HCl: C, 67.58; H, 6.63; N, 4.38. Found: C,
67.33; H, 6.97; N, 4.31. LC/MS (m/z) 284 (MH.sup.+); RT=2.12;
purity (UV, ELSD): 96%, 100%; yield: 0.26 g (46%).
[0168] Inhibition of the Uptake of [.sup.3H]Serotonin into Whole
Rat Brain Synaptosomes
[0169] The compounds were tested with respect to their 5-HT
reuptake inhibiting effect by measuring their ability to inhibit
the uptake of [3H]serotonin into whole rat brain synaptosomes in
vitro. The assay was performed as described by Hyttel
Psychopharmacology 1978, 60, 13.
[0170] S-HT.sub.2C Receptor Efficacy as Determined by
Fluorometry
[0171] The compounds were tested with respect to their efficacy on
5-HT.sub.2C receptor-expressing CHO cells (Euroscreen) as
determined by fluorometric imaging plate reader (FLIPR) analysis.
This assay was carried out according to Molecular Devices Inc.
instructions for their FLIPR Calcium Assay Kit and as modified from
Porter et al. British Journal of Pharmacology 1999, 128, 13.
[0172] Preferred compounds of the present invention exhibit
serotonin reuptake inhibition below 200 nM (IC.sub.50) in the assay
above. More preferred are the compounds which exhibit inhibition
below 100 nM and most preferably below 50 nM. Compounds of
particular interest exhibit serotonin reuptake inhibition below 10
nM;
* * * * *